Characterization of adverse events in injured patients at risk of hemorrhagic shock: a secondary analysis of three harmonized prehospital randomized clinical trials.

Background: The reporting of adverse events (AEs) is required and well defined in the execution of clinical trials, but is poorly characterized particularly in prehospital trials focusing on traumatic injury. In the setting of prehospital traumatic injury trials, no literature currently exists analyzing the clinical implications of AEs and their associations with mortality and morbidity. We sought to analyze AEs from three prehospital hemorrhagic shock trials and characterize their time course, incidence, severity, associated clinical outcomes, and relatedness. Methods: We performed a secondary analysis of three prehospital randomized clinical trials. We analyzed AEs at both the patient level as well as the individual AE level. We categorized patients who had no AEs, a single documented AE and those with multiple events (>1 AE). We characterized AE timing, severity, relatedness and attributable mortality outcomes. Results: We included 1490 patients from the three harmonized clinical trials, with 299 (20.1%) individual patients having at least a single AE documented with 529 AEs documented overall as a proportion of patients had multiple events. Over 44% of patients had a death-related misclassified AE. Patients with at least a single documented AE had a significantly higher 28-day mortality (log-rank χ2=81.27, p<0.001) compared with those without an AE documented. Patients with a single AE had a significant higher mortality than those with multiple AEs, potentially due to survival bias (log-rank χ2=11.80, p=0.006). When relatedness of each individual AE was characterized, over 97% of AEs were classified as 'definitely not related' or 'probably not related' to the intervention. Conclusions: AEs in hemorrhagic shock trials are common, occur early and are associated with mortality and survival bias. The potential for inaccurate reporting exists, and education and training remain essential for appropriate treatment arm comparison. The current results have important relevance to injury-related clinical trials. Trial registration numbers: NCT01818427, NCT02086500 and NCT03477006. Level of evidence: II.

Prehospital tranexamic acid is associated with a survival benefit without an increase in complications: results of two harmonized randomized clinical trials.

INTRODUCTION: Recent randomized clinical trials have demonstrated that prehospital tranexamic acid (TXA) administration following injury is safe and improves survival. However, the effect of prehospital TXA on adverse events, transfusion requirements and any dose response relationships require further elucidation. METHODS: A secondary analysis was performed using harmonized data from two large, double-blinded, randomized prehospital TXA trials. Outcomes, including 28-day mortality, pertinent adverse events and 24-hour red cell transfusion requirements were compared between TXA and placebo groups. Regression analyses were utilized to determine the independent associations of TXA after adjusting for study enrollment, injury characteristics and shock severity across a broad spectrum of injured patients. Dose response relationships were similarly characterized based upon grams of prehospital TXA administered. RESULTS: A total of 1744 patients had data available for secondary analysis and were included in the current harmonized secondary analysis. The study cohort had an overall mortality of 11.2% and a median injury severity score of 16 (IQR: 5-26). TXA was independently associated with a lower risk of 28-day mortality (HR: 0.72, 95% CI 0.54, 0.96, p = 0.03). Prehospital TXA also demonstrated an independent 22% lower risk of mortality for every gram of prehospital TXA administered (HR: 0.78, 95% CI 0.63, 0.96, p = 0.02). Multivariable linear regression verified that patients who received TXA were independently associated with lower 24-hour red cell transfusion requirements (ß: -0.31, 95% CI -0.61, -0.01, p = 0.04) with a dose-response relationship (ß: -0.24, 95% CI -0.45, -0.02, p = 0.03). There was no independent association of prehospital TXA administration on VTE, seizure, or stroke. CONCLUSIONS: In this secondary analysis of harmonized data from two large randomized interventional trials, prehospital TXA administration across a broad spectrum of injured patients is safe. Prehospital TXA is associated with a significant 28-day survival benefit, lower red cell transfusion requirements at 24 hours and demonstrates a dose-response relationship. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Missingness matters: a secondary analysis of thromboelastography measurements from a recent prehospital randomized tranexamic acid clinical trial.

Background: Tranexamic acid (TXA) has been hypothesized to mitigate coagulopathy in patients after traumatic injury. Despite previous prehospital clinical trials demonstrating a TXA survival benefit, none have demonstrated correlated changes in thromboelastography (TEG) parameters. We sought to analyze if missing TEG data contributed to this paucity of findings. Methods: We performed a secondary analysis of the Study of Tranexamic Acid During Air Medical and Ground Prehospital Transport Trial. We compared patients that received TEG (YES-TEG) and patients unable to be sampled (NO-TEG) to analyze subgroups in which to investigate TEG differences. TEG parameter differences across TXA intervention arms were assessed within subgroups disproportionately present in the NO-TEG relative to the YES-TEG cohort. Generalized linear models controlling for potential confounders were applied to findings with p<0.10 on univariate analysis. Results: NO-TEG patients had lower prehospital systolic blood pressure (SBP) (100 (78, 140) vs 125 (88, 147), p<0.01), lower prehospital Glascow Coma Score (14 (3, 15) vs 15 (12, 15), p<0.01), greater rates of prehospital intubation (39.4% vs 24.4%, p<0.01) and greater mortality at 30 days (36.4% vs 6.8%, p<0.01). NO-TEG patients had a greater international normalized ratio relative to the YES-TEG subgroup (1.2 (1.1, 1.5) vs 1.1 (1.0, 1.2), p=0.04). Within a severe prehospital shock cohort (SBP<70), TXA was associated with a significant decrease in clot lysis at 30 min on multivariate analysis (ß=-27.6, 95% CI (-51.3 to -3.9), p=0.02). Conclusions: Missing data, due to the logistical challenges of sampling certain severely injured patients, may be associated with a lack of TEG parameter changes on TXA administration in the primary analysis. Previous demonstration of TXA's survival benefit in patients with severe prehospital shock in tandem with the current findings supports the notion that TXA acts at least partially by improving clot integrity. Level of evidence: Level II.

Mechanism matters: mortality and endothelial cell damage marker differences between blunt and penetrating traumatic injuries across three prehospital clinical trials.

Injury mechanism is an important consideration when conducting clinical trials in trauma. Mechanisms of injury may be associated with differences in mortality risk and immune response to injury, impacting the potential success of the trial. We sought to characterize clinical and endothelial cell damage marker differences across blunt and penetrating injured patients enrolled in three large, prehospital randomized trials which focused on hemorrhagic shock. In this secondary analysis, patients with systolic blood pressure < 70 or systolic blood pressure < 90 and heart rate > 108 were included. In addition, patients with both blunt and penetrating injuries were excluded. The primary outcome was 30-day mortality. Mortality was characterized using Kaplan-Meier and Cox proportional-hazards models. Generalized linear models were used to compare biomarkers. Chi squared tests and Wilcoxon rank-sum were used to compare secondary outcomes. We characterized data of 696 enrolled patients that met all secondary analysis inclusion criteria. Blunt injured patients had significantly greater 24-h (18.6% vs. 10.7%, log rank p = 0.048) and 30-day mortality rates (29.7% vs. 14.0%, log rank p = 0.001) relative to penetrating injured patients with a different time course. After adjusting for confounders, blunt mechanism of injury was independently predictive of mortality at 30-days (HR 1.84, 95% CI 1.06-3.20, p = 0.029), but not 24-h (HR 1.65, 95% CI 0.86-3.18, p = 0.133). Elevated admission levels of endothelial cell damage markers, VEGF, syndecan-1, TM, S100A10, suPAR and HcDNA were associated with blunt mechanism of injury. Although there was no difference in multiple organ failure (MOF) rates across injury mechanism (48.4% vs. 42.98%, p = 0.275), blunt injured patients had higher Denver MOF score (p < 0.01). The significant increase in 30-day mortality and endothelial cell damage markers in blunt injury relative to penetrating injured patients highlights the importance of considering mechanism of injury within the inclusion and exclusion criteria of future clinical trials.

AWAreness during REsuscitation - II: A multi-center study of consciousness and awareness in cardiac arrest.

INTRODUCTION: Cognitive activity and awareness during cardiac arrest (CA) are reported but ill understood. This first of a kind study examined consciousness and its underlying electrocortical biomarkers during cardiopulmonary resuscitation (CPR). METHODS: In a prospective 25-site in-hospital study, we incorporated a) independent audiovisual testing of awareness, including explicit and implicit learning using a computer and headphones, with b) continuous real-time electroencephalography(EEG) and cerebral oxygenation(rSO2) monitoring into CPR during in-hospital CA (IHCA). Survivors underwent interviews to examine for recall of awareness and cognitive experiences. A complementary cross-sectional community CA study provided added insights regarding survivors' experiences. RESULTS: Of 567 IHCA, 53(9.3%) survived, 28 of these (52.8%) completed interviews, and 11(39.3%) reported CA memories/perceptions suggestive of consciousness. Four categories of experiences emerged: 1) emergence from coma during CPR (CPR-induced consciousness [CPRIC]) 2/28(7.1%), or 2) in the post-resuscitation period 2/28(7.1%), 3) dream-like experiences 3/28(10.7%), 4) transcendent recalled experience of death (RED) 6/28(21.4%). In the cross-sectional arm, 126 community CA survivors' experiences reinforced these categories and identified another: delusions (misattribution of medical events). Low survival limited the ability to examine for implicit learning. Nobody identified the visual image, 1/28(3.5%) identified the auditory stimulus. Despite marked cerebral ischemia (Mean rSO2 = 43%) normal EEG activity (delta, theta and alpha) consistent with consciousness emerged as long as 35-60 minutes into CPR. CONCLUSIONS: Consciousness. awareness and cognitive processes may occur during CA. The emergence of normal EEG may reflect a resumption of a network-level of cognitive activity, and a biomarker of consciousness, lucidity and RED (authentic "near-death" experiences).

Prehospital tranexamic acid is associated with a dose-dependent decrease in syndecan-1 after trauma: A secondary analysis of a prospective randomized trial.

BACKGROUND: In the Study of Tranexamic Acid During Air and Ground Prehospital Transport (STAAMP) Trial, prehospital tranexamic acid (TXA) was associated with lower mortality in specific patient subgroups. The underlying mechanisms responsible for a TXA benefit remain incompletely characterized. We hypothesized that TXA may mitigate endothelial injury and sought to assess whether TXA was associated with decreased endothelial or tissue damage markers among all patients enrolled in the STAAMP Trial. METHODS: We collected blood samples from STAAMP Trial patients and measured markers of endothelial function and tissue damage including syndecan-1, soluble thrombomodulin (sTM), and platelet endothelial cell adhesion molecule-1 at hospital admission (0 hours) and 12 hours, 24 hours, and 72 hours after admission. We compared these marker values for patients in each treatment group during the first 72 hours, and modeled the relationship between TXA and marker concentration using regression analysis to control for potential confounding factors. RESULTS: We analyzed samples from 766 patients: 383 placebo, 130 abbreviated dosing, 119 standard dosing, and 130 repeat dosing. Lower levels of syndecan-1, TM, and platelet endothelial cell adhesion molecule measured within the first 72 hours of hospital admission were associated with survival at 30 days ( p < 0.001). At hospital admission, syndecan-1 was lower in the TXA group (28.30 [20.05, 42.75] vs. 33.50 [23.00, 54.00] p = 0.001) even after controlling for patient, injury, and prehospital factors ( p = 0.001). For every 1 g increase in TXA administered over the first 8 hours of prehospital transport and hospital admission, there was a 4-ng/mL decrease in syndecan-1 at 12 hours controlling for patient, injury, and treatment factors ( p = 0.03). CONCLUSION: Prehospital TXA was associated with decreased syndecan-1 at hospital admission. Syndecan-1 measured 12 hours after admission was inversely related to the dose of TXA received. Early prehospital and in-hospital TXA may decrease endothelial glycocalyx damage or upregulate vascular repair mechanisms in a dose-dependent fashion. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Evaluation of critical care burden following traumatic injury from two randomized controlled trials.

Trauma resuscitation practices have continued to improve with new advances targeting prehospital interventions. The critical care burden associated with severely injured patients at risk of hemorrhage has been poorly characterized. We aim to describe the individual and additive effects of multiorgan failure (MOF) and nosocomial infection (NI) on delayed mortality and resource utilization. A secondary analysis of harmonized data from two large prehospital randomized controlled trials (Prehospital Air Medical Plasma (PAMPer) Trial and Study of Tranexamic Acid during Air and Ground Medical Prehospital Transport (STAAMP) Trial) was conducted. Only those patients who survived beyond the first 24 hours post-injury and spent at least one day in the ICU were included. Patients were stratified by development of MOF only, NI only, both, or neither and diagnosis of early (≤ 3 days) versus late MOF (> 3 days). Risk factors of NI and MOF, time course of these ICU complications, associated mortality, and hospital resource utilization were evaluated. Of the 869 patients who were enrolled in PAMPer and STAAMP and who met study criteria, 27.4% developed MOF only (n = 238), 10.9% developed NI only (n = 95), and 15.3% were diagnosed with both MOF and NI (n = 133). Patients developing NI and/or MOF compared to those who had an uncomplicated ICU course had greater injury severity, lower GCS, and greater shock indexes. Early MOF occurred in isolation, while late MOF more often followed NI. MOF was associated with 65% higher independent risk of 30-day mortality when adjusting for cofounders (OR 1.65; 95% CI 1.04-2.6; p = 0.03), however NI did not significantly affect odds of mortality. NI was individually associated with longer mechanical ventilation, ICU stay, hospital stay, and rehabilitation requirements, and the addition of MOF further increased the burden of inpatient and post-discharge care. MOF and NI remain common complications for those who survive traumatic injury. MOF is a robust independent predictor of mortality following injury in this cohort, and NI is associated with higher resource utilization. Timing of these ICU complications may reveal differences in pathophysiology and offer targets for continued advancements in treatment.

Burnout reduction in acute care surgeons: Impact of faculty schedule change at a level 1 trauma and tertiary care center.

BACKGROUND: Acute care surgeons are prone to burnout because of heavy workload, concurrent clinical responsibilities, and busy in-house call. Modifiable burnout factors have been identified, but few studies have looked for longitudinal effects after change is implemented. We hypothesized that optimizing faculty workflow could decrease burnout without compromising productivity. METHODS: We streamlined the faculty schedule at our institution to eliminate 24-hour call by creating weekly blocks of 12-hour day and night call, free from other clinical obligations. Protected academic time was added. The Maslach Burnout Inventory and Areas of Worklife Survey for health care providers were given to faculty, as well as close friends or family, at baseline, 6 months, and 12 months. Maslach Burnout Inventory and Areas of Worklife Survey proprietary formulas were used to assess change in factors contributing to burnout. Our primary outcome measure was the presence of factors contributing to burnout. Chart delinquency, relative value units, and academic projects were secondary outcome measures assessing clinical productivity change. RESULTS: Survey completion rates were 92% for faculty and 80% for family. All burnout risk factors improved at 6 and 12 months. In surgeon and family groups, the following improvements were noted in the mean scores of risk factors at 1 year: workload (74%, 68%), control (38%, 16%), reward (14%, 24%), fairness (69%, 22%), emotional exhaustion (27.5%, 24%), depersonalization (37.5%, 14%), personal accomplishment (12.5%, 2%), community (3%, 5%), values (10%, 15%), and over-all burnout (12.5%, 23.3%). There was a reduction in charts reaching delinquent status. Relative value unit production did not decrease. CONCLUSION: This study demonstrates that implementing a weekly, 12-hour call schedule can improve factors leading to burnout. Improvements were noted in surgeon and family groups alike, signifying both subjective improvements and observed change in the surgeons' behavior, without compromising clinical productivity. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Prehospital synergy: Tranexamic acid and blood transfusion in patients at risk for hemorrhage.

BACKGROUND: Growing evidence supports improved survival with prehospital blood products. Recent trials show a benefit of prehospital tranexamic acid (TXA) administration in select subgroups. Our objective was to determine if receiving prehospital packed red blood cells (pRBC) in addition to TXA improved survival in injured patients at risk of hemorrhage. METHODS: We performed a secondary analysis of all scene patients from the Study of Tranexamic Acid during Air and ground Medical Prehospital transport trial. Patients were randomized to prehospital TXA or placebo. Some participating EMS services utilized pRBC. Four resuscitation groups resulted: TXA, pRBC, pRBC+TXA, and neither. Our primary outcome was 30-day mortality and secondary outcome was 24-hour mortality. Cox regression tested the association between resuscitation group and mortality while adjusting for confounders. RESULTS: A total of 763 patients were included. Patients receiving prehospital blood had higher Injury Severity Scores in the pRBC (22 [10, 34]) and pRBC+TXA (22 [17, 36]) groups than the TXA (12 [5, 21]) and neither (10 [4, 20]) groups (p < 0.01). Mortality at 30 days was greatest in the pRBC+TXA and pRBC groups at 18.2% and 28.6% compared with the TXA only and neither groups at 6.6% and 7.4%, respectively. Resuscitation with pRBC+TXA was associated with a 35% reduction in relative hazards of 30-day mortality compared with neither (hazard ratio, 0.65; 95% confidence interval, 0.45-0.94; p = 0.02). No survival benefit was observed in 24-hour mortality for pRBC+TXA, but pRBC alone was associated with a 61% reduction in relative hazards of 24-hour mortality compared with neither (hazard ratio, 0.39; 95% confidence interval, 0.17-0.88; p = 0.02). CONCLUSION: For injured patients at risk of hemorrhage, prehospital pRBC+TXA is associated with reduced 30-day mortality. Use of pRBC transfusion alone was associated with a reduction in early mortality. Potential synergy appeared only in longer-term mortality and further work to investigate mechanisms of this therapeutic benefit is needed to optimize the prehospital resuscitation of trauma patients. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Plasma metagenomic sequencing to detect and quantify bacterial DNA in ICU patients suspected of sepsis: A proof-of-principle study.

BACKGROUND: Timely recognition of sepsis and identification of pathogens can improve outcomes in critical care patients but microbial cultures have low accuracy and long turnaround times. In this proof-of-principle study, we describe metagenomic sequencing and analysis of nonhuman DNA in plasma. We hypothesized that quantitative analysis of bacterial DNA (bDNA) levels in plasma can enable detection and monitoring of pathogens. METHODS: We enrolled 30 patients suspected of sepsis in the surgical trauma intensive care unit and collected plasma samples at the time of diagnostic workup for sepsis (baseline), and 7 days and 14 days later. We performed metagenomic sequencing of plasma DNA and used computational classification of sequencing reads to detect and quantify total and pathogen-specific bDNA fraction. To improve assay sensitivity, we developed an enrichment method for bDNA based on size selection for shorter fragment lengths. Differences in bDNA fractions between samples were evaluated using t test and linear mixed-effects model, following log transformation. RESULTS: We analyzed 72 plasma samples from 30 patients. Twenty-seven samples (37.5%) were collected at the time of infection. Median total bDNA fraction was 1.6 times higher in these samples compared with samples with no infection (0.011% and 0.0068%, respectively, p < 0.001). In 17 patients who had active infection at enrollment and at least one follow-up sample collected, total bDNA fractions were higher at baseline compared with the next sample (p < 0.001). Following enrichment, bDNA fractions increased in paired samples by a mean of 16.9-fold. Of 17 samples collected at the time when bacterial pathogens were identified, we detected pathogen-specific DNA in 13 plasma samples (76.5%). CONCLUSION: Bacterial DNA levels in plasma are elevated in critically ill patients with active infection. Pathogen-specific DNA is detectable in plasma, particularly after enrichment using selection for shorter fragments. Serial changes in bDNA levels may be informative of treatment response. LEVEL OF EVIDENCE: Epidemiologic/Prognostic, Level V.

Early Prehospital Tranexamic Acid Following Injury Is Associated With a 30-day Survival Benefit: A Secondary Analysis of a Randomized Clinical Trial.

OBJECTIVE: We sought to characterize the timing of administration of prehospital tranexamic acid (TXA) and associated outcome benefits. BACKGROUND: TXA has been shown to be safe in the prehospital setting post-injury. METHODS: We performed a secondary analysis of a recent prehospital randomized TXA clinical trial in injured patients. Those who received prehospital TXA within 1 hour (EARLY) from time of injury were compared to those who received prehospital TXA beyond 1 hour (DELAYED). We included patients with a shock index of >0.9. Primary outcome was 30-day mortality. Kaplan-Meier and Cox Hazard regression were utilized to characterize mortality relationships. RESULTS: EARLY and DELAYED patients had similar demographics, injury characteristics, and shock severity but DELAYED patients had greater prehospital resuscitation requirements and longer prehospital times. Stratified Kaplan-Meier analysis demonstrated significant separation for EARLY patients (N = 238, log-rank chi-square test, 4.99; P = 0.03) with no separation for DELAYED patients (N = 238, log-rank chi-square test, 0.04; P = 0.83). Stratified Cox Hazard regression verified, after controlling for confounders, that EARLY TXA was associated with a 65% lower independent hazard for 30-day mortality [hazard ratio (HR) 0.35, 95% confidence interval (CI) 0.19-0.65, P = 0.001] with no independent survival benefit found in DELAYED patients (HR 1.00, 95% CI 0.63-1.60, P = 0.999). EARLY TXA patients had lower incidence of multiple organ failure and 6-hour and 24-hour transfusion requirements compared to placebo. CONCLUSIONS: Administration of prehospital TXA within 1 hour from injury in patients at risk of hemorrhage is associated with 30-day survival benefit, lower incidence of multiple organ failure, and lower transfusion requirements.

Randomized Clinical Trial of 14-French (14F) Pigtail Catheters versus 28-32F Chest Tubes in the Management of Patients with Traumatic Hemothorax and Hemopneumothorax.

INTRODUCTION: Traditional management of traumatic hemothorax/hemopneumothorax (HTX/HPTX) has been insertion of large-bore 32-40 French (Fr) chest tubes (CTs). Retrospective studies have shown 14Fr percutaneous pigtail catheters (PCs) are equally effective as CTs. Our aim was to compare effectiveness between PCs and CTs by performing the first randomized controlled trial (RCT). We hypothesize PCs work equally as well as CTs in management of traumatic HTX/HPTX. METHODS: Prospective RCT comparing 14Fr PCs to 28-32Fr CTs for management of traumatic HTX/HPTX from 07/2015 to 01/2018. We excluded patients requiring emergency tube placement or who refused. Primary outcome was failure rate defined as retained HTX or recurrent PTX requiring additional intervention. Secondary outcomes included initial output (IO), tube days and insertion perception experience (IPE) score on a scale of 1-5 (1 = tolerable experience, 5 = worst experience). Unpaired Student's t-test, chi-square and Wilcoxon rank-sum test were utilized with significance set at P < 0.05. RESULTS: Forty-three patients were enrolled. Baseline characteristics between PC patients (N = 20) and CT patients (N = 23) were similar. Failure rates (10% PCs vs. 17% CTs, P = 0.49) between cohorts were similar. IO (median, 650 milliliters[ml]; interquartile range[IR], 375-1087; for PCs vs. 400 ml; IR, 240-700; for CTs, P = 0.06), and tube duration was similar, but PC patients reported lower IPE scores (median, 1, "I can tolerate it"; IR, 1-2) than CT patients (median, 3, "It was a bad experience"; IR, 3-4, P = 0.001). CONCLUSION: In patients with traumatic HTX/HPTX, 14Fr PCs were equally as effective as 28-32Fr CTs with no significant difference in failure rates. PC patients, however, reported a better insertion experience. www.ClinicalTrials.gov Registration ID: NCT02553434.

Tranexamic Acid During Prehospital Transport in Patients at Risk for Hemorrhage After Injury: A Double-blind, Placebo-Controlled, Randomized Clinical Trial.

IMPORTANCE: In-hospital administration of tranexamic acid after injury improves outcomes in patients at risk for hemorrhage. Data demonstrating the benefit and safety of the pragmatic use of tranexamic acid in the prehospital phase of care are lacking for these patients. OBJECTIVE: To assess the effectiveness and safety of tranexamic acid administered before hospitalization compared with placebo in injured patients at risk for hemorrhage. DESIGN, SETTING, AND PARTICIPANTS: This pragmatic, phase 3, multicenter, double-blind, placebo-controlled, superiority randomized clinical trial included injured patients with prehospital hypotension (systolic blood pressure ≤90 mm Hg) or tachycardia (heart rate ≥110/min) before arrival at 1 of 4 US level 1 trauma centers, within an estimated 2 hours of injury, from May 1, 2015, through October 31, 2019. INTERVENTIONS: Patients received 1 g of tranexamic acid before hospitalization (447 patients) or placebo (456 patients) infused for 10 minutes in 100 mL of saline. The randomization scheme used prehospital and in-hospital phase assignments, and patients administered tranexamic acid were allocated to abbreviated, standard, and repeat bolus dosing regimens on trauma center arrival. MAIN OUTCOMES AND MEASURES: The primary outcome was 30-day all-cause mortality. RESULTS: In all, 927 patients (mean [SD] age, 42 [18] years; 686 [74.0%] male) were eligible for prehospital enrollment (460 randomized to tranexamic acid intervention; 467 to placebo intervention). After exclusions, the intention-to-treat study cohort comprised 903 patients: 447 in the tranexamic acid arm and 456 in the placebo arm. Mortality at 30 days was 8.1% in patients receiving tranexamic acid compared with 9.9% in patients receiving placebo (difference, -1.8%; 95% CI, -5.6% to 1.9%; P = .17). Results of Cox proportional hazards regression analysis, accounting for site, verified that randomization to tranexamic acid was not associated with a significant reduction in 30-day mortality (hazard ratio, 0.81; 95% CI, 0.59-1.11, P = .18). Prespecified dosing regimens and post-hoc subgroup analyses found that prehospital tranexamic acid were associated with significantly lower 30-day mortality. When comparing tranexamic acid effect stratified by time to treatment and qualifying shock severity in a post hoc comparison, 30-day mortality was lower when tranexamic acid was administered within 1 hour of injury (4.6% vs 7.6%; difference, -3.0%; 95% CI, -5.7% to -0.3%; P < .002). Patients with severe shock (systolic blood pressure ≤70 mm Hg) who received tranexamic acid demonstrated lower 30-day mortality compared with placebo (18.5% vs 35.5%; difference, -17%; 95% CI, -25.8% to -8.1%; P < .003). CONCLUSIONS AND RELEVANCE: In injured patients at risk for hemorrhage, tranexamic acid administered before hospitalization did not result in significantly lower 30-day mortality. The prehospital administration of tranexamic acid after injury did not result in a higher incidence of thrombotic complications or adverse events. Tranexamic acid given to injured patients at risk for hemorrhage in the prehospital setting is safe and associated with survival benefit in specific subgroups of patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02086500.

Group A emergency-release plasma in trauma patients requiring massive transfusion.

BACKGROUND: Both groups A and AB plasma have been approved for emergency-release transfusion in acutely bleeding trauma patients before blood grouping being performed. The safety profile associated with this practice has not been well characterized, particularly in patients requiring massive transfusion. METHODS: This secondary analysis of the Pragmatic, Randomized, Optimal Platelet and Plasma Ratios trial examined whether exposure to group A emergency-release plasma (ERP) was noninferior to group AB ERP. We also examined patients whose blood groups were compatible with group A ERP versus patients whose blood groups were incompatible with group A ERP. Outcomes included 30-day mortality and complication rates including systemic inflammatory response syndrome, infection, renal injury, pulmonary dysfunction, and thromboembolism. RESULTS: Of the 680 patients predicted to receive a massive transfusion, 584 (85.9%) received at least 1 U of ERP. Of the 584 patients analyzed, 462 (79.1%) received group AB and 122 (20.9%) received group A ERP. Using a hazard ratio (HR) of 1.35 as the noninferiority margin, transfusion with group A versus group AB ERP was not associated with increased thromboembolic rates (HR, 0.52; 95% confidence interval [CI], 0.31-0.90). Mortality (HR, 1.15; 95% CI, 0.91-1.45) and nonfatal complication rates (HR, 1.24; 95% CI, 0.87-1.77) were inconclusive. In the subgroup analysis, transfusion with incompatible ERP (group B or AB patients receiving group A ERP) was not associated with increased nonfatal complications (HR, 1.02; 95% CI, 0.80-1.30). There were no reported hemolytic transfusion reactions. CONCLUSION: The use of ERP is common in patients requiring massive transfusion and facilitates the rapid balanced resuscitation of patients who have sustained blood loss. Group A ERP is an acceptable option for patients requiring massive transfusion, especially if group AB ERP is not readily available. LEVEL OF EVIDENCE: Therapeutic/Care Management, level IV; Prognostic, level III.

A Multi-Institutional Analysis of Damage Control Laparotomy in Elderly Trauma Patients: Do Geriatric Trauma Protocols Matter?

BACKGROUND: Trauma centers are receiving increasing numbers of older trauma patients. There is a lack of literature on the outcomes for elderly trauma patients who undergo damage control laparotomy (DCL). We hypothesized that trauma centers with geriatric protocols would have better outcomes in elderly patients after DCL. METHODS: A retrospective chart review of consecutive adult trauma patients with DCL at 8 level 1 trauma centers was conducted from 2012 to 2018. Patients aged 40 or older were included. Age ≥ 55 years was defined as elderly. Demographics, injury information, clinical outcomes, including mortality, and complications were recorded. Univariate and multivariate analyses were performed. RESULTS: A total of 379 patients with DCLs were identified with an average age of 54.8 ± 0.4 years with 39.3% (n = 149/379) of patients aged ≥ 55. Geriatric protocols or a consulting geriatric service was present at 37.5% (n = 3/8) of institutions. Age ≥ 55 was a significant risk factor for in-hospital mortality (OR 2, 95% CI 1.0-4.0, P = .04). Institutions without dedicated geriatric trauma protocols/services had higher overall in-hospital mortality on both univariate (57.9% vs 34.3%, P = .02) and multivariate analyses (OR 2.1, 95% CI 1.3-3.4, P < .001). CONCLUSIONS: Surgical management of older trauma patients remains a challenge. Geriatric protocols or dedicated services were found to be associated with improved outcomes. Future efforts should focus on standardizing the availability of these resources at trauma centers.

Retrospective Analysis of Low-Molecular-Weight Heparin and Unfractionated Heparin in Pediatric Trauma Patients: A Comparative Analysis.

BACKGROUND: Chemoprophylaxis with either unfractionated heparin (UFH) or Low-Molecular-Weight Heparin (LMWH) are recommended to prevent Venous Thromboembolism (VTE) after trauma. Experimental work has shown beneficial effects of LMWH in animal models, but it is unknown if similar effects exist in humans. We hypothesized that treatment with LMWH is associated with a survival benefit when compared to UFH. METHODS: We performed a retrospective analysis of our level I trauma center database from January 2009 to June 2018. Pediatric patients (age < 18) were included if they received either LMWH or UFH during their stay. Outcome measures included mortality, VTE complications, and hospital length of stay (HLOS). RESULTS: A total of 354 patients were included. Patients who received LMWH had lower mortality compared to those who received UFH. After multivariate logistic regression, LMWH was still independently associated with improved survival. No association was found between LMWH and UFH regarding deep vein thrombosis (DVT) or pulmonary embolism (PE) rates. No association was found between LMWH with HLOS. CONCLUSIONS: LMWH was associated with improved survival compared to UFH in our pediatric trauma patients. This was independent of injury severity or VTE complications. Further studies are required to understand better the mechanisms by which LMWH improves survival. LEVEL OF EVIDENCE: 3.

Review of massive transfusion protocols in the injured, bleeding patient.

PURPOSE OF REVIEW: Massive haemorrhage is a significant cause of mortality and morbidity in a variety of clinical settings, although most research has been related to trauma patients. Military studies from recent conflicts found that higher ratios of plasma to red blood cells (RBCs) were associated with increased survival in injured soldiers, and subsequent trials in civilian populations showed similar decreased mortality. Over the last decade, massive transfusion protocols (MTPs) have become an important component in the treatment of the massively bleeding patient. This review is intended to summarize the more recent findings and trends in massive transfusion. RECENT FINDINGS: There have been several observational studies suggesting that higher ratios of plasma to RBC and platelets to RBC are associated with improved survival but there is a paucity of randomized studies relating to specific ratios, dosages, timing, and guidance. Other studies have developed and assessed scoring systems used to initiate MTPs and specific tests used to guide MTPs. Finally, the specific blood components and adjuncts that constitute a MTP are the subject of further ongoing research. SUMMARY: The absence of a universal definition of massive bleeding or massive transfusion, heterogeneity in patients suffering from massive bleeding, and the difficulty in predicting which patients will require a massive transfusion all contribute to the difficulty of studying massive transfusion. However, there is evidence that higher plasma : RBC ratios correlate with improved survival, and that adjuncts to transfusion play a key role. Furthermore, recent validations of massive haemorrhage scoring systems should allow more consistent and appropriate triggering of massive transfusions.

Pediatric Liver Injury: Physical Examination, Fast and Serum Transaminases Can Serve as a Guide.

BACKGROUND: The aim of our study was to determine if the combination of physical examination (PE), serum transaminases along with Focused Assessment with Sonography in Trauma (FAST) would effectively rule out major hepatic injuries (HIs) after blunt abdominal trauma (BAT) in hemodynamically stable pediatric patients. METHODS: We conducted a 9-year retrospective study of pediatric patients (<18 y) with BAT. We collected data on liver enzymes (aspartate transaminase [AST] and alanine transaminase [ALT]), FAST, and PE findings. Definitive diagnosis and staging of HI were based on abdominal CT scanning. The sensitivity and specificity of ALT/AST, FAST, and PE were then calculated individually and in combination. RESULTS: We identified a total of 423 pediatric patients with BAT. Mean age was 11 y, median abdominal Abbreviated Injury Scale was 3 [2-4], and mean ED-SBP was 132 mm Hg. One hundred ninety-eight patients had HI of which 107 were major HI, defined by the American Association for the Surgery of Trauma as ≥grade III. Using ROC curve analysis, optimum ALT and AST thresholds were determined to be 90 U/L and 120 U/L, respectively. The sensitivity of FAST was 50% while that of PE was 40%. Combining PE with AST/ALT and FAST had an overall sensitivity of 97%, a specificity of 95%, a positive predictive value of 87%, and a negative predictive value of 98%. CONCLUSIONS: In hemodynamically stable pediatric blunt abdominal trauma patients, CT scanning can be avoided using a combination of readily available tests thus avoiding unnecessary radiation exposure. However, pediatric patients with positive PE, FAST, and elevated AST/ALT may eventually require CT scan to further evaluate liver injuries.

Nationwide Analysis of Resuscitative Endovascular Balloon Occlusion of the Aorta in Civilian Trauma.

Importance: The need for improved methods of hemorrhage control and resuscitation has resulted in a reappraisal of resuscitative endovascular balloon occlusion of the aorta (REBOA). However, there is a paucity of data regarding the use of REBOA on a multi-institutional level in the United States. Objective: To evaluate the outcomes in trauma patients after REBOA placement. Design, Setting, and Participants: A case-control retrospective analysis was performed of the 2015-2016 American College of Surgeons Trauma Quality Improvement Program data set, a national multi-institutional database of trauma patients in the United States. A total of 593 818 adult trauma patients (aged ≥18 years) were analyzed and 420 patients were matched and included in the study; patients who were dead on arrival or were transferred from other facilities were excluded. Trauma patients who underwent REBOA placement in the ED were identified and matched with a similar cohort of patients (the no-REBOA group). Both groups were matched in a 1:2 ratio using propensity score matching for demographics, vital signs, mechanism of injury, injury severity score, head abbreviated injury scale score, each body region abbreviated injury scale score, pelvic fractures, lower extremity vascular injuries and fractures, and number and grades of intra-abdominal solid organ injuries. Main Outcomes and Measures: Outcome measures were the rates of complications and mortality. Results: Of 593 818 trauma patients, 420 patients (the REBOA group, 140 patients; 36 women and 104 men; mean [SD] age, 44 [20] years; the no-REBOA group, 280 patients; 77 women and 203 men; mean [SD] age, 43 [19] years) were matched and included in the analysis. Among the REBOA group, median injury severity score was 29 (interquartile range [IQR], 18-38) and 129 patients (92.1%) had a blunt mechanism of injury. There was no significant difference between groups in median 4-hour blood transfusion (REBOA: packed red blood cells, 6 U [IQR, 3-8 U]; platelets, 4 U [IQR, 3-9 U], and plasma, 3 U [IQR, 2-5 U]; and no-REBOA: packed red blood cells, 7 U [IQR, 3-9 U]; platelets, 4 U [IQR, 3-8 U], and plasma, 3 U [IQR, 2-6 U]) or 24-hour blood transfusion (REBOA: packed red blood cells, 9 U [IQR, 5-20 U]; platelets, 7 U [IQR, 3-13 U], and plasma, 9 U [IQR, 6-20 U]; and no-REBOA: packed red blood cells, 10 U [IQR, 4-21 U]; platelets, 8 U [IQR, 3-12 U], and plasma, 10 U [IQR, 7-20 U]), median hospital length of stay (REBOA, 8 days [IQR, 1-20 days]; and no-REBOA, 10 days [IQR, 5-22 days]), or median intensive care unit length of stay (REBOA, 5 days [IQR, 2-14 days]; and no-REBOA, 6 days [IQR, 3-15 days]). The mortality rate was higher in the REBOA group as compared with the no-REBOA group (50 [35.7%] vs 53 [18.9%]; P = .01). Patients who underwent REBOA placement were also more likely to develop acute kidney injury (15 [10.7%] vs 9 [3.2%]; P = .02) and more likely to undergo lower extremity amputation (5 [3.6%] vs 2 [0.7%]; P = .04). Conclusions and Relevance: Placement of REBOA in severely injured trauma patients was associated with a higher mortality rate compared with a similar cohort of patients with no placement of REBOA. Patients in the REBOA group also had higher rates of acute kidney injury and lower leg amputations. There is a need for a concerted effort to clearly define when and in which patient population REBOA has benefit.

Operative spinal trauma: Thromboprophylaxis with low molecular weight heparin or a direct oral anticoagulant.

Essentials Operative spine trauma patients are at increased risk of venous thromboembolism (VTE). Direct oral anticoagulants (DOACs) may have a favorable efficacy and safety in spine trauma. Patients on DOACs had lower rates of VTE in comparison to low molecular weight heparin. DOACs did not augment the risk of surgical bleeding (transfusion, decompressive procedures). BACKGROUND: Spinal trauma patients are at high risk for venous thromboembolism (VTE). OBJECTIVE: To compare the impacts of direct oral anticoagulants (DOACs) and low molecular weight heparin (LMWH) as thromboprophylactic agents on outcomes in operative spinal trauma patients. METHODS: A 2-year (2015-2016) retrospective cohort analysis of such patients (spine Abbreviated Injury Scale [AIS] ≥ 3 and other AIS < 3) who received LMWH or DOACs was performed. Propensity score matching (1:2 ratio) followed stratification into two groups. Outcomes included rates of deep vein thrombosis (DVT) and/or pulmonary embolism (PE), packed red blood cell (pRBC) transfusion, operative interventions for spinal cord decompression, and mortality. RESULTS: Of 6036 patients, 810 (270 receiving DOACs; 540 receiving LMWH) were matched. The mean age was 62 ± 15 years, 58% were male, and the median Injury Severity Score was 12 (10-18). Matched groups were similar in demographics, injury parameters, emergency department vital signs, hospital stay, rates of inferior vena cava filter placement, and timing of initiation of thromboprophylaxis. The overall rate of in-hospital DVT was 5.6%, the overall rate of in-hospital PE was 1.6%, and the mortality rate was 2.5%. DOAC patients were less likely to develop DVT (1.8% vs 7.4%) and PE (0.3% vs 2.1%). There were no differences in postprophylaxis pRBC transfusion requirements, postprophylaxis decompressive procedures on the spinal cord, or mortality. CONCLUSION: In operative spinal trauma patients, thromboprophylaxis with DOACs appears to be associated with lower rates of DVT and PE. Further prospective clinical trials should evaluate the role of DOACs in preventing VTE events in spinal trauma patients.