Abstract

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 STAAMP 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 to 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 to neither (HR 0.65; 95%CI 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 h mortality compared to neither (HR 0.39; 95%CI 0.17-0.88, p = 0.02). CONCLUSIONS 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, Level III.

Abstract

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 1hr (EARLY) from time of injury were compared to those who received prehospital TXA beyond 1hr (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 = .03) with no separation for DELAYED patients (N=238, log-rank chi-square test, 0.04; P = .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 (HR 0.35, 95%CI 0.19-0.65, P = .001) with no independent survival benefit found in DELAYED patients (HR 1.00, 95%CI 0.63-1.59, P = .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.

Abstract

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.

Abstract

INTRODUCTION Administration of tranexamic acid (TXA) in coagulopathy of trauma gained popularity after the CRASH-2 trial. The aim of our analysis was to analyze the role of TXA in severely injured trauma patients with admission hyperfibrinolysis. METHODS We reviewed the prospectively collected Pragmatic, Randomized Optimal Platelet and Plasma Ratios database. We included patients with admission hyperfibrinolysis (Ly30 >3%) on thromboelastography. Patients were stratified into two groups (TXA and No-TXA) and were matched in 1:2 ratio using propensity score matching for demographics, admission vitals, and injury severity. Primary outcome measures were 6-, 12-, and 24-hour and 30-day mortality; 24-hour transfusion requirements; time to achieve hemostasis; and rebleeding after hemostasis requiring intervention. Secondary outcome measures were thrombotic complications. RESULTS We analyzed 680 patients. Of those, 118 had admission hyperfibrinolysis, and 93 patients (TXA: 31 patients; No-TXA: 62 patients) were matched. Matched groups were similar in age (p = 0.33), gender (p = 0.84), race (p = 0.81), emergency department (ED) Glasgow Coma Scale (p = 0.34), ED systolic blood pressure (p = 0.28), ED heart rate (p = 0.43), mechanism of injury (p = 0.45), head Abbreviated Injury Scale score (p = 0.68), injury severity score (p = 0.56), and blood products ratio (p = 0.44). Patients who received TXA had a lower 6-hour mortality rate (34% vs. 13%, p = 0.04) and higher 24-hour transfusion of plasma (15 vs. 10 units, p = 0.03) compared with the No-TXA group. However, there was no difference in 12-hour (p = 0.24), 24-hour (p = 0.25), and 30-day mortality (p = 0.82). Similarly, there was no difference in 24-hour transfusion of RBC (p = 0.11) or platelets (p = 0.13), time to achieve hemostasis (p = 0.65), rebleeding requiring intervention (p = 0.13), and thrombotic complications (p = 0.98). CONCLUSION Tranexamic acid was associated with increased 6-hour survival but does not improve long-term outcomes in severely injured trauma patients with hemorrhage who develop hyperfibrinolysis. Moreover, TXA administration was not associated with thrombotic complications. Further randomized clinical trials will identify the subset of trauma patients who may benefit from TXA. LEVEL OF EVIDENCE Therapeutic study, level III.

Abstract

BACKGROUND Often the clinician is faced with a diagnostic and therapeutic dilemma in patients with concomitant traumatic brain injury (TBI) and hemorrhagic shock (HS), as rapid deterioration from either can be fatal. Knowledge about outcomes after concomitant TBI and HS may help prioritize the emergent management of these patients. We hypothesized that patients with concomitant TBI and HS (TBI + HS) had worse outcomes and required more intensive care compared with patients with only one of these injuries. METHODS This is a post hoc analysis of the Pragmatic, Randomized Optimal Platelets and Plasma Ratios (PROPPR) trial. TBI was defined by a head Abbreviated Injury Scale score greater than 2. HS was defined as a base excess of -4 or less and/or shock index of 0.9 or greater. The primary outcome for this analysis was mortality at 30 days. Logistic regression, using generalized estimating equations, was used to model categorical outcomes. RESULTS Six hundred seventy patients were included. Patients with TBI + HS had significantly higher lactate (median, 6.3; interquartile range, 4.7-9.2) compared with the TBI group (median, 3.3; interquartile range, 2.3-4). TBI + HS patients had higher activated prothrombin times and lower platelet counts. Unadjusted mortality was higher in the TBI + HS (51.6%) and TBI (50%) groups compared with the HS (17.5%) and neither group (7.7%). Adjusted odds of death in the TBI and TBI + HS groups were 8.2 (95% confidence interval, 3.4-19.5) and 10.6 (95% confidence interval, 4.8-23.2) times higher, respectively. Ventilator, intensive care unit-free and hospital-free days were lower in the TBI and TBI + HS groups compared with the other groups. Patients with TBI + HS or TBI had significantly greater odds of developing a respiratory complication compared with the neither group. CONCLUSION The addition of TBI to HS is associated with worse coagulopathy before resuscitation and increased mortality. When controlling for multiple known confounders, the diagnosis of TBI alone or TBI+HS was associated with significantly greater odds of developing respiratory complications. LEVEL OF EVIDENCE Prognostic study, level II.

Abstract

BACKGROUND Often the clinician is faced with a diagnostic and therapeutic dilemma in patients with concomitant traumatic brain injury (TBI) and hemorrhagic shock (HS), as rapid deterioration from either can be fatal. Knowledge about outcomes following concomitant TBI and HS may help prioritize the emergent management of these patients. We hypothesized that patients with concomitant TBI and HS (TBI+HS) had worse outcomes and required more intensive care compared to patients with only one of these injuries. METHODS This is a post-hoc analysis of the Pragmatic, Randomized Optimal Platelets and Plasma Ratios (PROPPR) trial. TBI was defined by a head abbreviated injury scale >2. HS was defined as a base excess ≤ -4 and/or shock index ≥ 0.9. The primary outcome for this analysis was mortality at 30 days. Logistic regression, using generalized estimating equations (GEE), was used to model categorical outcomes. RESULTS 670 patients were included. Patients with TBI+HS had significantly higher lactate (median 6.3; IQR 4.7,9.2) compared to the TBI group (median 3.3; IQR 2.3,4). TBI+HS patients had higher activated prothrombin times and lower platelet counts. Unadjusted mortality was higher in the TBI+HS (51.6%) and TBI (50%) groups compared to the HS (17.5%) and neither group (7.7%). Adjusted odds of death in the TBI and TBI+HS groups were 8.2 (95% CI, 3.4-19.5) and 10.6 (95% CI, 4.8-23.2) times higher, respectively. Ventilator, ICU- and hospital-free days were lower in the TBI and TBI+HS groups compared to the other groups. Patients with TBI+HS or TBI had significantly greater odds of developing a respiratory complication compared to the neither group. CONCLUSIONS The addition of TBI to HS is associated with worse coagulopathy prior to resuscitation, and increased mortality. When conrolling for multiple known confounders, the diagnosis of TBI alone or TBI+HS was associated with significantly greater odds of developing respiratory complications. STUDY TYPE prognostic study LEVEL OF EVIDENCE II.

Abstract

BACKGROUND ACS-TQIP Best Practices recommends initial massive transfusion (MT) cooler delivery within 15 minutes of protocol activation, with a goal of 10 minutes. The current study sought to examine the impact of timing of first cooler delivery on patient outcomes. METHODS Patients predicted to receive MT at 12 level-1 trauma centers were randomized to two separate transfusion ratios as described in the PROPPR trial. ABC score or clinician gestalt prediction of MT was used to randomize patients and call for initial study cooler. In this planned sub-analysis, the time to MT protocol activation and time to delivery of the initial cooler were evaluated. The impact of these times on mortality and time to hemostasis were examined using both Wilcoxon rank sum and linear and logistic regression. RESULTS Among 680 patients, the median time from patient arrival to MT protocol activation was 9 minutes with a median time from MT activation call to delivery of first cooler of 8 minutes. An increase in both time to MT activation and time to arrival of first cooler were associated with prolonged time to achieving hemostasis (coef 1.09, p=0.001 and coef. 1.16, p < 0.001, respectively). Increased time to MT activation and time to arrival of first cooler were associated with increased mortality (OR 1.02, p=0.009 and OR 1.02, p = 0.012, respectively). Controlling for injury severity, physiology, resuscitation intensity, and treatment arm (1:1:1 vs. 1:1:2), increased time to arrival of first cooler was associated with an increased mortality at 24-hours (OR 1.05, p = 0.035) and 30-days (OR 1.05, p = 0.016). CONCLUSIONS Delays in MT protocol activation and delays in initial cooler arrival were associated with prolonged time to achieve hemostasis and an increase in mortality. Independent of products ratios, every minute from time of MT protocol activation to time of initial cooler arrival increases odds of mortality by 5%. LEVEL OF EVIDENCE Level II, Prognostic.

Abstract

IMPORTANCE Severely injured patients experiencing hemorrhagic shock often require massive transfusion. Earlier transfusion with higher blood product ratios (plasma, platelets, and red blood cells), defined as damage control resuscitation, has been associated with improved outcomes; however, there have been no large multicenter clinical trials. OBJECTIVE To determine the effectiveness and safety of transfusing patients with severe trauma and major bleeding using plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio. DESIGN, SETTING, AND PARTICIPANTS Pragmatic, phase 3, multisite, randomized clinical trial of 680 severely injured patients who arrived at 1 of 12 level I trauma centers in North America directly from the scene and were predicted to require massive transfusion between August 2012 and December 2013. INTERVENTIONS Blood product ratios of 1:1:1 (338 patients) vs 1:1:2 (342 patients) during active resuscitation in addition to all local standard-of-care interventions (uncontrolled). MAIN OUTCOMES AND MEASURES Primary outcomes were 24-hour and 30-day all-cause mortality. Prespecified ancillary outcomes included time to hemostasis, blood product volumes transfused, complications, incidence of surgical procedures, and functional status. RESULTS No significant differences were detected in mortality at 24 hours (12.7% in 1:1:1 group vs 17.0% in 1:1:2 group; difference, -4.2% [95% CI, -9.6% to 1.1%]; P=.12) or at 30 days (22.4% vs 26.1%, respectively; difference, -3.7% [95% CI, -10.2% to 2.7%]; P=.26). Exsanguination, which was the predominant cause of death within the first 24 hours, was significantly decreased in the 1:1:1 group (9.2% vs 14.6% in 1:1:2 group; difference, -5.4% [95% CI, -10.4% to -0.5%]; P=.03). More patients in the 1:1:1 group achieved hemostasis than in the 1:1:2 group (86% vs 78%, respectively; P=.006). Despite the 1:1:1 group receiving more plasma (median of 7 U vs 5 U, P<.001) and platelets (12 U vs 6 U, P<.001) and similar amounts of red blood cells (9 U) over the first 24 hours, no differences between the 2 groups were found for the 23 prespecified complications, including acute respiratory distress syndrome, multiple organ failure, venous thromboembolism, sepsis, and transfusion-related complications. CONCLUSIONS AND RELEVANCE Among patients with severe trauma and major bleeding, early administration of plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio did not result in significant differences in mortality at 24 hours or at 30 days. However, more patients in the 1:1:1 group achieved hemostasis and fewer experienced death due to exsanguination by 24 hours. Even though there was an increased use of plasma and platelets transfused in the 1:1:1 group, no other safety differences were identified between the 2 groups. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01545232.