1.
Effect of Out-of-Hospital Tranexamic Acid vs Placebo on 6-Month Functional Neurologic Outcomes in Patients With Moderate or Severe Traumatic Brain Injury
Rowell SE, Meier EN, McKnight B, Kannas D, May S, Sheehan K, Bulger EM, Idris AH, Christenson J, Morrison LJ, et al
Jama. 2020;324(10):961-974
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Abstract
IMPORTANCE Traumatic brain injury (TBI) is the leading cause of death and disability due to trauma. Early administration of tranexamic acid may benefit patients with TBI. OBJECTIVE To determine whether tranexamic acid treatment initiated in the out-of-hospital setting within 2 hours of injury improves neurologic outcome in patients with moderate or severe TBI. DESIGN, SETTING, AND PARTICIPANTS Multicenter, double-blinded, randomized clinical trial at 20 trauma centers and 39 emergency medical services agencies in the US and Canada from May 2015 to November 2017. Eligible participants (N = 1280) included out-of-hospital patients with TBI aged 15 years or older with Glasgow Coma Scale score of 12 or less and systolic blood pressure of 90 mm Hg or higher. INTERVENTIONS Three interventions were evaluated, with treatment initiated within 2 hours of TBI: out-of-hospital tranexamic acid (1 g) bolus and in-hospital tranexamic acid (1 g) 8-hour infusion (bolus maintenance group; n = 312), out-of-hospital tranexamic acid (2 g) bolus and in-hospital placebo 8-hour infusion (bolus only group; n = 345), and out-of-hospital placebo bolus and in-hospital placebo 8-hour infusion (placebo group; n = 309). MAIN OUTCOMES AND MEASURES The primary outcome was favorable neurologic function at 6 months (Glasgow Outcome Scale-Extended score >4 [moderate disability or good recovery]) in the combined tranexamic acid group vs the placebo group. Asymmetric significance thresholds were set at 0.1 for benefit and 0.025 for harm. There were 18 secondary end points, of which 5 are reported in this article: 28-day mortality, 6-month Disability Rating Scale score (range, 0 [no disability] to 30 [death]), progression of intracranial hemorrhage, incidence of seizures, and incidence of thromboembolic events. RESULTS Among 1063 participants, a study drug was not administered to 96 randomized participants and 1 participant was excluded, resulting in 966 participants in the analysis population (mean age, 42 years; 255 [74%] male participants; mean Glasgow Coma Scale score, 8). Of these participants, 819 (84.8%) were available for primary outcome analysis at 6-month follow-up. The primary outcome occurred in 65% of patients in the tranexamic acid groups vs 62% in the placebo group (difference, 3.5%; [90% 1-sided confidence limit for benefit, -0.9%]; P = .16; [97.5% 1-sided confidence limit for harm, 10.2%]; P = .84). There was no statistically significant difference in 28-day mortality between the tranexamic acid groups vs the placebo group (14% vs 17%; difference, -2.9% [95% CI, -7.9% to 2.1%]; P = .26), 6-month Disability Rating Scale score (6.8 vs 7.6; difference, -0.9 [95% CI, -2.5 to 0.7]; P = .29), or progression of intracranial hemorrhage (16% vs 20%; difference, -5.4% [95% CI, -12.8% to 2.1%]; P = .16). CONCLUSIONS AND RELEVANCE Among patients with moderate to severe TBI, out-of-hospital tranexamic acid administration within 2 hours of injury compared with placebo did not significantly improve 6-month neurologic outcome as measured by the Glasgow Outcome Scale-Extended. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01990768.
PICO Summary
Population
Out-of-hospital patients with traumatic brain injury aged 15 years or older (n= 1280).
Intervention
Bolus maintenance group: out-of-hospital tranexamic acid (1 g) bolus and in-hospital tranexamic acid (1 g) 8-hour infusion (n = 312).
Comparison
Bolus only group: out-of-hospital tranexamic acid (2 g) bolus and in-hospital placebo 8-hour infusion (n = 345). Placebo group: out-of-hospital placebo bolus and in-hospital placebo 8-hour infusion (n = 309).
Outcome
A total of 819 participants were available for primary outcome analysis at 6-month follow-up. The primary outcome (favorable neurologic function at 6 months) occurred in 65% of patients in the tranexamic acid groups vs 62% in the placebo group. There was no statistically significant difference in 28-day mortality between the tranexamic acid groups vs the placebo group (14% vs 17%); 6-month Disability Rating Scale score (6.8 vs 7.6); or progression of intracranial hemorrhage (16% vs 20%).
2.
TXA Administration in the Field Does Not Affect Admission TEG after Traumatic Brain Injury
Dixon AL, McCully BH, Rick EA, Dewey E, Farrell DH, Morrison LJ, McMullan J, Robinson BRH, Callum J, Tibbs B, et al
The journal of trauma and acute care surgery. 2020
Abstract
BACKGROUND No FDA-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 old with TBI (Glascow Coma Scale 3-12) and systolic blood pressure ≥90 mmHg were randomized prehospital to receive placebo bolus/placebo infusion (Placebo), 1 gram (g) TXA bolus/1g TXA infusion (Bolus Maintenance [BM]); or 2g TXA bolus/placebo infusion (Bolus Only [BO]). TEG was performed and coagulation measures including prothrombin time (PT), activated partial thromboplastin time (aPTT), international ratio (INR), fibrinogen, D-dimer, plasmin anti-plasmin (PAP), thrombin anti-thrombin (TAT), tissue plasminogen activator (tPA), and plasminogen activator inhibitor-1 (PAI-1) were quantified at admission and six hours later. RESULTS Of 966 patients receiving study drug, 700 had labs drawn at admission and six hours later. There were no statistically significant differences in TEG values, including LY30, between groups (p>0.05). No differences between PT, aPTT, INR, fibrinogen, TAT, tPA, and PAI-1 were demonstrated across treatment groups. Concentrations of D-dimer in TXA treatment groups were less than placebo at six hours (p<0.001). Concentrations of PAP were less in TXA treatment groups than placebo on admission (p<0.001) and six hours (p=0.02). No differences in D-dimer and PAP were observed between BM and BO. CONCLUSION While D-dimer and PAP levels reflect a lower degree of fibrinolysis following prehospital administration of TXA when compared to placebo in a large prehospital trial of patients with TBI, TEG obtained on admission and six hours later did not demonstrate any differences in fibrinolysis between the two TXA dosing regimens and placebo. LEVEL OF EVIDENCE III; Diagnostic.
3.
Outcomes after concomitant traumatic brain injury and hemorrhagic shock: a secondary analysis from the Pragmatic, Randomized Optimal Platelets and Plasma Ratios trial
Galvagno SM Jr, Fox EE, Appana SN, Baraniuk S, Bosarge PL, Bulger EM, Callcut RA, Cotton BA, Goodman M, Inaba K, et al
The Journal of Trauma and Acute Care Surgery. 2017;83((4)):668-674.
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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.