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

IMPORTANCE Tranexamic acid is widely available and used off-label in patients with bleeding traumatic injury, although the literature does not consistently agree on its efficacy and safety. OBJECTIVE To examine the association of tranexamic acid administration with mortality and thromboembolic events compared with no treatment or with placebo in patients with traumatic injury in the literature. DATA SOURCES On March 23, 2021, PubMed, Embase, and the Cochrane Library were searched for eligible studies published between 1986 and 2021. STUDY SELECTION Randomized clinical trials and observational studies investigating tranexamic acid administration compared with no treatment or placebo among patients with traumatic injury and traumatic brain injury who were 15 years or older were included. Included studies were published in English or German. The electronic search yielded 1546 records, of which 71 were considered for full-text screening. The selection process was performed independently by 2 reviewers. DATA EXTRACTION AND SYNTHESIS The study followed the Cochrane Handbook for Systematic Reviews of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data were extracted by 2 independent reviewers and pooled using the inverse-variance random-effects model. MAIN OUTCOMES AND MEASURES Outcomes were formulated before data collection and included mortality at 24 hours and 28 and 30 days (1 month) as well as the incidence of thromboembolic events and the amount of blood products administered. Owing to missing data, overall mortality was added and the amount of blood products administered was discarded. RESULTS Thirty-one studies with a total of 43 473 patients were included in the systematic review. The meta-analysis demonstrated that administration of tranexamic acid was associated with a significant decrease in 1-month mortality compared with the control cohort (risk ratio, 0.83 [95% CI, 0.71-0.97]; I2 = 35%). The results of meta-analyses for 24-hour and overall mortality and thromboembolic events were heterogeneous and could not be pooled. Further investigations on clinical heterogeneity showed that populations with trauma and trial conditions differed markedly. CONCLUSIONS AND RELEVANCE These findings suggest that tranexamic acid may be beneficial in various patient populations with trauma. However, reasonable concerns about potential thromboembolic events with tranexamic acid remain.

Abstract

OBJECTIVE To determine the efficacy of Mannitol combined with 6-aminocaproic acid in the treatment of patients with cerebral hemorrhage, as well as its impact on the immune system. METHODS The study subjects consisted of 122 patients with early intracerebral hemorrhage treated in our hospital from April 2019 to April 2022. Based on the different admission times, the participants were randomly divided into the control group and the study group in a ratio of 1:1. 6-Aminocaproic acid was used to treat patients in the control group, while Mannitol along with 6-aminocaproic acid was used to treat patients in the study group. Short form-36 health survey (SF-36) scores, hematoma volume changes, National Institutes of Health Stroke Scale (NIHSS), and Mini-Mental State Examination (MMSE) scores, clinical efficacy, and changes in the immune function in patients from the two groups were analyzed and compared. RESULTS The total efficacy of treatment in the study group was significantly higher than that in the control group (x (2) = 9,375, P < 0.001). Patients in the study group had significantly higher scores in social function, mental health, physical function, and physiological function compared to those in the control group (P < 0.05). After treatment, there was a significant reduction in NIHSS scores in patients from both groups, but a greater reduction was seen in patients from the study group (P < 0.05). After 2 weeks of treatment, the volume of cerebral edema was significantly smaller in patients from the study group than in those from the control group (P < 0.05). Before treatment, there was no significant difference in the number of CD4+ and CD8+ T lymphocytes between patients in the two groups. However, after treatment, patients in the study group had higher numbers of CD4+ T lymphocytes and lower numbers of CD8+ T lymphocytes compared to those in the control group (P < 0.05). CONCLUSIONS The combination of Mannitol and 6-aminocaproic acid appears to be very efficacious in the treatment of cerebral hemorrhage. It improves immune function, reduces neurological damage, and minimizes the volume of cerebral edema.

Abstract

BACKGROUND The antifibrinolytic drug tranexamic acid (TXA) improves survival in adults with traumatic hemorrhage; however, the drug has not been evaluated in a trial in injured children. We evaluated the feasibility of a large-scale trial evaluating the effects of TXA in children with severe hemorrhagic injuries. METHODS Severely injured children (0 up to 18(th) birthday) were randomized into a double-blind randomized trial of 1) TXA 15 mg/kg bolus dose, followed by 2 mg/kg/hr infusion over 8 hours, 2) TXA 30 mg/kg bolus dose, followed by 4 mg/kg/hr infusion over 8 hours, or 3) normal saline placebo bolus and infusion. The trial was conducted at 4 pediatric Level I trauma centers in the United States between June 2018 and March 2020. We enrolled patients under federal exception from informed consent (EFIC) procedures when parents were unable to provide informed consent. Feasibility outcomes included the rate of enrollment, adherence to intervention arms, and ability to measure the primary clinical outcome. Clinical outcomes included global functioning (primary), working memory, total amount of blood products transfused, intracranial hemorrhage progression, and adverse events. The target enrollment rate was at least 1.25 patients per site per month. RESULTS A total of 31 patients were randomized with a mean age of 10.7 years (standard deviation [SD] 5.0 years) and 22 (71%) patients were male. The mean time from injury to randomization was 2.4 hours (SD 0.6 hours). Sixteen (52%) patients had isolated brain injuries and 15 (48%) patients had isolated torso injuries. The enrollment rate using EFIC was 1.34 patients per site per month. All eligible enrolled patients received study intervention (9 patients TXA 15 mg/kg bolus dose, 10 patients TXA 30 mg/kg bolus dose, and 12 patients placebo) and had the primary outcome measured. No statistically significant differences in any of the clinical outcomes were identified. CONCLUSION Based on enrollment rate, protocol adherence, and measurement of the primary outcome in this pilot trial, we confirmed the feasibility of conducting a large-scale, randomized trial evaluating the efficacy of TXA in severely injured children with hemorrhagic brain and/or torso injuries using EFIC.

Abstract

IMPORTANCE Hyperintense foci on diffusion-weighted imaging (DWI) that are spatially remote from the acute hematoma occur in 20% of people with acute spontaneous intracerebral hemorrhage (ICH). Tranexamic acid, a hemostatic agent that is under investigation for treating acute ICH, might increase DWI hyperintense lesions (DWIHLs). OBJECTIVE To establish whether tranexamic acid compared with placebo increased the prevalence or number of remote cerebral DWIHLs within 2 weeks of ICH onset. DESIGN, SETTING, AND PARTICIPANTS This prospective nested magnetic resonance imaging (MRI) substudy of a randomized clinical trial (RCT) recruited participants from the multicenter, double-blind, placebo-controlled, phase 3 RCT (Tranexamic Acid for Hyperacute Primary Intracerebral Hemorrhage [TICH-2]) from July 1, 2015, to September 30, 2017, and conducted follow-up to 90 days after participants were randomized to either the tranexamic acid or placebo group. Participants had acute spontaneous ICH and included TICH-2 participants who provided consent to undergo additional MRI scans for the MRI substudy and those who had clinical MRI data that were compatible with the brain MRI protocol of the substudy. Data analyses were performed on an intention-to-treat basis on January 20, 2020. INTERVENTIONS The tranexamic acid group received 1 g in 100-mL intravenous bolus loading dose, followed by 1 g in 250-mL infusion within 8 hours of ICH onset. The placebo group received 0.9% saline within 8 hours of ICH onset. Brain MRI scans, including DWI, were performed within 2 weeks. MAIN OUTCOMES AND MEASURES Prevalence and number of remote DWIHLs were compared between the treatment groups using binary logistic regression adjusted for baseline covariates. RESULTS A total of 219 participants (mean [SD] age, 65.1 [13.8] years; 126 men [57.5%]) who had brain MRI data were included. Of these participants, 96 (43.8%) were randomized to receive tranexamic acid and 123 (56.2%) were randomized to receive placebo. No baseline differences in demographic characteristics and clinical or imaging features were found between the groups. There was no increase for the tranexamic acid group compared with the placebo group in DWIHL prevalence (20 of 96 [20.8%] vs 28 of 123 [22.8%]; odds ratio [OR], 0.71; 95% CI, 0.33-1.53; P = .39) or mean (SD) number of DWIHLs (1.75 [1.45] vs 1.81 [1.71]; mean difference [MD], -0.08; 95% CI, -0.36 to 0.20; P = .59). In an exploratory analysis, participants who were randomized within 3 hours of ICH onset or those with chronic infarcts appeared less likely to have DWIHLs if they received tranexamic acid. Participants with probable cerebral amyloid angiopathy appeared more likely to have DWIHLs if they received tranexamic acid. CONCLUSIONS AND RELEVANCE This substudy of an RCT found no evidence of increased prevalence or number of remote DWIHLs after tranexamic acid treatment in acute ICH. These findings provide reassurance for ongoing and future trials that tranexamic acid for acute ICH is unlikely to induce cerebral ischemic events. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN93732214.

Abstract

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

Abstract

BACKGROUND Urgent treatment with tranexamic acid (TXA) reduces bleeding deaths but there is disagreement about which patients should be treated. We examine the effects of TXA treatment in severely and non-severely injured trauma patients. STUDY DESIGN AND METHODS We did an individual patient data meta-analysis of randomized trials with over 1000 trauma patients that assessed the effects of TXA on survival. We defined the severity of injury according to characteristics at first assessment: systolic blood pressure of less than 90 mm Hg and a heart rate greater than 120 beats per minute or Glasgow Coma Scale score of less than nine or any GCS with one or more fixed dilated pupils. The primary measure was survival on the day of the injury. We examined the effect of TXA on survival in severely and non-severely injured patients and how these effects vary with the time from injury to treatment. RESULTS We obtained data for 32,944 patients from two randomized trials. Tranexamic acid significantly increased survival on the day of the injury (OR = 1.22, 95% CI 1.11-1.34; p < .01). The effect of tranexamic acid on survival in non-severely injured patients (OR = 1.25, 1.03-1.50) was similar to that in severely injured patients (OR = 1.22, 1.09-1.37) with no significant heterogeneity (p = .87). In severely and non-severely injured pateints, treatment within the first hour after injury was the most effective. DISCUSSION Early tranexamic acid treatment improves survival in both severely and non-severely injured trauma patients. Its use should not be restricted to the severely injured.

Abstract

BACKGROUND A 2-gram bolus of tranexamic acid (TXA) has been shown to reduce 28-day mortality in a RCT. This study investigates whether out-of-hospital TXA use is associated with adverse events or unfavorable outcomes in suspected TBI when intracranial hemorrhage (ICH) is absent on initial CT. METHODS This study utilized data from a 2015-2017, multicenter, randomized trial studying the effect of the following TXA doses on moderate to severe TBI: 2-gram bolus, 1-gram bolus plus 1-gram infusion over 8 hours, and a placebo bolus with placebo infusion. Of the 966 participants enrolled, 395 with an initial CT negative for ICH were included in this analysis. Fifteen adverse events (28-day incidence) were studied: MI, DVT, seizure, pulmonary embolism, ARDS, cardiac failure, liver failure, renal failure, CVA, cardiac arrest, cerebral vasospasm, "any thromboembolism", hypernatremia, AKI, and infection. Other unfavorable outcomes analyzed include mortality at 28 days & 6 months, GOSE ≤4 at discharge & 6 months, ICU-free days, ventilator-free days, hospital-free days, and combined unfavorable outcomes. In both study drug groups the incidence of dichotomous outcomes and quantity of ordinal outcomes were compared to placebo. RESULTS No statistically significant increase in adverse events or unfavorable outcomes was found between either TXA dosing regimen and placebo. Demographics and injury scores were not statistically different other than two methods of injury which were overrepresented in the 1-gram TXA bolus +1-gram TXA infusion. CONCLUSIONS Administration of either a 2-gram TXA bolus or a 1-gram TXA bolus plus 1-gram TXA 8-hour infusion in suspected-TBIs without ICH is not associated with increased adverse events or unfavorable outcomes. Because the out-of-hospital 2-gram bolus is associated with a mortality benefit it should be administered in suspected-TBI. LEVELS OF EVIDENCE Level II, Therapeutic.

Abstract

BACKGROUND Tranexamic acid (TXA) is an antifibrinolytic drug associated with improved survival among trauma patients with haemorrhage. TXA is considered a primary haemostatic intervention in pre-hospital for treatment of bleeding alongside blood product transfusion. METHODS A Systematic Review and Meta-Analysis was conducted to investigate the impact of pre-hospital TXA on mortality among trauma patients with bleeding. A systematic search was conducted using the National Institute for Health and Care Excellence (NICE) Healthcare Databases Advanced Search (HDAS) library which contain the following of databases: EMBASE, Medline, PubMed, BNI, EMCARE, and HMIC. Other databases searched included SCOPUS and the Cochrane Central Register for Clinical Trials Library (CENTRAL). Quality assessment tools were applied among included studies; Cochrane Risk of Bias (ROB) for Randomised Control Trials RCTs and Newcastle-Ottawa Scale (NOS) for cohort observational studies. RESULTS A total of 797 publications were identified from the initial database search. After removing duplicates and applying inclusion/exclusion criteria, Four studies were included in the review and meta-analysis which identified a significant survival benefit in patients who received pre-hospital TXA vs no TXA. Three observational cohort and one RCT were included into the review with a total of 2347 patients (TXA: 1169 vs No TXA: 1178). There was a significant reduction in 24 hours mortality; Odds ratios (OR) 0.60 (95% CI: 0.37-0.99). No Statistical significant differences in 28 to 30 days mortality OR 0.69 (95% CI: 0.47-1.02), or VTE OR 1.49 (95% CI: 0.90 - 2.46) were found. CONCLUSION This review demonstrates that pre-hospital TXA is associated with significant reductions in the early (24 hour) mortality of trauma patients with suspected or confirmed haemorrhage but no increase in the incidence of VTE. LEVEL OF EVIDENCE (I) Systematic review and meta-analysis.

Abstract

Objective: Intracranial hemorrhage (ICH) is a common complication of traumatic brain, in which tranexamic acid has been recommended as an additional therapy to prevent a second bleeding. However, the effect of early administration of tranexamic acid for ICH patients remains controversial. Methods: A systematic search was performed in Cochrane Library, Medline, Embase, and Web of Science. Poor outcome refers to significant hemorrhage growth, new intracranial hemorrhage, new focal cerebral ischaemic lesions, the need for neurosurgery, or death. Study heterogeneity and publication bias were estimated. Results: Seven randomized controlled trials involving 3,192 participants were included in our meta-analysis. Tranexamic acid administration in ICH patients was associated with better outcomes of hematoma expansion (odd ratios [OR] 0.79; 95% confidence interval (CI) CI, 0.67-0.93; I (2) = 0%; P = 0.006) and growth of hemorrhagic lesions (weighted mean difference [WMD], -1.97 ml; 95% CI, -2.94 to -1.00; I (2) = 14%; P < 0.001) than the placebo. No difference was found between the mortality, poor outcome, neurosurgical intervention, new bleeding, and the duration of hospital stay. Moreover, no publication bias was found. Conclusion: Our analysis reveals that the early treatment with tranexamic acid can significantly reduce the incidence of hematoma expansion and the volume of hemorrhagic lesion, but does not exert considerable effects on mortality, poor outcome, neurosurgery, rebleeding, and the duration of stay.