Comparative effectiveness and safety of pharmacological interventions for secondary brain injury in adult traumatic brain injury: a network meta-analysis of randomized trials.
BMC Neurology · 2026-08-01 · Meta-analysis
Abstract
BACKGROUND: Traumatic brain injury (TBI) remains a leading cause of death and disability. We compared pharmacological and hyperosmolar interventions intended to mitigate secondary brain injury in adults with TBI. METHODS: We searched PubMed/MEDLINE, Embase, Cochrane CENTRAL, Web of Science from inception to 3 January 2026 without language restrictions. Eligible studies were randomized controlled trials enrolling adults with TBI that compared an eligible pharmacological or hyperosmolar intervention with placebo/standard care or with another eligible active intervention. We performed a frequentist random-effects network meta-analysis using odds ratios (ORs) with 95% confidence intervals (CIs); Placebo/Standard Care was the reference node. Certainty was assessed using a GRADE/CINeMA-informed approach. The protocol was registered in PROSPERO (CRD420261283150). RESULTS: Thirty-four trials (n = 23,165) were included. In the mortality network (28 trials; n = 18,088), TXA (OR 0.90, 95% CI 0.82-0.99) and erythropoietin (OR 0.64, 95% CI 0.43-0.97) were associated with lower mortality versus Placebo/Standard Care, but the TXA estimate was dominated by the Clinical Randomisation of an Antifibrinolytic in Significant Head injury-3 (CRASH-3) trial and the erythropoietin estimate was based on two trials with important clinical heterogeneity. In the favorable neurological outcome network (19 trials; n = 8,259), statins had a large but very low-certainty estimate (OR 4.71, 95% CI 2.12-10.47) based on two small trials. TXA (OR 1.07, 95% CI 0.85-1.35) and hypertonic saline (OR 0.90, 95% CI 0.74-1.10) showed no clear functional benefit. Safety networks were sparse; TXA was not associated with thromboembolism (OR 0.98, 95% CI 0.74-1.29) or acute kidney injury (OR 1.18, 95% CI 0.88-1.58). CONCLUSIONS: TXA has the most actionable mortality signal, but the network estimate adds limited information beyond the CRASH-3 trial. The apparent erythropoietin and statin effects should be interpreted cautiously because of sparse evidence, heterogeneity, and imprecision. Current evidence does not support routine use of most other pharmacological interventions to improve long-term neurological recovery after TBI. Larger, severity-stratified trials using standardized outcomes are needed. CLINICAL TRIAL NUMBER: Systematic review protocol registered in PROSPERO: CRD420261283150.
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Tags
Fluids & blood · Haemostatics · Hypertonic saline · Mortality & survival · Quality of life & function · Tranexamic acid
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