Reporting practices and impact of withdrawal of life-sustaining treatment on outcomes in acute brain injury clinical trials: a literature review and simulation study.

Overview

1. Department of Medicine, University Health Network, Toronto, ON Canada
2. Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON Canada
3. Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, ON Canada
4. Toronto Western Hospital Office 411-L, 2nd Floor McLaughlin 399 Bathurst St, Toronto, M5T 2S8 ON Canada
5. Department of Critical Care Medicine and Research Institute, Scarborough Health Network, Toronto, Canada
6. Department of Critical Care Medicine, Sunnybrook Health Sciences Centre, Toronto, Canada
7. Toronto General Hospital Research Institute, Toronto, ON Canada

Abstract

Background: Withdrawal of life-sustaining treatment (WLST) is common in clinical trials of patients with acute brain injuries (ABI), but current reporting practices and impact on trial-reported findings are unclear. We evaluated reporting practices of WLST in contemporary clinical trials of patients with ABI and quantified the magnitude of bias on treatment effect estimates in hypothetical trials.

Methods: We conducted a literature review of contemporary ABI randomized clinical trials and a simulation-based analysis. In the literature review, we included two-arm, randomized, superiority trials of adults with ABI (traumatic brain injury, intracranial hemorrhage, subarachnoid hemorrhage, ischemic stroke, or post–cardiac arrest brain injury) published in 10 high-impact journals from January 1, 2015 to December 19, 2024. We extracted WLST characteristics including frequency, timing, reasons, and neuro-prognostication criteria. In the simulation-based analysis, we evaluated the impact of WLST misclassification—defined as WLST occurring in patients who could have survived with a good neurological outcome—on observed treatment effects. For each scenario, we estimated the observed treatment effect after misclassification and calculated bias as the difference between observed and true treatment effects. We assessed both blinded and unblinded trials and binary and ordinal neurologic outcomes.

Results: Among 69 trials included in the literature review, 17 trials (24.6%) reported WLST frequency, 9 (13.0%) timing, 10 (14.5%) reasons, and 7 (10.1%) standardized neuro-prognostication criteria. In simulations of blinded trials, WLST misclassification consistently attenuated observed treatment effects. Increasing the fraction of misclassified WLST events led to progressively greater bias, making beneficial treatments appear less effective and harmful treatments appear less harmful. In unblinded trial simulations, the direction of bias varied by the magnitude of the true treatment effect and degree of misclassification. Findings were similar for binary and ordinal neurologic outcomes. Across all simulations, WLST misclassification reversed statistical conclusions in a median of 22.1% (interquartile range 17.4–32.4%) of trials.

Conclusions: WLST is poorly reported in contemporary ABI trials. Misclassification of WLST-related deaths leads to important bias in trial-reported treatment effects, potentially yielding underpowered studies and erroneous trial conclusions. Standardized, transparent WLST reporting is essential to strengthen ABI trial design and interpretation.

Supplementary Information: The online version contains supplementary material available at 10.1186/s13054-026-05929-7.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Statistical code used in this study is available from the corresponding author upon reasonable written request.

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Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 8 authors, 4 keywords, 5 MeSH terms, 1 funder, 34 references.

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This paper

Taran, S., Singh, J. M., Yarnell, C. J., McCredie, V. A., Scales, D. C., Ferguson, N. D., Liu, K., & Adhikari, N. K. J. (2026). Reporting practices and impact of withdrawal of life-sustaining treatment on outcomes in acute brain injury clinical trials: a literature review and simulation study. Critical care (London, England), 30(1), 181. https://doi.org/10.1186/s13054-026-05929-7

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