Phenobarbital Versus Benzodiazepine-Based Pathways for Alcohol Withdrawal Syndrome in Critically Ill Adults: A Systematic Review and Meta-Analysis.

To compare outcomes of phenobarbital-based versus benzodiazepine-based pathways for alcohol withdrawal syndrome (AWS) in critically ill adults and evaluate whether pathway design and timing of phenobarbital use affect treatment outcomes. A librarian-led search of MEDLINE, Embase, Cochrane Central, CINAHL, Web of Science, Scopus, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform was conducted through July 2024, with updates in December 2024, August 2025, and December 2025. Search concepts included phenobarbital, benzodiazepines, and alcohol withdrawal. Comparative studies of adults admitted or transferred to an intensive care unit (ICU) with AWS and treated with phenobarbital-based versus benzodiazepine-based pathways were included. Sixteen nonrandomized studies were included in the qualitative synthesis, and 12 treatment-oriented studies were included in the primary meta-analysis. Multiple reviewers independently screened studies, extracted data, and assessed risk of bias using Risk Of Bias In Non-randomized Studies-of Interventions (ROBINS-I). Phenobarbital-based pathways were not associated with significantly different intubation (11 studies; odds ratio (OR), 0.62; 95% confidence interval (CI), 0.20-1.87; I2 = 73%) or hospital length of stay (five studies; mean differences [MD], -1.75 days; 95% CI, -5.07 to 1.56; I2 = 63%) compared with benzodiazepine-based pathways. ICU length of stay was shorter with phenobarbital-based pathways (eight studies; MD, -0.60 days; 95% CI, -0.79 to -0.41; I2 = 0%). In exploratory subgroup analyses, front-loaded, protocolized phenobarbital-first pathways were associated with lower intubation and shorter hospital length of stay, but certainty of evidence was very low. This review distinguishes phenobarbital-first, protocolized ICU pathways from adjunctive or mixed phenobarbital strategies, suggesting that implementation design may influence outcomes. Although evidence remains very low certainty, these findings suggest that phenobarbital's role in ICU AWS may be pathway dependent. Front-loaded, protocolized phenobarbital-first pathways may be associated with favorable outcomes in exploratory analyses, but these findings should be considered hypothesis-generating and require confirmation in prospective randomized trials. CRD42024595819.