Melatonin and delirium in the intensive care units: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND Delirium is frequent in critically ill patients and is associated with increased mortality. Discrepancies were found in the results of recent randomized controlled trials (RCTs) regarding the effect of melatonin to prevent delirium onset in critically ill patients. METHODS We searched MEDLINE, Embase, and Web of Science from inception to 5 July 2025 for RCTs evaluating melatonin in critically ill patients. The primary outcome was the incidence of delirium. The main secondary outcome was mortality. We generated pooled risk ratios (RR). To base our conclusions on the highest quality of evidence, our primary analysis was based only on the trials with low to moderate risk of bias for each outcome. A secondary analysis was conducted, including all the trials. The study was registered with PROSPERO (CRD420251041661). FINDINGS Our primary analysis was based on six RCTs with 2209 patients and did not show any difference in the incidence of delirium attributable to the treatment with melatonin (RR 0.89, [95% confidence interval (CI) 0.73-1.09]). This result was consistent with the secondary analysis including thirteen RCTs with 2830 patients (RR 0.86, [95% CI 0.70-1.04]). No association was found between mortality and melatonin in the primary (seven RCTs, 2165 patients, RR 0.87, [95% CI 0.73-1.02]) and secondary (8 RCTs, 2396 patients, RR 0.92, [95% CI 0.79-1.06]) analyses. INTERPRETATION The results suggest that compared to placebo, melatonin does not reduce delirium incidence in critically ill patients. Similarly, no effect was observed on mortality.