Abstract
BACKGROUND: Delirium is a common and serious syndrome of acute brain dysfunction associated with negative outcomes. Melatonin may have a role in delirium prevention for critically ill adults based on data from noncritically ill patient populations. Our objective was to assess the feasibility of a multicenter, randomized, placebo-controlled trial testing the hypothesis that low-dose melatonin prevents delirium in adults who are critically ill. RESEARCH QUESTION: Does low-dose melatonin prevent delirium in critically ill adults? STUDY DESIGN AND METHODS: We conducted this 3-arm feasibility trial in 3 tertiary academic ICUs. Included participants were ≥ 18 years of age, confirmed free of delirium at enrollment, and anticipated to require a > 48-hour ICU stay. We randomized participants to nightly melatonin 0.5 mg, 2 mg, or placebo. Feasibility outcomes were protocol adherence and recruitment rates. Our primary feasibility target was ≥ 85% (± 5% margin of error) of drug doses administered as per protocol. Secondary objectives were to explore adverse drug effects, melatonin pharmacokinetics, and clinical outcomes. RESULTS: We screened 2,259 patients and excluded 1,863 patients (82.5%), resulting in 396 eligible patients, of whom 71 provided consent, for a recruitment rate of 0.8 patients/mo/site. Median age was 60.5 years (interquartile range [IQR], 48-67 years), and median admission Sequential Organ Failure Assessment score was 7 (IQR, 3-10). Percentage drug administration protocol adherence per patient was a median of 100% (IQR, 92.3%-100%) or a mean of 88.7% (SD, 24.4%). Twenty-five protocol violations occurred, with no differences between groups. Fourteen patients (20%) experienced delirium during the study period and 25 patients (36%) experienced subsyndromal delirium, with no differences between study groups. No serious adverse effects were detected. INTERPRETATION: Our trial protocol comparing 2 low doses of melatonin and placebo for delirium prevention in critically ill adults demonstrated feasibility for protocol adherence. However, trial eligibility rates were modest primarily because of delirium being present or the inability to screen. Consent rates also were low. This finding suggests that conducting delirium prevention trials that require delirium to be absent on enrollment is particularly challenging in the ICU. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02615340; URL: www. CLINICALTRIALS: gov.