Melatonin Low-Dose for Prevention of Delirium in Critically Ill Patients: A Multi-centre, Randomized, Placebo-controlled Feasibility Trial (MELLOW).

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 non-critically ill patient populations. Our objective was to assess the feasibility of a multi-centre, randomized, placebo-controlled trial testing the hypothesis that low-dose melatonin prevents delirium in critically ill adults.

Methods: We conducted this three-arm feasibility trial in three tertiary academic ICUs. Included participants were ≥18 years old, confirmed free from delirium at enrollment, and anticipated >48 hours intensive care unit (ICU) stay. We randomized participants to nightly melatonin 0.5mg or 2mg 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 2259 patients, excluding 1863 (82.5%), resulting in 396 eligible patients, of whom 71 consented; recruitment rate 0.8 patients/month/site. Median (IQR) age was 60.5 (48,67) years; median admission SOFA score 7 (3,10). Percentage drug administration protocol adherence per patient was median 100% (IQR 92.3%, 100%) or mean 88.7% (SD 24.4). There were 25 protocol violations with no differences between groups. Fourteen (20%) patients developed delirium during the study period; 25 (36%) experienced sub-syndromal delirium; no differences between study groups. No serious adverse effects were detected.

Conclusion: Our trial protocol comparing two 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 due to delirium being present or the inability to screen. Consent rates were also low. This finding suggests that conducting delirium prevention trials that require delirium to be absent on enrolment is particularly challenging in the ICU.