Feasibility of melatonin for prevention of delirium in critically ill patients: a protocol for a multicentre, randomised, placebo-controlled study

Abstract

IntroductionDelirium is highly prevalent in the intensive care unit (ICU) and is associated with adverse clinical outcomes. At this time, there is no drug that effectively prevents delirium in critically ill patients. Alterations in melatonin secretion and metabolism may contribute to the development of delirium. Administration of exogenous melatonin has been shown to prevent delirium in non-critically ill surgical and medical patients. This trial will demonstrate the feasibility of a planned multicentre, randomised controlled trial to test the hypothesis that melatonin can prevent delirium in critically ill patients compared with placebo.Methods and analysisThis feasibility trial is a randomised, 3-arm, placebo-controlled study of melatonin (2 vs 0.5 mg vs placebo, administered for a maximum of 14 days) for the prevention of delirium in critically ill patients. A total of 69 patients aged 18 years and older with an expected ICU length of stay >48 hours will be recruited from 3 Canadian ICUs. The primary outcome is protocol adherence (ie, overall proportion of study drug doses administered in the prescribed administration window). Secondary outcomes include pharmacokinetic parameters, incidence, time to onset, duration of delirium, number of delirium-free days, adverse events, self-reported sleep quality, rest-activity cycles measured by wrist actigraphy, duration of mechanical ventilation, ICU length of stay and mortality. Data will be analysed using an intention-to-treat approach.Ethics and disseminationThe study has been approved by Health Canada and the research ethics board of each study site. Trial results will be presented at international conferences and published in a peer-reviewed journal.Trial registration numberNCT02615340: Pre-results.

Different routes and formulations of melatonin in critically ill patients. A pharmacokinetic randomized study

“…It has been suggested that exogenous melatonin administration may play an important role as a prophylactic agent in preventing delirium in the critically ill patients. This hypothesis is actually explored in two randomized and controlled trials, that use melatonin in standard formulation administered orally or via nasogastric tube. Given the growing interest in the use of melatonin in ICU patients, it may be important to find the optimal formulation, delivery route and dosage schedule capable of mimicking the endogenous secretion pattern.…”

Melatonin and the Prevention and Management of Delirium: A Scoping Study

“…Future RCTs will need to include well-validated tools to identify delirium and ensure they are adequately powered to identify between-group differences. A number of published study protocols ( 59 , 60 ), including feasibility studies ( 61 , 62 ), suggest that such improvements in the available evidence of the efficacy of melatonin analogs to prevent delirium are forthcoming.…”

Abnormal Sleep, Circadian Rhythm Disruption, and Delirium in the ICU: Are They Related?

“…Further study is therefore needed. Based on available data, potentially effective interventions might include a combination of dexmedetomidine ( 62 ), oral melatonin ( 95 ), and cognitive behavioral sleep therapy ( 96 ) using modified polysomnography to quantify sleep quality and quantity ( 25 , 78 ) and understand to which extent sleep actually affects delirium occurrence.…”