Prophylactic Melatonin for Delirium in Intensive Care (Pro-MEDIC): study protocol for a randomised controlled trial

Abstract

BackgroundDelirium is an acute state of brain dysfunction characterised by fluctuating inattention and cognitive disturbances, usually due to illness. It occurs commonly in the intensive care unit (ICU), and it is associated with greater morbidity and mortality. It is likely that disturbances of sleep and of the day-night cycle play a significant role. Melatonin is a naturally occurring, safe and cheap hormone that can be administered to improve sleep. The main aim of this trial will be to determine whether prophylactic melatonin administered to critically ill adults, when compared with placebo, decreases the rate of delirium.MethodsThis trial will be a multi-centre, randomised, placebo-controlled study conducted in closed ICUs in Australia. Our aim is to enrol 850 adult patients with an expected ICU length of stay (LOS) of 72 h or more. Eligible patients for whom there is consent will be randomised to receive melatonin 4 mg enterally or placebo in a 1:1 ratio according to a computer-generated randomisation list, stratified by site. The study drug will be indistinguishable from placebo. Patients, doctors, nurses, investigators and statisticians will be blinded. Melatonin or placebo will be administered once per day at 21:00 until ICU discharge or 14 days after enrolment, whichever occurs first. Trained staff will assess patients twice daily to determine the presence or absence of delirium using the Confusion Assessment Method for the ICU score. Data will also be collected on demographics, the overall prevalence of delirium, duration and severity of delirium, sleep quality, participation in physiotherapy sessions, ICU and hospital LOS, morbidity and mortality, and healthcare costs. A subgroup of 100 patients will undergo polysomnographic testing to further evaluate the quality of sleep.DiscussionDelirium is a significant issue in ICU because of its frequency and associated poorer outcomes. This trial will be the largest evaluation of melatonin as a prophylactic agent to prevent delirium in the critically ill population. This study will also provide one of the largest series of polysomnographic testing done in ICU.Trial registrationAustralian New Zealand Clinical Trial Registry (ANZCTR) number: ACTRN12616000436471. Registered on 20 December 2015.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-016-1751-0) contains supplementary material, which is available to authorized users.

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.…”

“…Also, an altered pattern of circadian secretion was found in ICU septic patients compared to ICU patients without sepsis, and the absence of the melatonin circadian rhythm was associated with mechanical ventilation . These alterations are associated with sepsis severity, sleep disturbances and delirium that are per se associated with worse outcomes in terms of higher mortality, cognitive impairment, prolonged ventilator dependence, and increased hospital and ICU length of stay . Generally, sleep disruption has adverse short and long health effects including emotional distress and mood disorders, alterations in metabolism, impairment of immune, hormonal and cardiovascular system and gastrointestinal disorders .…”

Effectiveness of Melatonin for the Prevention of Intensive Care Unit Delirium

“…The majority of previous studies have evaluated melatonin's effect on postoperative delirium, elderly patients, or those admitted to the internal medicine ward. Recently, the Pro‐MEDIC trial has begun in New Zealand, which will be a multicenter, randomized, placebo‐controlled study that will evaluate melatonin for the prevention of delirium in the ICU . This study will be the first large evaluation of melatonin for delirium prevention in critically ill patients.…”

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.…”