title: Prophylactic Melatonin for Delirium in Intensive Care (Pro-MEDIC): study protocol for a randomised controlled trial.
abstract: Delirium 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.
  
  
  
  This 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.
  
  
  
  Delirium 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.
  
  
  
  Australian New Zealand Clinical Trial Registry (ANZCTR) number: ACTRN12616000436471 . Registered on 20 December 2015.
authors.affiliation: Intensive Care Unit, Department of Anaesthesia, Intensive Care and Pain Medicine, John Hunter Hospital, Lookout Road, New Lambton Heights, NSW, 2305, Australia. ed.martinez@hnehealth.nsw.gov.au.
authors.forename: F Eduardo
authors.identifier: http://orcid.org/0000-0002-7606-6685
authors.initials: FE
authors.lastname: Martinez
authors.affiliation: Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, Perth, WA, 6009, Australia.|Curtin University, Kent Street, Bentley, WA, 6102, Australia.|University of Western Australia, 35 Stirling Highway, Crawley, WA, 6009, Australia.
authors.forename: Matthew
authors.initials: M
authors.lastname: Anstey
authors.affiliation: Department of Psychiatry, Royal Perth Hospital, GPO Box X2213, Perth, WA, 6847, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Ford
authors.affiliation: Sir Charles Gairdner Hospital, Perth, WA, Australia.
authors.forename: Brigit
authors.initials: B
authors.lastname: Roberts
authors.affiliation: John Hunter Hospital, Lookout Road, New Lambton Heights, NSW, 2305, Australia.
authors.forename: Miranda
authors.initials: M
authors.lastname: Hardie
authors.affiliation: Sir Charles Gairdner Hospital, Perth, WA, Australia.
authors.forename: Robert
authors.initials: R
authors.lastname: Palmer
authors.affiliation: John Hunter Hospital, Lookout Road, New Lambton Heights, NSW, 2305, Australia.
authors.forename: Lynn
authors.initials: L
authors.lastname: Choo
authors.affiliation: Sleep Department, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, WA, 6009, Australia.|School of Medicine, University of Western Australia, 35 Stirling Highway, Crawley, Perth, WA, 6009, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Hillman
authors.affiliation: Respiratory and Sleep Medicine Department, John Hunter Hospital, Lookout Road, New Lambton, NSW, 2305, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Hensley
authors.affiliation: School of Population Health, University of Western Australia, 35 Stirling Highway, Crawley, Perth, WA, 6009, Australia.
authors.forename: Erin
authors.initials: E
authors.lastname: Kelty
authors.affiliation: Centre for Applied Statistics, University of Western Australia, 35 Stirling Highway, Crawley, Perth, WA, 6009, Australia.
authors.forename: Kevin
authors.initials: K
authors.lastname: Murray
authors.affiliation: Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, Perth, 6009, WA, Australia.|West Australian Sleep Disorders Research Institute, Internal Mailbox 201, , Queen Elizabeth II Medical Centre, Hospital Avenue, Nedlands, Perth, WA, 6009, Australia.|Faculty of Science, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, Perth, WA, 6009, Australia.
authors.forename: Bhajan
authors.initials: B
authors.lastname: Singh
authors.affiliation: Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, Perth, WA, 6009, Australia.|University of Western Australia, 35 Stirling Highway, Crawley, Perth, WA, 6009, Australia.
authors.forename: Bradley
authors.initials: B
authors.lastname: Wibrow
mesh_terms: D000284:Administration, Oral; D002985:Clinical Protocols; D003362:Cost-Benefit Analysis; D003422:Critical Care / Q000191:economics / Q000379:methods*; D003693:Delirium / Q000175:diagnosis / Q000503:physiopathology / Q000517:prevention & control* / Q000523:psychology; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D017048:Health Care Costs; D006801:Humans; D007362:Intensive Care Units / Q000191:economics; D008550:Melatonin / Q000008:administration & dosage* / Q000009:adverse effects / Q000191:economics; D009517:New South Wales; D011446:Prospective Studies; D012107:Research Design; D012890:Sleep / Q000187:drug effects*; D000068776:Sleep Aids, Pharmaceutical / Q000008:administration & dosage* / Q000009:adverse effects / Q000191:economics; D012893:Sleep Wake Disorders / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D013997:Time Factors; D016896:Treatment Outcome; D014904:Western Australia
chemical_list: D000068776:Sleep Aids, Pharmaceutical; D008550:Melatonin
keywords: Delirium; Intensive care unit; Melatonin; Sleep