title: Evaluating early administration of the hydroxymethylglutaryl-CoA reductase inhibitor simvastatin in the prevention and treatment of delirium in critically ill ventilated patients (MoDUS trial): study protocol for a randomized controlled trial.
abstract: BACKGROUND
  The incidence of delirium in ventilated patients is estimated at up to 82%, and it is associated with longer intensive care and hospital stays, and long-term cognitive impairment and mortality. The pathophysiology of delirium has been linked with inflammation and neuronal apoptosis. Simvastatin has pleiotropic properties; it penetrates the brain and, as well as reducing cholesterol, reduces inflammation when used at clinically relevant doses over the short term. This is a single centre randomised, controlled trial which aims to test the hypothesis that treatment with simvastatin will modify delirium incidence and outcomes.
  
  
  METHODS
  The ongoing study will include 142 adults admitted to the Watford General Hospital Intensive Care Unit who require mechanical ventilation in the first 72 hours of admission. The primary outcome is the number of delirium- and coma-free days in the first 14 days. Secondary outcomes include incidence of delirium, delirium- and coma-free days in the first 28 days, days in delirium and in coma at 14 and 28 days, number of ventilator-free days at 28 days, length of critical care and hospital stay, mortality, cognitive decline and healthcare resource use. Informed consent will be taken from patient's consultee before randomisation to receive either simvastatin (80 mg) or placebo once daily. Daily data will be recorded until day 28 after randomisation or until discharge from the ICU if sooner. Surviving patients will be followed up on at six months from discharge. Plasma and urine samples will be taken to investigate the biological effect of simvastatin on systemic markers of inflammation, as related to the number of delirium- and coma-free days, and the potential of cholinesterase activity and beta-amyloid as predictors of the risk of delirium and long-term cognitive impairment.
  
  
  CONCLUSIONS
  This trial will test the efficacy of simvastatin on reducing delirium in the critically ill. If patients receiving the statin show a reduced number of days in delirium compared with the placebo group, the inflammatory theory implicated in the pathogenesis of delirium will be strengthened.
  
  
  BACKGROUND
  The trial was registered with the International Standard Randomised Controlled Trial Registry ( ISRCTN89079989 ) on 26 March 2013.
authors.affiliation: Intensive Care Unit, Watford General Hospital, West Hertfordshire Hospitals NHS Trust, Vicarage Road, Watford, WD18 0HB, UK. a.casarin@nhs.net.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Casarin
authors.affiliation: Centre for Infection and Immunity, Queen's University of Belfast, Health Sciences Building, Lisburn Road, Belfast, BT9 7AE, UK. d.f.mcauley@qub.ac.uk.|Regional Intensive Care Unit, Royal Victoria Hospital, 274 Grosvenor Road, Belfast, BT12 6BA, UK. d.f.mcauley@qub.ac.uk.|Northern Ireland Clinical Trials Unit, Elliott Dynes Building, Royal Hospitals, 274 Grosvenor Road, Belfast, BT12 6BA, UK. d.f.mcauley@qub.ac.uk.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: McAuley
authors.affiliation: Anaesthetics Department, Neville Hall Hospital, Brecon Road, Abergavenny, NP7 7EG Gwent, UK. tma@jhmi.edu.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Alce
authors.affiliation: Intensive Care Unit, Watford General Hospital, West Hertfordshire Hospitals NHS Trust, Vicarage Road, Watford, WD18 0HB, UK. xiaobei.zhao@whht.nhs.uk.
authors.forename: Xiaobei
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Vanderbilt University School of Medicine, 2301 Vanderbilt Place, Nashville, TN, 37235, USA. wes.ely@vanderbilt.edu.|Tennessee Valley Veteran's Affairs Geriatric Research Education and Clinical Center (VA-GRECC), 1310 24th Ave. S, Nashville, TN, 37212-2637, USA. wes.ely@vanderbilt.edu.
authors.forename: E Wesley
authors.initials: EW
authors.lastname: Ely
authors.affiliation: Vanderbilt University School of Medicine, 2301 Vanderbilt Place, Nashville, TN, 37235, USA. james.c.jackson@Vanderbilt.Edu.|Department of Psychiatry, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN, 37232, USA. james.c.jackson@Vanderbilt.Edu.
authors.forename: Jim C
authors.initials: JC
authors.lastname: Jackson
authors.affiliation: Northern Ireland Clinical Trials Unit, Elliott Dynes Building, Royal Hospitals, 274 Grosvenor Road, Belfast, BT12 6BA, UK. Cliona.McDowell@nictu.hscni.net.
authors.forename: Cliona
authors.initials: C
authors.lastname: McDowell
authors.affiliation: Northern Ireland Clinical Trials Unit, Elliott Dynes Building, Royal Hospitals, 274 Grosvenor Road, Belfast, BT12 6BA, UK. Ashley.Agus@nictu.hscni.net.
authors.forename: Ashley
authors.initials: A
authors.lastname: Agus
authors.affiliation: Northern Ireland Clinical Trials Unit, Elliott Dynes Building, Royal Hospitals, 274 Grosvenor Road, Belfast, BT12 6BA, UK. Lynn.Murphy@nictu.hscni.net.
authors.forename: Lynn
authors.initials: L
authors.lastname: Murphy
authors.affiliation: Intensive Care Unit, Watford General Hospital, West Hertfordshire Hospitals NHS Trust, Vicarage Road, Watford, WD18 0HB, UK. valerie.page@whht.nhs.uk.|Faculty of Medicine, Imperial College, South Kensington Campus, London, SW7 2AZ, UK. valerie.page@whht.nhs.uk.
authors.forename: Valerie J
authors.initials: VJ
authors.lastname: Page
mesh_terms: D000110:Acetylcholinesterase / Q000097:blood; D016229:Amyloid beta-Peptides / Q000097:blood; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000009:adverse effects; D015415:Biomarkers / Q000097:blood; D002091:Butyrylcholinesterase / Q000097:blood; D002985:Clinical Protocols; D003071:Cognition / Q000187:drug effects; D016638:Critical Illness; D003693:Delirium / Q000097:blood / Q000175:diagnosis / Q000209:etiology / Q000401:mortality / Q000517:prevention & control* / Q000523:psychology; D004333:Drug Administration Routes; D004739:England; D017052:Hospital Mortality; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D018836:Inflammation Mediators / Q000097:blood; D007362:Intensive Care Units; D007902:Length of Stay; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000009:adverse effects; D012107:Research Design; D012121:Respiration, Artificial / Q000009:adverse effects* / Q000401:mortality; D012307:Risk Factors; D019821:Simvastatin / Q000008:administration & dosage* / Q000009:adverse effects; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D016229:Amyloid beta-Peptides; D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018836:Inflammation Mediators; D018696:Neuroprotective Agents; D019821:Simvastatin; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase