title: Prevention of ICU delirium and delirium-related outcome with haloperidol: a study protocol for a multicenter randomized controlled trial.
abstract: BACKGROUND
  Delirium is a frequent disorder in intensive care unit (ICU) patients with serious consequences. Therefore, preventive treatment for delirium may be beneficial. Worldwide, haloperidol is the first choice for pharmacological treatment of delirious patients. In daily clinical practice, a lower dose is sometimes used as prophylaxis. Some studies have shown the beneficial effects of prophylactic haloperidol on delirium incidence as well as on mortality, but evidence for effectiveness in ICU patients is limited. The primary objective of our study is to determine the effect of haloperidol prophylaxis on 28-day survival. Secondary objectives include the incidence of delirium and delirium-related outcome and the side effects of haloperidol prophylaxis.
  
  
  METHODS
  This will be a multicenter three-armed randomized, double-blind, placebo-controlled, prophylactic intervention study in critically ill patients. We will include consecutive non-neurological ICU patients, aged ≥ 18 years with an expected ICU length of stay >1 day. To be able to demonstrate a 15% increase in 28-day survival time with a power of 80% and alpha of 0.05 in both intervention groups, a total of 2,145 patients will be randomized; 715 in each group. The anticipated mortality rate in the placebo group is 12%. The intervention groups will receive prophylactic treatment with intravenous haloperidol 1 mg/q8h or 2 mg/q8h, and patients in the control group will receive placebo (sodium chloride 0.9%), both for a maximum period of 28-days. In patients who develop delirium, study medication will be stopped and patients will subsequently receive open label treatment with a higher (therapeutic) dose of haloperidol. We will use descriptive summary statistics as well as Cox proportional hazard regression analyses, adjusted for covariates.
  
  
  CONCLUSIONS
  This will be the first large-scale multicenter randomized controlled prevention study with haloperidol in ICU patients with a high risk of delirium, adequately powered to demonstrate an effect on 28-day survival.
  
  
  BACKGROUND
  Clinicaltrials.gov: NCT01785290.EudraCT number: 2012-004012-66.
authors.affiliation: Department of Intensive Care Medicine, Radboud University Nijmegen Medical Centre, P,O, box 9101, internal post 710, 6500HB Nijmegen, Netherlands. Mark.vandenBoogaard@radboudumc.nl.
authors.forename: Mark
authors.initials: M
authors.lastname: van den Boogaard
authors.forename: Arjen J
authors.initials: AJ
authors.lastname: Slooter
authors.forename: Roger J M
authors.initials: RJ
authors.lastname: Brüggemann
authors.forename: Lisette
authors.initials: L
authors.lastname: Schoonhoven
authors.forename: Michael A
authors.initials: MA
authors.lastname: Kuiper
authors.forename: Peter H J
authors.initials: PH
authors.lastname: van der Voort
authors.forename: Marga E
authors.initials: ME
authors.lastname: Hoogendoorn
authors.forename: Albert
authors.initials: A
authors.lastname: Beishuizen
authors.forename: Jeroen A
authors.initials: JA
authors.lastname: Schouten
authors.forename: Peter E
authors.initials: PE
authors.lastname: Spronk
authors.forename: Saskia
authors.initials: S
authors.lastname: Houterman
authors.forename: Johannes G
authors.initials: JG
authors.lastname: van der Hoeven
authors.forename: Peter
authors.initials: P
authors.lastname: Pickkers
mesh_terms: D003625:Data Collection; D003693:Delirium / Q000517:prevention & control*; D004311:Double-Blind Method; D004992:Ethics, Medical; D006220:Haloperidol / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007362:Intensive Care Units; D016016:Proportional Hazards Models; D018401:Sample Size; D016896:Treatment Outcome
chemical_list: D006220:Haloperidol