• Mark van den Boogaard, SlooterArjen J CAJCDepartment of Intensive Care Medicine and Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands., BrüggemannRoger J MRJMDepartment of Pharmacy Radboud University Medical Center, Nijmegen, the Netherlands., Lisette Schoonhoven, Albertus Beishuizen, J Wytze Vermeijden, Danie Pretorius, de KoningJanJDepartment of Intensive Care Medicine, Máxima Medical Center Veldhoven, the Netherlands., Koen S Simons, DennesenPaul J WPJWDepartment of Intensive Care Medicine, Haaglanden Medical Center, The Hague, the Netherlands., Peter H J Van der Voort, Saskia Houterman, J G van der Hoeven, Peter Pickkers, REDUCE Study Investigators, van der WoudeMargaretha C. E.Department of Intensive Care Medicine, Zuyderland Medical Center, Heerlen, the Netherlands, Anna Besselink, Lieuwe S Hofstra, Peter E Spronk, Walter van den Bergh, Dirk W Donker, Malaika Fuchs, Attila Karakus, M Koeman, Mirella van Duijnhoven, and Gerjon Hannink.
• Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
• JAMA. 2018 Feb 20; 319 (7): 680-690.

ImportanceResults of studies on use of prophylactic haloperidol in critically ill adults are inconclusive, especially in patients at high risk of delirium.ObjectiveTo determine whether prophylactic use of haloperidol improves survival among critically ill adults at high risk of delirium, which was defined as an anticipated intensive care unit (ICU) stay of at least 2 days.Design, Setting, And ParticipantsRandomized, double-blind, placebo-controlled investigator-driven study involving 1789 critically ill adults treated at 21 ICUs, at which nonpharmacological interventions for delirium prevention are routinely used in the Netherlands. Patients without delirium whose expected ICU stay was at least a day were included. Recruitment was from July 2013 to December 2016 and follow-up was conducted at 90 days with the final follow-up on March 1, 2017.InterventionsPatients received prophylactic treatment 3 times daily intravenously either 1 mg (n = 350) or 2 mg (n = 732) of haloperidol or placebo (n = 707), consisting of 0.9% sodium chloride.Main Outcome And MeasuresThe primary outcome was the number of days that patients survived in 28 days. There were 15 secondary outcomes, including delirium incidence, 28-day delirium-free and coma-free days, duration of mechanical ventilation, and ICU and hospital length of stay.ResultsAll 1789 randomized patients (mean, age 66.6 years [SD, 12.6]; 1099 men [61.4%]) completed the study. The 1-mg haloperidol group was prematurely stopped because of futility. There was no difference in the median days patients survived in 28 days, 28 days in the 2-mg haloperidol group vs 28 days in the placebo group, for a difference of 0 days (95% CI, 0-0; P = .93) and a hazard ratio of 1.003 (95% CI, 0.78-1.30, P=.82). All of the 15 secondary outcomes were not statistically different. These included delirium incidence (mean difference, 1.5%, 95% CI, -3.6% to 6.7%), delirium-free and coma-free days (mean difference, 0 days, 95% CI, 0-0 days), and duration of mechanical ventilation, ICU, and hospital length of stay (mean difference, 0 days, 95% CI, 0-0 days for all 3 measures). The number of reported adverse effects did not differ between groups (2 [0.3%] for the 2-mg haloperidol group vs 1 [0.1%] for the placebo group).Conclusions And RelevanceAmong critically ill adults at high risk of delirium, the use of prophylactic haloperidol compared with placebo did not improve survival at 28 days. These findings do not support the use of prophylactic haloperidol for reducing mortality in critically ill adults.Trial Registrationclinicaltrials.gov Identifier: NCT01785290.

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