• Lisa Smit, SlooterArjen J CAJCDepartments of Psychiatry, Intensive Care Medicine and UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.Department of Neurology, UZ Brussel and Vrije Universiteit Brussel, Brussel, John W Devlin, Zoran Trogrlic, HunfeldNicole G MNGMDepartment of Intensive Care Adults, Erasmus MC-University Medical Centre, Room Ne-415, PO BOX 2040, 3000 CA, Rotterdam, The Netherlands.Department of Hospital Pharmacy, Erasmus MC-University Medical Centre, Rotterdam, The Netherlands., Robert Jan Osse, Huibert H Ponssen, BrouwersArjen J B WAJBWDepartment of Intensive Care Adults, Franciscus Gasthuis & Vlietland, Rotterdam, The Netherlands., Jeannette F Schoonderbeek, Koen S Simons, Mark van den Boogaard, Judith A Lens, Dirk P Boer, GommersDiederik A M P JDAMPJDepartment of Intensive Care Adults, Erasmus MC-University Medical Centre, Room Ne-415, PO BOX 2040, 3000 CA, Rotterdam, The Netherlands., Wim J R Rietdijk, Mathieu van der Jagt, and EuRIDICE study group.
• Department of Intensive Care Adults, Erasmus MC-University Medical Centre, Room Ne-415, PO BOX 2040, 3000 CA, Rotterdam, The Netherlands.
• Crit Care. 2023 Oct 30; 27 (1): 413413.

BackgroundThe role of haloperidol as treatment for ICU delirium and related symptoms remains controversial despite two recent large controlled trials evaluating its efficacy and safety. We sought to determine whether haloperidol when compared to placebo in critically ill adults with delirium reduces days with delirium and coma and improves delirium-related sequelae.MethodsThis multi-center double-blind, placebo-controlled randomized trial at eight mixed medical-surgical Dutch ICUs included critically ill adults with delirium (Intensive Care Delirium Screening Checklist ≥ 4 or a positive Confusion Assessment Method for the ICU) admitted between February 2018 and January 2020. Patients were randomized to intravenous haloperidol 2.5 mg or placebo every 8 h, titrated up to 5 mg every 8 h if delirium persisted until ICU discharge or up to 14 days. The primary outcome was ICU delirium- and coma-free days (DCFDs) within 14 days after randomization. Predefined secondary outcomes included the protocolized use of sedatives for agitation and related behaviors, patient-initiated extubation and invasive device removal, adverse drug associated events, mechanical ventilation, ICU length of stay, 28-day mortality, and long-term outcomes up to 1-year after randomization.ResultsThe trial was terminated prematurely for primary endpoint futility on DSMB advice after enrolment of 132 (65 haloperidol; 67 placebo) patients [mean age 64 (15) years, APACHE IV score 73.1 (33.9), male 68%]. Haloperidol did not increase DCFDs (adjusted RR 0.98 [95% CI 0.73-1.31], p = 0.87). Patients treated with haloperidol (vs. placebo) were less likely to receive benzodiazepines (adjusted OR 0.41 [95% CI 0.18-0.89], p = 0.02). Effect measures of other secondary outcomes related to agitation (use of open label haloperidol [OR 0.43 (95% CI 0.12-1.56)] and other antipsychotics [OR 0.63 (95% CI 0.29-1.32)], self-extubation or invasive device removal [OR 0.70 (95% CI 0.22-2.18)]) appeared consistently more favorable with haloperidol, but the confidence interval also included harm. Adverse drug events were not different. Long-term secondary outcomes (e.g., ICU recall and quality of life) warrant further study.ConclusionsHaloperidol does not reduce delirium in critically ill delirious adults. However, it may reduce rescue medication requirements and agitation-related events in delirious ICU patients warranting further evaluation.Trial RegistrationClinicalTrials.gov (#NCT03628391), October 9, 2017.© 2023. The Author(s).

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