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Randomized Controlled Trial
. 2023 Oct 30;27(1):413.
doi: 10.1186/s13054-023-04692-3.

Efficacy of haloperidol to decrease the burden of delirium in adult critically ill patients: the EuRIDICE randomized clinical trial

Lisa Smit  1 , Arjen J C Slooter  2   3 , John W Devlin  4   5 , Zoran Trogrlic  1 , Nicole G M Hunfeld  1   6 , Robert Jan Osse  7 , Huibert H Ponssen  8 , Arjen J B W Brouwers  9 , Jeannette F Schoonderbeek  10 , Koen S Simons  11 , Mark van den Boogaard  12 , Judith A Lens  13 , Dirk P Boer  14 , Diederik A M P J Gommers  1 , Wim J R Rietdijk  6 , Mathieu van der Jagt  15 ; EuRIDICE study group
Affiliations
Randomized Controlled Trial

Efficacy of haloperidol to decrease the burden of delirium in adult critically ill patients: the EuRIDICE randomized clinical trial

Lisa Smit et al. Crit Care. .

Abstract

Background: The 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.

Methods: This 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.

Results: The 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.

Conclusions: Haloperidol 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 registration: ClinicalTrials.gov (#NCT03628391), October 9, 2017.

Keywords: Antipsychotic; Critical care; Delirium; Haloperidol; Randomized controlled trial.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Flow of participants in the EuRIDICE trial. aNone of the patients who withdrew informed consent rejected the use of their yet collected data. They, however, refused further participation in the trial
See this image and copyright information in PMC

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