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Effect of Haloperidol on Survival Among Critically Ill Adults With a High Risk of DeliriumThe REDUCE Randomized Clinical Trial

Educational Objective
To learn the effect of prophylactic haloperidol on survival among critically ill adults at high risk of delirium.
1 Credit CME
Key Points

Question  What is the effect of prophylactic haloperidol on survival among critically ill adults?

Findings  In this multicenter randomized trial involving 1789 critically ill patients at high risk of delirium, the median number of days patients survived in 28 days was 28 days in the 2-mg haloperidol group vs 28 days in the placebo group, a nonsignificant difference.

Meaning  The use of prophylactic haloperidol therapy did not improve survival among critically ill adults at high risk of delirium.

Abstract

Importance  Results of studies on use of prophylactic haloperidol in critically ill adults are inconclusive, especially in patients at high risk of delirium.

Objective  To 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 Participants  Randomized, 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.

Interventions  Patients 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 Measures  The 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.

Results  All 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 Relevance  Among 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 Registration  clinicaltrials.gov Identifier: NCT01785290

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Article Information

Corresponding Author: Mark van den Boogaard, PhD, Department of Intensive Care Medicine, Radboud University Medical Center, PO Box 9101, Internal Post 710, 6500HB Nijmegen, the Netherlands (mark.vandenBoogaard@radboudumc.nl).

Accepted for Publication: January 10, 2018.

Corrections: This article was corrected on April 10, 2018, to add authors to the byline, affiliations, and contributions and on April 23, 2018, to correct the listing of coauthors in the REDUCE study group.

REDUCE Study Coauthors include Margaretha C. E. van der Woude, MD; Anna Besselink, MD; Lieuwe S. Hofstra, MD, PhD; Peter E. Spronk, MD, PhD; Walter van den Bergh, MD, PhD; Dirk W. Donker, MD, PhD; Malaika Fuchs, MD; Attila Karakus, MD, PhD; M. Koeman, MD, PhD; Mirella van Duijnhoven, MD; Gerjon Hannink, PhD.

Affiliations of REDUCE Study Coauthors: Department of Intensive Care Medicine and Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands (Donker); Department of Intensive Care Medicine, Zuyderland Medical Center, Heerlen, the Netherlands (van der Woude); Department of Intensive Care Medicine, Amphia Hospital, Breda, the Netherlands (Besselink); Department of Intensive Care Medicine, Scheper Hospital, Emmen, the Netherlands (Hofstra); Department of Intensive Care Medicine, Gelre Hospital, Apeldoorn, the Netherlands (Spronk); Department of Critical Care, University Medical Center Groningen, University of Groningen, the Netherlands (van den Bergh); Department of Intensive Care Medicine, Canisius Wilhelmina Hospital, Nijmegen, the Netherlands (Fuchs); Department of Intensive Care Medicine, Diakonessenhuis Utrecht, the Netherlands (Karakus); Department of Intensive Care Medicine, HagaZiekenhuis, The Hague, the Netherlands (Koeman); Department of Intensive Care Medicine, VieCuri Medical Center, Venlo, the Netherlands (van Duijnhoven); Department of Orthopedics, Radboud University Medical Center, Nijmegen, the Netherlands (Hannink).

Author Contributions: Drs van den Boogaard and Pickkers had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: van den Boogaard, Slooter, Brüggemann, van der Hoeven, Pickkers.

Acquisition, analysis, or interpretation of data: van den Boogaard, Slooter, Schoonhoven, Beishuizen, Vermeijden, Pretorius, de Koning, Simons, Dennesen, Van der Voort, Houterman, van der Hoeven, Pickkers, van der Woude, Besselink, Hofstra, Spronk, van den Bergh, Donker, Fuchs, Karakus, Koeman, van Duijnhoven, Hannink.

Drafting of the manuscript: van den Boogaard, Slooter, Brüggemann, Van der Voort, Houterman, Pickkers, Hannink.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: van den Boogaard, Houterman, Pickkers, Hannink.

Obtained funding: van den Boogaard, Brüggemann, Pickkers.

Administrative, technical, or material support: van den Boogaard, Slooter, Brüggemann, Schoonhoven, Beishuizen, Vermeijden, Pretorius, de Koning, Simons, Dennesen, Van der Voort, Houterman, van der Woude, Hofstra, Spronk, Donker, Karakus, Koeman, van Duijnhoven.

Supervision: van den Boogaard, Slooter, van der Hoeven, Pickkers.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Brüggemann reported that he has received grant support, consultant, and speaker fees from Pfizer, Merck Sharp, & Dohme, Astellas, and Gilead. No other disclosures were reported.

Funding/Support: This study was partly funded by zonMw program Goed Gebruik Geneesmiddelen (dossier No. 836031004).

Role of the Funder/Sponsor: ZonMw had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

REDUCE Study Investigators: M. van den Boogaard, PhD, Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, the Netherlands; A. J. C. Slooter, MD, PhD, Department of Intensive Care Medicine and Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands; R. J. M. Brüggemann, PhD, Department of Pharmacy Radboud University, Nijmegen Medical Center Nijmegen, the Netherlands; L. Schoonhoven, PhD, Faculty of Health Sciences, University of Southampton, Southampton, and the National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care, Wessex, United Kingdom, and the Scientific Institute for Quality of Healthcare, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands; A. Beishuizen, MD, PhD, Department of Intensive Care Medicine, Medical Spectrum Twente, Enschede, the Netherlands; J. W. Vermeijden, MD, PhD, Department of Intensive Care Medicine, Medical Spectrum Twente, Enschede, the Netherlands; D Pretorius, MD, Department of Intensive Care Medicine, St Jansdal Hospital Harderwijk, the Netherlands; J. de Koning, MD, Department of Intensive Care, Medicine, Máxima Medical Center Veldhoven, the Netherlands; K. S. Simons, MD, Department of Intensive Care Medicine, Jeroen Bosch Hospital Den-Bosch, the Netherlands; P. J.W. Dennesen, MD, PhD, Department of Intensive Care Medicine, Haaglanden Medical Center, The Hague, the Netherlands; P. H. J. van der Voort, MD, PhD, Department of Intensive Care Medicine, Amsterdam, and TIAS School for Business and Society, Tilburg University, Tilburg, the Netherlands; S. Houterman, PhD, Catharina Hospital, Eindhoven, the Netherlands; J. G. van der Hoeven, MD, PhD, Department of Intensive Care Medicine, Radboud, University Nijmegen Medical Center, Nijmegen, the Netherlands; P. Pickkers, MD, PhD, Department of Intensive Care Medicine, Radboud, University Nijmegen Medical Center, Nijmegen, the Netherlands; M. C. E. van der Woude, MD, Department Intensive Care Medicine, Zuyderland Medical Center, Heerlen, the Netherlands; A. Besselink, MD, Department Intensive Care Medicine, Amphia Hospital, Breda, the Netherlands; L.S. Hofstra, MD, PhD, Scheper Hospital, Emmen, the Netherlands; P. E. Spronk, MD, PhD, Department Intensive Care Medicine, Gelre Hospital, the Netherlands; W. van den Bergh, MD, PhD, Department of Critical Care, University Medical Center Groningen, University of Groningen, the Netherlands; D.W. Donker, MD, PhD, Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, the Netherlands; M. Fuchs, MD, Department Intensive Care Medicine, Canisius Wilhelmina Hospital, Nijmegen, the Netherlands; A. Karakus, MD, PhD, Department of Intensive Care Medicine, Diakonessenhuis Utrecht, the Netherlands; M. Koeman, MD, PhD, Department of Intensive Care Medicine, HagaZiekenhuis, The Hague, the Netherlands; M. van Duijnhoven, MD, Department of Intensive Care Medicine, VieCuri Medical Center, Venlo, the Netherlands; and G. Hannink, PhD, Radboud University Medical Center, the Netherlands.

Additional Contributions: We thank all coinvestigators, their research nurses, and their intensive care teams for their contribution to this trial. Furthermore, we would like to thank Dr Michael Kuiper, hospital Medical Centre Leeuwarden, and Marga Hoogendoorn, MSc, hospital ISALA Zwolle, for the inclusion of a small number of patients in their hospital in the early phase of the study. Lastly, we wish to thank the data and safety monitoring board members, Gert-Jan Scheffer, MD, (anaesthesiologist), Monica Pop-Purceleanu, MD (psychiatrist), and Ton de Haan, MSc (statistician) for their willingness to perform interim and safety analyses. None named herein received compensation.

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