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JAMA. 2018 Feb 20;319(7):680-690. doi: 10.1001/jama.2018.0160.

Effect of Haloperidol on Survival Among Critically Ill Adults With a High Risk of Delirium: The REDUCE Randomized Clinical Trial.

Author information

1
Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
2
Department of Intensive Care Medicine and Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
3
Department of Pharmacy Radboud University Medical Center, Nijmegen, the Netherlands.
4
Faculty of Health Sciences, University of Southampton, Southampton, United Kingdom.
5
National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care, Wessex, United Kingdom.
6
Scientific Institute for Quality of Healthcare, Radboud University Medical Center, Nijmegen, the Netherlands.
7
Department of Intensive Care Medicine, Medical Spectrum Twente, Enschede, the Netherlands.
8
Department of Intensive Care Medicine, St Jansdal Hospital Harderwijk, the Netherlands.
9
Department of Intensive Care Medicine, Máxima Medical Center Veldhoven, the Netherlands.
10
Department of Intensive Care Medicine, Jeroen Bosch Hospital Den-Bosch, the Netherlands.
11
Department of Intensive Care Medicine, Haaglanden Medical Center, The Hague, the Netherlands.
12
Department of Intensive Care Medicine, Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands.
13
TIAS School for Business and Society, Tilburg University, Tilburg, the Netherlands.
14
Catharina Hospital, Eindhoven, the Netherlands
15
Department of Intensive Care Medicine, Zuyderland Medical Center, Heerlen, the Netherlands
16
Department of Intensive Care Medicine, Amphia Hospital, Breda, the Netherlands
17
Department of Intensive Care Medicine, Scheper Hospital, Emmen, the Netherlands
18
Department of Intensive Care Medicine, Gelre Hospital, Apeldoorn, the Netherlands
19
Department of Critical Care, University Medical Center Groningen, University of Groningen, the Netherlands
20
Department of Intensive Care Medicine, Canisius Wilhelmina Hospital, Nijmegen, the Netherlands
21
Department of Intensive Care Medicine, Diakonessenhuis Utrecht, the Netherlands
22
Department of Intensive Care Medicine, HagaZiekenhuis, The Hague, the Netherlands
23
Department of Intensive Care Medicine, VieCuri Medical Center, Venlo, the Netherlands
24
Department of Orthopedics, Radboud University Medical Center, Nijmegen, the Netherlands

Erratum in

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.

PMID:
29466591
PMCID:
PMC5839284
DOI:
10.1001/jama.2018.0160
[Indexed for MEDLINE]
Free PMC Article

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