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Effect of haloperidol on survival among critically ill adults with a high risk of delirium: The REDUCE randomized clinical trial

Effect of haloperidol on survival among critically ill adults with a high risk of delirium: The REDUCE randomized clinical trial
Effect of haloperidol on survival among critically ill adults with a high risk of delirium: The REDUCE randomized clinical trial
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 1mg (n = 350) or 2mg (n = 732) of haloperidol or placebo (n = 707), consisting of 0.9% sodium chloride.

MAIN OUTCOME AND MEASURES The primary outcomewas 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
0098-7484
680-690
Van Den Boogaard, Mark
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Slooter, Arjen J.C.
b655a34a-8109-4baf-a463-189d403212fc
Brüggemann, Roger J.M.
0d16fa0b-dc4e-4ca1-88d0-74ecd073b62d
Schoonhoven, Lisette
46a2705b-c657-409b-b9da-329d5b1b02de
Beishuizen, Albertus
0403a954-d9f1-4254-b35f-a50efb7345b7
Vermeijden, J. Wytze
fea6c8b1-d33c-4248-a15c-21b5291de962
Pretorius, Danie
b18ee0a2-86c8-42ef-b0e8-e7b3cc11830b
De Koning, Jan
d8d957ac-b25d-401c-bbb9-01efd9f1a6d9
Simons, Koen S.
e276578a-1001-4f9d-816f-c3c345cd4a09
Dennesen, Paul J.W.
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Van Der Voort, Peter H.J.
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Houterman, Saskia
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Van Der Hoeven, J.G.
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Pickkers, Peter
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Van Den Boogaard, Mark
4751824c-6a51-4bc8-8854-97f4579e045b
Slooter, Arjen J.C.
b655a34a-8109-4baf-a463-189d403212fc
Brüggemann, Roger J.M.
0d16fa0b-dc4e-4ca1-88d0-74ecd073b62d
Schoonhoven, Lisette
46a2705b-c657-409b-b9da-329d5b1b02de
Beishuizen, Albertus
0403a954-d9f1-4254-b35f-a50efb7345b7
Vermeijden, J. Wytze
fea6c8b1-d33c-4248-a15c-21b5291de962
Pretorius, Danie
b18ee0a2-86c8-42ef-b0e8-e7b3cc11830b
De Koning, Jan
d8d957ac-b25d-401c-bbb9-01efd9f1a6d9
Simons, Koen S.
e276578a-1001-4f9d-816f-c3c345cd4a09
Dennesen, Paul J.W.
f085e642-12c2-49ba-a57c-9aa48bd331a5
Van Der Voort, Peter H.J.
42a581c9-53c2-4169-8d1b-bcbf32cbd514
Houterman, Saskia
36dd3d8d-fe5f-441d-90bf-460628b7ca96
Van Der Hoeven, J.G.
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Pickkers, Peter
516df191-7ae2-457e-a7f7-abd6ca935687

Van Den Boogaard, Mark, Slooter, Arjen J.C., Brüggemann, Roger J.M., Schoonhoven, Lisette, Beishuizen, Albertus, Vermeijden, J. Wytze, Pretorius, Danie, De Koning, Jan, Simons, Koen S., Dennesen, Paul J.W., Van Der Voort, Peter H.J., Houterman, Saskia, Van Der Hoeven, J.G. and Pickkers, Peter (2018) Effect of haloperidol on survival among critically ill adults with a high risk of delirium: The REDUCE randomized clinical trial. JAMA, 319 (7), 680-690. (doi:10.1001/jama.2018.0160).

Record type: Article

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 1mg (n = 350) or 2mg (n = 732) of haloperidol or placebo (n = 707), consisting of 0.9% sodium chloride.

MAIN OUTCOME AND MEASURES The primary outcomewas 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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Revised_clean_JAMA17-6588_20171129 - Accepted Manuscript
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Figure 1: Flowchart for patient enrollment
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Figure 2: 90 days
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Figure 2: 28 days
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eFigure 1: Time Sequential Analysis
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eFigure 2a: Forrest plot with interaction for 28 days
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eFigure 2b: Forrest plot with interaction for 90 days
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eFigure 2c: Forrest plot with interaction for delirium incidence
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More information

Accepted/In Press date: 10 January 2018
e-pub ahead of print date: 20 February 2018
Published date: 20 February 2018

Identifiers

Local EPrints ID: 418583
URI: http://eprints.soton.ac.uk/id/eprint/418583
ISSN: 0098-7484
PURE UUID: eda02ded-3d20-402a-8f73-cafd372ee1fc
ORCID for Lisette Schoonhoven: ORCID iD orcid.org/0000-0002-7129-3766

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Date deposited: 12 Mar 2018 17:30
Last modified: 24 Feb 2021 05:01

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