Haloperidol for the treatment of delirium in critically ill patients: an updated systematic review with meta-analysis and trial sequential analysis

Nina Christine Andersen-Ranberg; Marija Barbateskovic; Anders Perner; Marie Oxenbøll Collet; Lone Musaeus Poulsen; Mathieu van der Jagt; Lisa Smit; Jørn Wetterslev; Ole Mathiesen; Mathias Maagaard

doi:10.1186/s13054-023-04621-4

Haloperidol for the treatment of delirium in critically ill patients: an updated systematic review with meta-analysis and trial sequential analysis

Nina Christine Andersen-Ranberg^*, Marija Barbateskovic, Anders Perner, Marie Oxenbøll Collet, Lone Musaeus Poulsen, Mathieu van der Jagt, Lisa Smit, Jørn Wetterslev, Ole Mathiesen, Mathias Maagaard

^*Corresponding author for this work

Intensive Care

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Background:

Haloperidol is frequently used in critically ill patients with delirium, but evidence for its effects has been sparse and inconclusive. By including recent trials, we updated a systematic review assessing effects of haloperidol on mortality and serious adverse events in critically ill patients with delirium.

Methods:

This is an updated systematic review with meta-analysis and trial sequential analysis of randomised clinical trials investigating haloperidol versus placebo or any comparator in critically ill patients with delirium. We adhered to the Cochrane handbook, the PRISMA guidelines and the grading of recommendations assessment, development and evaluation statements. The primary outcomes were all-cause mortality and proportion of patients with one or more serious adverse events or reactions (SAEs/SARs). Secondary outcomes were days alive without delirium or coma, delirium severity, cognitive function and health-related quality of life.

Results:

We included 11 RCTs with 15 comparisons (n = 2200); five were placebo-controlled. The relative risk for mortality with haloperidol versus placebo was 0.89; 96.7% CI 0.77 to 1.03; I ² = 0% (moderate-certainty evidence) and for proportion of patients experiencing SAEs/SARs 0.94; 96.7% CI 0.81 to 1.10; I ² = 18% (low-certainty evidence). We found no difference in days alive without delirium or coma (moderate-certainty evidence). We found sparse data for other secondary outcomes and other comparators than placebo.

Conclusions:

Haloperidol may reduce mortality and likely result in little to no change in the occurrence of SAEs/SARs compared with placebo in critically ill patients with delirium. However, the results were not statistically significant and more trial data are needed to provide higher certainty for the effects of haloperidol in these patients. Trial registration: CRD42017081133, date of registration 28 November 2017.

Original language	English
Article number	329
Journal	Critical Care
Volume	27
Issue number	1
DOIs	https://doi.org/10.1186/s13054-023-04621-4
Publication status	Published - 26 Aug 2023

Bibliographical note

Funding Information:
No specific funding was received for this systematic review. NCAN and LMP received funding from the Regional Medicines Fund. OMAT, MOC and AP received grants from the Novo Nordisk Foundation. OMAT has received funding from the Independent Research Fund Denmark and Sygeforsikring ‘danmark’. AP has received grants from Innovations Fund Denmark and Pfizer. The Departments of Intensive Care at Zealand University Hospital and Rigshospitalet have conducted contract research for AM-Pharma. MvdJ and LS received funding for the EuRIDICE trial from ZonMw.

Publisher Copyright:
© 2023, BioMed Central Ltd., part of Springer Nature.

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Haloperidol for the treatment of delirium in critically ill patientsFinal published version, 1.43 MBLicence: CC BY

Cite this

Andersen-Ranberg, N. C., Barbateskovic, M., Perner, A., Oxenbøll Collet, M., Musaeus Poulsen, L., van der Jagt, M., Smit, L., Wetterslev, J., Mathiesen, O., & Maagaard, M. (2023). Haloperidol for the treatment of delirium in critically ill patients: an updated systematic review with meta-analysis and trial sequential analysis. Critical Care, 27(1), Article 329. https://doi.org/10.1186/s13054-023-04621-4

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title = "Haloperidol for the treatment of delirium in critically ill patients: an updated systematic review with meta-analysis and trial sequential analysis",

abstract = "Background: Haloperidol is frequently used in critically ill patients with delirium, but evidence for its effects has been sparse and inconclusive. By including recent trials, we updated a systematic review assessing effects of haloperidol on mortality and serious adverse events in critically ill patients with delirium. Methods: This is an updated systematic review with meta-analysis and trial sequential analysis of randomised clinical trials investigating haloperidol versus placebo or any comparator in critically ill patients with delirium. We adhered to the Cochrane handbook, the PRISMA guidelines and the grading of recommendations assessment, development and evaluation statements. The primary outcomes were all-cause mortality and proportion of patients with one or more serious adverse events or reactions (SAEs/SARs). Secondary outcomes were days alive without delirium or coma, delirium severity, cognitive function and health-related quality of life.Results: We included 11 RCTs with 15 comparisons (n = 2200); five were placebo-controlled. The relative risk for mortality with haloperidol versus placebo was 0.89; 96.7% CI 0.77 to 1.03; I 2 = 0% (moderate-certainty evidence) and for proportion of patients experiencing SAEs/SARs 0.94; 96.7% CI 0.81 to 1.10; I 2 = 18% (low-certainty evidence). We found no difference in days alive without delirium or coma (moderate-certainty evidence). We found sparse data for other secondary outcomes and other comparators than placebo. Conclusions: Haloperidol may reduce mortality and likely result in little to no change in the occurrence of SAEs/SARs compared with placebo in critically ill patients with delirium. However, the results were not statistically significant and more trial data are needed to provide higher certainty for the effects of haloperidol in these patients. Trial registration: CRD42017081133, date of registration 28 November 2017.",

author = "Andersen-Ranberg, {Nina Christine} and Marija Barbateskovic and Anders Perner and {Oxenb{\o}ll Collet}, Marie and {Musaeus Poulsen}, Lone and {van der Jagt}, Mathieu and Lisa Smit and J{\o}rn Wetterslev and Ole Mathiesen and Mathias Maagaard",

note = "Funding Information: No specific funding was received for this systematic review. NCAN and LMP received funding from the Regional Medicines Fund. OMAT, MOC and AP received grants from the Novo Nordisk Foundation. OMAT has received funding from the Independent Research Fund Denmark and Sygeforsikring {\textquoteleft}danmark{\textquoteright}. AP has received grants from Innovations Fund Denmark and Pfizer. The Departments of Intensive Care at Zealand University Hospital and Rigshospitalet have conducted contract research for AM-Pharma. MvdJ and LS received funding for the EuRIDICE trial from ZonMw. Publisher Copyright: {\textcopyright} 2023, BioMed Central Ltd., part of Springer Nature.",

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doi = "10.1186/s13054-023-04621-4",

language = "English",

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journal = "Critical Care",

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Andersen-Ranberg, NC, Barbateskovic, M, Perner, A, Oxenbøll Collet, M, Musaeus Poulsen, L, van der Jagt, M , Smit, L, Wetterslev, J, Mathiesen, O & Maagaard, M 2023, 'Haloperidol for the treatment of delirium in critically ill patients: an updated systematic review with meta-analysis and trial sequential analysis', Critical Care, vol. 27, no. 1, 329. https://doi.org/10.1186/s13054-023-04621-4

TY - JOUR

T1 - Haloperidol for the treatment of delirium in critically ill patients

T2 - an updated systematic review with meta-analysis and trial sequential analysis

AU - Andersen-Ranberg, Nina Christine

AU - Barbateskovic, Marija

AU - Perner, Anders

AU - Oxenbøll Collet, Marie

AU - Musaeus Poulsen, Lone

AU - van der Jagt, Mathieu

AU - Smit, Lisa

AU - Wetterslev, Jørn

AU - Mathiesen, Ole

AU - Maagaard, Mathias

N1 - Funding Information: No specific funding was received for this systematic review. NCAN and LMP received funding from the Regional Medicines Fund. OMAT, MOC and AP received grants from the Novo Nordisk Foundation. OMAT has received funding from the Independent Research Fund Denmark and Sygeforsikring ‘danmark’. AP has received grants from Innovations Fund Denmark and Pfizer. The Departments of Intensive Care at Zealand University Hospital and Rigshospitalet have conducted contract research for AM-Pharma. MvdJ and LS received funding for the EuRIDICE trial from ZonMw. Publisher Copyright: © 2023, BioMed Central Ltd., part of Springer Nature.

PY - 2023/8/26

Y1 - 2023/8/26

N2 - Background: Haloperidol is frequently used in critically ill patients with delirium, but evidence for its effects has been sparse and inconclusive. By including recent trials, we updated a systematic review assessing effects of haloperidol on mortality and serious adverse events in critically ill patients with delirium. Methods: This is an updated systematic review with meta-analysis and trial sequential analysis of randomised clinical trials investigating haloperidol versus placebo or any comparator in critically ill patients with delirium. We adhered to the Cochrane handbook, the PRISMA guidelines and the grading of recommendations assessment, development and evaluation statements. The primary outcomes were all-cause mortality and proportion of patients with one or more serious adverse events or reactions (SAEs/SARs). Secondary outcomes were days alive without delirium or coma, delirium severity, cognitive function and health-related quality of life.Results: We included 11 RCTs with 15 comparisons (n = 2200); five were placebo-controlled. The relative risk for mortality with haloperidol versus placebo was 0.89; 96.7% CI 0.77 to 1.03; I 2 = 0% (moderate-certainty evidence) and for proportion of patients experiencing SAEs/SARs 0.94; 96.7% CI 0.81 to 1.10; I 2 = 18% (low-certainty evidence). We found no difference in days alive without delirium or coma (moderate-certainty evidence). We found sparse data for other secondary outcomes and other comparators than placebo. Conclusions: Haloperidol may reduce mortality and likely result in little to no change in the occurrence of SAEs/SARs compared with placebo in critically ill patients with delirium. However, the results were not statistically significant and more trial data are needed to provide higher certainty for the effects of haloperidol in these patients. Trial registration: CRD42017081133, date of registration 28 November 2017.

AB - Background: Haloperidol is frequently used in critically ill patients with delirium, but evidence for its effects has been sparse and inconclusive. By including recent trials, we updated a systematic review assessing effects of haloperidol on mortality and serious adverse events in critically ill patients with delirium. Methods: This is an updated systematic review with meta-analysis and trial sequential analysis of randomised clinical trials investigating haloperidol versus placebo or any comparator in critically ill patients with delirium. We adhered to the Cochrane handbook, the PRISMA guidelines and the grading of recommendations assessment, development and evaluation statements. The primary outcomes were all-cause mortality and proportion of patients with one or more serious adverse events or reactions (SAEs/SARs). Secondary outcomes were days alive without delirium or coma, delirium severity, cognitive function and health-related quality of life.Results: We included 11 RCTs with 15 comparisons (n = 2200); five were placebo-controlled. The relative risk for mortality with haloperidol versus placebo was 0.89; 96.7% CI 0.77 to 1.03; I 2 = 0% (moderate-certainty evidence) and for proportion of patients experiencing SAEs/SARs 0.94; 96.7% CI 0.81 to 1.10; I 2 = 18% (low-certainty evidence). We found no difference in days alive without delirium or coma (moderate-certainty evidence). We found sparse data for other secondary outcomes and other comparators than placebo. Conclusions: Haloperidol may reduce mortality and likely result in little to no change in the occurrence of SAEs/SARs compared with placebo in critically ill patients with delirium. However, the results were not statistically significant and more trial data are needed to provide higher certainty for the effects of haloperidol in these patients. Trial registration: CRD42017081133, date of registration 28 November 2017.

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U2 - 10.1186/s13054-023-04621-4

DO - 10.1186/s13054-023-04621-4

M3 - Article

C2 - 37633991

AN - SCOPUS:85168744668

SN - 1364-8535

VL - 27

JO - Critical Care

JF - Critical Care

IS - 1

M1 - 329

ER -

Haloperidol for the treatment of delirium in critically ill patients: an updated systematic review with meta-analysis and trial sequential analysis

Abstract

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