Haloperidol in treating delirium, reducing mortality, and preventing delirium occurrence: Bayesian and frequentist meta-analyses

Abstract

Background: Although haloperidol is commonly used to treat or prevent delirium in intensive care unit (ICU) patients, the evidence remains inconclusive. This study aimed to comprehensively evaluate the efficacy and safety of haloperidol for delirium treatment and prevention in ICU patients.

Methods: We searched MEDLINE, the cochrane central register of controlled trials, EMBASE, ClinicalTrial.gov, and PubMed without language restrictions from database inception to June 27, 2024. We included double-blind randomized controlled trials (RCTs) on haloperidol versus placebo for treating and preventing delirium in adult ICU patients. In addition to frequentist analyses, Bayesian analysis was used to calculate the posterior probabilities of any benefit/harm and clinically important benefit/harm (CIB/CIH). The primary outcomes for delirium treatment were all-cause mortality and serious adverse events (SAEs). For delirium prevention, the primary outcomes included incident delirium, all-cause mortality, and SAEs. The secondary outcomes for efficacy were delirium-or coma-free days, ventilator-free days, length of stay in ICU, length of stay in hospital, and rescue benzodiazepine use. The secondary outcomes for safety were QTc prolongation and extrapyramidal syndrome.

Results: We included seven RCTs on delirium treatment (n = 1767) and five on delirium prevention (n = 2509). The Bayesian analysis showed that, compared to placebo for delirium treatment, haloperidol had a 68% probability of achieving CIB (defined as risk difference [RD] < -0.02) in reducing all-cause mortality, a 2% probability of achieving CIH (RD > 0.02) in causing SAEs, and a 78% probability of achieving CIB (RD < -0.02) in reducing the need for rescue benzodiazepine use. The probabilities of haloperidol causing CIH (RD > 0.02) across all other safety outcomes were low (all < 50%). In frequentist analysis on delirium treatment, the pooled estimated RD for haloperidol compared to placebo was -0.05 (-0.09, -0.00; I² = 0%) for rescue benzodiazepine use. In Bayesian analysis on delirium prevention, haloperidol had a 12% probability of achieving CIB in all-cause mortality, a 34% probability of achieving CIB in delirium incidence, and a 0% probability of achieving CIB in SAEs. Importantly, haloperidol had a 65% probability of causing CIH (risk ratio > 1.1) for QTc prolongation, while the posterior probabilities of achieving CIB across all efficacy outcomes were low (all < 50%). In frequentist analysis on delirium prevention, all primary and secondary outcomes were not statistically significant in frequentist analysis.

Conclusion: Our study supported the use of haloperidol for delirium treatment in adult ICU patients, but not for delirium prevention.

Keywords: Bayesian meta-analysis; Delirium; Haloperidol; Intensive care unit patients; Mortality.

Fig. 1

Flow chart of study selection. From: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. https://doi.org/10.1136/bmj.n7

Fig. 2

Posterior probability of haloperidol versus placebo for delirium treatment on the primary outcomes. The distribution chart on the right, yellow represents the probability of exceeding the clinical important benefit, while pink represents the probability of being below the clinical important benefit. For the values on the left, yellow represents the benefit values, and pink represents the harm values. Abbreviation: CIB = clnically imporant benefit; CIH = clinically imporant harm. ^aDotted line indicates clinical important benefit, and solid line indicates no difference. ^bThe cut-off point for clinically important benefit is −0.02 for risk difference and 0.9 for risk ratio, while the cut-off point for clinically important harm is 0.02 for risk difference and 1.1 for risk ratio

Fig. 3

Haloperidol for delirium treatment using frequentist meta-analysis. Dichotomous outcomes of delirium treatment presented as A Risk ratio B Risk difference. Continuous outcomes of delirium treatment presented as (C) mean difference (day) (B) Ratio of means. Abbreviation: CI = confidence interval; ICU = intensive care unit; MD = mean difference; RD = risk difference; RoM = ratio of means; RR = Risk ratio. ^aInterpret grey-shaded results according to the grey-shaded directional indications