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; I² = 0% (moderate-certainty evidence) and for proportion of patients experiencing SAEs/SARs 0.94; 96.7% CI 0.81 to 1.10; I² = 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.

Keywords: Antipsychotics; Delirium; Haloperidol; Meta-analysis; Systematic review.

Fig. 1

PRISMA flow diagram

Fig. 2

Forest plot of all-cause mortality in placebo-controlled trials. Forest plot of all-cause mortality in placebo-controlled trials. Three trials were at overall low risk of bias, and two trials were at overall high risk of bias. Size of the squares reflects the size of the trial (sample size). The horizontal bars represent 96.7% confidence intervals

Fig. 3

Trial sequential analysis of all-cause mortality in placebo-controlled trials. Trial sequential analysis of all-cause mortality for placebo-controlled trials (3 trials at overall low risk of bias and 2 trials at overall high risk of bias). We used a control event proportion of 38.6%, α of 3.3% (two-sided), β of 10% (power of 90%), diversity of 20% and a priori relative risk reduction or increase (RRR/RRI) of 20%. The z-curve (blue line) did not cross the trial sequential boundaries for benefit or harm (red outward sloping lines) or the inner-wedge futility line (red inward sloping red lines). The green dashed line shows the conventional boundaries for benefit/harm (alpha 0.033)