Haloperidol for the treatment of delirium in critically ill patients: A systematic review with meta-analysis and Trial Sequential Analysis

Background: Haloperidol is the most frequently used drug to treat delirium in the critically ill patients. Yet, no systematic review has focussed on the effects of haloperidol in critically ill patients with delirium. Methods: We conducted a systematic review with meta-analysis and Trial Sequential Analysis of randomized clinical trials (RCTs) assessing the effects of haloperidol vs any intervention on all-cause mortality, serious adverse reactions/events, days alive without delirium, health-related quality of life (HRQoL), cognitive function and delirium severity in critically ill patients with delirium. We also report on QTc prolongation, delirium resolution and extrapyramidal symptoms. Results: We included 8 RCTs with 11 comparisons (n = 951). We adjudicated one trial as having overall low risk of bias. Three trials used rescue haloperidol; excluding these, we did not find an effect of haloperidol vs control on all-cause mortality (RR 1.01; 95% CI 0.33-3.06; I² = 0%; 112 participants; 3 trials; 4 comparisons; very low certainty) or delirium severity (SMD −0.15; 95% CI −0.61-0.30; I² = 27%; 134 participants; 3 trials; 4 comparisons; very low certainty). No trials reported adequately on serious adverse reactions/events. Only one trial reported on days alive without delirium, cognitive function and QTc prolongation, and no trials reported on HRQoL. Sensitivity analyses, including trials using rescue haloperidol, did not change the results. Conclusions: The evidence for the use of haloperidol to treat critically ill patients with delirium is sparse, of low quality and inconclusive. We therefore have no certainty regarding any beneficial, harmful or neutral effects of haloperidol in these patients.