Haloperidol, clonidine and resolution of delirium in critically ill patients: a prospective cohort study

Abstract

Purpose: Haloperidol and clonidine are commonly used to treat agitation in delirious intensive care unit (ICU) patients, but it is unclear whether these agents may shorten the duration of delirium. The objective of this study was to determine whether haloperidol, clonidine, or their combined administration to delirious ICU patients results in delirium resolution.

Methods: This was a cohort study on a mixed ICU, excluding patients with a primary neurological disorder. The main outcome was the probability of delirium resolution, using propensity score matching and Markov multinomial logistic regression models for daily transitions. Secondary outcomes were delirium duration, number of delirium days, ventilation days, length of stay in the ICU and hospital, and ICU mortality.

Results: A total of 3614 patients were included (1165 delirious [32%]; 2449 non-delirious [68%]). Delirium occurred on 4708 (18.9%) of 24,906 days. The probability of delirium resolution was lower in delirious patients who received haloperidol (OR 0.47, 95% CI 0.39-0.57), clonidine (OR 0.78, 95% CI 0.63-0.97), or both (OR 0.45, 95% CI 0.36-0.56) compared to untreated delirious patients. Delirious patients who received haloperidol, clonidine, or both had generally longer delirium duration, more delirium and ventilation days, and spent more time in the ICU and in hospital than untreated delirious patients. These agents had no effect on ICU mortality.

Conclusion: Haloperidol and clonidine use in delirious ICU patients may be associated with reduced probability of delirium resolution. This finding, however, merits further investigation given inherent limitations of this observational analysis.

Keywords: Clonidine; Critical care; Delirium; Haloperidol; Intensive care unit.

Fig. 1

Daily transitions of mental status including administration of haloperidol and clonidine on delirium day X with median dosages. CI confidence interval, IQR interquartile range, Mcg microgram, Mg milligram, OR Odds ratio. ^a509 (10.8%) patients were deceased or discharged on day X + 1 and for 117 (2.5%) patients the mental status on the following day was missing. ^bSignificant (p < 0.001) difference in frequency of administration as compared to delirium or unarousable on day X + 1, tested with logistic regression models, adjusted for age, APACHE IV score, admission type (acute surgery, elective surgery, medical reason), patients’ mental status on day X, modified SOFA score, metabolic acidosis, use of ventilation, and administration of any antipsychotic other than haloperidol, benzodiazepines, propofol and opioids. Adjusted OR (95%CI) for haloperidol only was 0.66 (0.55–0.78) and for both haloperidol and clonidine 0.59 (0.48–0.73). ^cSignificant (p < 0.05) difference in dose of administered medication as compared to delirium or unarousable on day X + 1, tested with linear regression models, adjusted for age, APACHE IV score, admission type (acute surgery, elective surgery, medical reason), patients’ mental status on day X, modified SOFA score, metabolic acidosis, use of ventilation, and administration of any antipsychotic other than haloperidol, benzodiazepines, propofol and opioids. Adjusted OR (95% CI) for haloperidol only was 0.96 (0.93–0.98), for clonidine only 0.88 (0.83–0.93), for haloperidol in case of both haloperidol and clonidine administration 0.95 (0.92–0.98) and for clonidine in case of both haloperidol and clonidine administration 0.9 (0.85–0.95)