Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness

Abstract

Background: There are conflicting data on the effects of antipsychotic medications on delirium in patients in the intensive care unit (ICU).

Methods: In a randomized, double-blind, placebo-controlled trial, we assigned patients with acute respiratory failure or shock and hypoactive or hyperactive delirium to receive intravenous boluses of haloperidol (maximum dose, 20 mg daily), ziprasidone (maximum dose, 40 mg daily), or placebo. The volume and dose of a trial drug or placebo was halved or doubled at 12-hour intervals on the basis of the presence or absence of delirium, as detected with the use of the Confusion Assessment Method for the ICU, and of side effects of the intervention. The primary end point was the number of days alive without delirium or coma during the 14-day intervention period. Secondary end points included 30-day and 90-day survival, time to freedom from mechanical ventilation, and time to ICU and hospital discharge. Safety end points included extrapyramidal symptoms and excessive sedation.

Results: Written informed consent was obtained from 1183 patients or their authorized representatives. Delirium developed in 566 patients (48%), of whom 89% had hypoactive delirium and 11% had hyperactive delirium. Of the 566 patients, 184 were randomly assigned to receive placebo, 192 to receive haloperidol, and 190 to receive ziprasidone. The median duration of exposure to a trial drug or placebo was 4 days (interquartile range, 3 to 7). The median number of days alive without delirium or coma was 8.5 (95% confidence interval [CI], 5.6 to 9.9) in the placebo group, 7.9 (95% CI, 4.4 to 9.6) in the haloperidol group, and 8.7 (95% CI, 5.9 to 10.0) in the ziprasidone group (P=0.26 for overall effect across trial groups). The use of haloperidol or ziprasidone, as compared with placebo, had no significant effect on the primary end point (odds ratios, 0.88 [95% CI, 0.64 to 1.21] and 1.04 [95% CI, 0.73 to 1.48], respectively). There were no significant between-group differences with respect to the secondary end points or the frequency of extrapyramidal symptoms.

Conclusions: The use of haloperidol or ziprasidone, as compared with placebo, in patients with acute respiratory failure or shock and hypoactive or hyperactive delirium in the ICU did not significantly alter the duration of delirium. (Funded by the National Institutes of Health and the VA Geriatric Research Education and Clinical Center; MIND-USA ClinicalTrials.gov number, NCT01211522 .).

Figure 1.. Screening, Randomization, Follow-up, and Analysis.

The numbers of patients excluded for each criterion sum to more than the total excluded because some patients met more than one exclusion criterion. ICU denotes intensive care unit.

Figure 2.. Effects of Haloperidol, Ziprasidone, and Placebo on Days Alive without Delirium or Coma, Days with Delirium, and Days with Coma.

In analyses that were adjusted for age, preexisting cognitive impairment, Clinical Frailty Score and Charlson Comorbidity Index score at baseline, and modified Sequential Organ Failure Assessment score and Richmond Agitation–Sedation Scale score at randomization, there were no significant differences between the trial groups with respect to the primary end point (days alive without delirium or coma) and with respect to the secondary end points of mental status (durations of delirium and coma).

Figure 3.. Effects of Haloperidol, Ziprasidone, and Placebo on 90-Day Survival.

Shown are Kaplan–Meier curves of the probability of survival. In analyses that were adjusted for age, preexisting cognitive impairment, Clinical Frailty Score and Charlson Comorbidity Index score at baseline, and modified Sequential Organ Failure Assessment score and Richmond Agitation–Sedation Scale score at randomization, there were no significant differences in 90-day survival between the trial groups. Results have not been adjusted for multiple comparisons. The shading indicates the 95% confidence intervals.