Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: the MIND randomized, placebo-controlled trial

Abstract

Objective: To demonstrate the feasibility of a placebo-controlled trial of antipsychotics for delirium in the intensive care unit and to test the hypothesis that antipsychotics would improve days alive without delirium or coma.

Design: Randomized, double-blind, placebo-controlled trial.

Setting: Six tertiary care medical centers in the US.

Patients: One hundred one mechanically ventilated medical and surgical intensive care unit patients.

Intervention: Patients were randomly assigned to receive haloperidol or ziprasidone or placebo every 6 hrs for up to 14 days. Twice each day, frequency of study drug administration was adjusted according to delirium status, level of sedation, and side effects.

Measurements and main outcomes: The primary end point was the number of days patients were alive without delirium or coma. During the 21-day study period, patients in the haloperidol group spent a similar number days alive without delirium or coma (median [interquartile range], 14.0 [6.0-18.0] days) as did patients in the ziprasidone (15.0 [9.1-18.0] days) and placebo groups (12.5 [1.2-17.2] days; p = 0.66). No differences were found in secondary clinical outcomes, including ventilator-free days (p = .25), hospital length of stay (p = .68), and mortality (p = .81). Ten (29%) patients in the haloperidol group reported symptoms consistent with akathisia, compared with six (20%) patients in the ziprasidone group and seven (19%) patients in the placebo group (p = .60), and a global measure of extrapyramidal symptoms was similar between treatment groups (p = .46).

Conclusions: A randomized, placebo-controlled trial of antipsychotics for delirium in mechanically ventilated intensive care unit patients is feasible. Treatment with antipsychotics in this limited pilot trial did not improve the number of days alive without delirium or coma, nor did it increase adverse outcomes. Thus, a large trial is needed to determine whether use of antipsychotics for intensive care unit delirium is appropriate.

Trial registration: ClinicalTrials.gov NCT00096863.

Figure 1. CONSORT flow diagram showing enrollment, randomization, and follow-up of the study population

Abbreviations: NMS, neuroleptic malignant syndrome *Two patients were excluded after randomization, before study drug was administered, due to ventricular tachycardia. No outcomes data could be collected for these two patients after their withdrawal.

Figure 2. Haloperidol plasma concentrations on study day two according to study group

For patients in the haloperidol group, the median [interquartile range] haloperidol plasma concentration was 4.5 [2.85–5.8] ng/mL. Alternatively, all but two patients in the ziprasidone group and three in the placebo group had undetectable haloperidol plasma concentrations.

Figure 3. Line graph of percentage of patients alive without delirium or coma during the 21-day study period according to treatment group

Acute brain dysfunction, in the form of delirium or coma, was common at enrollment in all treatment groups and resolved gradually throughout the course of the trial. Treatment with antipsychotics did not significantly affect the number of days patients were alive without delirium or coma; the median [interquartile range] delirium/coma-free days was 14.0 [6.0–18.0] days in the haloperidol group vs. 15.0 [9.1–18.0] days in the ziprasidone group vs. 12.5 [1.2–17.2] days in the placebo group) (p = 0.66).

Figure 4. Sedative exposure according to treatment group and study day

During the trial, patients in the three treatment groups received similar doses per day of benzodiazepines (p = 0.10), opiates (p = 0.87), and propofol (p = 0.16). These graphs display the median dose of these sedatives received by patients in each treatment group according to study day. Benzodiazepine doses are displayed in lorazepam equivalents; opiate doses are displayed in fentanyl equivalents. For each class of sedative, the number of patients in each group who received any sedative is also shown according to study day. Abbreviations: HAL, haloperidol; ZIP, ziprasidone; PBO, placebo