No reduction in delirium with the use of haloperidol or ziprasidone in critically ill patients

Reference

Girard TD, Exline MC, Carson SS, et al, for the MIND-USA Investigators. Haloperidol and ziprasidone for treatment of delirium in critical illness. N Engl J Med. 2018 Oct 22. doi: 10.1056/NEJMoa1808217. [Epub ahead of print]

Synopsis

This study included critically ill patients with delirium who were using invasive/noninvasive mechanical ventilation, taking vasopressors, or requiring an intra-aortic balloon pump. The patients were randomized to receive either intravenous haloperidol 2.5 mg, ziprasidone 5 mg, or a placebo of 0.5 mL normal saline. Patients 70 years or older received half these doses. Doses were administered every 12 hours and were doubled up to the maximum dose if a patient still had delirium, or halved to a minimum dose if the patient did not have delirium for 2 consecutive assessments, and withheld if a patient did not have delirium for 4 consecutive assessments. Therapy was continued for 14 days or until ICU discharge. Therapy was stopped permanently if a patient developed torsades de pointes, neuroleptic malignant syndrome, or a severe drug reaction. Of the 20,000 patients screened for eligibility over a 6-year period, 566 patients both agreed to participate and met the criteria for randomization. Patients in the 3 groups had similar baseline characteristics and almost 90% had hypoactive delirium at the time of randomization. Analysis was by intention to treat. As compared with placebo, the use of either haloperidol or ziprasidone did not significantly increase the median number of days alive without delirium or coma (8.5 days with placebo, 7.9 days with haloperidol, 8.7 days with ziprasidone; P = 0.26 for overall effect across all 3 groups). Additionally, there were no differences in 30-day or 90-day survival, ICU discharge or readmission, or hospital discharge. Excessive sedation was the most common safety endpoint and did not differ among the groups.