A high quality trial published in the New England Journal of Medicine involved random and blinded assignment of patients with acute respiratory failure or shock + hypoactive or hyperactive delirium to either receive IV haloperidol (maximum dose, 20 mg daily), ziprasidone (maximum dose, 40 mg daily), or placebo. The dose was halved or doubled at 12-hour intervals on the basis of the presence or absence of delirium, as well as side effects associated with the intervention.

The study examined 566 patients – 89% had hypoactive delirium and 11% had hyperactive delirium. Median duration of exposure to a trial drug or placebo was 4 days, 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 number of days alive without delirium or coma during the 14-day intervention period, or the secondary end points that included included 30-day and 90-day survival, time to freedom from mechanical ventilation, and time to ICU and hospital discharge. The frequency of extrapyramidal symptoms did not vary between groups. These two agents failed to favourably influence the course of delirium in hospitalised patients in the ICU – the question then remains – how to manage this clinical issue?