MIND USA

NEJM

December 27, 2018

Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness.

What was the research question?

  • Does the use of haloperidol or ziprasidone reduce the duration of delirium or improve outcomes in critically ill patients with hypoactive or hyperactive delirium?


How did they do it?

  • A randomized, double-blind, placebo-controlled trial at 16 medical centers in the United States.

  • 566 patients with acute respiratory failure or shock and hypoactive or hyperactive delirium were randomized to receive intravenous boluses of haloperidol (maximum dose, 20 mg daily) (192 patients), ziprasidone (maximum dose, 40 mg daily) (190 patients), or placebo (184 patients).

  • 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.


What did they find?

  • At randomization, 90% of patients were receiving invasive mechanical ventilation. Rate of delirium was 48% (566 patients out of 1183), of whom 89% had hypoactive delirium and 11% had hyperactive delirium.

  • The median number of days alive without delirium or coma was not significantly different with the use of haloperidol, ziprasidone, or placebo (7.9 vs. 8.7 vs. 8.5, P=0.26).

  • There was no significant effect with the use of haloperidol or ziprasidone, as compared with placebo 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.


Are there any limitations?

  • The study was powered to detect a 2-day difference and cannot rule out a benefit of less than two days.

  • Could not rule out a benefit on other phenotypes of delirium.

  • The study lacks the power to detect any rare side effects of the study medication such as torsade de point.


What does it mean?

  • Among patients with acute respiratory failure or shock and hypoactive or hyperactive delirium in the ICU, the use of haloperidol or ziprasidone, as compared with placebo does not alter the duration of delirium.

MIND USA