Prophylactic haloperidol did not prevent delirium or improve survival in a placebo-controlled trial of 1,789 critically ill adults at 21 ICUs in the Netherlands.

Haloperidol is used routinely in ICUs to both treat and prevent delirium, which strikes up to half of ICU patients and is associated with prolonged mechanical ventilation, longer ICU and hospital stays, and increased mortality. Results of past studies have been mixed, with some showing a benefit for haloperidol in the ICU and others not.

“These findings do not support the use of prophylactic haloperidol in critically ill adults,” said the authors of a new study, led by Mark van den Boogaard, PhD, of Radboud University Medical Center, Nijmegen, the Netherlands ( JAMA. 2018 Feb 20;319[7]:680-90 ).

The subjects were all expected to be in the ICU for at least 2 days, and were not delirious at baseline. The patients were randomly assigned to receive one of two treatments or a placebo three times daily, with 350 receiving 1 mg of haloperidol; 732 receiving 2 mg of haloperidol; and 707 receiving a 0.9% sodium chloride placebo. The 1-mg haloperidol arm was stopped early because of futility.

The ICUs also used nonpharmacologic interventions to prevent delirium, including early mobilization and noise reduction.

There was no statistically significant difference in survival at the primary endpoint of 28 days following entrance into the study. At that point, 83.3% of the patients who received 2-mg does of haloperidol and 82.7% of the of the subjects who received the placebo were alive (absolute difference 0.6%, 95% confidence interval –3.4% to 4.6%).

Prophylactic haloperidol had no effect on reducing the incidence of delirium, which was diagnosed in 33.3% of haloperidol subjects and 33.0% of placebo patients. Likewise, there were no significant differences between the groups in the number of delirium-free and coma-free days, duration of mechanical ventilation, and ICU and hospital length of stay. The number of reported adverse events with treatment also did not differ significantly between the groups: 0.3% in the 2-mg haloperidol group versus 0.1% in the placebo arm.

The duration of prophylactic therapy was a median of 2 days, but a subgroup analysis in patients treated for more than 2 days also did not show any benefits with haloperidol.

“The study population included severely ill ICU adults whose brains may have been too seriously affected for haloperidol to exert a prophylactic effect, since in non-ICU adults, prophylactic haloperidol may have beneficial effects. But the subgroup of patients with a low severity of illness score also demonstrated no beneficial effects,” the investigators said.

Subjects were a mean of 66.6 years old; 61.4% were men. Most of the ICU admissions were urgent and for medical or surgical reasons.

This study was supported by ZonMw, the Netherlands Organization for Health Research and Development. Dr. van den Boogaard had no disclosures. One author reported grants and consultant and speaker fees from Pfizer, Merck, Astellas, and Gilead, among others.

SOURCE: van den Boogaard M, et al. JAMA. 2018 Feb 20;319(7):680-90.


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