Haloperidol for ICU Delirium Yields No Significant Improvement in Outcomes

Haloperidol treatment in the intensive care unit (ICU) among patients with delirium failed to produce a significantly greater number of days alive and out of the hospital, according to study findings published in The New England Journal of Medicine.

Delirium, the most common sign of acute brain dysfunction among critically ill patients, may affect up to 50% of patients treated in the ICU and is most frequently treated with haloperidol, even though clinical practice guidelines do not support this practice. Researchers sought to assess whether haloperidol for patients in the ICU with delirium led to a greater number of days alive and out of the hospital at 90 days after the initiation of treatment.

Between June 2018 and April 2022, researchers conducted the Agents Intervening against Delirium in the Intensive Care Unit (AID-ICU) trial (ClinicalTrials.gov Identifier: NCT03392376), a multicenter, blinded, placebo-controlled trial of patients who were admitted to the ICU for an acute condition in 16 ICUs in Denmark, Finland, Spain, Italy and the United Kingdom. All enrolled patients had delirium (ie, an acute disturbance in attention and awareness) which was determined via a positive result on either the Confusion Assessment Method for the ICU (CAM-ICU) or the Intensive Care Delirium Screening Checklist (ICDSC). Patients were randomly assigned to receive intravenous haloperidol (2.5 mg 3 times daily plus 2.5 mg as needed up to a total maximum daily dose of 20 mg) or to the placebo group.

Haloperidol or placebo was administered to patients for as long as delirium continued in the ICU and as needed for recurrences. A total of 987 patients were included in the final analysis: 501 in the haloperidol group (median age, 70; 35.3% women) and 486 in the placebo group (median age, 71; 33.1% women). Of these patients, 447 patients had hyperactive delirium and 540 patients had hypoactive delirium. Primary outcome data were available for 963 patients. Researchers found the most significant risk factors for delirium were active tobacco smoking (31% in haloperidol group; 30% in placebo group), receipt of benzodiazepines in hospital prior to the study (33% haloperidol; 29% placebo), and alcohol overconsumption (17% haloperidol; 16% placebo).

At 90 days, the mean number of days alive and out of the hospital for patients in the haloperidol group was 35.8 (95% CI, 32.9-38.6) vs 32.9 (95% CI, 29.9-35.8) in the placebo group, with an adjusted mean difference of 2.9 days (95% CI, -1.2 to 7.0; P =.22).

In the haloperidol group, researchers noted mortality at 90 days was 36.3% vs 43.3% mortality in the placebo group, with an adjusted absolute difference of -6.9% (95% CI, -13.0% to -0.6%). Serious adverse reactions occurred in 11 patients in the haloperidol group and in 9 patients in the placebo group. The number of days alive without delirium or coma was 57.7 for the haloperidol group and 53.9 for the placebo group.

Study limitations include the inclusion of fewer patients with hypoactive delirium vs hyperactive delirium; a lack of data on comorbid conditions; the composite nature of the primary outcome; a lack of data on other sedatives, pain medications, or nonpharmacologic interventions; and patients withdrawing from the trial.

Researchers concluded that “Among patients in the ICU with delirium, treatment with haloperidol did not lead to a significantly greater number of days alive and out of the hospital at 90 days than placebo.” They further added, “Although our results suggest that mortality may have been lower with haloperidol than with placebo, no conclusions may be drawn.”