By Arzo Hamidi, PharmD, BCCCP
Clinical Pharmacy Specialist, Adult Critical Care, Rush University Medical Center, Chicago
SYNOPSIS: The use of scheduled intravenous haloperidol in intensive care unit patients with delirium did not result in additional days alive and out of the hospital at 90 days as compared to placebo.
SOURCE: Andersen-Ranberg NC, Poulsen LM, Perner A, et al. Haloperidol for the treatment of delirium in ICU patients. N Engl J Med 2022;387:2425-2436.
In this international, blinded, parallel-group, placebo-controlled, randomized trial, adult intensive care unit (ICU) patients were screened for delirium twice daily using either the Confusion Assessment Method for the ICU (CAM-ICU) or Intensive Care Delirium Screening Checklist (ICDSC). Patients were assigned to receive either intravenous (IV) haloperidol 2.5 mg (5 mg/mL) three times daily with additional as-needed doses up to a daily maximum dose of 20 mg or placebo. Placebo was given as saline in equivalent volumes compared to the intervention. Rescue medications to manage delirium were allowed as per the provider. The intervention was stopped if the patient did not have delirium on two consecutive assessments. The intervention could be resumed if the patient had another episode of delirium. Follow-up was a maximum of 90 days or until discharge or death from the ICU, with the primary outcome being days alive and out of the hospital. Other antipsychotics were not allowed.
A total of 987 patients were included, with 501 in the haloperidol group and 486 in the placebo group. The median age was 70 years, and most patients were male. One-third of patients received benzodiazepines prior to randomization, more than 60% of patients required mechanical ventilation, and more than 50% of patients required vasopressors or inotropes. More than half of the patients had hypoactive delirium (55%) compared to hyperactive delirium (45%).
For the primary outcome of number of days alive and out of the hospital at 90 days, this was 35.8 (95% confidence interval [CI], 32.9-38.6) days in the intervention group and 32.9 (95% CI, 29.9-35.8) days in the placebo group (P = 0.22). At 90 days, 36% of patients in the haloperidol group had died compared to 43% of patients in the placebo group. The length of hospital stay was 29 days in the haloperidol group vs. 26 days in the placebo group. Nearly 60% of patients in either group required rescue medications, with an alpha-2 agonist being the most commonly used. Overall, the number of serious adverse reactions was similar and low among groups.
COMMENTARY
This trial showed no improvement in survival at 90 days in ICU patients with delirium who received scheduled IV haloperidol. Subgroup analyses were done based on type of delirium, age, sex, and admission type (medical vs. surgical). The adjusted mean differences in each of these groups showed no significant differences in the primary outcome between the intervention group and placebo.
This trial included nearly 1,000 patients, a relatively large sample size for ICU patients with delirium. This study included both patients with hypoactive and hyperactive delirium to include a broader patient population that often is managed as delirium in clinical practice. At baseline, one-third of patients had at least one risk factor for delirium. The most commonly reported risk factors in this population included receiving benzodiazepines before randomization, tobacco smoking, alcohol overconsumption, and history of mental illness.
In assessing the impact of pharmacological treatment of delirium, there are challenges with delirium assessment. The study coordinators did not clarify if additional education was completed prior to the study to minimize any subjective assessment using either the CAM-ICU or ICDSC, although the scoring tools used for assessment of delirium in this study are standardized and validated tools to minimize any bias in this assessment. This study also did not address any nonpharmacological interventions that may have affected the duration of patients with delirium. Additionally, although other antipsychotics were not allowed per protocol, about 13% of patients in both intervention and placebo groups received open-label rescue antipsychotics in addition to the other open-label rescue medications.
Notably, the median daily dose was 8.3 mg in the haloperidol group and 9 mg in the placebo group, indicating that more than 70% of patients received additional as-needed doses. The median duration of trial intervention was only about three days in both groups, which is a short interval in light of the primary outcome being a follow-up through 90 days. The length of ICU admission was not reported to assess if patients stopped receiving the intervention because patients did not have delirium anymore or if they were discharged from the ICU. The most common monitoring that occurs with haloperidol is QTc monitoring. This study found that the incidence of QT prolongation was less than 2%, and other adverse events were rare.
Currently, there are no strong recommendations for pharmacological treatment of ICU delirium, and this trial does not support adding scheduled IV haloperidol to increase the number of days alive and out of the hospital.
