In this episode, I’ll discuss haloperidol for ICU delirium.
Despite efforts to reduce the incidence of ICU delirium with light sedation techniques, many patients still end up with delirium during their stay in the ICU. Some of these patients develop agitated delirium that requires treatment so the patient does not harm themselves or staff caring for them. Despite no medication clearly demonstrating a reduction in ICU delirium, many studies have been done especially with antipsychotics like haloperidol in an effort to find a protocol that will reduce the duration, incidence, or mortality from ICU delirium.
In December 2022 the AID-ICU trial was published in New England Journal of Medicine. This was a multicenter, blinded, placebo-controlled trial in which adult ICU patients with delirium who had been admitted for an acute condition received IV haloperidol 2.5 mg 3 times daily plus 2.5 mg as needed up to a total maximum daily dose of 20 mg or placebo. The primary outcome was the number of days alive and out of the hospital at 90 days after randomization. 1000 patients were randomized. The authors found that treatment with haloperidol did not lead to a significantly greater number of days alive and out of the hospital at 90 days compared to placebo. Adverse event rates were similar between groups.
In March 2023 a pre-planned, secondary Bayesian analysis of the AID–ICU trial was published in the journal Intensive Care Medicine. This group of authors used adjusted Bayesian linear and logistic regression models to judge the probabilities for any benefit/harm, clinically important benefit/harm, and no clinically important differences with haloperidol treatment. This analysis found that although the 95% confidence interval for the primary outcome of days alive and out of hospital to day 90 was -1.1 to 6.9, there was a 92% probability for any benefit and 82% for clinically important benefit with haloperidol. When the same analysis was applied to mortality as an outcome, there was a 99% probability for any benefit and 94% for clinically important benefit with haloperidol.
In October 2023 the journal Critical Care published a randomized trial looking at the efficacy of haloperidol to decrease the burden of delirium in adult critically ill patients. The authors sought to determine whether haloperidol when compared to placebo in critically ill adults with delirium reduces days with delirium and coma and improves delirium-related sequelae. The trial plan was for patients to be randomized to intravenous haloperidol 2.5 mg or placebo every 8 h, titrated up to 5 mg every 8 h if delirium persisted until ICU discharge or up to 14 days. However after 132 patients were enrolled, the trial data safety and monitoring board recommended the trial be terminated for futility in regards to the primary outcome. Secondary outcome measures were numerically favorable for haloperidol including the need for open-label haloperidol or other antipsychotics, and self-extubation or invasive device removal. However none of these secondary outcomes reached statistical significance. In addition, some of these outcomes are not clinically meaningful as no one would give scheduled haloperidol with the primary purpose being to reduce the need for giving prn haloperidol.
While there continues to be great interest in studying haloperidol and its effects on patients with ICU delirium, these recent studies do not support the use of routine, scheduled IV haloperidol to all ICU delirium patients. Antipsychotics will continue to play an important role in the management of agitated delirium to keep patients from self-extubation or invasive device removal however it seems routine use will need to wait until a successful protocol is published.
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