Delirium is a common acute state of confusion observed in critically ill patients and is associated with adverse short-term and long-term outcomes. Assessing the risk of delirium involves considering both predisposing and precipitating factors. The presence of multiple predisposing factors lowers the threshold for delirium onset, requiring fewer precipitating factors.
Accurate diagnosis is essential for effective delirium management. Using a validated instrument such as the Confusion Assessment Method algorithm is recommended to assess relevant features. Once diagnosed, patients undergo a comprehensive evaluation to identify and address any reversible causes contributing to delirium. Nonpharmacological interventions are the preferred approach for managing behavioral disturbances, reserving medication usage for situations where patient safety is at risk. In such cases, low doses of high-potency antipsychotic agents are often used as the off-label treatment, targeting specific behaviors and discontinuing use as soon as possible.
How would you approach a 65-year-old patient who underwent abdominal surgery developed delirium without agitation on day#4 in the ICU?
0%Continue nonpharmacological interventions
0%Start escalating dosages of haloperidol
0%Start quetiapine and increase as needed
The Evidence
The MIND-USA trial, a randomized, double-blind, placebo-controlled study, included 1183 patients with acute respiratory failure or shock who were randomly assigned to receive placebo, haloperidol, or ziprasidone. Among the participants, 48% developed delirium during the trial, with the majority having hypoactive delirium (89%) and the rest having hyperactive delirium (11%). The median number of days alive without delirium or coma did not significantly differ between the groups (8.5 in placebo, 7.9 in haloperidol, and 8.7 in ziprasidone). There were no significant differences in secondary endpoints or the frequency of extrapyramidal symptoms. The trial's conclusion was that antipsychotics were not effective in treating delirium [1].
Two systematic reviews commissioned by the Agency for Healthcare Research and Quality in 2019, also concluded that antipsychotics did not demonstrate effectiveness in either treatment or prevention of delirium [2-3].
The first systematic review assessed the benefits and harms of using antipsychotics to treat delirium in adult inpatients and was published in 2019. The review included 16 randomized controlled trials and 10 observational studies. The findings indicate that there were no significant differences in sedation status, delirium duration, hospital length of stay, or mortality when comparing haloperidol or second-generation antipsychotics to placebo. Moreover, there were no notable differences in delirium severity and cognitive functioning between haloperidol and second-generation antipsychotics [2].
The second systematic review examined the benefits and harms of using antipsychotics for delirium prevention in adults. The review included 14 studies and found no significant differences in delirium incidence, duration, hospital length of stay, and mortality between haloperidol and placebo. Limited evidence suggested that second-generation antipsychotics may lower delirium incidence in postoperative patients. However, there was insufficient evidence for other outcomes such as cognitive function and delirium severity [3].
Following the 2018 MIND-USA trial, critical care guidelines recommended against the widespread use of antipsychotics for the treatment or prevention of ICU delirium. However, it is worth emphasizing that around 90% of the MIND-USA trial participants had hypoactive delirium without agitation. As a result, these guidelines unintentionally discouraged the use of antipsychotics in agitated patients with delirium, despite limited evidence to support this approach.
The AID-ICU trial was conducted across 16 European ICUs with 1000 patients with delirium and compared the administration of haloperidol (in doses of 2.5 mg, up to 20 mg/day) with a placebo. 45% of patients had hyperactive delirium. The trial reported intriguing results regarding the use of haloperidol in ICU delirium. While there was no significant difference in the number of days alive and out of the hospital at 90 days between the haloperidol and placebo groups, a closer examination revealed a potential reduction in 90-day mortality (7%) in the haloperidol group. However, mortality was not a primary outcome, and further investigation is needed [4].
The AID-ICU trial raises questions and highlights the need for further research to identify the subgroup of ICU patients who may benefit from haloperidol treatment and understand the underlying mechanisms. In the meantime, clinicians should individualize treatment based on patient characteristics, target symptoms (mainly hyperactive delirium), and closely monitor for adverse events while using the lowest effective dose for the shortest duration possible.
Conclusion
Current evidence does not support the routine use of antipsychotic medications for the treatment or prevention of delirium in critically ill patients. The findings from clinical trials highlight the importance of individualized patient management, focusing on nonpharmacological interventions and cautious use of antipsychotics when necessary. Future research is needed to identify specific patient subgroups that may benefit from antipsychotic treatment and to explore the underlying mechanisms of action.
References:
Girard TD, Exline MC, Carson SS, et al. Haloperidol and ziprasidone for treatment of delirium in critical illness. N Engl J Med 2018;379:2506-2516. Link
Nikooie R, Neufeld KJ, Oh ES, et al. Antipsychotics for treating delirium in hospitalized adults: a systematic review. Ann Intern Med 2019;171:485-495. Link
Oh ES, Needham DM, Nikooie R, et al. Antipsychotics for preventing delirium in hospitalized adults: a systematic review. Ann Intern Med 2019;171:474-484. Link
Andersen-Ranberg NC, Poulsen LM, et al. AID-ICU Trial Group. Haloperidol for the Treatment of Delirium in ICU Patients. N Engl J Med. 2022 Dec 29;387(26):2425-2435. doi: 10.1056/NEJMoa2211868. Epub 2022 Oct 26. PMID: 36286254. Link