AID-ICU: Haloperidol for Delirium in ICU Patients (2018)

“Haloperidol had no significant effect on the number of days alive and out of the hospital at 90 days. We found no evidence of a beneficial effect of haloperidol on delirium.”

  • The AID-ICU Trial Investigators

1. Publication Details

  • Trial Title: Haloperidol for the Treatment of Delirium in ICU Patients
  • Citation: Andersen-Ranberg NC, Poulsen LM, Perner A, et al. Haloperidol for the Treatment of Delirium in ICU Patients. N Engl J Med. 2022;387(26):2425-2435. DOI: 10.1056/NEJMoa2211488
  • Published: December 29, 2022, in The New England Journal of Medicine
  • Author: Nina C. Andersen-Ranberg, M.D.
  • Funding: The Novo Nordisk Foundation and others.

2. Keywords

  • Delirium, ICU, Critical Care, Haloperidol, Antipsychotics, Randomized Controlled Trial

3. The Clinical Question

  • In adult ICU patients with delirium (Population), does treatment with intravenous haloperidol (Intervention) compared to placebo (Comparison) increase the number of days alive and out of the hospital at 90 days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Delirium is a common and serious form of organ dysfunction in critically ill patients, associated with prolonged hospitalization, long-term cognitive impairment, and increased mortality. Haloperidol has been widely used off-label for decades to treat delirium in the ICU, despite a lack of high-quality evidence supporting its efficacy.
  • Knowledge Gap: There was a critical need for a large, well-designed, placebo-controlled trial to definitively determine if haloperidol has any beneficial effect on patient-centered outcomes in ICU patients with delirium.
  • Proposed Hypothesis: The authors hypothesized that treatment with haloperidol would increase the number of days alive and out of the hospital at 90 days compared to placebo.

5. Study Design and Methods

  • Design: A multicenter, stratified, parallel-group, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: 18 intensive care units (ICUs) in Denmark, Finland, Italy, Spain, and the United Kingdom.
  • Trial Period: Enrollment ran from June 2018 to February 2022.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) admitted to the ICU who had delirium, as assessed by the Confusion Assessment Method for the ICU (CAM-ICU) or the Intensive Care Delirium Screening Checklist (ICDSC).
    • Exclusion Criteria: Included known allergy to haloperidol, prolonged QTc interval, and pregnancy.
  • Intervention: Patients received intravenous haloperidol 2.5 mg three times daily, with an additional 2.5 mg as needed, up to a maximum daily dose of 20 mg.
  • Control: Patients received a matching intravenous placebo (0.9% saline) on the same schedule.
  • Management Common to Both Groups: All patients were managed with standard ICU care, including non-pharmacologic delirium prevention and management strategies (the ABCDEF bundle) and other supportive care.
  • Power and Sample Size: The authors calculated that a sample size of 1000 patients would provide 90% power to detect a 3-day difference in the primary outcome. (Power is a study’s ability to find a real difference between treatments if one truly exists; 90% power means the study had a 90% chance of detecting the specified effect, which is considered very high).
  • Outcomes:
    • Primary Outcome: The number of days alive and out of the hospital at 90 days after randomization.
    • Secondary Outcomes: Included mortality at 90 days, days with delirium or coma, and serious adverse events.

6. Key Results

  • Enrollment and Baseline: 1000 patients were randomized (510 to haloperidol and 490 to placebo). The baseline characteristics were well-matched between the groups.
  • Trial Status: The trial was stopped for futility by the data and safety monitoring board after the second planned interim analysis, as it was highly unlikely that a benefit would be found.
  • Primary Outcome: There was no significant difference in the primary outcome. The mean number of days alive and out of the hospital was 35.8 in the haloperidol group and 32.9 in the placebo group (mean difference, 2.9 days; 95% CI, -0.9 to 6.8; p=0.13).
  • Secondary Outcomes: There were no significant differences between the groups in 90-day mortality or in the number of days spent with delirium or in a coma.
  • Adverse Events: There was no significant difference in the incidence of serious adverse events between the two groups.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a linear regression model.
  • Primary Outcome Analysis: The primary outcome was a comparison of the mean number of days alive and out of the hospital between the two groups.
  • Key Statistic(s) Reported: Adjusted mean difference: 2.9 days (95% CI, -0.9 to 6.8; P-value: 0.13).
  • Interpretation of Key Statistic(s):
    • Mean Difference:
      • Calculation: The paper reports the adjusted mean difference as 2.9 days.
      • Clinical Meaning: A mean difference of 2.9 days in favor of haloperidol was observed, but this was not statistically significant.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was -0.9 to 6.8 days.
      • Clinical Meaning: Since this range crosses the line of no effect (0), it confirms that the result is not statistically significant. Clinically, this means the true effect could range from a small harm (0.9 fewer days) to a moderate benefit (6.8 more days).
    • P-value: The p-value of 0.13 is higher than the 0.05 threshold, indicating the result is not statistically significant and likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the trial was neutral, ARR and NNT are not applicable.
  • Subgroup Analyses: No significant differences were found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The large, multicenter, randomized, double-blind, placebo-controlled design is the gold standard for minimizing bias.
  • Generalizability: The inclusion of 18 diverse ICUs across several countries increases the external validity of the findings.
  • Statistical Power: The study was large and adequately powered to detect a clinically meaningful difference.
  • Patient-Centered Outcomes: The primary outcome of days alive and out of the hospital is a robust and patient-centered composite outcome.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a very low risk of bias.
  • External Validity (Generalizability): The study investigated haloperidol for the treatment of established delirium; the results do not apply to its use for prevention or for the management of severe agitation.
  • Other: The trial was stopped early for futility, which is an appropriate reason but means the study did not complete its full planned enrollment.

10. Conclusion of the Authors

  • Treatment with haloperidol did not significantly increase the number of days alive and out of the hospital at 90 days as compared with placebo.

11. To Summarize

  • Impact on Current Practice: This high-quality trial provides strong evidence that refutes the long-standing practice of using haloperidol to treat delirium in the ICU. It supports the de-adoption of this common practice.
  • Specific Recommendations:
    • Patient Selection: For adult ICU patients with delirium.
    • Actionable Intervention: Do not administer haloperidol with the expectation of reducing the duration of delirium or improving major clinical outcomes.
  • What This Trial Does NOT Mean: This trial does NOT mean that haloperidol has no role in the ICU. Its findings are specific to the treatment of delirium itself and do not apply to its potential use for managing severe agitation or as a sedative.
  • Implementation Caveats: The findings of this trial reinforce that the primary management strategy for ICU delirium should be non-pharmacologic, focusing on the ABCDEF bundle (e.g., pain management, early mobility, sleep promotion).

12. Context and Related Studies

  • Building on Previous Evidence: The AID-ICU trial (2022) was designed to provide a definitive answer to a question that had been explored in many smaller, less conclusive studies, such as the MIND-USA trial (2018), which also found no benefit for haloperidol.
  • Influence on Subsequent Research: This trial, along with others, provides a clear and consistent message that antipsychotics are not effective for treating the core symptoms of ICU delirium.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial definitively answered its primary question regarding the efficacy of haloperidol for delirium.
  • Future Directions: Research in ICU delirium has largely shifted away from antipsychotics and is now focused on prevention strategies, the long-term cognitive outcomes of delirium, and the potential role of other novel pharmacologic agents.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a very common and important clinical problem for which the existing standard of care was not evidence-based.
  • Methods: The study design was of the highest quality (large, multicenter, double-blind RCT), providing a very low risk of bias. The patient population was appropriate, and the primary outcome was patient-centered.
  • Results: The study reported a clear neutral finding for its primary outcome, with a confidence interval that crossed the line of no effect. The lack of benefit was consistent across all major secondary outcomes.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The high external validity of this pragmatic trial means its findings are broadly applicable to the care of general ICU patients with delirium.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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