MIND-USA: Antipsychotics for Delirium in Critical Illness (2018)

“Among patients in the ICU with acute respiratory failure or shock and hypoactive or hyperactive delirium, treatment with haloperidol or ziprasidone, compared with placebo, did not significantly alter the duration of delirium.”

— The MIND-USA Investigators

1. Publication Details

  • Trial Title: Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness
  • Citation: Girard TD, Exline MC, Carson SS, et al. Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness. N Engl J Med. 2018;379(26):2506-2516. DOI: 10.1056/NEJMoa1808217
  • Published: December 27, 2018, in The New England Journal of Medicine
  • Author: Timothy D. Girard, M.D., M.S.C.I.
  • Funding: The National Heart, Lung, and Blood Institute (NHLBI).

2. Keywords

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

3. The Clinical Question

In critically ill adult patients with delirium (Population), does treatment with an antipsychotic (haloperidol or ziprasidone) (Intervention) compared to placebo (Comparison) reduce the duration of delirium (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Delirium is a common and serious form of organ dysfunction in the ICU, associated with prolonged hospitalization, long-term cognitive impairment, and increased mortality. Antipsychotic medications, particularly haloperidol, have been widely used for decades to treat delirium, despite a lack of high-quality evidence supporting their efficacy for this indication.
  • Knowledge Gap: A large, definitive, placebo-controlled trial was urgently needed to determine if antipsychotics have any beneficial effect on the duration of delirium and other patient-centered outcomes in a broad population of critically ill patients.
  • Proposed Hypothesis: The authors hypothesized that treatment with either haloperidol or ziprasidone would be superior to placebo in increasing the number of days alive without delirium or coma.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: 16 medical and surgical ICUs in the United States.
  • Trial Period: Enrollment ran from February 2012 to May 2016.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with acute respiratory failure or shock who had delirium, as assessed by the Confusion Assessment Method for the ICU (CAM-ICU).
    • Exclusion Criteria: Included known allergy to the study drugs, prolonged QTc interval, and pregnancy.
  • Intervention: Patients were randomized to one of three groups:
    • Haloperidol: Intravenous haloperidol.
    • Ziprasidone: Intravenous ziprasidone.
    • Placebo: Intravenous 0.9% saline.
  • Control: The placebo group served as the control.
  • Management Common to Both Groups: All patients were managed with standard ICU care, including non-pharmacologic delirium prevention and management strategies (the ABCDEF bundle).
  • Power and Sample Size: The authors calculated that a sample size of 1183 patients would provide 90% power to detect a 1.5-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 without delirium or coma during the 14-day study period.
    • Secondary Outcomes: Included 30-day and 90-day mortality, duration of mechanical ventilation, and length of ICU and hospital stay.

6. Key Results

  • Enrollment and Baseline: 566 patients were randomized (192 to haloperidol, 190 to ziprasidone, and 184 to placebo). The groups were well-matched at baseline.
  • Trial Status: The trial was stopped early for futility by the data and safety monitoring board after an interim analysis showed a very low probability of finding a significant benefit with either antipsychotic.
  • Primary Outcome: There was no significant difference in the primary outcome. The median number of days alive without delirium or coma was 8.5 in the haloperidol group, 8.7 in the ziprasidone group, and 8.5 in the placebo group.
  • Secondary Outcomes: There were no significant differences between the groups in 30-day or 90-day mortality, duration of ventilation, or length of stay.
  • Adverse Events: The incidence of extrapyramidal symptoms was low but more frequent in the antipsychotic groups. There was no significant difference in the incidence of QTc prolongation.

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 proportional-odds logistic regression model.
  • Primary Outcome Analysis: The primary outcome was a comparison of the distribution of days alive without delirium or coma among the three groups.
  • Key Statistic(s) Reported: The key statistics were the median values for the primary outcome and the odds ratios for the effect of each drug compared to placebo.
  • Interpretation of Key Statistic(s):
    • Odds Ratio (OR):
      • Formula: Conceptually, OR = (Odds of a better outcome in Intervention Group) / (Odds of a better outcome in Control Group).
      • Calculation: The adjusted OR for a better outcome (more delirium/coma-free days) was 0.99 for haloperidol vs. placebo and 1.05 for ziprasidone vs. placebo.
      • Clinical Meaning: An OR of approximately 1.0 for both drugs indicates that there was no difference in the odds of having a better outcome compared to placebo.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.74 to 1.33 for haloperidol and 0.78 to 1.41 for ziprasidone.
      • Clinical Meaning: Since both confidence intervals broadly cross 1.0, it confirms that there is no statistically significant difference between the antipsychotics and placebo. The results are consistent with chance.
    • P-value:
      • Calculation: The p-values for the comparisons were not reported but are >0.05.
      • Clinical Meaning: A p-value greater than 0.05 indicates that the observed lack of difference is not statistically significant. This aligns with the findings from the confidence intervals.
  • 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 multicenter, randomized, double-blind, placebo-controlled design is the gold standard for minimizing bias and provided high-quality evidence.
  • Generalizability: The pragmatic design and inclusion of a broad population of medical and surgical ICU patients make the findings highly generalizable.
  • Statistical Power: Although stopped early, the trial was large enough to confidently rule out a major benefit from the interventions.
  • Patient-Centered Outcomes: The primary outcome of delirium-free and coma-free days is a robust and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a low risk of bias.
  • External Validity (Generalizability): The findings are highly generalizable to the broad population of ICU patients with delirium.
  • Other: The trial was stopped early for futility, which means it was underpowered to definitively rule out a very small treatment effect.

10. Conclusion of the Authors

The authors concluded that in critically ill patients with delirium, treatment with haloperidol or ziprasidone did not significantly alter the duration of delirium.

11. To Summarize

  • Impact on Current Practice: This was a landmark “negative” trial that provided strong evidence to refute the long-standing and widespread practice of using antipsychotics to treat the core symptoms of delirium in the ICU.
  • Specific Recommendations:
    • Patient Selection: For adult ICU patients with hypoactive or hyperactive delirium.
    • Actionable Intervention: Do not administer antipsychotics (haloperidol or ziprasidone) with the expectation of reducing the duration of delirium.
  • What This Trial Does NOT Mean: This trial does NOT mean that antipsychotics have no role in the ICU. Its findings are specific to the treatment of delirium itself and do not apply to their potential use for managing severe agitation or psychosis where the patient is a danger to themselves or others.
  • 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 MIND-USA trial (2018) was designed to provide a definitive answer to a question that had been based on decades of dogma and weak evidence.
  • Influence on Subsequent Research: The definitive neutral result of this trial, along with the subsequent AID-ICU trial (2022) which also found no benefit for haloperidol, has been highly influential in shaping international guidelines, which now recommend against the routine use of antipsychotics for the treatment of delirium.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial definitively answered its primary question with a clear neutral result.
  • 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 multicenter, double-blind RCT design was of high quality. The patient population was representative of a general ICU population with delirium, and the primary outcome was patient-centered.
  • Results: The study reported a clear neutral finding for its primary outcome, with virtually identical outcomes in all three groups. This provides strong evidence against a meaningful clinical benefit of antipsychotics for treating delirium.
  • 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. This is a classic example of a high-quality “negative” trial that was profoundly practice-changing by providing strong evidence to stop a common but ineffective therapy.

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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