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Design and Participants: This prespecified, long-term follow-up to the randomized, double-blind, placebo-controlled phase 3 MIND-USA Study (16 hospitals) investigated the effects of antipsychotic treatment of delirious, critically ill patients on long-term outcomes. Adults who had been admitted to intensive care units (ICUs) between 2011 and 2017 with respiratory failure or septic or cardiogenic shock were eligible if they had delirium. Participants were randomized—using a computer-generated, permuted-block randomization scheme with stratification by site and age—to receive (1:1:1) intravenous placebo, haloperidol, or ziprasidone for up to 14 days. Dosages were age-stratified (lower for age >70 yrs [haloperidol 1.25-2.5 mg; ziprasidone 2.5-5 mg]). Investigators and participants were masked to assignment. Validated telephone-administered tests and questionnaires assessed survivors’ cognitive, functional, psychological, quality-of-life, and employment outcomes at 3- and 12-months post-randomization. Analyses (intention to treat) included multivariable logistic regression.
Results: Participants (N=566) were aged median 58 years (IQR=49-65); 58% male; and 81% White, 15% Black, and 4% other. One-year survival and follow-up rates were similar between groups, and a third of each group was cognitively impaired at both 3-month and 12-month follow-ups. More than 50% of survivors in each group had cognitive and/or physical limitations that precluded employment at both follow-ups. At both follow-ups, neither haloperidol (adjusted odds ratio 1.2 [95% CI=0.73-2.0] at 3 months and 1.1 [0.60-2.1] at 12 months) nor ziprasidone (1.1 [0.59-2.0] at 3 months and 0.94 [0.62-1.4] at 12 months) altered cognitive outcomes. Also, no evidence was found that functional, psychological, quality of life, or employment outcomes improved with haloperidol or ziprasidone.
Commentary: This large, well-designed trial reminds clinicians managing patients in the ICU that delirium is incredibly common and associated with numerous negative consequences: increased mortality (35%-41% of patients died within 3 months), cognitive impairments (29%-33%), and inability to be employed (>80%) at 12 months. Unfortunately, use of a first-generation(haloperidol) or second-generation (ziprasidone) antipsychotic failed to mitigate negative long-term outcomes of delirium. Notably, long-term outcomes for patients treated with haloperidol were not worsened compared to placebo, which contradicts other studies that showed signals for concern for haloperidol for delirium. Clinicians should counsel caregivers that patients with ICU delirium are likely to experience persistent changes to cognition, function, and quality of life.
Bottom Line: Neither haloperidol nor ziprasidone demonstrated improved long-term clinical outcomes for patients with ICU-associated delirium, nor were they associated with worsened outcomes compared to placebo.
Reviewer: Mary K. Buss, MD MPH, UConn Health, Farmington, CT
References:
1. Wilson JE, Mart MF, Cunningham C, et al. Delirium. Nat Rev Dis Primers. 2020;6:90.
2. Shehabi Y, Riker RR, Bokesch PM, Wisemandle W, Shintani A, Ely EW. Delirium duration and mortality in lightly sedated, mechanically ventilated intensive care patients. Crit Care Med. 2010;38:2311-2318.
3. Girard TD, Jackson JC, Pandharipande PP, et al. Delirium as a predictor of long-term cognitive impairment in survivors of critical illness. Crit Care Med. 2010;38:1513-1520.
Source: Mart MF, Boehm LM, Kiehl AL, et al. Long-term outcomes after treatment of delirium during critical illness with antipsychotics (MIND-USA): a randomised, placebo-controlled, phase 3 trial. Lancet Respir Med. 2024;12(8):599-607. doi:10.1016/S2213-2600(24)00077-8.
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