Long-term outcomes after treatment of delirium during critical illness with antipsychotics (MIND-USA): a randomised, placebo-controlled, phase 3 trial

Background: Delirium is common during critical illness and is associated with long-term cognitive impairment and disability. Antipsychotics are frequently used to treat delirium, but their effects on long-term outcomes are unknown. We aimed to investigate the effects of antipsychotic treatment of delirious, critically ill patients on long-term cognitive, functional, psychological, and quality-of-life outcomes.

Methods: This prespecified, long-term follow-up to the randomised, double-blind, placebo-controlled phase 3 MIND-USA Study was conducted in 16 hospitals throughout the USA. Adults (aged ≥18 years) who had been admitted to an intensive care unit with respiratory failure or septic or cardiogenic shock were eligible for inclusion in the study if they had delirium. Participants were randomly assigned-using a computer-generated, permuted-block randomisation scheme with stratification by trial site and age-in a 1:1:1 ratio to receive intravenous placebo, haloperidol, or ziprasidone for up to 14 days. Investigators and participants were masked to treatment group assignment. 3 months and 12 months after randomisation, we assessed survivors’ cognitive, functional, psychological, quality-of-life, and employment outcomes using validated telephone-administered tests and questionnaires. This trial was registered with ClinicalTrials.gov, NCT01211522, and is complete.

Findings: Between Dec 7, 2011, and Aug 12, 2017, we screened 20 914 individuals, of whom 566 were eligible and consented or had consent provided to participate. Of these 566 patients, 184 were assigned to the placebo group, 192 to the haloperidol group, and 190 to the ziprasidone group. 1-year survival and follow-up rates were similar between groups. Cognitive impairment was common in all three treatment groups, with a third of survivors impaired at both 3-month and 12-month follow-up in all groups. More than half of the surveyed survivors in each group had cognitive or physical limitations (or both) that precluded employment at both 3-month and 12-month follow-up. At both 3 months and 12 months, neither haloperidol (adjusted odds ratio 1·22 [95% CI 0·73-2.04] at 3 months and 1·12 [0·60-2·11] at 12 months) nor ziprasidone (1·07 [0·59-1·96] at 3 months and 0·94 [0·62-1·44] at 12 months) significantly altered cognitive outcomes, as measured by the Telephone Interview for Cognitive Status T score, compared with placebo. We also found no evidence that functional, psychological, quality-of-life, or employment outcomes improved with haloperidol or ziprasidone compared with placebo.

Interpretation: In delirious, critically ill patients, neither haloperidol nor ziprasidone had a significant effect on cognitive, functional, psychological, or quality-of-life outcomes among survivors. Our findings, along with insufficient evidence of short-term benefit and frequent inappropriate continuation of antipsychotics at hospital discharge, indicate that antipsychotics should not be used routinely to treat delirium in critically ill adults.

Funding: National Institutes of Health and the US Department of Veterans Affairs.

Authors: 

Matthew F Mart ¹, Leanne M Boehm ², Amy L Kiehl ³, Michelle N Gong ⁴, Atul Malhotra ⁵, Robert L Owens ⁵, Babar A Khan ⁶, Margaret A Pisani ⁷, Gregory A Schmidt ⁸, R Duncan Hite ⁹, Matthew C Exline ¹⁰, Shannon S Carson ¹¹, Catherine L Hough ¹², Peter Rock ¹³, Ivor S Douglas ¹⁴, Daniel J Feinstein ¹⁵, Robert C Hyzy ¹⁶, William D Schweickert ¹⁷, David L Bowton ¹⁸, Andrew Masica ¹⁹, Onur M Orun ²⁰, Rameela Raman ²⁰, Brenda T Pun ³, Cayce Strength ³, Mark L Rolfsen ²¹, Pratik P Pandharipande ²², Nathan E Brummel ²³, Christopher G Hughes ²², Mayur B Patel ²⁴, Joanna L Stollings ²⁵, E Wesley Ely ¹, James C Jackson ¹, Timothy D Girard ²⁶

Affiliations

¹Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center, Nashville, TN, USA; Veterans Affairs Tennessee Valley Health System Geriatric Research, Education, and Clinical Center (GRECC), Nashville, TN, USA.

²Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center, Nashville, TN, USA; Veterans Affairs Tennessee Valley Health System Geriatric Research, Education, and Clinical Center (GRECC), Nashville, TN, USA; Vanderbilt University School of Nursing, Nashville, TN, USA.

³Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center, Nashville, TN, USA.

⁴Division of Critical Care Medicine, Division of Pulmonary Medicine, Department of Medicine, Montefiore Healthcare System/Albert Einstein College of Medicine, New York, NY, USA.

⁵Division of Pulmonary, Critical Care and Sleep Medicine, University of California San Diego, La Jolla, CA, USA.

⁶Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.

⁷Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Yale University School of Medicine, New Haven, CT, USA.

⁸Division of Pulmonary, Critical Care and Occupational Medicine, University of Iowa, Iowa City, IA, USA.

⁹Division of Pulmonary Disease and Critical Care Medicine, Department of Medicine, University of Cincinnati, Cincinnati, OH, USA.

¹⁰Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University College of Medicine, Columbus, OH, USA.

¹¹Division of Pulmonary Diseases and Critical Care Medicine, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA.

¹²Division of Pulmonary and Critical Care Medicine, Department of Medicine, Oregon Health and Science University School of Medicine, Portland, OR, USA.

¹³Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA.

¹⁴Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.

¹⁵Novant Healthcare, Winston-Salem, NC, USA.

¹⁶Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.

¹⁷Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.

¹⁸Department of Anesthesiology, Section on Critical Care, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

¹⁹Texas Health Resources, Arlington, TX, USA.

²⁰Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA; Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center, Nashville, TN, USA.

²¹Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center, Nashville, TN, USA.

²²Division of Anesthesiology Critical Care Medicine, Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA; Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center, Nashville, TN, USA.

²³Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center, Nashville, TN, USA; Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University College of Medicine, Columbus, OH, USA.

²⁴Section of Surgical Sciences, Division of Acute Care Surgery, Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA; Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center, Nashville, TN, USA.

²⁵Department of Pharmaceutical Services, Vanderbilt University Medical Center, Nashville, TN, USA; Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center, Nashville, TN, USA.

²⁶Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center, Nashville, TN, USA; Center for Research, Investigation, and Systems Modeling of Acute Illness (CRISMA), Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.