Published in the journal Lancet Respiratory Medicine. Here is a link to the article.
Regenstrief Institute authors: Babar Khan M.D.
Abstract
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. Mart1, Leanne M. Boehm2, Amy L. Kiehl3, Michelle N. Gong4, Atul Malhotra5, Robert L. Owens5, Babar A. Khan6, Margaret A. Pisani7, Gregory A. Schmidt8, R. Duncan Hite9, Matthew C. Exline10, Shannon S. Carson11, Catherine L. Hough12, Peter Rock13, Ivor S. Douglas14, Daniel J. Feinstein15, Robert C. Hyzy16, William D. Schweickert17, David L. Bowton18, Andrew Masica19, Onur M. Orun20, Rameela Raman20, Brenda T. Pun3, Cayce Strength3, Mark L. Rolfsen21, Pratik P. Pandharipande22, Nathan E. Brummel23, Christopher G. Hughes22, Mayur B. Patel24, Joanna L. Stollings25, E. Wesley Ely1, James C. Jackson1, Timothy D. Girard26
Author 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. Electronic address: timothy.girard@pitt.edu.
