• Timothy D Girard, Matthew C Exline, Shannon S Carson, Catherine L Hough, Peter Rock, Michelle N Gong, Ivor S Douglas, Atul Malhotra, Robert L Owens, Daniel J Feinstein, Babar Khan, Margaret A Pisani, Robert C Hyzy, Gregory A Schmidt, William D Schweickert, R Duncan Hite, David L Bowton, Andrew L Masica, Jennifer L Thompson, Rameela Chandrasekhar, Brenda T Pun, Cayce Strength, Leanne M Boehm, James C Jackson, Pratik P Pandharipande, Nathan E Brummel, Christopher G Hughes, Mayur B Patel, Joanna L Stollings, Gordon R Bernard, Robert S Dittus, E Wesley Ely, and MIND-USA Investigators.
• From the Clinical Research, Investigation, and Systems Modeling of Acute Illness Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh (T.D.G.); the Pulmonary, Critical Care, and Sleep Medicine Division, Department of Medicine, Ohio State University Wexner Medical Center, Columbus (M.C.E.), and the Department of Critical Care Medicine, Respiratory Institute, Cleveland Clinic Foundation, Cleveland (R.D.H.) - both in Ohio; the Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill (S.S.C.), the Section on Critical Care, Department of Anesthesiology, Wake Forest Baptist Health, Winston-Salem (D.L.B.), and Cone Health System, Greensboro (D.J.F.) - all in North Carolina; the Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington School of Medicine, Seattle (C.L.H.); the Department of Anesthesiology, University of Maryland School of Medicine, Baltimore (P.R.); the Division of Critical Care Medicine, Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, New York (M.N.G.); the Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, Denver Health Medical Center, Denver (I.S.D.); the Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of California at San Diego, San Diego (A.M., R.L.O.); the Division of Pulmonary, Critical Care, Sleep, and Occupational Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis (B.K.); the Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale University School of Medicine, New Haven, CT (M.A.P.); the Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor (R.C.H.); the Division of Pulmonary, Critical Care, and Occupational Medicine, Department of Medicine, University of Iowa Hospitals and Clinics, Iowa City (G.A.S.); , and the Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia (W.D.S.); the Center for Clinical Effectiveness, Baylor Scott and White Health, Dallas (A.L.M.); and the Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center (J.L.T., R.C., B.T.P., C.S., L.M.B., J.C.J., P.P.P., N.E.B., C.G.H., M.B.P., J.L.S., G.R.B., R.S.D., E.W.E.), the Center for Health Services Research (R.C., J.C.J., C.S., N.E.B., R.S.D., E.W.E.), the Center for Quality Aging (N.E.B., E.W.E.), the Division of Allergy, Pulmonary, and Critical Care Medicine (J.C.J., C.S., N.E.B., G.R.B., E.W.E.), the Division of General Internal Medicine and Public Health (R.S.D.), Department of Medicine, the Department of Biostatistics (J.L.T., R.C.), the Department of Psychiatry (J.C.J.), the Division of Anesthesiology Critical Care Medicine, Department of Anesthesiology (P.P.P., C.G.H.), the Division of Trauma and Surgical Critical Care, Department of Surgery (M.B.P.), and the Department of Pharmaceutical Services (J.L.S.), Vanderbilt University School of Medicine, Vanderbilt University School of Nursing (L.M.B.), and the Anesthesia Service (P.P.P., C.G.H.), Research Service (J.C.J.), Surgical Service (M.B.P.), and Geriatric Research, Education, and Clinical Center Service (R.S.D., E.W.E.), Department of Veterans Affairs Medical Center, Tennessee Valley Healthcare System - all in Nashville.
• N. Engl. J. Med. 2018 Dec 27; 379 (26): 2506-2516.

BackgroundThere are conflicting data on the effects of antipsychotic medications on delirium in patients in the intensive care unit (ICU).MethodsIn a randomized, double-blind, placebo-controlled trial, we assigned patients with acute respiratory failure or shock and hypoactive or hyperactive delirium to receive intravenous boluses of haloperidol (maximum dose, 20 mg daily), ziprasidone (maximum dose, 40 mg daily), or placebo. The volume and dose of a trial drug or placebo was halved or doubled at 12-hour intervals on the basis of the presence or absence of delirium, as detected with the use of the Confusion Assessment Method for the ICU, and of side effects of the intervention. The primary end point was the number of days alive without delirium or coma during the 14-day intervention period. Secondary end points included 30-day and 90-day survival, time to freedom from mechanical ventilation, and time to ICU and hospital discharge. Safety end points included extrapyramidal symptoms and excessive sedation.ResultsWritten informed consent was obtained from 1183 patients or their authorized representatives. Delirium developed in 566 patients (48%), of whom 89% had hypoactive delirium and 11% had hyperactive delirium. Of the 566 patients, 184 were randomly assigned to receive placebo, 192 to receive haloperidol, and 190 to receive ziprasidone. The median duration of exposure to a trial drug or placebo was 4 days (interquartile range, 3 to 7). The median number of days alive without delirium or coma was 8.5 (95% confidence interval [CI], 5.6 to 9.9) in the placebo group, 7.9 (95% CI, 4.4 to 9.6) in the haloperidol group, and 8.7 (95% CI, 5.9 to 10.0) in the ziprasidone group (P=0.26 for overall effect across trial groups). The use of haloperidol or ziprasidone, as compared with placebo, had no significant effect on the primary end point (odds ratios, 0.88 [95% CI, 0.64 to 1.21] and 1.04 [95% CI, 0.73 to 1.48], respectively). There were no significant between-group differences with respect to the secondary end points or the frequency of extrapyramidal symptoms.ConclusionsThe use of haloperidol or ziprasidone, as compared with placebo, in patients with acute respiratory failure or shock and hypoactive or hyperactive delirium in the ICU did not significantly alter the duration of delirium. (Funded by the National Institutes of Health and the VA Geriatric Research Education and Clinical Center; MIND-USA ClinicalTrials.gov number, NCT01211522 .).

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