Objective: To demonstrate the feasibility of a placebo-controlled trial of antipsychotics for delirium in the intensive care unit and to test the hypothesis that antipsychotics would improve days alive without delirium or coma.
Design: Randomized, double-blind, placebo-controlled trial.
Setting: Six tertiary care medical centers in the US.
Patients: One hundred one mechanically ventilated medical and surgical intensive care unit patients.
Intervention: Patients were randomly assigned to receive haloperidol or ziprasidone or placebo every 6 hrs for up to 14 days. Twice each day, frequency of study drug administration was adjusted according to delirium status, level of sedation, and side effects.
Measurements and Main Outcomes: The primary end point was the number of days patients were alive without delirium or coma. During the 21-day study period, patients in the haloperidol group spent a similar number days alive without delirium or coma (median [interquartile range], 14.0 [6.0–18.0] days) as did patients in the ziprasidone (15.0 [9.1–18.0] days) and placebo groups (12.5 [1.2–17.2] days; p = 0.66). No differences were found in secondary clinical outcomes, including ventilator-free days (p = .25), hospital length of stay (p = .68), and mortality (p = .81). Ten (29%) patients in the haloperidol group reported symptoms consistent with akathisia, compared with six (20%) patients in the ziprasidone group and seven (19%) patients in the placebo group (p = .60), and a global measure of extrapyramidal symptoms was similar between treatment groups (p = .46).
Conclusions: A randomized, placebo-controlled trial of antipsychotics for delirium in mechanically ventilated intensive care unit patients is feasible. Treatment with antipsychotics in this limited pilot trial did not improve the number of days alive without delirium or coma, nor did it increase adverse outcomes. Thus, a large trial is needed to determine whether use of antipsychotics for intensive care unit delirium is appropriate.
Trial Registration: ClinicalTrials.gov, number NCT00096863.
From Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine (TDG, BTP, GRB, EWE) and Center for Health Services Research (TDG, RSD, EWE), Department of Anesthesiology, Division of Critical Care (PPP), Department of Biostatistics (JLT, AKS), and Department of Psychiatry (HYM), Vanderbilt University School of Medicine, Nashville, TN; Department of Medicine, Division of Pulmonary and Critical Care Medicine (SSC), University of North Carolina, Chapel Hill, NC; Department of Internal Medicine, Division of Pulmonary Diseases, Critical Care, and Occupational Medicine (GAS), University of Iowa Carver College of Medicine, Iowa City, IA; Moses H. Cone Memorial Hospital (PEW), Greensboro, NC; Department of Medicine (AEC), Saint Thomas Hospital, Nashville, TN; Geriatric Research, Education, and Clinical Center Service (TDG, RSD, EWE) and Anesthesia Service (PPP), Department of Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, TN.
This investigator-initiated study was aided by receipt of study drug from Pfizer, Inc., who had no role in the design or conduct of the trial; in the collection, analysis, or interpretation of the data; or in the preparation, review, approval, or publication strategy of this manuscript. Dr Girard received support from the National Institutes of Health (HL007123), the Hartford Geriatrics Health Outcomes Research Scholars Award Program, the Vanderbilt Physician Scientist Development Program, and the VA Tennessee Valley Geriatric Research, Education and Clinical Center (GRECC). Dr Pandharipande received support from the VA Clinical Science Research and Development Service (VA Career Development Award), the ASCCA-FAER-Abbott Physician Scientist Award, and the Vanderbilt Physician Scientist Development Program. Dr Ely received support from the VA Clinical Science Research and Development Service (VA Merit Review Award), the VA Tennessee Valley GRECC, and the National Institutes of Health (AG027472).
Mind Trial Investigators: From Vanderbilt University School of Medicine, Nashville, TN: Timothy D. Girard, MD, MSCI, Pratik P. Pandharipande, MD, MSCI, Brenda T. Pun, MSN, Bryan Cotton, MD, Russell R. Miller, MD, MPH, Jennifer L. Thompson, MPH, Ayumi K. Shintani, PhD, MPH, Herbert Y. Meltzer, MD, Paul W. Ragan, MD, Sharlet Anderson, MS, Joyce Okahashi, RN, Gordon R. Bernard, MD, Robert S Dittus, MD, MPH, and E. Wesley Ely, MD, MPH. From University of North Carolina, Chapel Hill, NC: Shannon S. Carson, MD, Peter Rock, MD, Lydia H. Chang, MD, and Kayvon Salimi, MD. From University of Iowa Carver College of Medicine, Iowa City, IA: Gregory A. Schmidt, MD. From Moses H. Cone Memorial Hospital, Greensboro, NC: Patrick E. Wright, MD. From Saint Thomas Hospital, Nashville, TN: Angelo E. Canonico, MD. From Department of Veterans Affairs Medical Center, TN Valley Healthcare System, Nashville, TN: Timothy D. Girard, MD, MSCI, Pratik P. Pandharipande, MD, MSCI, Bryan A. Cotton, MD, Robert S. Dittus, MD, MPH, and E. Wesley Ely, MD, MPH.
Dr. Girard has stock ownership in Pfizer, Inc. Dr. Meltzer has received grant support from Abbott, ACADIA, Dainippon Sumitomo, Eli Lilly, Janssen, Minster, Pfizer, Roche, Solvay. He has also consulted for Astellas, Lundbeck, and Wyeth. Dr. Dittus has received grant support from Pfizer. Dr. Pandharipande has received honoraria and grant support from Hospira, Inc. Dr. Pun has received honoraria from Hospira, Inc. Dr. Ely has received honoraria and grant support from Pfizer, Lilly, Hospira, and Aspect. The remaining authors have not disclosed any potential conflicts of interest.
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