Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: The MIND randomized, placebo-controlled trial

Timothy D. Girard; Pratik P. Pandharipande; Shannon S. Carson; Gregory A. Schmidt; Patrick E. Wright; Angelo E. Canonico; Brenda T. Pun; Jennifer L. Thompson; Ayumi K. Shintani; Herbert Y. Meltzer; Gordon R. Bernard; Robert S. Dittus; E. Wesley Ely

doi:10.1097/CCM.0b013e3181c58715

Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: The MIND randomized, placebo-controlled trial

Timothy D. Girard, Pratik P. Pandharipande, Shannon S. Carson, Gregory A. Schmidt, Patrick E. Wright, Angelo E. Canonico, Brenda T. Pun, Jennifer L. Thompson, Ayumi K. Shintani, Herbert Y. Meltzer, Gordon R. Bernard, Robert S. Dittus, E. Wesley Ely

Psychiatry and Behavioral Sciences

Research output: Contribution to journal › Article › peer-review

379 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	428-437
Number of pages	10
Journal	Critical care medicine
Volume	38
Issue number	2
DOIs	https://doi.org/10.1097/CCM.0b013e3181c58715
State	Published - Feb 2010

Funding

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 ).

Keywords

Antipsychotic agents
Clinical trial
Delirium
Haloperidol
Intensive care units
Ziprasidone

ASJC Scopus subject areas

Critical Care and Intensive Care Medicine

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10.1097/CCM.0b013e3181c58715

Cite this

Girard, T. D., Pandharipande, P. P., Carson, S. S., Schmidt, G. A., Wright, P. E., Canonico, A. E., Pun, B. T., Thompson, J. L., Shintani, A. K., Meltzer, H. Y., Bernard, G. R., Dittus, R. S., & Ely, E. W. (2010). Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: The MIND randomized, placebo-controlled trial. Critical care medicine, 38(2), 428-437. https://doi.org/10.1097/CCM.0b013e3181c58715

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title = "Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: The MIND randomized, placebo-controlled trial",

abstract = "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.",

keywords = "Antipsychotic agents, Clinical trial, Delirium, Haloperidol, Intensive care units, Ziprasidone",

author = "Girard, {Timothy D.} and Pandharipande, {Pratik P.} and Carson, {Shannon S.} and Schmidt, {Gregory A.} and Wright, {Patrick E.} and Canonico, {Angelo E.} and Pun, {Brenda T.} and Thompson, {Jennifer L.} and Shintani, {Ayumi K.} and Meltzer, {Herbert Y.} and Bernard, {Gordon R.} and Dittus, {Robert S.} and Ely, {E. Wesley}",

note = "Funding Information: 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 ). ",

year = "2010",

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doi = "10.1097/CCM.0b013e3181c58715",

language = "English (US)",

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Girard, TD, Pandharipande, PP, Carson, SS, Schmidt, GA, Wright, PE, Canonico, AE, Pun, BT, Thompson, JL, Shintani, AK, Meltzer, HY, Bernard, GR, Dittus, RS & Ely, EW 2010, 'Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: The MIND randomized, placebo-controlled trial', Critical care medicine, vol. 38, no. 2, pp. 428-437. https://doi.org/10.1097/CCM.0b013e3181c58715

TY - JOUR

T1 - Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium

T2 - The MIND randomized, placebo-controlled trial

AU - Girard, Timothy D.

AU - Pandharipande, Pratik P.

AU - Carson, Shannon S.

AU - Schmidt, Gregory A.

AU - Wright, Patrick E.

AU - Canonico, Angelo E.

AU - Pun, Brenda T.

AU - Thompson, Jennifer L.

AU - Shintani, Ayumi K.

AU - Meltzer, Herbert Y.

AU - Bernard, Gordon R.

AU - Dittus, Robert S.

AU - Ely, E. Wesley

N1 - Funding Information: 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 ).

PY - 2010/2

Y1 - 2010/2

N2 - 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.

AB - 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.

KW - Antipsychotic agents

KW - Clinical trial

KW - Delirium

KW - Haloperidol

KW - Intensive care units

KW - Ziprasidone

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Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: The MIND randomized, placebo-controlled trial

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