Haloperidol and ziprasidone for treatment of delirium in critical illness

T. D. Girard, M. C. Exline, S. S. Carson, C. L. Hough, P. Rock, M. N. Gong, I. S. Douglas, A. Malhotra, R. L. Owens, D. J. Feinstein, Babar Khan, M. A. Pisani, R. C. Hyzy, G. A. Schmidt, W. D. Schweickert, R. D. Hite, D. L. Bowton, A. L. Masica, J. L. Thompson, R. Chandrasekhar & 12 others B. T. Pun, C. Strength, L. M. Boehm, J. C. Jackson, P. P. Pandharipande, N. E. Brummel, C. G. Hughes, M. B. Patel, J. L. Stollings, G. R. Bernard, R. S. Dittus, E. W. Ely

Research output: Contribution to journalArticle

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Abstract

BACKGROUND There are conflicting data on the effects of antipsychotic medications on delirium in patients in the intensive care unit (ICU). METHODS In 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. RESULTS Written 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. CONCLUSIONS The 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.)

Original languageEnglish (US)
Pages (from-to)2506-2516
Number of pages11
JournalNew England Journal of Medicine
Volume379
Issue number26
DOIs
StatePublished - Dec 27 2018

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Delirium
Haloperidol
Critical Illness
Placebos
Intensive Care Units
Confidence Intervals
Therapeutics
Coma
Respiratory Insufficiency
Shock
ziprasidone
Confusion
National Institutes of Health (U.S.)
Informed Consent
Artificial Respiration
Geriatrics
Pharmaceutical Preparations
Antipsychotic Agents
Odds Ratio
Safety

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Girard, T. D., Exline, M. C., Carson, S. S., Hough, C. L., Rock, P., Gong, M. N., ... Ely, E. W. (2018). Haloperidol and ziprasidone for treatment of delirium in critical illness. New England Journal of Medicine, 379(26), 2506-2516. https://doi.org/10.1056/NEJMoa1808217

Haloperidol and ziprasidone for treatment of delirium in critical illness. / Girard, T. D.; Exline, M. C.; Carson, S. S.; Hough, C. L.; Rock, P.; Gong, M. N.; Douglas, I. S.; Malhotra, A.; Owens, R. L.; Feinstein, D. J.; Khan, Babar; Pisani, M. A.; Hyzy, R. C.; Schmidt, G. A.; Schweickert, W. D.; Hite, R. D.; Bowton, D. L.; Masica, A. L.; Thompson, J. L.; Chandrasekhar, R.; Pun, B. T.; Strength, C.; Boehm, L. M.; Jackson, J. C.; Pandharipande, P. P.; Brummel, N. E.; Hughes, C. G.; Patel, M. B.; Stollings, J. L.; Bernard, G. R.; Dittus, R. S.; Ely, E. W.

In: New England Journal of Medicine, Vol. 379, No. 26, 27.12.2018, p. 2506-2516.

Research output: Contribution to journalArticle

Girard, TD, Exline, MC, Carson, SS, Hough, CL, Rock, P, Gong, MN, Douglas, IS, Malhotra, A, Owens, RL, Feinstein, DJ, Khan, B, Pisani, MA, Hyzy, RC, Schmidt, GA, Schweickert, WD, Hite, RD, Bowton, DL, Masica, AL, Thompson, JL, Chandrasekhar, R, Pun, BT, Strength, C, Boehm, LM, Jackson, JC, Pandharipande, PP, Brummel, NE, Hughes, CG, Patel, MB, Stollings, JL, Bernard, GR, Dittus, RS & Ely, EW 2018, 'Haloperidol and ziprasidone for treatment of delirium in critical illness', New England Journal of Medicine, vol. 379, no. 26, pp. 2506-2516. https://doi.org/10.1056/NEJMoa1808217
Girard TD, Exline MC, Carson SS, Hough CL, Rock P, Gong MN et al. Haloperidol and ziprasidone for treatment of delirium in critical illness. New England Journal of Medicine. 2018 Dec 27;379(26):2506-2516. https://doi.org/10.1056/NEJMoa1808217
Girard, T. D. ; Exline, M. C. ; Carson, S. S. ; Hough, C. L. ; Rock, P. ; Gong, M. N. ; Douglas, I. S. ; Malhotra, A. ; Owens, R. L. ; Feinstein, D. J. ; Khan, Babar ; Pisani, M. A. ; Hyzy, R. C. ; Schmidt, G. A. ; Schweickert, W. D. ; Hite, R. D. ; Bowton, D. L. ; Masica, A. L. ; Thompson, J. L. ; Chandrasekhar, R. ; Pun, B. T. ; Strength, C. ; Boehm, L. M. ; Jackson, J. C. ; Pandharipande, P. P. ; Brummel, N. E. ; Hughes, C. G. ; Patel, M. B. ; Stollings, J. L. ; Bernard, G. R. ; Dittus, R. S. ; Ely, E. W. / Haloperidol and ziprasidone for treatment of delirium in critical illness. In: New England Journal of Medicine. 2018 ; Vol. 379, No. 26. pp. 2506-2516.
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abstract = "BACKGROUND There are conflicting data on the effects of antipsychotic medications on delirium in patients in the intensive care unit (ICU). METHODS In 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. RESULTS Written 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. CONCLUSIONS The 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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TY - JOUR

T1 - Haloperidol and ziprasidone for treatment of delirium in critical illness

AU - Girard, T. D.

AU - Exline, M. C.

AU - Carson, S. S.

AU - Hough, C. L.

AU - Rock, P.

AU - Gong, M. N.

AU - Douglas, I. S.

AU - Malhotra, A.

AU - Owens, R. L.

AU - Feinstein, D. J.

AU - Khan, Babar

AU - Pisani, M. A.

AU - Hyzy, R. C.

AU - Schmidt, G. A.

AU - Schweickert, W. D.

AU - Hite, R. D.

AU - Bowton, D. L.

AU - Masica, A. L.

AU - Thompson, J. L.

AU - Chandrasekhar, R.

AU - Pun, B. T.

AU - Strength, C.

AU - Boehm, L. M.

AU - Jackson, J. C.

AU - Pandharipande, P. P.

AU - Brummel, N. E.

AU - Hughes, C. G.

AU - Patel, M. B.

AU - Stollings, J. L.

AU - Bernard, G. R.

AU - Dittus, R. S.

AU - Ely, E. W.

PY - 2018/12/27

Y1 - 2018/12/27

N2 - BACKGROUND There are conflicting data on the effects of antipsychotic medications on delirium in patients in the intensive care unit (ICU). METHODS In 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. RESULTS Written 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. CONCLUSIONS The 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.)

AB - BACKGROUND There are conflicting data on the effects of antipsychotic medications on delirium in patients in the intensive care unit (ICU). METHODS In 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. RESULTS Written 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. CONCLUSIONS The 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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