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November - 2018

   

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Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness

Timothy D. Girard, M.D., M.S.C.I., Matthew C. Exline, M.D., M.P.H., Shannon S. Carson for the MIND-USA Investigators New Eng J Med, 2018, Online first

Comment

Delirium affects over half our ventilated patients, and is associated with longer length of stay, increased mortality, care issues such as device removal, and long term cognition. As our focus on this problem intensifies, so does our desire to understand the best pharmaceutical options to reduce its efficacy and impact. There is a lot to choose from - older agents such as haloperidol and benzodiazepine, and newer agents such as quetiapine, olanzapine, ziprasidone, and dexmedetomidine. 

This prospective, double blind trial performed in 16 US centres, randomised 566 patients with acute respiratory failure or shock and hypoactive or hyperactive delirium, 1:1:1 to receive;

  • IV boluses of haloperidol (maximum dose, 20 mg daily) vs ziprasidone (maximum dose, 40 mg daily) vs 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 (CAM)
  • Delirium was 89% hypoactive and 11% hyperactive
  • Median trial drug exposure was 4 days, median daily dose of haloperidol was 11mg, ziprasidone 20mg. 21% received open-label antipsychotic during trial, this was similar between groups.
  • Primary end point was number of days alive without delirium or coma during the 14-day intervention period. This occurred in 8.5 (95% CI, 5.6 to 9.9) placebo group, 7.9 (95% CI, 4.4 to 9.6) haloperidol group, and 8.7 (95% CI, 5.9 to 10.0) 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). 
  • No interaction was observed in sub-groups between treatment allocation and outcome, including hyperactive delirium.
  • There was no difference in secondary end points including 30-day and 90-day survival, time to freedom from mechanical ventilation, time to ICU and hospital discharge, extrapyramidal symptoms and excessive sedation.

Overall the use of haloperidol or ziprasidone, as compared with placebo, in patients with acute respiratory failure or shock, did not alter the course of delirium. This is a predominantly hypoactive delirium study, so there may be effects in hyperactive delirium unable to analysed. Can we really treat delirium with placebo, and expect only 20% of delirious patients will receive “open-label” antipsychotics or sedatives? It would be interesting to know the long-term psychological and cognitive comparisons between groups.

 

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 inter- vention. 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 representa- tives. 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 sig- nificant 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.

November


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