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Antipsychotic drugs failed to shorten ICU delirium

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Less confidence in antipsychotics for ICU delirium

In a comment published with this study, Thomas P. Bleck, MD, of the department of neurologic sciences at Rush Medical College, Chicago, wrote, “A change in mental status in a patient in intensive care can be one of the most vexing problems. In the past 2 decades, the idea has arisen that antipsychotic drugs – and particularly dopamine antagonists, which ameliorate thought disorders in psychotic patients – could help patients with disordered thinking in other contexts, such as the intensive care unit. However, yet another trial has now called this idea into question.”

He noted that, in the study group, a bolus of placebo was just as effective as a bolus of active medication, which may be because of the majority of patients having hypoactive delirium, which the active drugs may not impact.

“I would still consider using dopamine agonists in patients at imminent risk of injurious behaviors but have less confidence in their benefits than I once had,” Dr. Bleck wrote.

Dr. Bleck did not report any conflicts of interest.



The antipsychotic medications haloperidol and ziprasidone are no better than placebo in altering the duration of delirium in patients in intensive care, new research has found.

ICU monitor copyright Andrei Malov/Thinkstock

In a paper published in the New England Journal of Medicine, researchers reported the results of a randomized, double-blind, placebo-controlled trial in 566 patients with acute respiratory failure or shock and hypoactive or hyperactive delirium. Participants were randomized either to a maximum of 20 mg IV haloperidol daily, maximum 40 mg ziprasidone daily, or placebo.

At the end of the 14-day intervention period, the placebo group had a median of 8.5 days alive without delirium or coma, the haloperidol group had a median of 7.9 days, and the ziprasidone group had a median of 8.7 days. The difference between groups was not statistically significant.

There were also no significant differences between the three groups in the secondary end point of duration of delirium and coma, 30-day and 90-day survival, time to freedom from mechanical ventilation, ICU discharge, ICU readmission, or hospital discharge.

Timothy D. Girard, MD, from the department of critical care at the University of Pittsburgh, and his coauthors wrote that their findings echoed those of two previous placebo-controlled trials in smaller numbers of ICU patients.

“One possible reason that we found no evidence that the use of haloperidol or ziprasidone resulted in a fewer days with delirium or coma than placebo is that the mechanism of brain dysfunction that is considered to be targeted by antipsychotic medications – increased dopamine signaling – may not play a major role in the pathogenesis of delirium during critical illness,” they wrote.

“In the current trial, approximately 90% of the patients received one or more doses of sedatives or analgesics, and the doses of sedatives and offtrial antipsychotic medications and the durations of exposures to those agents were similar in all trial groups,” the authors added.

Most of the patients in the trial had hypotensive delirium, which made it difficult to assess the effects of antipsychotics on hypertensive delirium.

The authors also commented that the patients enrolled were a mixed group, so their findings did not rule out the possibility that certain subgroups of patients – such as nonintubated patients with hyperactive delirium, those with alcohol withdrawal, or with other delirium phenotypes – may still benefit from antipsychotics.

Patients treated with ziprasidone were more likely to experience prolongation of the corrected QT interval. Two patients in the haloperidol group developed torsades de pointes but neither had received haloperidol in the 4 days preceding the onset of the arrhythmia.

One patient in each group – including the placebo group – experienced extrapyramidal symptoms and had treatment withheld. One patient in the haloperidol group also had the trial drug withheld because of suspected neuroleptic malignant syndrome, but this was later ruled out, and one patient had haloperidol withheld because of dystonia.

The dose of haloperidol used in the study was considered high, the authors said, but they left open the possibility that even higher doses might help. However, they also noted that doses of 25 mg and above were known to have adverse effects on cognition, which is why they chose the 20-mg dosage.

The study was supported by the National Institutes of Health and the Department of Veterans Affairs Geriatric Research Education and Clinical Center. Most authors declared support from the NIH or VA during the course of the study. Four authors also reported fees and grants from private industry outside the context of the study.

SOURCE: Girard TD et al. N Engl J Med.2018 Oct 22. doi: 10.1056/NEJMoa1808217.

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