Certain antipsychotics in critically ill patients weren't effective treatments for delirium, results from a major randomized trial showed.
For patients in the , neither haloperidol (Haldol) nor ziprasidone (Geodon) extended the number of days alive without delirium or coma -- the trial's primary endpoint -- reported E. Wesley Ely, MD, MPH, of Vanderbilt University Medical Center in Nashville, and colleagues (P=0.26 for overall effect):
- Haloperidol: 7.9 days (95% CI 4.4-9.6)
- Ziprasidone: 8.7 days (95% CI 5.9-10.0)
- Placebo: 8.5 days (95% CI 5.6-9.9)
Treatment with these antipsychotics didn't increase the odds of days without delirium among adults patients in the ICU when compared with placebo, either:
- Haloperidol: OR 0.88 (95% CI 0.64-1.21)
- Ziprasidone: OR 1.04 (95% CI 0.73-1.48)
Patients in MIND-USA were enrolled if they had acute respiratory failure or shock along with hypoactive or hyperactive delirium. Results were presented at the European Society of Intensive Care Medicine annual meeting and published simultaneously in the .
"This study uproots 40 years of clinical practice and took over 15 years from the time we started this line of inquiry to get to this point in discovery," Ely told ֱ. "It is one of the most negative trials I've ever seen, which translates into something very positive for patient care."
"It was nutty that for 40 years we were treating patients with an entire class of drugs, antipsychotics, without any proof they worked for delirium," Ely continued. "The practice is very widespread to use antipsychotics for delirium. It is happening right now in many tens of thousands of patients, and over the year probably millions of patients in many settings receive antipsychotics for delirium -- nursing homes, hospitals, ICUs."
"We undertook the study with equipoise. Not knowing but feeling confident that either answer, whatever is truth, would change medicine," said Ely.
Previous trials looking at haloperidol, in particular -- and trials -- yielded mixed findings on the benefit of this drug on ICU delirium. But Thomas Bleck, MD, MCCM, of Rush Medical College in Chicago, pointed out in an that the current trial approaches this topic from a new and "clinically relevant" angle, specifically looking at whether commonly used dopamine antagonists including haloperidol show any benefit as immediate treatment once delirium has already begun in these patients.
The randomized, double-blind trial, which was held across 16 U.S. medical centers, included 1,183 adult patients in the medical or surgical ICU with either invasive or noninvasive positive pressure ventilation, vasopressors or an intra-aortic balloon pump. Delirium was identified using the Confusion Assessment Methods for the ICU CAM-ICU. Individuals receiving active treatments were delivered an intravenous bolus of up to 20 mg of haloperidol or 40 mg of ziprasidone, daily, over the course of a 14-day intervention period.
None of the secondary efficacy endpoints were significantly different between groups, either. These included time to ICU and hospital discharge, days to freedom from mechanical ventilation, as well as mortality at 30 and 90 days.
Similarly, safety endpoints also didn't significantly differ between treatments, which included frequency of excessive sedation as well as frequency of extrapyramidal symptoms, although prolongation of the correct QT interval was slightly more common with ziprasidone.
"The study is good news for patients, but it still needs more data going forward," said Ely. "It is wonderful news for patients because it will help their physicians to avoid giving them drugs for delirium when that is not going to help them, and also the ICU teams will be able to direct their care for the delirium in more established and successful directions, such as the ."
"There will still be some appropriate use of antipsychotics in the ICU, but it is for difficult to control patients who are being dangerous to themselves or others, and the antipsychotic meds can help with symptom control without suppressing respirations, so that can be very clinically helpful and safe."
Bleck commented that the researchers "deserve credit for conducting a difficult trial, but it would have been astounding if there were a single magic bullet for the restitution of normal brain function in ICU patients with delirium."
Disclosures
The trial was funded by the National Institutes of Health and the VA Geriatric Research Education and Clinical Center.
Girard reported grants from National Institutes of Health, during the conduct of the study. Ely reported grants from NIH and the VA during the conduct of the study, and personal fees from Orion Pharmaceuticals, Pfizer Pharmaceuticals, Köhler, and Masimo outside the submitted work. Other study authors also reported disclosures.
Editorialist Bleck reported no disclosures.
Primary Source
New England Journal of Medicine
Girard T, et al “Haloperidol and ziprasidone for treatment of delirium in critical illness” N Engl J Med 2018; DOI: 10.1056/NEJMoa1808217.
Secondary Source
New England Journal of Medicine
Bleck T “Dopamine antagonists in ICU delirium” N Engl J Med 2018; DOI: 10.1056/NEJMe1813382.