Research suggests longstanding ICU conventions for treating delirium have failed to benefit patients.

At least one third of all ICU patients experience delirium, with even higher proportions in specialty ICUs and among mechanically ventilated patients. A new study published in the New England Journal of Medicine reports that critically ill patients are not benefiting from antipsychotic medications used for more than four decades. In fact, many drugs given to sedate ICU patients are increasing the chances — and duration — of delirium.

The large, 16-site MIND USA (Modifying the INcidence of Delirium) study sought to answer whether typical or atypical antipsychotics — haloperidol or ziprasidone — affected delirium, survival, length of stay or safety.

“After extensive investigation with medical centers across the country, we found that patients who get these potentially dangerous drugs are not experiencing improvements in delirium, coma, length of stay or survival,” said senior author Wes Ely, M.D., professor of medicine and co-director of the CIBS (Critical Illness, Brain Dysfunction and Survivorship) Center at Vanderbilt University Medical Center.

“For years, antipsychotics have been given in the ICU to reduce agitation, delusions and hallucinations, and it was also thought they could improve cognition and attention,” said Jo Ellen Wilson, M.D., a consulting psychiatrist at Vanderbilt and member of the CIBS Center research team. “The MIND study provides data that can help us recommend evidence-based interventions beyond antipsychotics for critically ill patients.”

Evaluating Antipsychotics in the ICU

In the double-blind, placebo-controlled MIND trial, researchers screened nearly 21,000 patients at 16 U.S. medical centers between 2011 and 2017. Patients were enrolled if they were receiving mechanical ventilation (Vent/Bipap) or were in shock on vasopressors. Of 1,183 patients enrolled, 566 (48 percent) became delirious and were randomized into groups receiving either intravenous haloperidol, ziprasidone or placebo (saline).

The volume and dose of a trial drug or placebo was halved or doubled at 12-hour intervals based on the presence or absence of delirium as detected with the Confusion Assessment Method for the ICU, developed by Ely and his colleagues, and on the 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.

The investigators found no significant difference in duration of delirium or coma among participants on IV haloperidol (up to 20 mg per day) or IV ziprasidone (up to 40 mg per day) compared to placebo. Similarly, there were no significant differences among participants on either antipsychotic medication compared to placebo in 30-day and 90-day mortality rates. Patients spent statistically similar amounts of time on ventilators, in the ICU and in the hospital.

“We’ve been working on this hypothesis for almost two decades,” Ely said. “We’re not saying to never use sedation drugs. We’re saying, ‘Let’s modify our patient management, the way we use the drugs.’ Use them to get the patient comfortable while initiating life support, then as soon as they’re on the ventilator, cut them way back and let them wake up.”

Reinventing the ICU Environment

Recently, other national studies published in The Lancet Respiratory Medicine and Critical Care Medicine tested the ABCDEF care bundle protocol, developed as part of the Society of Critical Care Medicine’s ICU Liberation Campaign. ABCDEF details the optimal clinical management of critically ill patients by providing the least amount of sedation to keep them safe and comfortable while also managing their delirium, involving their families and getting them mobilized early.

The ABCDEF care bundle study followed 15,226 patients at 68 medical centers across the United States. Researchers found implementing the ABCDEF bundle saved lives, reduced length of stay, reduced delirium and coma, lowered hospital readmissions and made patients less likely to be transferred to nursing homes.

“The culture of the ICU has traditionally been dictated by de facto norms over the past 20-30 years,” Ely said. “Before research began to change things, the critical care world believed in keeping a patient deeply sedated, immobilized and without a lot of engagement with their loved ones. Progress has been made, but there is still work to be done to increase the practice of ICU Liberation.”

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E. Wesley Ely, M.D.

Wesley Ely, M.D., M.P.H., is the Grant W. Liddle Chair in Medicine, a professor of medicine in the Division of Allergy, Pulmonary, and Critical Care Medicine, and co-director of the Critical Illness, Brain Dysfunction and Survivorship (CIBS) Center. His research focuses on improving the care and outcomes of critically ill patients with ICU-acquired brain disease.

Jo Ellen Wilson, M.D.

Jo Ellen Wilson, M.D., M.P.H. is assistant professor of Psychiatry. Her current research includes a prospective cohort study studying the prevalence and clinical relevance of catatonia in the critical care setting.