Haloperidol, Ziprasidone Ineffective For Delirium in Critical Illness

This is for our readers who also take care of ICU patients.

AUTHOR: Bob Kronemyer

Anesthesiology News

Two antipsychotic medications that are often used to treat delirium in the ICU, namely haloperidol and ziprasidone, do not significantly alter the duration of the disturbance, according to a study in The New England Journal of Medicine (2018;379:2506-2516).

“After 40 years of attempting to treat delirium with antipsychotics, we now know that this is unsuccessful therapy, at least among critical patients,” said principal investigator E. Wesley Ely, MD, MPH, the co-director of the Critical Illness, Brain Dysfunction and Survivorship Center at Vanderbilt University, in Nashville, Tenn.

Dr. Ely and his colleagues conducted the study to elucidate the truth about these two drugs. “We did not know for sure if we were helping people, turning our attention to useless therapy and away from other potentially advantageous treatments, or even possibly hurting people,” he said.

The trial’s design randomly assigned 566 patients with acute respiratory failure or shock and hypoactive or hyperactive delirium to one of three treatment protocols, each lasting 14 days: IV boluses of haloperidol (maximum dose, 20 mg daily), ziprasidone (maximum dose, 40 mg daily) or placebo.

The primary end point was the number of days alive without delirium or coma during the 14-day intervention: a median of 8.5 days (95% CI, 5.6-9.9 days) in the placebo group compared with 7.9 days (95% CI, 4.4-9.6 days) in the haloperidol group and 8.7 days (95% CI, 5.9-10 days) in the ziprasidone group. The researchers found no significant effect of the drugs over placebo (odds ratio: haloperidol, 0.88 [95% CI, 0.64-1.21] and ziprasidone, 1.04 [95% CI, 0.73-1.48]).

In addition, the frequency of extrapyramidal symptoms did not differ significantly among the three groups.

Changing Methods And Protocols

In another study, Dr. Ely, who also is the associate director of research at the U.S. Department of Veterans Affairs Tennessee Valley Geriatric Research Education and Clinical Centers, in Nashville, and his colleagues found that patients treated more routinely with a safety checklist called the ABCDEF bundle had better results (Crit Care Med 2019;47[1]:3-14). ABCDEF is short for assess, prevent and manage pain; both spontaneous awakening and spontaneous breathing trials; choice of analgesia and sedation; delirium: assess, prevent and manage; ICU early mobility and exercise; and family engagement and empowerment.

Dr. Ely said he believed there is a clearer path to reducing delirium when both studies’ results are considered together. “Based on the fact that antipsychotics did not help in the current study and that we showed a highly successful approach with the ICU Liberation Collaborative, it will be better for patients if ICU teams consider programs like the ABCDEF bundle as their approach to delirium rather than hoping for a magic bullet medication.”

By following these guidelines, the risk for mental impairment after an ICU stay can be reduced by 25% to 30%, Dr. Ely said.

Dr. Ely and his colleagues are now turning their attention to what type of dementia patients develop after critical care. “This will allow us to design even more specific types of treatment to prevent and treat brain dysfunction during and after critical illness,” he said.

Still Many Unknowns

Joseph A. Hyder, MD, PhD, an associate professor of anesthesiology in the Division of Critical Care at Mayo Clinic, in Rochester, Minn., congratulated the study authors for striving to improve care for patients suffering from this common and disturbing condition.

“The findings of this study, however, are not surprising,” Dr. Hyder said. “Because delirium is a very poorly understood condition that seems to have many possible causes, it would be surprising if a single medication with specific effects treated the condition once it is present.”

In addition, Dr. Hyder believed the patient composition was not well suited to the issues under investigation. “Nearly 90% of the patients had hypoactive delirium, a type of delirium that most intensivists would not consider to be treatable with these medications in the first place. Rather, intensivists preferentially give these medications to patients with hyperactive delirium to minimize dangerous behaviors and promote nighttime sleep. The current study was not designed to study these possible treatment effects.”

Moreover, what is lacking in the study “is a motivating question that very specifically addresses a mechanistic or clinical problem in current practice,” Dr. Hyder said. “This limitation is understandable, of course, because this trial has been years in the making and reflects the best thinking from years ago. Even now, very little is known about the condition.”

Dr. Hyder believed that patients in the ICU with delirium should be permitted to act as normally as possible, while avoiding self-harm. He, too, embraces the ABCDEF bundle. “When it comes to medications and delirium, less is more. Medications are often considered a last resort when a patient with hyperactive delirium needs interventions to prevent self-harm.”