NASHVILLE, TN—For more than 40 years, haloperidol and ziprasidone have been given to critically ill patients who develop delirium in hospital intensive care units.

Now, a study led by VA researchers is likely to change that practice after determining that the drugs don’t have the intended effects.

The report in the New England Journal of Medicine noted that no evidence was found that the antipsychotic medicines affected delirium, survival, safety or the length of ICU or hospital stay.1

Modifying the Incidence of Delirium USA (MIND USA) researchers pointed out that no significant difference was documented in duration of delirium or coma among those participants on haloperidol or ziprasidone compared to placebo. In addition, no significant benefit was found for either antipsychotic medication compared to placebo in 30-day and 90-day mortality or time on the ventilator or in the ICU and hospital.

“We found, after extensive investigation with medical centers all over the country, that the patients who get these potentially dangerous drugs are not experiencing any improvements whatsoever in delirium, coma, length of stay or survival,” explained senior author by E. Wesley Ely, MD, MPH, associate director of Research for the VA Geriatric Research Education Clinical Center, professor of Medicine at Vanderbilt University School of Medicine and co-director of the Critical Illness, Brain Dysfunction and Survivorship Center at Vanderbilt University Medical Center.

The findings are contrary to decades of practice. Background information in the article stated that antipsychotic medications have been used to treat delirium in ICU patients for four decades without definitive understanding of their effectiveness.

“Antipsychotics have often been used to treat delirium. The evidence from this study suggests the need to reexamine that practice,” asserted Deputy Director Marie A. Bernard, MD, of the National Institute on Aging, which co-funded the study with the VA.

Delirium is the most common manifestation of acute brain dysfunction during critical illness, affecting 50 to 75% of patients who receive mechanical ventilation in ICUs. Clinicians are anxious to treat the condition, because patients with delirium have higher mortality, longer periods of mechanical ventilation and hospital stays, higher costs and a higher risk of long-term cognitive impairment than patients who do not have delirium.

Also causing problems for medical staff is that hyperactive delirium can lead to unplanned removal of devices. Hypoactive delirium, on the other hand, prevents participation in nursing interventions, physical therapy and occupational therapy, according to background information in the article.

Ely and colleagues screened nearly 21,000 patients at 16 U.S. medical centers, all of whom were either on mechanical ventilation or in shock. Of those, 566 became delirious and were randomized into three groups by what treatment they received, either intravenous haloperidol, ziprasidone or placebo (saline). For the randomized, double-blind, placebo-controlled trial, patients with acute respiratory failure or shock and hypoactive or hyperactive delirium received either intravenous boluses of haloperidol (maximum dose, 20 mg daily), ziprasidone (maximum dose, 40 mg daily) or placebo.

Researchers halved or doubled the volume and dose of a trial drug or placebo at 12-hour intervals based on 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 intervention.

Defined as the primary end point was the number of days alive without delirium or coma during the 14-day intervention period, while secondary end points included 30-day and 90-day survival, time to freedom from mechanical ventilation and time to ICU and hospital discharge. Extrapyramidal symptoms and excessive sedation were the safety end points.

With a median duration of exposure to a trial drug or placebo of four days, 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).

Researchers concluded that 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). In addition, no significant between-group differences with respect to the secondary end points or the frequency of extrapyramidal symptoms were detected.

“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,” study authors concluded.

The severely ill participants, who varied greatly in terms of age, conditions and admission diagnoses, had a 73% 30-day survival rate and 64% 90-day survival rate. The study authors found no evidence of major harm from the antipsychotics but cite other research suggesting safety concerns—including increased mortality—associated with antipsychotic use in non-ICU geriatric populations.

“Every day, there are many thousands of patients receiving unnecessary antipsychotics in the critical care setting that are bringing risk and cost without benefit with respect to the outcomes measured in this NIA-sponsored MIND-USA study,” Ely emphasized.

Also released late last month was Ely’s companion ICU Liberation Collaborative investigation, while details how to best care for critically ill patients in the ICU by using the ABCDEF Bundle.

That study followed 15,000 patients at 70 medical centers across the United States and found that higher performance of the ABCDEF bundle saved lives, reduced length of stay, reduced delirium and coma, hospital readmissions and made patients less likely to be transferred to nursing homes, Ely said.

The study in Critical Care Medicine reported that complete ABCDEF bundle performance was associated with lower likelihood of seven outcomes:2

  • Hospital death within seven days (adjusted hazard ratio, 0.32; CI, 0.17–0.62),
  • Next-day mechanical ventilation (adjusted odds ratio [AOR], 0.28; CI, 0.22–0.36),
  • Coma (AOR, 0.35; CI, 0.22–0.56), delirium (AOR, 0.60; CI, 0.49–0.72), Physical restraint use (AOR, 0.37; CI, 0.30–0.46),
  • ICU readmission (AOR, 0.54; CI, 0.37–0.79), and
  • Discharge to a facility other than home (AOR, 0.64; CI, 0.51–0.80).

The Vanderbilt-led research which also involved the Tennessee Valley VA Geriatric Research Education Clinical Center, concluded, “ABCDEF bundle performance showed significant and clinically meaningful improvements in outcomes including survival, mechanical ventilation use, coma, delirium, restraint-free care, ICU readmissions, and post-ICU discharge disposition.”

“In the ICU Liberation Collaborative investigation, we used a safety bundle much like what your airplane pilots use to help you get safely to your destination,” Ely added. “We try and provide the least amount of sedation to keep people safe and comfortable in the ICU while also managing their delirium, involving their families, getting them mobilized and walking around. ICU teams all over the world are working together to create a new culture of critical care for patients and families.”

1. Girard TD, Exline MC, Carson SS, Hough CL, et. Al. MIND-USA Investigators. Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness. N Engl J Med. 2018 Oct 22. doi: 10.1056/NEJMoa1808217. [Epub ahead of print] PubMed PMID: 30346242.

2. Pun BT, Balas MC, Barnes-Daly MA, Thompson JL, et. Al. Caring for Critically Ill Patients with the ABCDEF Bundle: Results of the ICU Liberation Collaborative in Over 15,000 Adults. Crit Care Med. 2018 Oct 18. doi: 10.1097/CCM.0000000000003482. [Epub ahead of print] PubMed PMID: 30339549.