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Effect of Flumazenil on Hypoactive Delirium in the ICU: A Double-Blind, Placebo-Controlled Pilot Study
Kendra J Schomer1, Jeremiah J Duby1, Rachelle L Firestone1
1Department of Pharmacy, University of California Davis Medical Center, Scramento, CA.
Insights
Flumazenil may offer a potential treatment for hypoactive delirium in critically ill patients exposed to benzodiazepines. However, this pilot study found no significant difference in delirium-free days, warranting further investigation.
Area of Science:
- Critical care medicine
- Neuroscience
- Pharmacology
Background:
- Hypoactive delirium is common in critically ill patients, often associated with benzodiazepine use.
- Benzodiazepines can prolong delirium and sedation, impacting patient recovery.
- Effective treatments for benzodiazepine-induced delirium are limited.
Purpose of the Study:
- To evaluate if flumazenil can reverse hypoactive delirium in critically ill patients.
- To determine if flumazenil increases delirium-free days after benzodiazepine exposure.
Main Methods:
- A single-center, double-blinded, randomized placebo-controlled pilot study was conducted.
- Critically ill patients with hypoactive delirium and benzodiazepine exposure were enrolled.
- Patients received a flumazenil test dose, with responders randomized to flumazenil or placebo infusion.
Main Results:
- 88% of patients responded to the flumazenil test dose.
- No significant difference was observed in delirium-free days between flumazenil and placebo groups (12.7 vs 9.2 days).
- Delirium resolution rates and ICU length of stay were similar between groups; no serious adverse events were reported.
Conclusions:
- Flumazenil shows potential as a treatment for hypoactive delirium linked to benzodiazepine exposure.
- The study could not definitively establish a clinical benefit due to early termination and pilot nature.
- Larger, powered studies are necessary to confirm the efficacy and safety of flumazenil for this indication.
Abstract:
To determine whether the use of flumazenil reverses hypoactive delirium and increases delirium-free days in critically ill patients who were exposed to benzodiazepine therapy during the ICU admission.
Design:
This was a single-center, double-blinded, randomized placebo-controlled pilot study.
Setting:
Adult ICUs at a large academic medical center in the United States.
Patients:
Adult, critically ill patients with benzodiazepine exposure and hypoactive delirium based on the Confusion Assessment Method-ICU and Richmond Agitation Sedation Scale assessments were considered for enrollment.
Interventions:
Patients received a test dose of flumazenil starting at 0.1 mg intravenously and titrated up every 5 minutes by 0.1 mg increments up to a maximum total dose of 2 mg. Patients who demonstrated a Richmond Agitation Sedation Scale score increase of greater than 1 point were considered responders and randomized to flumazenil (0.05-0.3 mg/hr) or placebo infusion for up to 72 hours. Confusion Assessment Method-ICU scores were assessed twice daily for resolution of delirium.
Measurements And Main Results:
The trial was stopped early based on the observed size effect and power analysis. Twenty-two of the 25 patients responded to the flumazenil test dose (88%). The median number of delirium-free days alive without coma within 14 days of enrollment was similar between the two infusion groups (12.7 vs 9.2; p = 0.19). There was no difference in the probability of delirium resolution within the first 14 days with 90% versus 70% in the flumazenil and placebo groups, respectively (p = 0.2). There was no statistical difference (odds ratio, 0.17; 95% CI, 0.022-1.23; p = 0.079) in delirium- and coma-free days at the end of the study drug infusion. There was no difference between groups in ICU length of stay (7.8 ± 4.8 vs 7 ± 8; p = 0.74). No serious adverse events occurred.
Conclusions:
This study found that flumazenil test dose and infusion present a potential option for hypoactive delirium associated with benzodiazepine exposure; however, the possible benefit is unknown. Larger studies are warranted to further evaluate these findings.
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