Effect of Flumazenil on Hypoactive Delirium in the ICU: A Double-Blind, Placebo-Controlled Pilot Study

Kendra J Schomer; Jeremiah J Duby; Rachelle L Firestone; Erin L Louie; Christian M Sebat; Dawn M Love; Christine S Cocanour; Timothy E Albertson

doi:10.1097/CCE.0000000000000085

Effect of Flumazenil on Hypoactive Delirium in the ICU: A Double-Blind, Placebo-Controlled Pilot Study

Crit Care Explor. 2020 Mar 24;2(3):e0085. doi: 10.1097/CCE.0000000000000085. eCollection 2020 Mar.

Authors

Kendra J Schomer¹, Jeremiah J Duby¹, Rachelle L Firestone¹, Erin L Louie¹, Christian M Sebat², Dawn M Love³, Christine S Cocanour⁴, Timothy E Albertson^{2

5}

Affiliations

¹ Department of Pharmacy, University of California Davis Medical Center, Scramento, CA.
² Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, School of Medicine, University of California Davis Medical Center, Sacramento, CA.
³ Department of Patient Care Services, Medical Intensive Care Unit, University of California Davis Medical Center, Sacramento, CA.
⁴ Division of Trauma and Emergency Surgery, Department of Surgery, School of Medicine, University of California Davis Medical Center, Sacramento, CA.
⁵ Department of Veterans Affairs, VA Northern California Health Care System, Mather, CA.

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.

Keywords: benzodiazepine; benzodiazepine antagonist; critical care; delirium; flumazenil; hypoactive delirium.