Impact of Flumazenil on the Emergence Delirium

The Impact of Administration of Flumazenil on the Emergence Delirium in Patients Anesthetized With Remimazolam: a Prospective Randomized Single-blind Study

Flumazenil rapidly antagonizes benzodiazepines (BZDs); it may induce agitation, seizure, or delirium, especially when applied to patients who have taken BZDs for a long time. On the contrary, it may help patients regain consciousness in a stable and calm state by appropriately reversing the central nervous system depressant effects of BZDs. In this study, we aim to investigate the impact of flumazenil on the emergence delirium in patients anesthetized with remimazolam, the short-acting BZD drug.

Study Overview

• Status: Completed
• Conditions: Anesthesia, General
• Intervention / Treatment: Drug: Flumazenil

• Study Type: Interventional
• Enrollment (Actual): 68
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Byung Gun Lim, MD, PhD; Phone Number: 82-10-3828-9205; Email: bglim9205@korea.ac.kr
• Study Contact Backup: Name: Hye Bin Kim, MD, PhD; Phone Number: 82-10-9183-5617; Email: aneshbkim@gmail.com

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 08308
    • Korea University Guro Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adult patients aged 19 years or older undergoing surgery under general anesthesia

Exclusion Criteria:

• Peripheral nerve block or Neuraxial block
• Uncontrolled hypertension (HTN) (systolic blood pressure (SBP) ≥180 mmHg)
• Uncontrolled diabetes mellitus (DM) (HbA1c ≥9.0%)
• Hepatic dysfunction (Total bilirubin ≥3.0 mg/mL or Liver enzyme ≥Upper normal limit x 2.5)
• Renal dysfunction (Estimated glomerular filtration rate (eGFR) <30 ml/min/1.73m2 or Dialysis)
• Moderate or severe chronic obstructive pulmonary disease or Respiratory failure
• Emergency
• Hepatectomy or Liver transplantation
• Intraoperative cardiopulmonary bypass (CPB) or extracorporeal membrane oxygenation (ECMO) use
• Head trauma, Increased intracranial pressure, Craniotomy
• Chronic use of benzodiazepines (BZDs)
• Anxiety, Alcohol/Drug dependence, Addiction to tricyclic antidepressants (TCAs)
• Allergic reaction to BZDs, flumazenil, or other drugs used in general anesthesia
• Severe allergy or Anaphylaxis history
• Lactose-related genetic disorders
• Myasthenia gravis or Myasthenia gravis syndrome
• Myocardial infarction or Cerebrovascular events within 6 months
• Symptomatic coronary artery disease
• Organic brain disease
• Cognitive impairment (Inability to understand informed consent)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Flumazenil group; After discontinuation of remimazolam administration, flumazenil is administered to help the patient recover consciousness.	Drug: Flumazenil; After cessation of remimazolam infusion, flumazenil 0.2 mg is administered intravenously over 15 seconds. If consciousness is not adequately restored within 3-5 minutes, a second dose of 0.1 mg intravenously over 15 seconds is administered. If necessary, 0.1 mg may be administered repeatedly at 3-5 minute intervals, and the maximum dose of 1 mg should not be exceeded.
No Intervention: Control group; After discontinuation of remimazolam administration, wait until the patient's consciousness is restored naturally without flumazenil administration.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of emergence delirium	Richmond Agitation & Sedation Scale (RASS) ≥1 is considered emergence delirium.	From emergence to postanesthesia care unit (PACU) discharge (Immediately after extubation, 15 min after PACU admission, PACU discharge) [within 2 hrs after surgery]

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of postoperative delirium (POD)	3-Minute Diagnostic Assessment for Delirium using the Confusion Assessment Method (3D-CAM) is used for the evaluation of POD.	From PACU to postoperative day 5(until the discharge date if discharged before 5 days after surgery) [2 times a day in the morning/afternoon]
Severity of POD	CAM-severity (CAM-S) is utilized to determine the severity of POD if it occurs.	From PACU to postoperative day 5
Duration of POD	3D-CAM is utilized to check the duration of POD.	From PACU to postoperative day 5
Level of consciousness	Richmond Agitation & Sedation Scale (RASS) is used to evaluate the patients level of consciousness.	From emergence to PACU discharge (Immediately after extubation, 15 min after PACU admission, PACU discharge) [within 2 hrs after surgery
Incidence of resedation	Richmond Agitation & Sedation Scale (RASS) ≤-2 is diagnosed as resedation.	From emergence to PACU discharge (Immediately after extubation, 15 min after PACU admission, PACU discharge) [within 2 hrs after surgery
Time to eye-opening	Time taken for patients to open their eyes when their name is gently called after discontinuation of remimazolam.	After remimazolam cessation to eye-opening [within 30 min after remimazolam cessation]
Time to extubation	Time taken for patients to maintain spontaneous breathing and be extubated after remimazolam discontinuation.	After remimazolam cessation to extubation [within 30 min after remimazolam cessation]
Preoperative anxiety	Amsterdam Preoperative Anxiety and Information Scale (APAIS) is used to evaluate the patient's anxiety before surgery	1 day before surgery
Postoperative nausea/vomiting (PONV)	Confirm PONV through patient's symptoms and signs.	From immediately after extubation to PACU discharge [within 2 hours after surgery]
Postoperative hospital length of stay	Calculate the days from the date of surgery to the date of hospital discharge.	From the day of surgery to the day of hospital discharge [within 1 month]
Postoperative pain	Numeric rating scale (NRS) or Visual analogue scale (VAS) is used to determine the patient's pain severity (*NRS and VAS are measured on a 0-10 scale, and the higher the score, the more severe the patient's pain)	From PACU admission to postoperative day 5

Collaborators and Investigators

• Sponsor: Korea University Guro Hospital
• Investigators: Principal Investigator: Byung Gun Lim, MD, PhD, Korea University Guro Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 5, 2023
• Primary Completion (Actual): August 11, 2023
• Study Completion (Actual): August 11, 2023

Study Registration Dates

• First Submitted: December 28, 2022
• First Submitted That Met QC Criteria: December 28, 2022
• First Posted (Actual): January 12, 2023

Study Record Updates

• Last Update Posted (Actual): September 6, 2023
• Last Update Submitted That Met QC Criteria: September 3, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Remimazolam, Flumazenil, Emergence delirium, Delirium
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Nervous System Diseases; Postoperative Complications; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Delirium; Emergence Delirium; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Protective Agents; GABA Modulators; GABA Agents; Antidotes; Flumazenil
• Other Study ID Numbers: 2022GR0520

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: We have no plans yet to share individual participant data (IPD) with other researchers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No