Impact of Flumazenil on the Emergence Delirium

Study Overview
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Brief Summary
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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.

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

Conditions
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Anesthesia, General

Intervention / Treatment
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* Drug: Flumazenil


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Flumazenil group<br>After discontinuation of remimazolam administration, flumazenil is administered to help the patient recover consciousness. | Drug: Flumazenil<br>* 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.<br>|
| No Intervention: Control group<br>After discontinuation of remimazolam administration, wait until the patient's consciousness is restored naturally without flumazenil administration. | |

What is the study measuring?
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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 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 | 
| 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] | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Remimazolam, Flumazenil, Emergence delirium, Delirium