Remimazolam-Flumazenil Versus Sevoflurane for Hysteroscopic Day Surgery

Remimazolam With Planned Flumazenil Reversal Versus Sevoflurane-based Balanced Anesthesia for Hysteroscopic Day Surgery: A Randomized Controlled Trial

This prospective, single-center, randomized controlled trial aims to compare remimazolam anesthesia with planned flumazenil reversal and sevoflurane-based balanced anesthesia in adult women undergoing ambulatory hysteroscopic surgery.

Participants will be randomly assigned in a 1:1 ratio to receive either remimazolam for induction and maintenance followed by flumazenil reversal or propofol induction followed by sevoflurane-based balanced anesthesia. The primary outcome is anesthesia-controlled time, defined as the sum of induction time and emergence time. Secondary outcomes include recovery profiles, postoperative symptoms, quality of recovery, hemodynamic stability, and the incidence of re-sedation. The study will evaluate whether a remimazolam-flumazenil strategy can improve operating room efficiency while maintaining recovery quality and safety comparable to conventional sevoflurane-based anesthesia in the ambulatory surgery setting.

Study Overview

• Status: Not yet recruiting
• Conditions: General Anesthesia; Hysteroscopy; Ambulatory Surgery
• Intervention / Treatment: Drug: Remimazolam; Drug: Flumazenil; Drug: Sevoflurane; Drug: propofol

Detailed Description

Ambulatory surgery has become an increasingly important component of modern healthcare systems because it enables rapid recovery, early discharge, efficient utilization of hospital resources, and improved patient satisfaction. The success of ambulatory surgery depends largely on the ability to provide anesthetic care that ensures rapid emergence, minimal postoperative symptoms, and timely discharge without compromising patient safety. Hysteroscopic surgery is one of the most commonly performed ambulatory gynecologic procedures and therefore represents an ideal model for evaluating anesthetic strategies designed to optimize perioperative efficiency and recovery.

Sevoflurane-based balanced anesthesia, typically consisting of intravenous induction followed by maintenance with a volatile anesthetic agent, remains one of the most widely used anesthetic techniques for ambulatory surgery. Although this approach provides reliable hypnosis and favorable surgical conditions, recovery is dependent on anesthetic elimination and individual patient characteristics. Furthermore, volatile anesthetics may contribute to postoperative nausea and vomiting, which remain among the most common causes of delayed discharge and patient dissatisfaction following ambulatory procedures.

Remimazolam is a novel ultra-short-acting benzodiazepine anesthetic that is rapidly metabolized by nonspecific tissue esterases. Compared with conventional anesthetic agents, remimazolam demonstrates predictable pharmacokinetics, limited accumulation, reduced respiratory depression, and favorable hemodynamic stability. Several clinical studies have shown that remimazolam may reduce the incidence and severity of hypotension compared with propofol while providing effective hypnosis for general anesthesia. However, concerns remain regarding delayed awakening and the possibility of residual sedation, particularly in short ambulatory procedures where rapid recovery is essential.

A unique characteristic of remimazolam is the availability of flumazenil, a specific benzodiazepine receptor antagonist capable of rapidly reversing its sedative effects. Planned administration of flumazenil at the end of surgery may allow faster and more predictable emergence than spontaneous recovery alone. Despite this theoretical advantage, evidence supporting a structured remimazolam-flumazenil anesthetic strategy in ambulatory surgery remains limited. Most previous investigations have focused on pharmacodynamic comparisons between remimazolam and propofol, whereas direct comparisons with inhalational balanced anesthesia have been relatively scarce. In addition, few studies have evaluated outcomes that are directly relevant to operating room efficiency and perioperative workflow.

The concept of anesthesia-controlled time has been proposed as a clinically meaningful measure of anesthetic efficiency because it incorporates both induction and emergence phases of anesthesia. Unlike isolated measurements of induction time or awakening time, anesthesia-controlled time reflects the overall contribution of anesthetic management to operating room utilization and turnover. Reductions in anesthesia-controlled time may improve operating room throughput, increase institutional efficiency, and facilitate patient flow in ambulatory surgery centers.

This prospective, single-center, randomized controlled trial is designed to compare remimazolam anesthesia with planned flumazenil reversal and sevoflurane-based balanced anesthesia in adult women undergoing ambulatory hysteroscopic surgery. Eligible participants will be randomly assigned in a 1:1 ratio to receive either remimazolam for induction and maintenance followed by flumazenil reversal at the end of surgery or propofol induction followed by sevoflurane-based balanced anesthesia. Standardized perioperative management protocols will be applied to both groups, including opioid administration, neuromuscular blockade, supraglottic airway management, and electroencephalographic monitoring using the Patient State Index (PSI).

The primary outcome will be anesthesia-controlled time, defined as the sum of induction time and emergence time. Induction time will be measured from initiation of the anesthetic agent to successful placement of the supraglottic airway device, while emergence time will be measured from discontinuation of the primary anesthetic agent to removal of the airway device. This endpoint was selected because it directly reflects operating room efficiency and represents a clinically relevant outcome in ambulatory surgical practice.

Secondary outcomes will evaluate multiple aspects of recovery quality and patient safety. These outcomes include time to achieve an Aldrete score of at least 9, duration of stay in the post-anesthesia care unit, postoperative nausea and vomiting, sore throat, surgical pain, shivering, dizziness, vasopressor requirements, and quality of recovery assessed using the validated Quality of Recovery-15 (QoR-15) questionnaire. The incidence of re-sedation will be evaluated using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale together with electroencephalographic monitoring data. Additional recovery variables, including time to eye opening, time to PSI recovery, and time to airway device removal, will also be assessed.

The investigators hypothesize that remimazolam anesthesia with planned flumazenil reversal will reduce anesthesia-controlled time and improve perioperative efficiency while maintaining recovery quality and safety comparable to conventional sevoflurane-based balanced anesthesia. The findings of this study may provide clinically relevant evidence regarding the optimal anesthetic strategy for ambulatory hysteroscopic surgery and may support broader implementation of remimazolam-based anesthesia in short-duration surgical procedures.

• Study Type: Interventional
• Enrollment (Estimated): 124
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Jiwon Han, MD, PhD; Phone Number: +82-10-3447-1988; Email: yesuroon@gmail.com
• Study Contact Backup: Name: Haesun Jung, MD; Phone Number: 82-10-9452-0448; Email: sunnyj0107@gmail.com

Study Locations

• South Korea
  • Gyeonggi-do
    • Gwangmyeong, Gyeonggi-do, South Korea, 14353
      • Chung-Ang University Gwangmyeong Hospital
      • Contact: Haesun Jung, MD; Phone Number: 82-10-9452-0448; Email: sunnyj0107@gmail.com
      • Contact: Jiwon Han, MD, PhD; Phone Number: 82-10-3447-1988; Email: yesuroon@gmail.com
      • Principal Investigator: Jiwon Han, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Female patients aged 20 years or older.
• Scheduled to undergo ambulatory hysteroscopic surgery under general anesthesia.
• Able to provide written informed consent.
• American Society of Anesthesiologists (ASA) physical status I-III.

Exclusion Criteria:

• Known hypersensitivity to benzodiazepines, remimazolam, or flumazenil.
• Chronic use of benzodiazepines or opioids.
• Severe hepatic dysfunction (Child-Pugh class B or C).
• Severe renal dysfunction (estimated glomerular filtration rate <30 mL/min/1.73 m²).
• Epilepsy or other significant neurologic disorders.
• Pregnancy or breastfeeding.
• Body mass index (BMI) ≥35 kg/m².
• Severe obstructive sleep apnea.
• Uncontrolled serious systemic disease that may preclude ambulatory surgery.
• Refusal or inability to provide informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: remimazolam-fumazeil group; Participants will receive remimazolam for induction and maintenance of general anesthesia. At the end of surgery, flumazenil will be administered to facilitate rapid emergence from anesthesia. Standardized perioperative management, including fentanyl, rocuronium, supraglottic airway management, and postoperative monitoring, will be applied.	Drug: Remimazolam; Remimazolam will be administered at 12 mg/kg/h for induction of anesthesia until loss of consciousness, followed by maintenance at 1-2 mg/kg/h until the end of surgery.; Drug: Flumazenil; Flumazenil 0.5 mg will be administered intravenously at the end of surgery to reverse remimazolam-induced sedation. Additional doses of 0.2 mg may be administered if necessary, up to a maximum total dose of 1.0 mg.
Active Comparator: sevoflurane group; Participants will receive propofol for induction of general anesthesia followed by maintenance with sevoflurane-based balanced anesthesia. Standardized perioperative management will be applied similarly to the experimental group.	Drug: Sevoflurane; Sevoflurane will be administered at 1.5-3.5 vol% for maintenance of anesthesia following propofol induction. At the end of surgery, sevoflurane administration will be discontinued and washout will be facilitated using fresh gas flow of 6 L/min.; Drug: propofol; Propofol 2 mg/kg will be administered intravenously for induction of anesthesia before initiation of sevoflurane maintenance.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anesthesia-Controlled Time	Anesthesia-controlled time is defined as the sum of induction time and emergence time. Induction time is measured from initiation of the anesthetic agent to successful placement of the supraglottic airway device. Emergence time is measured from discontinuation of the primary anesthetic agent to removal of the supraglottic airway device.	From initiation of anesthesia to removal of the supraglottic airway device during emergence from anesthesia, assessed up to 120 minutes.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Aldrete Score ≥9	Time required to achieve an Aldrete score of at least 9 following admission to the post-anesthesia care unit (PACU).	Up to 30 minutes after PACU admission
Length of Stay in PACU	Duration of stay in the post-anesthesia care unit.	From admission to the post-anesthesia care unit until discharge from the post-anesthesia care unit, assessed up to 2 hours.
Postoperative Symptoms During the Acute Recovery Phase	Postoperative symptoms during the acute recovery phase will be assessed in the post-anesthesia care unit using 11-point Numeric Rating Scales. Symptoms include nausea, sore throat, surgical pain, shivering, and dizziness, each scored from 0 to 10, with 0 indicating no symptom and 10 indicating the worst imaginable symptom. The occurrence of vomiting will also be recorded.	During PACU stay, up to 30 minutes after PACU admission
Quality of Recovery-15 (QoR-15) Score	Quality of recovery assessed using the Quality of Recovery-15 (QoR-15) questionnaire. The QoR-15 is a validated patient-reported outcome measure ranging from 0 to 150 points, with higher scores indicating better postoperative recovery.	24 hours after surgery
Incidence of Re-sedation	Occurrence of re-sedation defined as a Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score ≤3.	From PACU admission through discharge from the ambulatory surgery center, assessed up to 8 hours after surgery.

Collaborators and Investigators

• Sponsor: Chung-Ang University Gwangmyeong Hospital
• Investigators: Principal Investigator: Jiwon Han, Chung-Ang University Gwangmyeong Hospital

Publications and helpful links

General Publications

• Stark PA, Myles PS, Burke JA. Development and psychometric evaluation of a postoperative quality of recovery score: the QoR-15. Anesthesiology. 2013 Jun;118(6):1332-40. doi: 10.1097/ALN.0b013e318289b84b.
• Doi M, Morita K, Takeda J, Sakamoto A, Yamakage M, Suzuki T. Efficacy and safety of remimazolam versus propofol for general anesthesia: a multicenter, single-blind, randomized, parallel-group, phase IIb/III trial. J Anesth. 2020 Aug;34(4):543-553. doi: 10.1007/s00540-020-02788-6. Epub 2020 May 16.
• Kilpatrick GJ, McIntyre MS, Cox RF, Stafford JA, Pacofsky GJ, Lovell GG, Wiard RP, Feldman PL, Collins H, Waszczak BL, Tilbrook GS. CNS 7056: a novel ultra-short-acting Benzodiazepine. Anesthesiology. 2007 Jul;107(1):60-6. doi: 10.1097/01.anes.0000267503.85085.c0.

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): June 1, 2028

Study Registration Dates

• First Submitted: June 15, 2026
• First Submitted That Met QC Criteria: June 17, 2026
• First Posted (Actual): June 23, 2026

Study Record Updates

• Last Update Posted (Actual): June 23, 2026
• Last Update Submitted That Met QC Criteria: June 17, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: hysteroscopy; sevoflurane; general anesthesia; remimazolam; ambulatory surgery; flumazenil; day surgery; recovery profile; anesthesia controlled time
• Additional Relevant MeSH Terms: Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Ethers; Hydrocarbons; Hydrocarbons, Cyclic; Hydrocarbons, Aromatic; Phenols; Benzene Derivatives; Hydrocarbons, Halogenated; Benzazepines; Benzodiazepines; Hydrocarbons, Fluorinated; Methyl Ethers; Benzodiazepinones; Sevoflurane; Propofol; Flumazenil; remimazolam
• Other Study ID Numbers: 2604-323-074

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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