Response Surface Modeling of Remimazolam and Sevoflurane

Response Surface Model Between Remimazolam and Sevoflurane; Comparison of the Minto and the Greco Model

This prospective randomized open-label study aims to investigate the pharmacodynamic interaction between remimazolam and sevoflurane during general anesthesia using response surface modeling. Although remimazolam has favorable hemodynamic stability compared with propofol, its hypnotic effect may be less predictable and poorly correlated with conventional sedation monitoring indices such as the bispectral index (BIS). In clinical practice, remimazolam and sevoflurane are often combined during induction and maintenance of anesthesia; however, the optimal interaction between these agents remains unclear.

This study will evaluate whether the interaction between remimazolam and sevoflurane is synergistic, additive, or infra-additive using two representative response surface interaction models: the Minto model and the Greco model. BIS values and predicted effect-site concentrations will be analyzed using NONMEM software.

Study Overview

• Status: Recruiting
• Conditions: Laparoscopic Surgery
• Intervention / Treatment: Drug: Remimazolam (Byfavo); Drug: Sevoflurane (Volatile Anesthetic)

Detailed Description

Remimazolam is a recently developed ultra-short-acting benzodiazepine anesthetic with favorable pharmacokinetic characteristics, including a short context-sensitive decrement time and relatively stable hemodynamics. Despite these advantages, remimazolam may exhibit weaker hypnotic potency and inconsistent correlations with conventional anesthetic depth monitors such as BIS.

In current clinical practice, anesthesiologists frequently combine remimazolam with volatile anesthetics such as sevoflurane during induction or maintenance of anesthesia. However, the pharmacodynamic interaction between remimazolam and sevoflurane has not been fully elucidated.

The present study will investigate the interaction between remimazolam and sevoflurane using response surface modeling. The study will enroll adult patients undergoing elective laparoscopic surgery under general anesthesia. Various combinations of remimazolam infusion rates and end-tidal sevoflurane concentrations will be administered during anesthetic induction. BIS values and predicted effect-site concentrations will be collected and analyzed.

Pharmacodynamic interaction analyses will be performed using NONMEM nonlinear mixed-effects modeling software. Both the Minto interaction model and the Greco interaction model will be applied to determine whether the interaction between remimazolam and sevoflurane is synergistic, additive, or infra-additive.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Hee Young Kim, MD, PhD; Phone Number: 82-55-360-2129; Email: anekhy@gmail.com

Study Locations

• South Korea
  • Yangsan, South Korea, 50612
    • Recruiting
    • Pusan National University Yangsan Hospital
    • Contact: Hee Young Kim, MD, PhD; Phone Number: 82-55-360-2129; Email: anekhy@gmail.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Adults aged 20 to 80 years
• Scheduled for elective surgery under general anesthesia at Pusan National University Yangsan Hospital
• American Society of Anesthesiologists (ASA) physical status I or II
• Able to provide written informed consent

Exclusion Criteria:

• Known allergy to remimazolam or sevoflurane
• Renal, hepatic, neuromuscular, or neurological disease
• Use of medications affecting the central nervous system
• Chronic psychoactive drug use
• Ischemic heart disease
• Pregnant women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Remimazolam and Sevoflurane Combination During Anesthetic Induction; Participants undergoing elective surgery under general anesthesia will receive varying combinations of remimazolam and sevoflurane during anesthetic induction to evaluate pharmacodynamic interactions using response surface modeling.	Drug: Remimazolam (Byfavo); Remimazolam will be administered at infusion rates ranging from 0 to 6 mg/kg/h using an infusion pump with pharmacokinetic simulation software.; Drug: Sevoflurane (Volatile Anesthetic); Sevoflurane will be administered by inhalation with targeted end-tidal concentrations between 0 and 2 vol%.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Interaction coefficient (α) between remimazolam and sevoflurane derived from the Minto response surface model	The interaction coefficient (α) describing the pharmacodynamic interaction between remimazolam effect-site concentration and end-tidal sevoflurane concentration will be estimated using the Minto response surface model based on BIS values collected during anesthetic induction.	During anesthetic induction
Interaction parameter between remimazolam and sevoflurane derived from the Greco response surface model	The pharmacodynamic interaction parameter describing the interaction between remimazolam effect-site concentration and end-tidal sevoflurane concentration will be estimated using the Greco response surface model based on BIS values collected during anesthetic induction.	During anesthetic induction

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
BIS response according to hypnotic combinations	Bispectral Index (BIS) values will be continuously recorded during anesthetic induction according to predefined combinations of remimazolam effect-site concentration and end-tidal sevoflurane concentration. The BIS is a processed electroencephalographic monitoring scale ranging from 0 to 100, where lower values indicate deeper levels of hypnosis and higher values indicate lighter levels of sedation or consciousness.	During anesthetic induction
Loss of consciousness (LOC)	Time to loss of consciousness during induction	During anesthetic induction
Recovery of consciousness (ROC)	Time to recovery of consciousness	During emergence from anesthesia
Heart rate	Heart rate (beats per minute) will be recorded at 5-minute intervals during the intraoperative period.	Intraoperative period
Systolic blood pressure	Systolic blood pressure (mmHg) will be recorded at 5-minute intervals during the intraoperative period.	Intraoperative period
Mean blood pressure	Mean blood pressure (mmHg) will be recorded at 5-minute intervals during the intraoperative period.	Intraoperative period
Cardiac output	Cardiac output (L/min) will be recorded at 5-minute intervals during the intraoperative period.	Intraoperative period
Cardiac index	Cardiac index (L/min/m²) will be recorded at 5-minute intervals during the intraoperative period.	Intraoperative period
Stroke volume variation	Stroke volume variation (%) will be recorded at 5-minute intervals during the intraoperative period.	Intraoperative period
Pulse pressure variation	Pulse pressure variation (%) will be recorded at 5-minute intervals during the intraoperative period.	Intraoperative period
Peripheral oxygen saturation	Peripheral oxygen saturation (%) will be recorded at 5-minute intervals during the intraoperative period.	Intraoperative period

Collaborators and Investigators

• Sponsor: Pusan National University Yangsan Hospital
• Investigators: Principal Investigator: Hee Young Kim, MD, PhD, Pusan National University Yangsan Hospital, Yangsan, South Korea

Publications and helpful links

General Publications

• Choe S, Choi BM, Lee YH, Lee SH, Lee EK, Kim KS, Noh GJ. Response surface modelling of the pharmacodynamic interaction between propofol and remifentanil in patients undergoing anaesthesia. Clin Exp Pharmacol Physiol. 2017 Jan;44(1):30-40. doi: 10.1111/1440-1681.12677.
• Jeon S, Kwon JY, Kim HK, Kim TK. Synergism between rocuronium and cisatracurium: comparison of the Minto and Greco interaction models. Korean J Anesthesiol. 2016 Aug;69(4):341-9. doi: 10.4097/kjae.2016.69.4.341. Epub 2016 Jun 22.
• Byung-Moon Choi: An overview of pharmacodynamic drug interaction with isobole and response surface model in anesthesia. APM 2016; 11: 1-13

Study record dates

Study Major Dates

• Study Start (Actual): May 15, 2026
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: May 14, 2026
• First Submitted That Met QC Criteria: May 27, 2026
• First Posted (Actual): June 2, 2026

Study Record Updates

• Last Update Posted (Actual): June 2, 2026
• Last Update Submitted That Met QC Criteria: May 27, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: general anesthesia
• Additional Relevant MeSH Terms: Organic Chemicals; Ethers; Hydrocarbons; Hydrocarbons, Halogenated; Hydrocarbons, Fluorinated; Methyl Ethers; Sevoflurane; remimazolam
• Other Study ID Numbers: 05-2023-090

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