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NCT Number: NCT07620782

Response Surface Modeling of Remimazolam and Sevoflurane

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.

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Key information

Conditions

Laparoscopic Surgery

Age range

20 year–80 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Pusan National University Yangsan Hospital

Yangsan, 50612, South Korea

Location status: Recruiting

Location contact

Hee Young Kim, MD, PhD

CONTACT

[email protected]

82-55-360-2129

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Remimazolam (Byfavo)

Drug

Remimazolam will be administered at infusion rates ranging from 0 to 6 mg/kg/h using an infusion pump with pharmacokinetic simulation software.

Sevoflurane (Volatile Anesthetic)

Drug

Sevoflurane will be administered by inhalation with targeted end-tidal concentrations between 0 and 2 vol%.

Primary outcomes

  1. Interaction coefficient (α) between remimazolam and sevoflurane derived from the Minto response surface model

    Time frame: During anesthetic induction

    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.

  2. Interaction parameter between remimazolam and sevoflurane derived from the Greco response surface model

    Time frame: During anesthetic induction

    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.

Secondary outcomes

  1. BIS response according to hypnotic combinations

    Time frame: During anesthetic induction

    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.

  2. Loss of consciousness (LOC)

    Time frame: During anesthetic induction

    Time to loss of consciousness during induction

  3. Recovery of consciousness (ROC)

    Time frame: During emergence from anesthesia

    Time to recovery of consciousness

  4. Heart rate

    Time frame: Intraoperative period

    Heart rate (beats per minute) will be recorded at 5-minute intervals during the intraoperative period.

  5. Systolic blood pressure

    Time frame: Intraoperative period

    Systolic blood pressure (mmHg) will be recorded at 5-minute intervals during the intraoperative period.

  6. Mean blood pressure

    Time frame: Intraoperative period

    Mean blood pressure (mmHg) will be recorded at 5-minute intervals during the intraoperative period.

  7. Cardiac output

    Time frame: Intraoperative period

    Cardiac output (L/min) will be recorded at 5-minute intervals during the intraoperative period.

  8. Cardiac index

    Time frame: Intraoperative period

    Cardiac index (L/min/m²) will be recorded at 5-minute intervals during the intraoperative period.

  9. Stroke volume variation

    Time frame: Intraoperative period

    Stroke volume variation (%) will be recorded at 5-minute intervals during the intraoperative period.

  10. Pulse pressure variation

    Time frame: Intraoperative period

    Pulse pressure variation (%) will be recorded at 5-minute intervals during the intraoperative period.

  11. Peripheral oxygen saturation

    Time frame: Intraoperative period

    Peripheral oxygen saturation (%) will be recorded at 5-minute intervals during the intraoperative period.

Study contacts

Contact information is provided by the study sponsor or research team.

Hee Young Kim, MD, PhD

CONTACT

[email protected]

82-55-360-2129

Sponsors and collaborators

Lead sponsor

Pusan National University Yangsan Hospital

Other

Registry information

Official study title

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

Important dates

Study start
2026
Primary completion
2027
Study completion
2027
First posted
Jun 2, 2026
Registry last updated
Jun 2, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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