Response Surface Modeling of Remimazolam and Sevoflurane

Official title

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

Overview

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.

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.

Interventions

• 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%.

Primary outcome measures

• Interaction coefficient (α) between remimazolam and sevoflurane derived from the Minto response surface model [Time frame: During anesthetic induction]
• Interaction parameter between remimazolam and sevoflurane derived from the Greco response surface model [Time frame: During anesthetic induction]

Secondary outcome measures (11)

• BIS response according to hypnotic combinations [Time frame: During anesthetic induction]
• Loss of consciousness (LOC) [Time frame: During anesthetic induction]
• Recovery of consciousness (ROC) [Time frame: During emergence from anesthesia]
• Heart rate [Time frame: Intraoperative period]
• Systolic blood pressure [Time frame: Intraoperative period]
• Mean blood pressure [Time frame: Intraoperative period]
• Cardiac output [Time frame: Intraoperative period]
• Cardiac index [Time frame: Intraoperative period]
• Stroke volume variation [Time frame: Intraoperative period]
• Pulse pressure variation [Time frame: Intraoperative period]
• Peripheral oxygen saturation [Time frame: Intraoperative period]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Basic science

Study locations

South Korea · 1 center

• Pusan National University Yangsan Hospital — Yangsan

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. PMID 27696490
• 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. PMID 27482310
• Byung-Moon Choi: An overview of pharmacodynamic drug interaction with isobole and response surface model in anesthesia. APM 2016; 11: 1-13

Identifiers

NCT: NCT07620782 · 05-2023-090

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗