title: Response surface modelling of the pharmacodynamic interaction between propofol and remifentanil in patients undergoing anaesthesia.
abstract: This study describes the pharmacodynamic interaction between propofol and remifentanil. Sixty patients who were scheduled for elective surgery under general anaesthesia (30 males/30 females) were enrolled. Patients were randomly allocated to receive one of 15 combinations of drug levels. Baseline electroencephalograms (EEGs) were recorded for 5 minutes prior to administering the drugs. Patients received a target-controlled infusion at one of four predefined doses of propofol (high, 3 μg/mL; medium, 1.5 μg/mL; low, 0.5 μg/mL; or no drug) and of remifentanil (high, 6 or 8 ng/mL; medium, 4 ng/mL; low, 2 ng/mL; or no drug). The occurrence of muscle rigidity, apnoea, and loss of consciousness (LOC) was monitored, and EEGs were recorded during the drug administration phase. Electroencephalographic approximate entropy (ApEn) and temporal linear mode complexity (TLMC) parameters at baseline and under steady state conditions were calculated off-line. Response surfaces were developed to map the interaction between propofol and remifentanil to the probability of occurrence for quantal responses (muscle rigidity, apnoea, LOC) and ApEn and TLMC measurements. Model parameters were estimated using non-linear mixed effects modelling. The response surface revealed infra-additive and synergistic effects for muscle rigidity and apnoea, respectively. The effects of the combined drugs on LOC and EEG parameters (eg, ApEn and TLMC) were additive. The C50estimates of remifentanil (ng/mL) and propofol (μg/mL) were 9.11 and 130 000 for muscle rigidity, 8.99 and 6.26 for apnoea, 13.9 and 3.04 for LOC, 23.4 and 10.4 for ApEn, and 14.8 and 6.51 for TLMC, respectively. The probability of occurrence for muscle rigidity declined when propofol was combined with remifentanil.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Pusan National University Hospital, Pusan, Korea.
authors.forename: SangMin
authors.initials: S
authors.lastname: Choe
authors.affiliation: Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Byung-Moon
authors.initials: BM
authors.lastname: Choi
authors.affiliation: Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Yong-Hun
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Division of Drug Safety Evaluation New Drug Development Center, Osong Medical Innovation Foundation, Chungju-si, Chungbuk, Korea.
authors.forename: Soo-Han
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Statistics, Ewha Womans University, Seoul, Korea.
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Lee
authors.affiliation: Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
authors.forename: Ki-Seong
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.|Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Gyu-Jeong
authors.initials: GJ
authors.lastname: Noh
mesh_terms: D000771:Anesthesia, Intravenous / Q000639:trends; D018686:Anesthetics, Intravenous; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D004359:Drug Therapy, Combination; D017558:Elective Surgical Procedures / Q000639:trends; D004569:Electroencephalography / Q000187:drug effects / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D008954:Models, Biological; D009127:Muscle Rigidity / Q000139:chemically induced / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism*; D015742:Propofol / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism*; D000077208:Remifentanil
chemical_list: D018686:Anesthetics, Intravenous; D010880:Piperidines; D000077208:Remifentanil; D015742:Propofol
keywords: interaction; propofol; remifentanil