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 C estimates 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.

Antinociceptive Agents as General Anesthetic Adjuncts: Supra-additive and Infra-additive Interactions

“…Hypnosis: Studies on the nature of propofol interactions with opioids regarding the hypnotic components of anesthesia mostly reported supra-additive results [50][51][52][53][54][55][56][57] ; however, some did not confirm synergy. 58,59 The absence of synergy with fentanyl 58 may be explained by its use in small (analgesic) doses, which was not sufficient to reveal sedative activity.…”

Anesthesia management of neonates and infants requiring intraoperative neurophysiological monitoring: A concise review

“…The additive effect was reported to achieve loss of consciousness (LOC). In an adult study, each Ce of remifentanil and propofol required for LOC in half of the patients (EC50 LOC ) was estimated to be 13.9 ng/mL and 3.04 mcg/mL, respectively 24 . Furthermore, the additive amnesic effect of remifentanil could facilitate the dose reduction in propofol or other anesthetics and minimize the suppression of IONM.…”

“…In an adult study, each Ce of remifentanil and propofol required for LOC in half of the patients (EC50 LOC ) was estimated to be 13.9 ng/mL and 3.04 mcg/ mL, respectively. 24 Furthermore, the additive amnesic effect of remifentanil could facilitate the dose reduction in propofol or other anesthetics and minimize the suppression of IONM. However, further studies are needed to accurately estimate the Ce of anesthetics in neonates and infants.…”

“…However, the types of interaction with propofol (i.e., additive or synergistic) toward MEPs is unknown. 28 In adults, the combination of subanesthetic doses of ketamine (0.5 mg/kg bolus, followed by 4 mcg/kg/min infusion, expected Ce 0.15-0.2 mg/L) 24,25 with propofol and remifentanil may help in reducing propofol and remifentanil doses while maintaining MEPs, 29 but this remains untested in neonates and infants. Ketamine clearance is mainly through the cytochrome oxygenase system (CYP3A4), and this is immature in neonates.…”

Performance of the Surgical Pleth Index and Analgesia Nociception Index in Healthy Volunteers and Parturients

“…An effect-site concentration of remifentanil 9.11 ng/mL was associated with a 50% probability of occurrence of muscle rigidity (Choe et al, 2017). According to the results of the pharmacodynamic model constructed in the previous study (Choe et al, 2017), the target concentration was set to 3 ng/mL because muscle rigidity may occur when the concentration of remifentanil exceeds 4 ng/mL. The two study periods were separated by a washout interval of 2 h to avoid carryover effects.…”