Equilibration rate constant, ke0, to determine effect-site concentration for the Masui remimazolam population pharmacokinetic model in general anesthesia patients

General Anesthesia With Remimazolam During Minimally Invasive Cardiac Surgery for Atrial Septal Defect: A Pediatric Case Report

“…During maintenance of anesthesia, a dose of 2 mg kg –1 h –1 or less of remimazolam is recommended for adults; however, the dose for pediatric patients has not been clarified. Methods for estimating predicted effect-site concentrations have been reported for adults 4,5 ; however, these methods are not indicated for children, whose circulating blood volume per body weight and cardiac output are different. As is true for many other drugs, changes in pharmacokinetics owing to dilution by CPB and changes in body temperature and protein-binding rates are difficult to predict, and cardiac surgery was not included in the aforementioned effect-site concentration simulations.…”

Caution!! Reappearance of remimazolam effect after a flumazenil bolus: a larger bolus of flumazenil and a lower total remimazolam clearance are higher risks

“…Then, free plasma remimazolam and flumazenil concentrations were calculated as total plasma concentrations multiplied by 0.08 for remimazolam and 0.686 for flumazenil because plasma protein binding rates are 92 and 31.4%, respectively [10,11]. Finally, modified effect-site concentrations of remimazolam and flumazenil were determined with corresponding equilibration rate constant, k e0 , using standard effect compartment model [9,12], with which modified effect-site concentration equal is the same as free plasma concentration at steady state. With the assumption of modified effect-site concentration, conventional effectsite concentration, which is used in medical devices such as target-controlled infusion pump or pharmacokinetic simulator in anesthesia information management system, can be calculated as modified effect-site concentration divided by (1 − plasma protein binding ratio).…”

“…Dashed line indicates remimazolam concentration of 0.16 μg mL −1 . All pharmacokinetic parameters and k e0 are applied from published articles [8,9,12] increase of the effect-site concentration. If both patients are sedated at remimazolam concentration ≥ 0.2 μg ml −1 (dashed line in Fig.…”

“…Without intensive observation, a flumazenil bolus > 0.2 mg is not recommended based on the pharmacokinetic simulations here. To recognize overdose of remimazolam, pharmacokinetic simulation during remimazolam anesthesia to observe effect-site concentration is useful with a published pharmacokinetic model [8,12]. The time course of effect-site concentration with the observation of clinical symptoms especially after the termination of remimazolam help to predict the time course of residual effect of remimazolam.…”

“…Figs A andBshow the remimazolam equivalent effect-site concentration with flumazenil bolus of 0.5 mg (bold line) and remimazolam effect-site concentration without flumazenil bolus (thin line) in a virtual male patient (male, 55 years, American Society of Anesthesiologists physical status III, 170 cm, and 70 kg) with total remimazolam clearance of 0.85 (typical clearance) and 0.61 (lower clearance) L min −1 , respectively. The other pharmacokinetic parameters and k e0 are applied from published articles[8,9,12]. In these simulations, remimazolam was administered at 12 mg kg −1 h −1 over 1.5 min (a bolus of 0.3 mg kg −1 ) followed by 1.1 over 28.5 min, 0.95 over 30 min, 0.8 over 120 min, and 0.7 mg kg −1 h −1 over 180 min (Fig.…”