Introduction: Propofol is used for the induction and maintenance of anaesthesia in neonates, infants and children. Clearance is the pharmacokinetic parameter that determines maintenance infusion rates and clearance matures over the first years of life. Postmenstrual age (PMA) is typically used to quantify clearance maturation as it accounts for maturation that begins in utero. Maturation models that consider the additional impact of birth on clearance have been proposed using postnatal age (PNA) [1]. This study reanalysed published propofol time-concentration data from premature neonates to adults.
Aim: To describe the impact of birth on the time-course of propofol clearance maturation.
Methods: Data were pooled from 10 studies and analysed using nonlinear mixed effects models. Theory-based allometric scaling using total body weight and a sigmoid hyperbolic model based on PMA were used to account for size and age related differences in propofol pharmacokinetics. Propofol pharmacokinetics were described using three-compartment distribution model with zero-order infusion input and first-order elimination. The impact of birth on clearance maturation was investigated using asymptotic exponential and sigmoid hyperbolic postnatal transition models [2].
Results: There were 3674 observations pooled from 366 individuals (25 weeks PMA – 80 years; 0.58 – 123 kg total body weight). The sigmoid hyperbolic postnatal transition model best described the time-course of propofol clearance maturation (objective function decrease -84 over PMA alone). Addition of PNA resulted in a clearance estimate that was reduced at birth in a full term neonate (40 weeks PMA) by 42% compared to maturation using PMA alone. The maximum increase in clearance with a PMA+PNA model was 32% at postnatal day 14 relative to PMA alone. There was no difference in the predicted clearance between PMA and PNA maturation models after 22 weeks PNA.
Conclusion: Maturation of propofol clearance determined using a postnatal transition model in addition to PMA resulted in a predicted clearance at birth that was 42% lower than clearance predicted using PMA alone. This would result in propofol maintenance infusion rates that are 42% lower to maintain a steady-state target concentration in term neonates than those determined from a PMA only model.
References
- Sandra L, Smits A, Allegaert K, Nicolaï J, Annaert P, Bouillon T. Population pharmacokinetics of propofol in neonates and infants: Gestational and postnatal age to determine clearance maturation. Br J Clin Pharmacol. 2021;87(4):2089-97.
- Anderson BJ, Holford NHG. Negligible impact of birth on renal function and drug metabolism. Pediatric Anesthesia. 2018;28(11):1015-21.