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Propofol pharmacokinetics in preterm and term neonates: the relevance of both postmenstrual and postnatal age

Introduction

Although disposition of propofol has been extensively studied in different populations of adult and paediatric age, data are still very limited. Preliminary data in neonates suggested that propofol clearance is significantly different compared with toddlers and children, with important interindividual variability in propofol clearance in neonates [1]. We therefore wanted to document covariates that contribute to interindividual variability in propofol pharmacokinetics in preterm and term neonates.

Methods

Population pharmacokinetics were estimated (nonlinear mixed effects model) based on arterial blood samples collected in (pre)term neonates after intravenous bolus administration of propofol (3 mg/kg, 10 s). Covariate analysis included post-menstrual age (PMA), postnatal age (PNA), gestational age, weight and creatinaemia.

Results

Two hundred and thirty-five arterial concentration–time points were collected in 25 neonates. The median weight was 2,930 (range 680–4,030) g, PMA 38 (27–43) weeks and PNA 8 (1–25) days. In a three-compartment model, PMA was the most predictive covariate for clearance (P < 0.001) when parameterized as [CLstd × (PMA/38)11.5]. The standardized propofol clearance (CLstd) at 38 weeks PMA was 0.029 l/min. The addition of a fixed value in neonates with a postnatal age ≥ 10 days further improved the model (P < 0.001) and resulted in the equation [CLstd × (PMA/38)11.5 + 0.03] for neonates ≥ 10 days old. Values for the central volume (1.32 l), peripheral volume 1 (15.4 l) and peripheral volume 2 (1.29 l) were not significantly influenced by any of the covariates (P > 0.001).

Conclusion

PMA and PNA contribute to the interindividual variability of propofol clearance with very fast maturation of clearance in neonatal life. This implicates that preterm neonates and neonates in the first week of postnatal life are at an increased risk for accumulation during either intermittent bolus or continuous administration of propofol.

References

  1. 1.

    Allegaert K, et al.: Crit Care. 2007, 11: S170. 10.1186/cc5586

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Allegaert, K., Peeters, M., Verbesselt, R. et al. Propofol pharmacokinetics in preterm and term neonates: the relevance of both postmenstrual and postnatal age. Crit Care 12, P274 (2008). https://doi.org/10.1186/cc6495

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Keywords

  • Interindividual Variability
  • Preterm Neonate
  • Term Neonate
  • Nonlinear Mixed Effect
  • Intermittent Bolus