Background and Objectives: From a previously validated paediatric population pharmacokinetic model, it was derived that non-linear morphine maintenance doses of 5 μg/kg1.5/h, with a 50 % dose reduction in neonates with a postnatal age (PNA) <10 days, yield similar morphine and metabolite concentrations across patients younger than 3 years. Compared with traditional dosing, this model-derived dosing regimen yields significantly reduced doses in neonates aged <10 days. Methods: Concentration predictions of the population model were prospectively evaluated in postoperative term neonates and infants up to the age of 1 year who received morphine doses according to the model-derived algorithm. The efficacy of this dosing algorithm was evaluated using morphine rescue medication and actual average infusion rates. Results: Morphine and metabolite concentrations were accurately predicted by the paediatric pharmacokinetic morphine model. With regard to efficacy, 5 out of 18 neonates (27.8 %) with a PNA of <10 days needed rescue medication versus 18 of the 20 older patients (90 %) (p = 0.06). The median (interquartile range [IQR]) total morphine rescue dose was 0 (0-20) μg/kg in younger patients versus 193 (19-362) μg/kg in older patients (p = 0.003). The median (IQR) actual average morphine infusion rate was 4.4 (4.0-4.8) μg/kg/h in younger patients versus 14.4 (11.3-23.4) μg/kg/h in older patients (p < 0.001). Conclusion: Morphine paediatric dosing algorithms corrected for pharmacokinetic differences alone yield effective doses that prevent over-dosing for neonates with a PNA <10 days. The fact that many neonates and infants with a PNA ≥10 days still required rescue medication warrants pharmacodynamic studies to further optimize the dosing algorithm for these patients.

Additional Metadata
Persistent URL dx.doi.org/10.1007/s40262-014-0135-4, hdl.handle.net/1765/57629
Journal Clinical Pharmacokinetics
Citation
Krekels, E.H.J, Tibboel, D, de Wildt, S.N, Ceelie, I, Dahan, A, van Dijk, M, … Knibbe, C.A.J. (2014). Evidence-based morphine dosing for postoperative neonates and infants. Clinical Pharmacokinetics, 53(6), 553–563. doi:10.1007/s40262-014-0135-4