Evidence-based morphine dosing for postoperative neonates and infants.
OBJECTIVE
From a previously validated paediatric population pharmacokinetic model, it was derived that non-linear morphine maintenance doses of 5 μg/kg(1.5)/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).


CONCLUSIONS
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.
Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands.
Elke H J
EH
Krekels
Dick
D
Tibboel
Saskia N
SN
de Wildt
Ilse
I
Ceelie
Albert
A
Dahan
Monique
M
van Dijk
Meindert
M
Danhof
Catherijne A J
CA
Knibbe
D000367:Age Factors; D000465:Algorithms; D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008954:Models, Biological; D009020:Morphine / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D010149:Postoperative Pain / Q000188:drug therapy*; D011446:Prospective Studies
D000701:Analgesics, Opioid; D009020:Morphine