Pharmacokinetics of Morphine and Its Metabolites in Infants and Young Children After Congenital Heart Surgery.
The objective of this study was to characterize morphine glucuronidation in infants and children following cardiac surgery for possible treatment individualization in this population. Twenty children aged 3 days to 6 years, admitted to the cardiovascular intensive care unit after congenital heart surgery, received an intravenous (IV) loading dose of morphine (0.15 mg/kg) followed by subsequent intermittent IV bolus doses based on a validated pain scale. Plasma samples were collected over 6 h after the loading dose and randomly after follow-up doses to measure morphine and its major metabolite concentrations. A population pharmacokinetic model was developed with the non-linear mixed effects software NONMEM. Parent disposition was adequately described by a linear two-compartment model. Effect of growth (size and maturation) on morphine parameters was accounted for by allometric body weight-based models. An intermediate compartment with Emax model best characterized glucuronide concentrations. Glomerular filtration rate was identified as a significant predictor of glucuronide formation time delay and maximum concentrations. Clearance of morphine in children with congenital heart disease is comparable to that reported in children without cardiac abnormalities of similar age. Children 1-6 months of age need higher morphine doses per kilogram to achieve an area under concentration-time curve comparable to that in older children. Pediatric patients with renal failure receiving morphine therapy are at increased risk of developing opioid toxicity due to accumulation of morphine metabolites.
Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California, 94305-5117, USA.|Department of Pharmaceutics and Industrial Pharmacy, Beni Suef University, Beni Suef, Egypt.
Mohammed H
MH
Elkomy
Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California, 94305-5117, USA. ddrover@stanford.edu.
David R
DR
Drover
Division of Pediatric Critical Care Medicine, Duke University Medical Center, Durham, North Carolina, USA.
Kristi L
KL
Glotzbach
Department of Anesthesiology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA.
Jeffery L
JL
Galinkin
Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.
Adam
A
Frymoyer
Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.
Felice
F
Su
Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California, 94305-5117, USA.|Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.
Gregory B
GB
Hammer
D061605:Administration, Intravenous; D000701:Analgesics, Opioid / Q000493:pharmacokinetics*; D001711:Biotransformation; D006348:Cardiac Surgical Procedures; D002648:Child; D002675:Child, Preschool; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D020719:Glucuronides / Q000378:metabolism; D006330:Heart Defects, Congenital / Q000601:surgery*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016014:Linear Models; D008297:Male; D015233:Models, Statistical; D009020:Morphine / Q000493:pharmacokinetics*; D010147:Pain Measurement / Q000187:drug effects; D011184:Postoperative Period; D051437:Renal Insufficiency / Q000378:metabolism
D000701:Analgesics, Opioid; D020719:Glucuronides; D009020:Morphine
NONMEM; metabolism; morphine; pediatric; pharmacokinetics