title: Morphine metabolite pharmacokinetics during venoarterial extra corporeal membrane oxygenation in neonates.
abstract: OBJECTIVE
  To examine morphine metabolite serum concentrations in neonates undergoing venoarterial extra corporeal membrane oxygenation (ECMO) and to quantify clearance differences between these neonates and those subjected to noncardiac major surgery.
  
  
  METHODS
  This was an observational study in level III referral centre. Fourteen neonates (< 7 days old) undergoing ECMO were included. Morphine and concomitant medications were given by protocol, adapted to the clinical conditions of the neonates. Pharmacokinetic findings were compared with those from a previous study in infants after noncardiac major surgery. Nonlinear mixed-effect modelling was used. Parameter estimates were standardised to a 70 kg person using allometric modeling
  
  
  RESULTS
  Morphine-3-glucuronide (M3G) was the predominant metabolite. Formation clearance to M3G at the start of ECMO on day 1 was lower than those in postoperative children, but matured more rapidly. After 10 days formation clearances of M3G in neonates on ECMO equalled those of postoperative children. Higher ECMO flows were associated with reduced formation clearances. Elimination clearances of M3G, but not morphine-6-glucuronide (M6G), were lower in the ECMO neonates; this was attributable to reduced renal clearance. These elimination clearances were correlated positively with ECMO flow and negatively with dopamine dose. Haemofiltration cleared M3G and M6G, but not morphine.
  
  
  CONCLUSIONS
  Formation clearance to M3G, the predominant metabolite, is reduced during the first 10 days of ECMO. Elimination clearance of M3G and M6G is related to creatinine clearance. ECMO flow had a small effect on metabolite clearance. Higher flows were associated with decreased formation clearances, possibly reflecting illness severity. Dopamine dose reflected decreased renal clearance.
authors.affiliation: Department of Pediatric Surgery, Erasmus MC-Sophia, Rotterdam, The Netherlands. j.peters@erasmusmc.nl
authors.forename: Jeroen W B
authors.initials: JW
authors.lastname: Peters
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Anderson
authors.forename: Sinno H P
authors.initials: SH
authors.lastname: Simons
authors.forename: Donald R A
authors.initials: DR
authors.lastname: Uges
authors.forename: Dick
authors.initials: D
authors.lastname: Tibboel
mesh_terms: D000328:Adult; D000465:Algorithms; D000701:Analgesics, Opioid / Q000493:pharmacokinetics*; D001499:Bayes Theorem; D001711:Biotransformation; D015331:Cohort Studies; D015199:Extracorporeal Membrane Oxygenation; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009020:Morphine / Q000493:pharmacokinetics*; D009022:Morphine Derivatives / Q000097:blood; D011153:Population; D011184:Postoperative Period; D014673:Vecuronium Bromide / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D000701:Analgesics, Opioid; D009022:Morphine Derivatives; C035349:morphine-6-glucuronide; D009020:Morphine; D014673:Vecuronium Bromide; C018108:morphine-3-glucuronide