PLoS ONE (Jan 2019)

Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia.

  • Laurent M A Favié,
  • Floris Groenendaal,
  • Marcel P H van den Broek,
  • Carin M A Rademaker,
  • Timo R de Haan,
  • Henrica L M van Straaten,
  • Peter H Dijk,
  • Arno van Heijst,
  • Jeroen Dudink,
  • Koen P Dijkman,
  • Monique Rijken,
  • Inge A Zonnenberg,
  • Filip Cools,
  • Alexandra Zecic,
  • Johanna H van der Lee,
  • Debbie H G M Nuytemans,
  • Frank van Bel,
  • Toine C G Egberts,
  • Alwin D R Huitema,
  • PharmaCool study group

DOI
https://doi.org/10.1371/journal.pone.0211910
Journal volume & issue
Vol. 14, no. 2
p. e0211910

Abstract

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ObjectiveMorphine is a commonly used drug in encephalopathic neonates treated with therapeutic hypothermia after perinatal asphyxia. Pharmacokinetics and optimal dosing of morphine in this population are largely unknown. The objective of this study was to describe pharmacokinetics of morphine and its metabolites morphine-3-glucuronide and morphine-6-glucuronide in encephalopathic neonates treated with therapeutic hypothermia and to develop pharmacokinetics based dosing guidelines for this population.Study designTerm and near-term encephalopathic neonates treated with therapeutic hypothermia and receiving morphine were included in two multicenter cohort studies between 2008-2010 (SHIVER) and 2010-2014 (PharmaCool). Data were collected during hypothermia and rewarming, including blood samples for quantification of morphine and its metabolites. Parental informed consent was obtained for all participants.Results244 patients (GA mean (sd) 39.8 (1.6) weeks, BW mean (sd) 3,428 (613) g, male 61.5%) were included. Morphine clearance was reduced under hypothermia (33.5°C) by 6.89%/°C (95% CI 5.37%/°C- 8.41%/°C, pConclusionsClearance of morphine and its metabolites in neonates is affected by therapeutic hypothermia. The regimen suggested by the simulations will be sufficient in the majority of patients. However, due to the large interpatient variability a higher dose might be necessary in individual patients to achieve the desired effect.Trial registrationwww.trialregister.nl NTR2529.