Published February 15, 2019 | Version v1
Dataset Open

Data from: Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia

  • 1. University Medical Center Utrecht
  • 2. Wilhelmina Children's Hospital
  • 3. Emma Kinderziekenhuis
  • 4. Department of Neonatology, Isala Clinics, Zwolle, the Netherlands*
  • 5. University Medical Center Groningen
  • 6. Department of Neonatology, Radboud university medical center-Amalia Children's Hospital, Nijmegen, the Netherlands*
  • 7. Sophia Children's Hospital
  • 8. Máxima Medisch Centrum
  • 9. Leiden University
  • 10. VU University Medical Center
  • 11. Vrije Universiteit Brussel
  • 12. Department of Neonatology, University Hospital Gent, Gent, Belgium*
  • 13. Clinical Research Coordinator PharmaCool Study, Amsterdam, the Netherlands*


Objective: Morphine 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 design: Term 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. Results: 244 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, p<0.001) and metabolite clearance by 4.91%/°C (95% CI 3.53%/°C – 6.22%/°C, p<0.001) compared to normothermia (36.5°C). Simulations showed that a loading dose of 50 μg/kg followed by continuous infusion of 5 μg/kg/h resulted in morphine plasma concentrations in the desired range (between 10 and 40 μg/L) during hypothermia. Conclusions: Clearance 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.



PONE-D-18-26939R2 final dataset.csv

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