Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia
Favié, Laurent M.A.; Groenendaal, Floris; van den Broek, Marcel P.H.; Rademaker, Carin M.A.; De Haan, Timo R.; Van Straaten, Henrica L.M.; Dijk, Peter H.; Van Heijst, Arno; Dudink, Jeroen; Dijkman, Koen P.; Rijken, Monique; Zonnenberg, Inge A.; Cools, Filip; Zecic, Alexandra; van der Lee, Johanna H.; Nuytemans, Debbie H.G.M.; van Bel, Frank; Egberts, Toine C.G.; Huitema, Alwin D.R.; the PharmaCool study group
(2019) PLoS ONE, volume 14, issue 2, pp.
(Article)
Abstract
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
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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 (33.5C) 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 (36.5C). 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.
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Keywords: perinatal asphyxia, Morphine, Therapeutic hypothermia, Pharmacokinetics, General Agricultural and Biological Sciences, General Biochemistry,Genetics and Molecular Biology, Journal Article
ISSN: 1932-6203
Publisher: Public Library of Science
Note: Funding Information: Netherlands Organization for Health Research and Development (ZonMw) Priority Medicines for Children (grant number: 40-41500-98-9002). The funder did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2019 Favié et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.
(Peer reviewed)