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Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia

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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375702/
https://www.ncbi.nlm.nih.gov/pubmed/30763356
http://dx.doi.org/10.1371/journal.pone.0211910
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author 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.
author_facet 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.
author_sort Favié, Laurent M. A.
collection PubMed
description 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. TRIAL REGISTRATION: www.trialregister.nl NTR2529.
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spelling pubmed-63757022019-03-01 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. PLoS One Research Article 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. TRIAL REGISTRATION: www.trialregister.nl NTR2529. Public Library of Science 2019-02-14 /pmc/articles/PMC6375702/ /pubmed/30763356 http://dx.doi.org/10.1371/journal.pone.0211910 Text en © 2019 Favié et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
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.
Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia
title Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia
title_full Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia
title_fullStr Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia
title_full_unstemmed Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia
title_short Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia
title_sort pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375702/
https://www.ncbi.nlm.nih.gov/pubmed/30763356
http://dx.doi.org/10.1371/journal.pone.0211910
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