Dataset Information

Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia.

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 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 ?g/kg followed by continuous infusion of 5 ?g/kg/h resulted in morphine plasma concentrations in the desired range (between 10 and 40 ?g/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.

SUBMITTER: Favie LMA

PROVIDER: S-EPMC6375702 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia.

Favié Laurent M A LMA Groenendaal Floris F van den Broek Marcel P H MPH Rademaker Carin M A CMA de Haan Timo R TR van Straaten Henrica L M HLM Dijk Peter H PH van Heijst Arno A Dudink Jeroen J Dijkman Koen P KP Rijken Monique M Zonnenberg Inge A IA Cools Filip F Zecic Alexandra A van der Lee Johanna H JH Nuytemans Debbie H G M DHGM van Bel Frank F Egberts Toine C G TCG Huitema Alwin D R ADR

PloS one 20190214 2

<h4>Objective</h4>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 th ...[more]

PMID: 30763356

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Project description:BackgroundTheophylline, a non-selective adenosine receptor antagonist, improves renal perfusion in the setting of hypoxia-ischemia and may offer therapeutic benefit in neonates with hypoxic-ischemic encephalopathy (HIE) undergoing hypothermia. We evaluated the pharmacokinetics and dose-exposure relationships of theophylline in this population to guide dosing strategies.MethodsA population pharmacokinetic analysis was performed in 22 neonates with HIE undergoing hypothermia who were part of a prospective study or retrospective chart review. Aminophylline (intravenous salt form of theophylline) was given per institutional standard of care for low urine output and/or rising serum creatinine (5 mg/kg intravenous (i.v.) load then 1.8 mg/kg i.v. q6h). The ability of different dosing regimens to achieve target concentrations (4-10 mg/L) associated with clinical response was examined.ResultsBirth weight was a significant predictor of theophylline clearance and volume of distribution (p < 0.05). The median half-life was 39.5 h (range 27.2-50.4). An aminophylline loading dose of 7 mg/kg followed by 1.6 mg/kg q12h was predicted to achieve target concentrations in 84% of simulated neonates.ConclusionsIn neonates with HIE undergoing hypothermia, theophylline clearance was low with a 50% longer half-life compared to full-term normothermic neonates without HIE. Dosing strategies need to consider the unique pharmacokinetic needs of this population.ImpactTheophylline is a potential renal-protective therapy in neonates with HIE undergoing therapeutic hypothermia; however, the pharmacokinetics and dose needs in this population are not known. Theophylline clearance was low in neonates with HIE undergoing therapeutic hypothermia with a 50% longer half-life compared to full-term normothermic neonates without HIE. As theophylline is advanced in clinical development, dosing strategies will need to consider the unique pharmacokinetic needs of neonates with HIE undergoing therapeutic hypothermia.

Project description:BackgroundHypothermia-treated and intubated infants with moderate or severe hypoxic-ischemic encephalopathy (HIE) usually receive morphine for sedation and analgesia (SA) during therapeutic hypothermia (TH) and endotracheal ventilation. Altered drug pharmacokinetics in this population increases the risk of drug accumulation. Opioids are neurotoxic in preterm infants. In term infants undergoing TH, the long-term effects of morphine exposure are unknown. We examined the effect of opioid administration during TH on neurodevelopmental outcome and time to extubation after sedation ended.MethodsIn this prospectively collected population-based cohort of 282 infants with HIE treated with TH (2007-2017), the cumulative opioid dose of morphine and equipotent fentanyl (10-60 µg/kg/h) administered during the first week of life was calculated. Clinical outcomes and concomitant medications were also collected. Of 258 survivors, 229 underwent Bayley-3 neurodevelopmental assessments of cognition, language and motor function at 18-24 months. Multivariate stepwise linear regression analysis was used to examine the relation between cumulative opioid dose and Bayley-3 scores. Three severity-groups (mild-moderate-severe) were stratified by early (<6 h) amplitude-integrated electroencephalography (aEEG) patterns.FindingsThe cumulative dose of opioid administered as SA during TH was median (IQR) 2121 µg/kg (1343, 2741). Time to extubation was independent of SA dose (p > 0.2). There was no significant association between cumulative SA dose and any of the Bayley-3 domains when analysing the entire cohort or any of the aEEG severity groups.InterpretationHigher cumulative opioid doses in TH-treated infants with HIE was not associated with worse Bayley-3 scores at 18-24 months of age.FundingThe Bristol cooling program was funded by the Children's Medical Research Charity SPARKS managing donations for our research from the UK and US, the UK Moulton Foundation, the Lærdal Foundation for Acute Medicine in Norway and the Norwegian Research Council (JKG).

Project description:BackgroundTherapeutic hypothermia (TH) reduces neonatal mortality and long-term neurodevelopmental impairment in infants with moderate-to-severe hypoxic-ischemic encephalopathy (HIE) caused by perinatal asphyxia. There is an increasing trend to apply TH in other indications and populations, such as infants with mild HIE or neonates with congenital heart defects (CHD), even though there is little evidence to support or refute this.ObjectiveThe aim of this survey was to analyze practice variations with respect to TH use in neonates with CHD and to assess expert opinions on this topic across tertiary neonatal departments in Germany.Methods/designA web-based survey was sent to all tertiary neonatal departments in Germany. The questionnaire contained 32 multiple-choice questions. The survey inquired current practices on TH in newborns with CHD and expert opinions on various clinical scenarios.Main resultsA total 80 (51.3%) neonatal departments partially completed the survey, and 69 (44.2%) respondents filled out the whole questionnaire. All 80 (100.0%) departments perform TH. TH is offered by 76 (95.0%) respondents to encephalopathic newborns with simple CHD. In infants with critical/complex CHD, TH is offered after perinatal asphyxial HIE and in newborns with encephalopathy after severe acidosis associated with cardiac complications by 25 (31.3%), or 17 (22.1%) respondents, respectively, whereas a clear majority of centers reject TH in these infants. Unclear effects of TH on any ongoing prostaglandin therapy (57.6 and 52.3%, respectively), an increased risk for adverse reactions during TH (51.6 and 52.3%, respectively) and lack of evidence (33.3 and 53.8%, respectively) are the most frequently cited reasons for not performing TH in these infants. The majority of experts from neonatal departments providing comprehensive care for neonates with severe CHD support the initiation of TH in encephalopathic neonates.DiscussionThe considerable heterogeneity in the use of TH in neonates with CHD emphasizes the need for further research to optimize treatment strategies for these patients.

Dataset Information

Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia.

Objective

Study design

Results

Conclusions

Trial registration

Publications

Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia.

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