Morphine and fentanyl exposure during therapeutic hypothermia does not impair neurodevelopment

Julia Gundersen; Elavazhagan Chakkarapani; Sally L Jary; David Menassa; Emma L Scull-Brown; Adam Frymoyer; Lars Walløe; Marianne Thoresen

doi:10.1016/j.eclinm.2021.100892

Morphine and fentanyl exposure during therapeutic hypothermia does not impair neurodevelopment

Julia Gundersen
, Elavazhagan Chakkarapani
, Sally L Jary
, David Menassa
, Emma L Scull-Brown
, Adam Frymoyer
, Lars Walløe
, Marianne Thoresen^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

30 Citations (Scopus)

134 Downloads (Pure)

Abstract

Background

Hypothermia-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.

Methods

In 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.

Findings

The 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.

Interpretation

Higher cumulative opioid doses in TH-treated infants with HIE was not associated with worse Bayley-3 scores at 18–24 months of age.

Funding

The 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).

Original language	English
Article number	100892
Number of pages	9
Journal	eClinicalMedicine
Volume	36
Early online date	5 Jun 2021
DOIs	https://doi.org/10.1016/j.eclinm.2021.100892
Publication status	Published - Jun 2021

Bibliographical note

Funding Information:
We thank the NHS and our Universities and funders in UK and Norway: SPARKS, The Moulton Foundation, The Norwegian Research Council, The Neonatal Society UK and charitable donations to cooling therapy. The staff maintaining the database were supported by the UK children's charity SPARKS and a linked external charitable donation. Equipment used to cool the patients and the aEEG machines to monitor the brain were supported by the Moulton foundation, the Lærdal foundation and charitable donations. Using the MRI-scanners were supported by grants, the NHS and the University of Bristol. Clinical and research staff were supported by the NHS, the University of Bristol and the University of Oslo through their salaries.

Funding Information:
We thank our funders, clinical collaborators and parents of patients for their support in carrying out treatment and for prospective data collection of infants undergoing Therapeutic Hypothermia as standard of care at St Michael's Hospital, Bristol since December 2006. All authors fulfil the four ICMJE criteria with 1: Substantial contribution to the conception, design and analysis of the work (MT, JKG, LW) and acquisition and interpretation of data (MT, JKG, LW, ESB, AF, SJ, EC). 2: Drafting the work or revising it critically for important intellectual content (MT, JKG, LW, AF, DAM, EC). 3: Final approval of the version to be submitted (MT, JKG, LW, AF, DAM, EC, SJ, ESB) and 4: Agreement to be accountable for all aspects of the work (MT, JKG, LW, AF, DAM, EC, SJ, ESB). We thank the NHS and our Universities and funders in UK and Norway: SPARKS, The Moulton Foundation, The Norwegian Research Council, The Neonatal Society UK and charitable donations to cooling therapy. The staff maintaining the database were supported by the UK children's charity SPARKS and a linked external charitable donation. Equipment used to cool the patients and the aEEG machines to monitor the brain were supported by the Moulton foundation, the L?rdal foundation and charitable donations. Using the MRI-scanners were supported by grants, the NHS and the University of Bristol. Clinical and research staff were supported by the NHS, the University of Bristol and the University of Oslo through their salaries. The datasets analysed in the current study are not publicly available due to restricted access until Apr1st 2023, when further information about the datasets will be made available from the corresponding author on reasonable request.

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© 2021 The Authors

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@article{befaf7e65521490ebb1e550d139c39a4,

title = "Morphine and fentanyl exposure during therapeutic hypothermia does not impair neurodevelopment",

abstract = "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 L{\ae}rdal Foundation for Acute Medicine in Norway and the Norwegian Research Council (JKG).",

author = "Julia Gundersen and Elavazhagan Chakkarapani and Jary, \{Sally L\} and David Menassa and Scull-Brown, \{Emma L\} and Adam Frymoyer and Lars Wall{\o}e and Marianne Thoresen",

note = "Funding Information: We thank the NHS and our Universities and funders in UK and Norway: SPARKS, The Moulton Foundation, The Norwegian Research Council, The Neonatal Society UK and charitable donations to cooling therapy. The staff maintaining the database were supported by the UK children's charity SPARKS and a linked external charitable donation. Equipment used to cool the patients and the aEEG machines to monitor the brain were supported by the Moulton foundation, the L{\ae}rdal foundation and charitable donations. Using the MRI-scanners were supported by grants, the NHS and the University of Bristol. Clinical and research staff were supported by the NHS, the University of Bristol and the University of Oslo through their salaries. Funding Information: We thank our funders, clinical collaborators and parents of patients for their support in carrying out treatment and for prospective data collection of infants undergoing Therapeutic Hypothermia as standard of care at St Michael's Hospital, Bristol since December 2006. All authors fulfil the four ICMJE criteria with 1: Substantial contribution to the conception, design and analysis of the work (MT, JKG, LW) and acquisition and interpretation of data (MT, JKG, LW, ESB, AF, SJ, EC). 2: Drafting the work or revising it critically for important intellectual content (MT, JKG, LW, AF, DAM, EC). 3: Final approval of the version to be submitted (MT, JKG, LW, AF, DAM, EC, SJ, ESB) and 4: Agreement to be accountable for all aspects of the work (MT, JKG, LW, AF, DAM, EC, SJ, ESB). We thank the NHS and our Universities and funders in UK and Norway: SPARKS, The Moulton Foundation, The Norwegian Research Council, The Neonatal Society UK and charitable donations to cooling therapy. The staff maintaining the database were supported by the UK children's charity SPARKS and a linked external charitable donation. Equipment used to cool the patients and the aEEG machines to monitor the brain were supported by the Moulton foundation, the L?rdal foundation and charitable donations. Using the MRI-scanners were supported by grants, the NHS and the University of Bristol. Clinical and research staff were supported by the NHS, the University of Bristol and the University of Oslo through their salaries. The datasets analysed in the current study are not publicly available due to restricted access until Apr1st 2023, when further information about the datasets will be made available from the corresponding author on reasonable request. Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = jun,

doi = "10.1016/j.eclinm.2021.100892",

language = "English",

volume = "36",

journal = "eClinicalMedicine",

issn = "2589-5370",

publisher = "Elsevier Limited",

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T1 - Morphine and fentanyl exposure during therapeutic hypothermia does not impair neurodevelopment

AU - Gundersen, Julia

AU - Chakkarapani, Elavazhagan

AU - Jary, Sally L

AU - Menassa, David

AU - Scull-Brown, Emma L

AU - Frymoyer, Adam

AU - Walløe, Lars

AU - Thoresen, Marianne

N1 - Funding Information: We thank the NHS and our Universities and funders in UK and Norway: SPARKS, The Moulton Foundation, The Norwegian Research Council, The Neonatal Society UK and charitable donations to cooling therapy. The staff maintaining the database were supported by the UK children's charity SPARKS and a linked external charitable donation. Equipment used to cool the patients and the aEEG machines to monitor the brain were supported by the Moulton foundation, the Lærdal foundation and charitable donations. Using the MRI-scanners were supported by grants, the NHS and the University of Bristol. Clinical and research staff were supported by the NHS, the University of Bristol and the University of Oslo through their salaries. Funding Information: We thank our funders, clinical collaborators and parents of patients for their support in carrying out treatment and for prospective data collection of infants undergoing Therapeutic Hypothermia as standard of care at St Michael's Hospital, Bristol since December 2006. All authors fulfil the four ICMJE criteria with 1: Substantial contribution to the conception, design and analysis of the work (MT, JKG, LW) and acquisition and interpretation of data (MT, JKG, LW, ESB, AF, SJ, EC). 2: Drafting the work or revising it critically for important intellectual content (MT, JKG, LW, AF, DAM, EC). 3: Final approval of the version to be submitted (MT, JKG, LW, AF, DAM, EC, SJ, ESB) and 4: Agreement to be accountable for all aspects of the work (MT, JKG, LW, AF, DAM, EC, SJ, ESB). We thank the NHS and our Universities and funders in UK and Norway: SPARKS, The Moulton Foundation, The Norwegian Research Council, The Neonatal Society UK and charitable donations to cooling therapy. The staff maintaining the database were supported by the UK children's charity SPARKS and a linked external charitable donation. Equipment used to cool the patients and the aEEG machines to monitor the brain were supported by the Moulton foundation, the L?rdal foundation and charitable donations. Using the MRI-scanners were supported by grants, the NHS and the University of Bristol. Clinical and research staff were supported by the NHS, the University of Bristol and the University of Oslo through their salaries. The datasets analysed in the current study are not publicly available due to restricted access until Apr1st 2023, when further information about the datasets will be made available from the corresponding author on reasonable request. Publisher Copyright: © 2021 The Authors

PY - 2021/6

Y1 - 2021/6

N2 - 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).

AB - 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).

U2 - 10.1016/j.eclinm.2021.100892

DO - 10.1016/j.eclinm.2021.100892

M3 - Article (Academic Journal)

C2 - 34308308

SN - 2589-5370

VL - 36

JO - eClinicalMedicine

JF - eClinicalMedicine

M1 - 100892

ER -

Morphine and fentanyl exposure during therapeutic hypothermia does not impair neurodevelopment

Abstract

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