Medical student / PhD University of Oslo University of Oslo Oslo , Norway
Background: Term-born infants with moderate or severe hypoxic-ischemic encephalopathy (HIE) undergoing 72h of therapeutic hypothermia (TH) are intubated and administered opioids for sedation and analgesia (SA). The need for SA can be highly variable during TH due to altered drug pharmacokinetics. There are no standardized guidelines on opioid dosing during TH, which is decided on evaluated clinical need. In premature infants, neonatal opioid exposure is associated with impaired cognition and motor function at 18 months. There are no published studies on dose-dependent long-term effect of opioid exposure during TH in term-born infants with HIE.
Objective: To examine any dose-dependent effect of morphine and fentanyl administered during TH on Bayley 3 scores at 18-24 months of age.
Design/Methods: We conducted a retrospective analysis of prospectively collected population-based cohort (2007-2017) of 304 (8% mortality) patients treated with TH at St. Michael’s regional cooling-centre using CoolCap/TOBY entry criteria. Elective intubation was commenced with 100µg/kg morphine bolus dose and 20µg/kg/h infusion, adjusted after clinical need. Per physicians’ choice, 33 infants also received fentanyl. The cumulative morphine and fentanyl (opioid) dose administered during the first week of life was collected. For morphine-equipotent conversion, fentanyl doses were multiplied by 40. Neurodevelopmental outcomes of cognition, language and motor function were assessed at 18-24 months using Bayley 3 (n=244). The relationship between the 7-day cumulative opioid dose and Bayley 3 scores were examined using multivariate linear regression controlling for sex, being outborn, weight, cardiopulmonary resuscitation, apgar10min, pH<1h, base excess<1h, HIE-grade, aEEG pattern<6h, inotropic support, anticonvulsive drugs, alanine aminotransferase, lactate dehydrogenase72h and intubation duration.
Results: The median (IQR) continuous opioid infusion duration was 86h (78-97). The median (IQR) cumulative first-week dose of administered opioids was 2190 µg/kg (1377-2841). We found no significant association between cumulative opioid dose and Bayley 3 scores for cognition (p=0.81), language (p=0.52) or motor function (p=0.76). Conclusion(s): To mitigate confounding with severity of encephalopathy and symptoms of discomfort, we controlled for HIE-severity in the analysis. Across a wide range of opioid doses, no negative association between cumulative opioid dose and Bayley 3 scores at 18-24 months was found.
Authors/Institutions: Julia K. Gundersen, University of Oslo, Oslo , , Norway; Ela Chakkarapani, University of Bristol, Bristol, , United Kingdom; Sally Jary, University of Bristol, Bristol, , United Kingdom; David A. Menassa, University of Oslo, Oslo , , Norway; Emma Scull-Brown, University of Bristol, Bristol, , United Kingdom; Adam Frymoyer, Stanford University, San Carlos, California, United States; Lars Walløe, University of Oslo, Oslo , , Norway; Marianne Thoresen, University of Bristol, Bristol, Avon, United Kingdom
