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Morphine Sedation During Therapeutic Hypothermia In Term Asphyxiated Infants Does Not Influence Bayley 3 Developmental Outcome At 18-24 Months Of Age

Julia K Gundersen1,2, Sally Jary1, Emma Scull-Brown1, Satomi Okano1, Mathias Karlsson1,3, Lars Walløe2, Ela Chakkarapani1, Marianne Thoresen1,2 
1. Translational Health Sciences, St. Michael’s Hospital, Bristol Medical School, University of Bristol, Bristol, UK 
2. Division of Physiology, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway 
3. Department of Medical Sciences, Biomedical Structure and Function, Uppsala University, Uppsala, Sweden 
In Bristol, we intubate infants treated with therapeutic hypothermia(TH) and start morphine infusion 10-20μg/kg/hr for sedation and analgesia(SA). Experimental evidence suggests that insufficient SA may impair hypothermic neuroprotection1. Adverse neurodevelopmental outcome was found in premature infants exposed to morphine2, however evidence is lacking whether morphine during TH or NT in term infants is harmful3. The aim was to examine whether morphine during TH has an effect on cognition, language or motor development. 
Clinical data (2006-16) on 259 term infants undergoing TH were prospectively collected. The CoolCap/Toby protocol with aEEG severity as an inclusion criterion was followed, in a single level 3 NICU, recruiting from 8 hospitals. 22 died and 61 survived with disability. Bayley3 language, cognition and motor scales were examined at 18-24 months, with adverse outcome scored <85. Two morphine variables were used in the analysis: a) the total first week morphine dose, b) the mean hourly infusion rate on day 2. In addition, previously developed outcome predictors4 were used in stepwise linear regression (SPSS) with Bayley3 as the dependent variable. 
The median total morphine dose was 2450mcg/kg (IQR=3240-1580). Most morphine was administered on day 2 with a median infusion rate of 40μg/kg/hr (fig). 67% of patients were off morphine during day 4. Only 3 variables were statistically significant at the 5% level; aEEG pattern <6hrs, number of anticonvulsant drugs used and the value of lactate dehydrogenase at 72h. Most importantly, no morphine variable entered the equation (p≈0.50) neither in the whole cohort, nor in those with adverse outcome only. In addition, there was no interaction between morphine and the significant outcome predictors in the model. 
Morphine Sedation During Therapeutic Hypothermia In Term Asphyxiated Infants Does Not Influence Bayley 3 Developmental Outcome At 18-24 Months Of Age
Continuous morphine infusion rate and total morphine dose during the first week of life did not predict cognition, language or motor Bayley3 scores. Thus, at 18-24months, we find no evidence that morphine has been harmful to term newborns undergoing TH. Follow up at school age and beyond is necessary. 
(1) Thoresen M et al Pediatr Res 2001 50 405-411,(2) Zwicker et al J Pediat 2016 172 81-87 e82, (3) de Graaf J et al Pain 2013 154 449-458, (4) Liu X et al Epilepsia 2017 58 1902-1911. Research ethics: CH09/H016/3 Fund: Wellcome, SPARKS 

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