{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T22:07:17Z","timestamp":1790719637563,"version":"4.1.0"},"reference-count":31,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:00:00Z","timestamp":1622505600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:00:00Z","timestamp":1622505600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2021,4,24]],"date-time":"2021-04-24T00:00:00Z","timestamp":1619222400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000883","name":"University of Bristol","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000883","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005366","name":"Universitetet i Oslo","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005366","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["thelancet.com","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["EClinicalMedicine"],"published-print":{"date-parts":[[2021,6]]},"DOI":"10.1016\/j.eclinm.2021.100892","type":"journal-article","created":{"date-parts":[[2021,6,4]],"date-time":"2021-06-04T23:37:18Z","timestamp":1622849838000},"page":"100892","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":27,"special_numbering":"C","title":["Morphine and fentanyl exposure during therapeutic hypothermia does not impair neurodevelopment"],"prefix":"10.1016","volume":"36","author":[{"given":"Julia K","family":"Gundersen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ela","family":"Chakkarapani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally","family":"Jary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5984-8407","authenticated-orcid":false,"given":"David A","family":"Menassa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Scull-Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Frymoyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Wall\u00f8e","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9615-9109","authenticated-orcid":false,"given":"Marianne","family":"Thoresen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"issue":"6","key":"10.1016\/j.eclinm.2021.100892_bib0001","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1038\/s41372-019-0349-2","article-title":"Respiratory management during therapeutic hypothermia for hypoxic-ischemic encephalopathy","volume":"39","author":"Szakmar","year":"2019","journal-title":"J Perinatol"},{"key":"10.1016\/j.eclinm.2021.100892_bib0002","doi-asserted-by":"crossref","DOI":"10.1038\/s41390-019-0744-6","article-title":"The influence of pain, agitation, and their management on the immature brain","author":"McPherson","year":"2020","journal-title":"Pediatr Res"},{"issue":"9460","key":"10.1016\/j.eclinm.2021.100892_bib0003","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/S0140-6736(05)17946-X","article-title":"Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial","volume":"365","author":"Gluckman","year":"2005","journal-title":"Lancet"},{"issue":"15","key":"10.1016\/j.eclinm.2021.100892_bib0004","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1056\/NEJMcps050929","article-title":"Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy","volume":"353","author":"Shankaran","year":"2005","journal-title":"N Engl J Med"},{"issue":"14","key":"10.1016\/j.eclinm.2021.100892_bib0005","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1056\/NEJMoa0900854","article-title":"Moderate hypothermia to treat perinatal asphyxial encephalopathy","volume":"361","author":"Azzopardi","year":"2009","journal-title":"N Engl J Med"},{"key":"10.1016\/j.eclinm.2021.100892_bib0006","first-page":"e771","volume":"126","author":"Simbruner","year":"2010"},{"key":"10.1016\/j.eclinm.2021.100892_bib0007","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.jpeds.2015.12.024","article-title":"Smaller cerebellar growth and poorer neurodevelopmental outcomes in very preterm infants exposed to neonatal morphine","volume":"172","author":"Zwicker","year":"2016","journal-title":"J Pediatr"},{"issue":"9422","key":"10.1016\/j.eclinm.2021.100892_bib0008","doi-asserted-by":"crossref","first-page":"1673","DOI":"10.1016\/S0140-6736(04)16251-X","article-title":"Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial","volume":"363","author":"Anand","year":"2004","journal-title":"Lancet"},{"issue":"1","key":"10.1016\/j.eclinm.2021.100892_bib0009","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.ntt.2011.10.008","article-title":"A pilot study of preemptive morphine analgesia in preterm neonates: effects on head circumference, social behavior, and response latencies in early childhood","volume":"34","author":"Ferguson","year":"2012","journal-title":"Neurotoxicol Teratol"},{"issue":"10","key":"10.1016\/j.eclinm.2021.100892_bib0010","doi-asserted-by":"crossref","first-page":"e76702","DOI":"10.1371\/journal.pone.0076702","article-title":"Neonatal pain-related stress predicts cortical thickness at age 7 years in children born very preterm","volume":"8","author":"Ranger","year":"2013","journal-title":"PLoS One"},{"issue":"2","key":"10.1016\/j.eclinm.2021.100892_bib0011","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.jpeds.2015.04.055","article-title":"Neonatal pain and infection relate to smaller cerebellum in very preterm children at school age","volume":"167","author":"Ranger","year":"2015","journal-title":"J Pediatr"},{"key":"10.1016\/j.eclinm.2021.100892_bib0012","doi-asserted-by":"crossref","first-page":"51","DOI":"10.3389\/fnbeh.2019.00051","article-title":"Hippocampus, Amygdala, and Thalamus volumes in very preterm children at 8 years: neonatal pain and genetic variation","volume":"13","author":"Chau","year":"2019","journal-title":"Front Behav Neurosci"},{"issue":"3","key":"10.1016\/j.eclinm.2021.100892_bib0013","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1203\/00006450-200109000-00017","article-title":"Twenty-four hours of mild hypothermia in unsedated newborn pigs starting after a severe global hypoxic-ischemic insult is not neuroprotective","volume":"50","author":"Thoresen","year":"2001","journal-title":"Pediatr Res"},{"issue":"1","key":"10.1016\/j.eclinm.2021.100892_bib0014","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1002\/ana.10402","article-title":"Head cooling with mild systemic hypothermia in anesthetized piglets is neuroprotective","volume":"53","author":"Tooley","year":"2003","journal-title":"Ann Neurol"},{"key":"10.1016\/j.eclinm.2021.100892_bib0015","doi-asserted-by":"crossref","first-page":"294","DOI":"10.3389\/fneur.2018.00294","article-title":"Fentanyl induces cerebellar internal granular cell layer apoptosis in healthy newborn pigs","volume":"9","author":"Sabir","year":"2018","journal-title":"Front Neurol."},{"issue":"2","key":"10.1016\/j.eclinm.2021.100892_bib0016","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1097\/ALN.0b013e318294934d","article-title":"Neither xenon nor fentanyl induces neuroapoptosis in the newborn pig brain","volume":"119","author":"Sabir","year":"2013","journal-title":"Anesthesiology"},{"issue":"1","key":"10.1016\/j.eclinm.2021.100892_bib0017","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1002\/jcph.775","article-title":"Decreased morphine clearance in neonates with hypoxic ischemic encephalopathy receiving hypothermia","volume":"57","author":"Frymoyer","year":"2016","journal-title":"J Clin Pharmacol"},{"issue":"2","key":"10.1016\/j.eclinm.2021.100892_bib0018","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0211910","article-title":"Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia","volume":"14","author":"Favi\u00e9","year":"2019","journal-title":"PloS One"},{"issue":"4","key":"10.1016\/j.eclinm.2021.100892_bib0019","doi-asserted-by":"crossref","first-page":"e844","DOI":"10.1542\/peds.2007-1987","article-title":"Elevated morphine concentrations in neonates treated with morphine and prolonged hypothermia for hypoxic ischemic encephalopathy","volume":"121","author":"Roka","year":"2008","journal-title":"Pediatrics"},{"issue":"11","key":"10.1016\/j.eclinm.2021.100892_bib0020","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1093\/bja\/59.11.1459","article-title":"Effects of temperature on the interaction of morphine with opioid receptors","volume":"59","author":"Puig","year":"1987","journal-title":"BJA Br J Anaesth"},{"key":"10.1016\/j.eclinm.2021.100892_bib0021","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/1471-2431-8-17","article-title":"The TOBY Study. Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy: a randomised controlled trial","volume":"8","author":"Azzopardi","year":"2008","journal-title":"BMC Pediatr"},{"issue":"2","key":"10.1016\/j.eclinm.2021.100892_bib0022","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1111\/apa.12784","article-title":"Cooling neonates who do not fulfil the standard cooling criteria - short- and long-term outcomes","volume":"104","author":"Smit","year":"2014","journal-title":"Acta Paediatr"},{"key":"10.1016\/j.eclinm.2021.100892_bib0023","volume":"15","year":"2021"},{"key":"10.1016\/j.eclinm.2021.100892_bib0024","article-title":"Test Review: Bayley, N. (2006). Bayley Scales of Infant and Toddler Development, Third Edition. San Antonio, TX: Harcourt Assessment","author":"Albers","year":"2016","journal-title":"J Psychoeduc Assess"},{"key":"10.1016\/j.eclinm.2021.100892_bib0025","first-page":"1394","volume":"85","author":"Gill","year":"2014"},{"key":"10.1016\/j.eclinm.2021.100892_bib0026","article-title":"MRI combined with early clinical variables are excellent outcome predictors for newborn infants undergoing therapeutic hypothermia after perinatal asphyxia","volume":"36","author":"Thoresen","year":"2021","journal-title":"Lancet EClinicalMedicine"},{"key":"10.1016\/j.eclinm.2021.100892_bib0027","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.jpeds.2017.04.041","article-title":"Amplitude-integrated electroencephalography improves the identification of infants with Encephalopathy for therapeutic hypothermia and predicts neurodevelopmental outcomes at 2 years of age","volume":"187","author":"Skranes","year":"2017","journal-title":"J Pediatr"},{"issue":"8","key":"10.1016\/j.eclinm.2021.100892_bib0028","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1038\/s41372-018-0126-7","article-title":"Association between sedation-analgesia and neurodevelopment outcomes in neonatal hypoxic-ischemic encephalopathy","volume":"38","author":"Natarajan","year":"2018","journal-title":"J Perinatol"},{"key":"10.1016\/j.eclinm.2021.100892_bib0029","article-title":"Preemptive morphine during therapeutic hypothermia after neonatal encephalopathy: a secondary analysis","author":"Liow","year":"2019","journal-title":"Ther Hypothermia Temp Manag"},{"issue":"6","key":"10.1016\/j.eclinm.2021.100892_bib0030","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1016\/j.pain.2011.02.017","article-title":"Long-term effects of routine morphine infusion in mechanically ventilated neonates on children's functioning: five-year follow-up of a randomized controlled trial","volume":"152","author":"de Graaf","year":"2011","journal-title":"Pain"},{"key":"10.1016\/j.eclinm.2021.100892_bib0031","first-page":"449","article-title":"Does neonatal morphine use affect neuropsychological outcomes at 8 to 9 years of age?","volume":"154","author":"de Graaf","year":"2013"}],"container-title":["EClinicalMedicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S2589537021001723?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S2589537021001723?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T19:07:02Z","timestamp":1762888022000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S2589537021001723"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6]]},"references-count":31,"alternative-id":["S2589537021001723"],"URL":"https:\/\/doi.org\/10.1016\/j.eclinm.2021.100892","relation":{},"ISSN":["2589-5370"],"issn-type":[{"value":"2589-5370","type":"print"}],"subject":[],"published":{"date-parts":[[2021,6]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Morphine and fentanyl exposure during therapeutic hypothermia does not impair neurodevelopment","name":"articletitle","label":"Article Title"},{"value":"EClinicalMedicine","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.eclinm.2021.100892","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2021 The Authors. Published by Elsevier Ltd.","name":"copyright","label":"Copyright"}],"article-number":"100892"}}