{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T11:36:59Z","timestamp":1792237019153,"version":"4.4.0"},"reference-count":23,"publisher":"American Academy of Pediatrics (AAP)","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,4,1]]},"abstract":"<jats:p>OBJECTIVES. Asphyxia and hypothermia may modify drug pharmacokinetics. We investigated whether analgesia with morphine in neonates with hypoxic ischemic encephalopathy undergoing prolonged moderate systemic hypothermia resulted in elevated serum morphine concentrations compared with normothermic infants.<\/jats:p>\n               <jats:p>PATIENTS AND METHODS. Infants from 1 center participating in a multicenter randomized study of moderate whole-body hypothermia after perinatal asphyxia (the Total Body Hypothermia Study) were randomly selected for treatment with hypothermia (n = 10) or for standard care on normothermia (n = 6). Hypothermia (33\u00b0C to 34\u00b0C) was started before 6 hours of age and maintained for 72 hours. All of the infants were treated with a continuous infusion of morphine-hydrochloride, with the rate adjusted according to clinical status. Serum morphine concentrations were determined at 6, 12, 24, 48, and 72 hours after birth.<\/jats:p>\n               <jats:p>RESULTS. Serum morphine concentrations at 24 to 72 hours after birth were (median [range]) 292 ng\/mL (137\u2013767 ng\/mL) in the hypothermia-treated infants and 206 ng\/mL (88\u2013327 ng\/mL) in the infants on normothermia, despite similar morphine infusion rates and cumulative doses. Morphine concentrations correlated with morphine infusion rate, cumulative dose, and treatment with hypothermia. Serum morphine concentrations reached a steady state after 24 hours in the normothermic infants but continued to increase throughout the assessment period in the hypothermia group. Morphine clearance was low in both groups: (median [range]) morphine clearance estimated from area under the curve was 0.69 mL\/min per kg (0.58\u20131.21 mL\/min per kg) in hypothermic group and 0.89 mL\/min per kg (0.65\u20131.33 mL\/min per kg) in infants on normothermia. Serum morphine concentrations &amp;gt;300 nL\/mL occurred more often in the hypothermia group and when the morphine infusion rate was &amp;gt;10 \u03bcg\/kg per h.<\/jats:p>\n               <jats:p>CONCLUSIONS. Infants with hypoxic ischemic encephalopathy have reduced morphine clearance and elevated serum morphine concentrations when morphine infusion rates are based on clinical state. Potentially toxic serum concentrations of morphine may occur with moderate hypothermia and infusion rates &amp;gt;10 \u03bcg\/kg per h.<\/jats:p>","DOI":"10.1542\/peds.2007-1987","type":"journal-article","created":{"date-parts":[[2008,4,1]],"date-time":"2008-04-01T20:25:58Z","timestamp":1207081558000},"page":"e844-e849","source":"Crossref","is-referenced-by-count":148,"title":["Elevated Morphine Concentrations in Neonates Treated With Morphine and Prolonged Hypothermia for Hypoxic Ischemic Encephalopathy"],"prefix":"10.1542","volume":"121","author":[{"given":"Aniko\u0301","family":"Ro\u0301ka","sequence":"first","affiliation":[{"name":"First Department of Paediatrics, Semmelweis University, Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kis Tamas","family":"Melinda","sequence":"additional","affiliation":[{"name":"First Department of Paediatrics, Semmelweis University, Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barna","family":"Va\u0301sa\u0301rhelyi","sequence":"additional","affiliation":[{"name":"Research Group of Paediatrics and Nephrology, Hungarian Academy of Sciences, Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tama\u0301s","family":"Machay","sequence":"additional","affiliation":[{"name":"First Department of Paediatrics, Semmelweis University, Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denis","family":"Azzopardi","sequence":"additional","affiliation":[{"name":"Division of Clinical Sciences, Hammersmith Campus, Imperial College London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miklo\u0301s","family":"Szabo\u0301","sequence":"additional","affiliation":[{"name":"First Department of Paediatrics, Semmelweis University, Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"417","published-online":{"date-parts":[[2008,4,1]]},"reference":[{"key":"2021120902093092500_R1","doi-asserted-by":"crossref","unstructured":"Gluckman PD, Wyatt JS, Azzopardi D, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet.\u20082005;365(9460):663\u2013670","DOI":"10.1016\/S0140-6736(05)70932-6"},{"key":"2021120902093092500_R2","doi-asserted-by":"crossref","unstructured":"Shankaran S, Laptook AR, Ehrenkranz RA, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med.\u20082005;353(15):1574\u20131584","DOI":"10.1056\/NEJMcps050929"},{"key":"2021120902093092500_R3","unstructured":"National Perinatal Epidemiology Unit. Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy: the TOBY Study. Available at: www.npeu.ox.ac.uk\/Toby. Accessed January 10, 2006"},{"key":"2021120902093092500_R4","unstructured":"Simbruner, G. Neonatal Neuro Network Trial. Available at: www.neonatal-research.at\/php\/detail.php?artnr=4367&ukatnr=11237&ukatname=Department&PHPSESSID=55f5686510032ad446fa93f0ea37379f. Accessed April 12, 2000"},{"key":"2021120902093092500_R5","unstructured":"Jacobs SE, Stewart M, Inder TE, Doyle LW, Morley CJ. Feasibility of a pragmatic randomised controlled trial of whole body cooling for term newborns with hypoxic-ischaemic encephalopathy. Presented in the Proceedings of the Hot Topics in Neonatology Meeting; December, 2002; Washington, DC"},{"key":"2021120902093092500_R6","doi-asserted-by":"crossref","unstructured":"Thoresen M, Satas S, Loberg EM, et al. Twenty-four hours of mild hypothermia in unsedated newborn pigs starting after a severe global hypoxic-ischemic insult is not neuroprotective. Pediatr Res.\u20082001;50(3):405\u2013411","DOI":"10.1203\/00006450-200109000-00017"},{"key":"2021120902093092500_R7","doi-asserted-by":"crossref","unstructured":"Erecinska M, Thoresen M, Silver IA. Effects of hypothermia on energy metabolism in Mammalian central nervous system. J Cereb Blood Flow Metab.\u20082003;23(5):513\u2013530","DOI":"10.1097\/01.WCB.0000066287.21705.21"},{"key":"2021120902093092500_R8","doi-asserted-by":"crossref","unstructured":"Laptook AR, Corbett RJ, Sterett R, Garcia D, Tollefsbol G. Quantitative relationship between brain temperature and energy utilization rate measured in vivo using 31P and 1H magnetic resonance spectroscopy. Pediatr Res.\u20081995;38(6):919\u2013925","DOI":"10.1203\/00006450-199512000-00015"},{"key":"2021120902093092500_R9","doi-asserted-by":"crossref","unstructured":"Fritz HG, Holzmayr M, Walter B, Moeritz KU, Lupp A, Bauer R. The effect of mild hypothermia on plasma fentanyl concentration and biotransformation in juvenile pigs. Anesth Analg.\u20082005;100(4):996\u20131002","DOI":"10.1213\/01.ANE.0000146517.17910.54"},{"key":"2021120902093092500_R10","doi-asserted-by":"crossref","unstructured":"Iida Y, Nishi S, Asada A. Effect of mild therapeutic hypothermia on phenytoin pharmacokinetics. Ther Drug Monit.\u20082001;23(3):192\u2013197","DOI":"10.1097\/00007691-200106000-00002"},{"key":"2021120902093092500_R11","doi-asserted-by":"crossref","unstructured":"Michelsen LG, Holford NH, Lu W, Hoke JF, Hug CC, Bailey JM. The pharmacokinetics of remifentanil in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass. Anesth Analg.\u20082001;93(5):1100\u20131105","DOI":"10.1097\/00000539-200111000-00006"},{"key":"2021120902093092500_R12","unstructured":"Thoresen M, Stone J, Hoem NO, Brun C, Satas S, Tooley J. Hypothermia after perinatal asphyxia more than doubles the plasma half-life of phenobarbitone [abstract]. Pediatr Res.\u20082003;53(5):873"},{"key":"2021120902093092500_R13","doi-asserted-by":"crossref","unstructured":"Shah P, Riphagen S, Beyene J, Perlman M. Multiorgan dysfunction in infants with post-asphyxial hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed.\u20082004;89(2):F152\u2013F155","DOI":"10.1136\/adc.2002.023093"},{"key":"2021120902093092500_R14","doi-asserted-by":"crossref","unstructured":"Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress: a clinical and electroencephalographic study. Arch Neurol.\u20081976;33(10):696\u2013705","DOI":"10.1001\/archneur.1976.00500100030012"},{"key":"2021120902093092500_R15","doi-asserted-by":"crossref","unstructured":"Thompson CM, Puterman AS, Linley LL, et al. The value of a scoring system for hypoxic ischaemic encephalopathy in predicting neurodevelopmental outcome. Acta Paediatr.\u20081997;86(7):757\u2013761","DOI":"10.1111\/j.1651-2227.1997.tb08581.x"},{"key":"2021120902093092500_R16","doi-asserted-by":"crossref","unstructured":"Saarenmaa E, Neuvonen PJ, Rosenberg P, Fellman V. Morphine clearance and effects in newborn infants in relation to gestational age. Clin Pharmacol Ther.\u20082000;68(2):160\u2013166","DOI":"10.1067\/mcp.2000.108947"},{"key":"2021120902093092500_R17","doi-asserted-by":"crossref","unstructured":"Bouwmeester NJ, van den Anker JN, Hop WC, Anand KJ, Tibboel D. Age- and therapy-related effects on morphine requirements and plasma concentrations of morphine and its metabolites in postoperative infants. Br J Anaesth.\u20082003;90(5):642\u2013652","DOI":"10.1093\/bja\/aeg121"},{"key":"2021120902093092500_R18","doi-asserted-by":"crossref","unstructured":"Chay PC, Duffy BJ, Walker JS. Pharmacokinetic-pharmacodynamic relationships of morphine in neonates. Clin Pharmacol Ther.\u20081992;51(3):334\u2013342","DOI":"10.1038\/clpt.1992.30"},{"key":"2021120902093092500_R19","doi-asserted-by":"crossref","unstructured":"Lynn A, Nespeca MK, Bratton SL, Strauss SG, Shen DD. Clearance of morphine in postoperative infants during intravenous infusion: the influence of age and surgery. Anesth Analg.\u20081998;86(5):958\u2013963","DOI":"10.1213\/00000539-199805000-00008"},{"key":"2021120902093092500_R20","doi-asserted-by":"crossref","unstructured":"Geiduschek JM, Lynn AM, Bratton SL, et al. Morphine pharmacokinetics during continuous infusion of morphine sulfate for infants receiving extracorporeal membrane oxygenation. Crit Care Med.\u20081997;25(2):360\u2013364","DOI":"10.1097\/00003246-199702000-00027"},{"key":"2021120902093092500_R21","doi-asserted-by":"crossref","unstructured":"Hall RW, Kronsberg SS, Barton BA, Kaiser JR, Anand KJ. Morphine, hypotension, and adverse outcomes among preterm neonates: who's to blame? Secondary results from the NEOPAIN trial. Pediatrics.\u20082005;115(5):1351\u20131359","DOI":"10.1542\/peds.2004-1398"},{"key":"2021120902093092500_R22","doi-asserted-by":"crossref","unstructured":"Ro\u0301ka A, Vasarhelyi B, Bodrogi E, Machay T, Szabo M. Changes in laboratory parameters indicating cell necrosis and organ dysfunction in asphyxiated neonates on moderate systemic hypothermia. Acta Paediatr.\u20082007;96(8):1118\u20131121","DOI":"10.1111\/j.1651-2227.2007.00361.x"},{"key":"2021120902093092500_R23","doi-asserted-by":"crossref","unstructured":"de Wildt SN, Kearns GL, Leeder JS, van den Anker JN. Glucuronidation in humans: pharmacogenetic and developmental aspects. Clin Pharmacokinet.\u20081999;36(6):439\u2013452","DOI":"10.2165\/00003088-199936060-00005"}],"container-title":["Pediatrics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/publications.aap.org\/pediatrics\/article-pdf\/121\/4\/e844\/1123272\/zpe0040800e844.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/publications.aap.org\/pediatrics\/article-pdf\/121\/4\/e844\/1123272\/zpe0040800e844.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T09:36:07Z","timestamp":1639042567000},"score":1,"resource":{"primary":{"URL":"https:\/\/publications.aap.org\/pediatrics\/article\/121\/4\/e844\/70792\/Elevated-Morphine-Concentrations-in-Neonates"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,4,1]]},"references-count":23,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2008,4,1]]},"published-print":{"date-parts":[[2008,4,1]]}},"URL":"https:\/\/doi.org\/10.1542\/peds.2007-1987","relation":{},"ISSN":["0031-4005","1098-4275"],"issn-type":[{"value":"0031-4005","type":"print"},{"value":"1098-4275","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,4,1]]}}}