1 Lutz IC, et al. BMJ Paediatrics Open 2020;4:e000685. doi:10.1136/bmjpo-2020-000685 Open access Pharmacokinetics during therapeutic hypothermia for neonatal hypoxic ischaemic encephalopathy: a literature review Isabelle Claire Lutz, 1 Karel Allegaert , 2,3 Jan N de Hoon , 4 Heleen Marynissen 4 To cite: Lutz IC, Allegaert K, de Hoon JN, et al. Pharmacokinetics during therapeutic hypothermia for neonatal hypoxic ischaemic encephalopathy: a literature review. BMJ Paediatrics Open 2020;4:e000685. doi:10.1136/ bmjpo-2020-000685 Received 7 April 2020 Revised 19 May 2020 Accepted 22 May 2020 1 Faculty of Medicine, Katholieke Universiteit Leuven, Leuven, Belgium 2 Department of Development and Regeneration, KU Leuven, Leuven, Belgium 3 Intensive Care and Pediatric Surgery, Erasmus MC Sophia, Rotterdam, The Netherlands 4 Department of Pharmaceutical and Pharmacological Sciences, Center for Clinical Pharmacology, KU Leuven, Leuven, Belgium Correspondence to Dr Karel Allegaert; karel. allegaert@uzleuven.be Review © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. What is known about the subject? ► Therapeutic hypothermia has a neuroprotec- tive effect for neonates with hypoxic ischaemic hypothermia. ► Hypoxic ischaemic asphyxia and lowering the core body temperature has impact on the pharmacoki- netics, up to the level that dosing regimens for these neonates should be adapted. What this study adds? ► Compared with the latest structured review (2015) on pharmacokinetics during hypothermia for four compounds (gentamicin, topiramate, phenobarbital, morphine), the current systematic search provides data on 15 compounds, refecting the relevant prog- ress made. ► A signifcant decrease in clearance is observed in neonates during therapeutic hypothermia, be it that the extent differs between routes of elimination and compounds, but most pronounced for renal elim- ination (phenobarbital no difference, midazolam metabolite −21%, lidocaine −24%; morphine −21% to −47%, gentamicin −25% to −35%, amikacin −40%) during hypothermia. ABSTRACT Background Neonatal hypoxic ischaemic encephalopathy due to perinatal asphyxia, can result in severe neurodevelopmental disability or mortality. Hypothermia is at present the only proven neuroprotective intervention. During hypothermia, the neonate may need a variety of drugs with their specifc pharmacokinetic profle. The aim of this paper is to determine the effect that hypothermia for neonates suffering from hypoxic ischaemic encephalopathy has on the pharmacokinetics and to what extent dosing regimens need adjustments. Method A systematic search was performed on PubMed, Embase and Cochrane Library of literature (2000–2020) using a combination of the following search terms: therapeutic hypothermia, neonate, hypoxic ischemic encephalopathy and pharmacokinetics. Titles and abstracts were screened, and inclusion/exclusion criteria were applied. Finally, relevant full texts were read, and secondary inclusion was applied on the identifed articles. Results A total of 380 articles were retrieved, and 34 articles included after application of inclusion/exclusion criteria and duplicate removal, two additional papers were included as suggested by the reviewers. Twelve out of 36 studies on 15 compounds demonstrated a signifcant decrease in clearance, be it that the extent differs between routes of elimination and compounds, most pronounced for renal elimination (phenobarbital no difference, midazolam metabolite −21%, lidocaine −24%; morphine −21% to −47%, gentamicin −25% to −35%, amikacin −40%) during hypothermia. The data as retrieved in literature were subsequent compared with the dosing regimen as stated in the Dutch paediatric formulary. Conclusion Depending on the drug-specifc disposition characteristics, therapeutic hypothermia in neonates with hypoxic ischaemic encephalopathy affects pharmacokinetics. INTRODUCTION Neonatal hypoxic ischaemic encephalopathy (HIE), brain damage sustained as a result of perinatal asphyxia, occurs in 1.5 out of 1000 births 1 and can result in severe neurodevelop- mental disability or mortality in respectively 24.9% and 34.1% of cases. 2 Perinatal asphyxia is a condition characterised by a persistently low Apgar score (≤5) assessed at 5 and 10 min after birth, or metabolic acidosis, defined as a pH of <7.0 and/or base deficit of ≥16 mmol/L, measured in the fetal umbilical artery or arte- rial blood within 1 hour after birth. 3 4 The HIE severity can be categorised by the Sarnat score into mild, moderate and severe brain injury based on the abnormality of level of consciousness, spontaneous activity, posture, tone, primitive reflexes and autonomic func- tion. 5 Alternatively, the Thompson score is another scoring system that uses similar criteria like Sarnat but also includes the pres- ence of seizures and fontanelle tension; both scores can be used for prognosis and provide prognostic value and quantify HIE into mild, moderate and severe. 6 on November 25, 2021 by guest. 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