{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T18:23:35Z","timestamp":1789151015404,"version":"build-2803163510"},"reference-count":70,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T00:00:00Z","timestamp":1625097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001505","name":"Health Research Council of New Zealand","doi-asserted-by":"publisher","award":["18\/225"],"award-info":[{"award-number":["18\/225"]}],"id":[{"id":"10.13039\/501100001505","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001505","name":"Health Research Council of New Zealand","doi-asserted-by":"publisher","award":["17\/601"],"award-info":[{"award-number":["17\/601"]}],"id":[{"id":"10.13039\/501100001505","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001505","name":"Health Research Council of New Zealand","doi-asserted-by":"publisher","award":["16\/003"],"award-info":[{"award-number":["16\/003"]}],"id":[{"id":"10.13039\/501100001505","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Seizures are common in newborn infants with hypoxic-ischemic encephalopathy and are highly associated with adverse neurodevelopmental outcomes. The impact of seizure activity on the developing brain and the most effective way to manage these seizures remain surprisingly poorly understood, particularly in the era of therapeutic hypothermia. Critically, the extent to which seizures exacerbate brain injury or merely reflect the underlying evolution of injury is unclear. Current anticonvulsants, such as phenobarbital and phenytoin have poor efficacy and preclinical studies suggest that most anticonvulsants are associated with adverse effects on the developing brain. Levetiracetam seems to have less potential neurotoxic effects than other anticonvulsants but may not be more effective. Given that therapeutic hypothermia itself has significant anticonvulsant effects, randomized controlled trials of anticonvulsants combined with therapeutic hypothermia, are required to properly determine the safety and efficacy of these drugs. Small clinical studies suggest that prophylactic phenobarbital administration may improve neurodevelopmental outcomes compared to delayed administration; however, larger high-quality studies are required to confirm this. In conclusion, there is a distinct lack of high-quality evidence for whether and to what extent neonatal seizures exacerbate brain damage after hypoxia-ischemia and how best to manage them in the era of therapeutic hypothermia.<\/jats:p>","DOI":"10.3390\/ijms22137121","type":"journal-article","created":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T12:03:27Z","timestamp":1625141007000},"page":"7121","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Treating Seizures after Hypoxic-Ischemic Encephalopathy\u2014Current Controversies and Future Directions"],"prefix":"10.3390","volume":"22","author":[{"given":"Kelly Q.","family":"Zhou","sequence":"first","affiliation":[{"name":"The Department of Physiology, The University of Auckland, Auckland 1023, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"McDouall","sequence":"additional","affiliation":[{"name":"The Department of Physiology, The University of Auckland, Auckland 1023, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul P.","family":"Drury","sequence":"additional","affiliation":[{"name":"The Department of Physiology, The University of Auckland, Auckland 1023, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8937-0846","authenticated-orcid":false,"given":"Christopher A.","family":"Lear","sequence":"additional","affiliation":[{"name":"The Department of Physiology, The University of Auckland, Auckland 1023, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenta H. T.","family":"Cho","sequence":"additional","affiliation":[{"name":"The Department of Physiology, The University of Auckland, Auckland 1023, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Bennet","sequence":"additional","affiliation":[{"name":"The Department of Physiology, The University of Auckland, Auckland 1023, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0656-7035","authenticated-orcid":false,"given":"Alistair J.","family":"Gunn","sequence":"additional","affiliation":[{"name":"The Department of Physiology, The University of Auckland, Auckland 1023, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne O.","family":"Davidson","sequence":"additional","affiliation":[{"name":"The Department of Physiology, The University of Auckland, Auckland 1023, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,1]]},"reference":[{"key":"ref_1","first-page":"CD003311","article-title":"Cooling for newborns with hypoxic ischaemic encephalopathy","volume":"1","author":"Jacobs","year":"2013","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Edwards, A.D., Brocklehurst, P., Gunn, A.J., Halliday, H., Juszczak, E., Levene, M., Strohm, B., Thoresen, M., Whitelaw, A., and Azzopardi, D. (2010). Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: Synthesis and meta-analysis of trial data. BMJ, 340.","DOI":"10.1136\/bmj.c363"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"198","DOI":"10.3389\/fneur.2015.00198","article-title":"Therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy\u2014Where to from here?","volume":"6","author":"Davidson","year":"2015","journal-title":"Front. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1111\/dmcn.13215","article-title":"Seizure burden and neurodevelopmental outcome in neonates with hypoxic-ischemic encephalopathy","volume":"58","author":"Kharoshankaya","year":"2016","journal-title":"Dev. Med. Child Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Lin, Y.K., Hwang-Bo, S., Seo, Y.M., and Youn, Y.A. (2021). Clinical seizures and unfavorable brain MRI patterns in neonates with hypoxic ischemic encephalopathy. Medicine, 100.","DOI":"10.1097\/MD.0000000000025118"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.seizure.2020.10.021","article-title":"Seizure burden and neurodevelopmental outcome in newborns with hypoxic-ischemic encephalopathy treated with therapeutic hypothermia: A single center observational study","volume":"83","author":"Basti","year":"2020","journal-title":"Seizure"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1038\/s41390-019-0319-6","article-title":"Evaluating anti-epileptic drugs in the era of therapeutic hypothermia","volume":"85","author":"Davidson","year":"2019","journal-title":"Pediatr. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.jpeds.2016.03.035","article-title":"Contemporary Profile of Seizures in Neonates: A Prospective Cohort Study","volume":"174","author":"Glass","year":"2016","journal-title":"J. Pediatr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1111\/j.0953-816X.2003.03152.x","article-title":"Developmental changes in GABAergic actions and seizure susceptibility in the rat hippocampus","volume":"19","author":"Khazipov","year":"2004","journal-title":"Eur. J. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/S0166-2236(03)00068-7","article-title":"Cation-chloride co-transporters in neuronal communication, development and trauma","volume":"26","author":"Payne","year":"2003","journal-title":"Trends Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.1523\/JNEUROSCI.1421-05.2006","article-title":"The chloride transporter Na(+)-K(+)-Cl- cotransporter isoform-1 contributes to intracellular chloride increases after in vitro ischemia","volume":"26","author":"Pond","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.siny.2013.02.003","article-title":"Mechanisms and effects of seizures in the immature brain","volume":"18","author":"Nardou","year":"2013","journal-title":"Semin. Fetal Neonatal Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"347","DOI":"10.3389\/fncel.2015.00347","article-title":"Prenatal Hypoxia-Ischemia Induces Abnormalities in CA3 Microstructure, Potassium Chloride Co-Transporter 2 Expression and Inhibitory Tone","volume":"9","author":"Jantzie","year":"2015","journal-title":"Front. Cell. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1016\/j.clp.2009.08.001","article-title":"Neonatal seizures: An update on mechanisms and management","volume":"36","author":"Jensen","year":"2009","journal-title":"Clin. Perinatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"362","DOI":"10.3389\/fncel.2015.00362","article-title":"Neonatal seizures alter NMDA glutamate receptor GluN2A and 3A subunit expression and function in hippocampal CA1 neurons","volume":"9","author":"Zhou","year":"2015","journal-title":"Front. Cell. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1212\/WNL.58.4.542","article-title":"Seizure-associated brain injury in term newborns with perinatal asphyxia","volume":"58","author":"Miller","year":"2002","journal-title":"Neurology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.jpeds.2009.03.040","article-title":"Clinical Neonatal Seizures are Independently Associated with Outcome in Infants at Risk for Hypoxic-Ischemic Brain Injury","volume":"155","author":"Glass","year":"2009","journal-title":"J. Pediatr."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e1302","DOI":"10.1542\/peds.2014-3777","article-title":"Treating EEG Seizures in Hypoxic Ischemic Encephalopathy: A Randomized Controlled Trial","volume":"136","author":"Srinivasakumar","year":"2015","journal-title":"Pediatrics"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e358","DOI":"10.1542\/peds.2009-0136","article-title":"Effect of treatment of subclinical neonatal seizures detected with aEEG: Randomized, controlled trial","volume":"125","author":"Toet","year":"2010","journal-title":"Pediatrics"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Peeples, E.S., Rao, R., Dizon, M.L.V., Johnson, Y.R., Joe, P., Flibotte, J., Hossain, T., Smith, D., Hamrick, S., and DiGeronimo, R. (2021). Predictive models of neurodevelopmental outcomes after neonatal hypoxic-ischemic encephalopathy. Pediatrics, 147.","DOI":"10.1542\/peds.2020-022962"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1177\/0883073810380915","article-title":"Clinical seizures in neonatal hypoxic-ischemic encephalopathy have no independent impact on neurodevelopmental outcome: Secondary analyses of data from the neonatal research network hypothermia trial","volume":"26","author":"Kwon","year":"2011","journal-title":"J. Child Neurol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1016\/j.clp.2009.07.012","article-title":"The long-term effects of neonatal seizures","volume":"36","author":"Holmes","year":"2009","journal-title":"Clin. Perinatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.braindev.2008.04.001","article-title":"Development of epilepsy in newborns with moderate hypoxic-ischemic encephalopathy and neonatal seizures","volume":"31","author":"Pisani","year":"2009","journal-title":"Brain Dev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1902","DOI":"10.1111\/epi.13914","article-title":"Reduced infancy and childhood epilepsy following hypothermia-treated neonatal encephalopathy","volume":"58","author":"Liu","year":"2017","journal-title":"Epilepsia"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1002\/ana.410180303","article-title":"Status epilepticus in well-oxygenated rats causes neuronal necrosis","volume":"18","author":"Nevander","year":"1985","journal-title":"Ann. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.eplepsyres.2015.11.005","article-title":"Widespread neuronal injury in a model of cholinergic status epilepticus in postnatal day 7 rat pups","volume":"120","author":"Torolira","year":"2016","journal-title":"Epilepsy Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1111\/j.1600-0404.2007.00804.x","article-title":"Inflammation contributes to seizure-induced hippocampal injury in the neonatal rat brain","volume":"115","author":"Sankar","year":"2007","journal-title":"Acta Neurol. Scand."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1007\/s00702-014-1291-2","article-title":"Early life seizures in female rats lead to anxiety-related behavior and abnormal social behavior characterized by reduced motivation to novelty and deficit in social discrimination","volume":"122","author":"Castelhano","year":"2015","journal-title":"J. Neural Transm."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.yebeh.2017.04.031","article-title":"Single neonatal status epilepticus does not impair cognitive function in rats","volume":"72","author":"Barbosa","year":"2017","journal-title":"Epilepsy Behav."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1038\/sj.jcbfm.9600087","article-title":"Cerebral oxygenation during post-asphyxial seizures in near-term fetal sheep","volume":"25","author":"Gonzalez","year":"2005","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1002\/ana.410320511","article-title":"Suppression of postischemic epileptiform activity with MK-801 improves neural outcome in fetal sheep","volume":"32","author":"Tan","year":"1992","journal-title":"Ann. Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.nbd.2016.12.023","article-title":"Different response to antiepileptic drugs according to the type of epileptic events in a neonatal ischemia-reperfusion model","volume":"99","author":"Morin","year":"2017","journal-title":"Neurobiol. Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1203\/00006450-199811000-00018","article-title":"Lactate and pyruvate changes in the cerebral gray and white matter during posthypoxic seizures in newborn pigs","volume":"44","author":"Thoresen","year":"1998","journal-title":"Pediatr. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1203\/00006450-200110000-00005","article-title":"Prolonged seizures exacerbate perinatal hypoxic-ischemic brain damage","volume":"50","author":"Wirrell","year":"2001","journal-title":"Pediatr. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.brainres.2004.02.070","article-title":"Preventing hyperthermia decreases brain damage following neonatal hypoxic-ischemic seizures","volume":"1011","author":"Yager","year":"2004","journal-title":"Brain Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1542\/peds.2006-2839","article-title":"Determinants of outcomes after head cooling for neonatal encephalopathy","volume":"119","author":"Wyatt","year":"2007","journal-title":"Pediatrics"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1542\/peds.2007-1673","article-title":"Elevated temperature after hypoxic-ischemic encephalopathy: Risk factor for adverse outcomes","volume":"122","author":"Laptook","year":"2008","journal-title":"Pediatrics"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1111\/epi.16778","article-title":"Phenobarbital and midazolam suppress neonatal seizures in a noninvasive rat model of birth asphyxia, whereas bumetanide is ineffective","volume":"62","author":"Johne","year":"2021","journal-title":"Epilepsia"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1203\/PDR.0b013e3181d4ff4d","article-title":"Phenobarbital augments hypothermic neuroprotection","volume":"67","author":"Barks","year":"2010","journal-title":"Pediatr. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1038\/pr.2017.266","article-title":"The effects of adding prophylactic phenobarbital to therapeutic hypothermia in the term-equivalent hypoxic-ischemic rat","volume":"83","author":"Krishna","year":"2018","journal-title":"Pediatr. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"105245","DOI":"10.1016\/j.nbd.2020.105245","article-title":"Brain pathology caused in the neonatal macaque by short and prolonged exposures to anticonvulsant drugs","volume":"149","author":"Noguchi","year":"2021","journal-title":"Neurobiol. Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/s12640-018-9872-8","article-title":"Caffeine Protects against Anticonvulsant-Induced Impaired Neurogenesis in the Developing Rat Brain","volume":"34","author":"Endesfelder","year":"2018","journal-title":"Neurotox. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"15089","DOI":"10.1073\/pnas.222550499","article-title":"Antiepileptic drugs and apoptotic neurodegeneration in the developing brain","volume":"99","author":"Bittigau","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1002\/ana.23600","article-title":"Neonatal exposure to antiepileptic drugs disrupts striatal synaptic development","volume":"72","author":"Forcelli","year":"2012","journal-title":"Ann. Neurol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1124\/jpet.107.126250","article-title":"Antiepileptic Drug-Induced Neuronal Cell Death in the Immature Brain: Effects of Carbamazepine, Topiramate, and Levetiracetam as Monotherapy versus Polytherapy","volume":"323","author":"Kim","year":"2007","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1111\/dmcn.12724","article-title":"Neonatal seizures in hypoxic-ischaemic encephalopathy\u2014Risks and benefits of anticonvulsant therapy","volume":"57","author":"Shetty","year":"2015","journal-title":"Dev. Med. Child Neurol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1056\/NEJM199908123410704","article-title":"Phenobarbital compared with phenytoin for the treatment of neonatal seizures","volume":"341","author":"Painter","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.pediatrneurol.2017.04.016","article-title":"Seizures in preterm neonates: A multicenter observational cohort study","volume":"72","author":"Glass","year":"2017","journal-title":"Pediatr. Neurol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Evans, D.J., Levene, M.I., and Tsakmakis, M. (2007). Anticonvulsants for preventing mortality and morbidity in full term newborns with perinatal asphyxia. Cochrane Database Syst. Rev., CD001240.","DOI":"10.1002\/14651858.CD001240.pub2"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1186\/s13052-021-01027-2","article-title":"Treating the symptom or treating the disease in neonatal seizures: A systematic review of the literature","volume":"47","author":"Falsaperla","year":"2021","journal-title":"Ital. J. Pediatr."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1152\/jn.00279.2011","article-title":"A new mechanism for antiepileptic drug action: Vesicular entry may mediate the effects of levetiracetam","volume":"106","author":"Meehan","year":"2011","journal-title":"J. Neurophysiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1177\/0883073810384263","article-title":"Levetiracetam for treatment of neonatal seizures","volume":"26","author":"Abend","year":"2011","journal-title":"J. Child Neurol."},{"key":"ref_53","first-page":"320","article-title":"Effectiveness of Levetiracetam as a First-Line Anticonvulsant for Neonatal Seizures","volume":"24","author":"Kreimer","year":"2019","journal-title":"J. Pediatr. Pharmacol. Ther."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3683548","DOI":"10.1155\/2019\/3683548","article-title":"Short-Term Neurodevelopmental Outcome in Term Neonates Treated with Phenobarbital versus Levetiracetam: A Single-Center Experience","volume":"2019","author":"Falsaperla","year":"2019","journal-title":"Behav. Neurol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1007\/s13312-019-1586-3","article-title":"Levetiracetam versus Phenobarbitone in Neonatal Seizures\u2014A Randomized Controlled Trial","volume":"56","author":"Gowda","year":"2019","journal-title":"Indian Pediatr."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Hooper, R.G., Ramaswamy, V.V., Wahid, R.M., Satodia, P., and Bhulani, A. (2021). Levetiracetam as the first-line treatment for neonatal seizures: A systematic review and meta-analysis. Dev. Med. Child Neurol.","DOI":"10.1136\/bmjpo-2021-RCPCH.103"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Sharpe, C., Reiner, G.E., Davis, S.L., Nespeca, M., Gold, J.J., Rasmussen, M., Kuperman, R., Harbert, M.J., Michelson, D., and Joe, P. (2020). Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial. Pediatrics, 145.","DOI":"10.1542\/peds.2019-3182"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1097\/WNP.0000000000000525","article-title":"Assessing the Feasibility of Providing a Real-Time Response to Seizures Detected with Continuous Long-Term Neonatal Electroencephalography Monitoring","volume":"36","author":"Sharpe","year":"2019","journal-title":"J. Clin. Neurophysiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/S0022-3476(98)70458-5","article-title":"High-dose phenobarbital therapy in term newborn infants with severe perinatal asphyxia: A randomized, prospective study with three-year follow-up","volume":"132","author":"Hall","year":"1998","journal-title":"J. Pediatr."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"F267","DOI":"10.1136\/archdischild-2011-300716","article-title":"Cooling and seizure burden in term neonates: An observational study","volume":"97","author":"Low","year":"2012","journal-title":"Arch. Dis. Child. Fetal Neonatal Ed."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/s00381-016-3321-x","article-title":"Therapeutic hypothermia for neonatal hypoxic ischemic encephalopathy is associated with short-term reduction of seizures after discharge from the neonatal intensive care unit","volume":"33","author":"Ghosh","year":"2017","journal-title":"Childs Nerv. Syst."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1177\/0883073811408092","article-title":"Hypothermia is correlated with seizure absence in perinatal stroke","volume":"26","author":"Harbert","year":"2011","journal-title":"J. Child Neurol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Shipley, L., Mistry, A., and Sharkey, D. (2021). Outcomes of neonatal hypoxic-ischaemic encephalopathy in centres with and without active therapeutic hypothermia: A nationwide propensity score-matched analysis. Arch. Dis. Child. Fetal Neonatal Ed.","DOI":"10.1136\/archdischild-2020-320966"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/S1474-4422(14)70303-5","article-title":"Bumetanide for the treatment of seizures in newborn babies with hypoxic ischaemic encephalopathy (NEMO): An open-label, dose finding, and feasibility phase 1\/2 trial","volume":"14","author":"Pressler","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1002\/ana.25959","article-title":"A Pilot Randomized, Controlled, Double-Blind Trial of Bumetanide to Treat Neonatal Seizures","volume":"89","author":"Soul","year":"2021","journal-title":"Ann. Neurol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1177\/000992289903800702","article-title":"Late cognitive effects of early treatment with phenobarbital","volume":"38","author":"Sulzbacher","year":"1999","journal-title":"Clin. Pediatr."},{"key":"ref_67","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":"ref_68","doi-asserted-by":"crossref","unstructured":"Young, L., Berg, M., and Soll, R. (2016). Prophylactic barbiturate use for the prevention of morbidity and mortality following perinatal asphyxia. Cochrane Database Syst. Rev., CD001240.","DOI":"10.1002\/14651858.CD001240.pub3"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1203\/00006450-199909000-00005","article-title":"Cerebral hypothermia is not neuroprotective when started after postischemic seizures in fetal sheep","volume":"46","author":"Gunn","year":"1999","journal-title":"Pediatr. Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"40","DOI":"10.3389\/fnins.2014.00040","article-title":"The mechanisms and treatment of asphyxial encephalopathy","volume":"8","author":"Wassink","year":"2014","journal-title":"Front. 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