{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T18:03:44Z","timestamp":1789495424591,"version":"build-2803163510"},"reference-count":54,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2021,6,18]],"date-time":"2021-06-18T00:00:00Z","timestamp":1623974400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"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"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2021,7]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>We have previously shown that high\u2010dose constant infusion of recombinant human erythropoietin (rEPO) from 30\u00a0min to 72 h after asphyxia in preterm fetal sheep reduced histological injury and improved electrophysiological recovery.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>This study shows that a high\u2010dose infusion of rEPO from 6 to 72\u00a0h after asphyxia did not improve EEG recovery, oligodendrocyte and neuronal survival at 1\u00a0week post\u2010asphyxia.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Of concern, intermittent rEPO boluses started 6\u00a0h after asphyxia were associated with impaired EEG recovery and bilateral cystic injury of temporal lobe intragyral white matter.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Intermittent boluses of rEPO were associated with significantly increased cerebral vascular resistance and hypoperfusion, particularly after the first dose, but did not affect seizures, suggesting mismatch between perfusion and brain activity.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Recombinant human erythropoietin (rEPO) is a promising treatment for hypoxic\u2010ischaemic brain injury. Disappointingly, a large randomized controlled trial in preterm infants found that prophylactic, repeated high\u2010dose rEPO boluses started within 24\u00a0h of birth did not improve neurodevelopmental outcomes. We examined whether initiation of a continuous infusion of rEPO at the end of the latent phase after hypoxic\u2010ischaemia (HI) might improve outcomes compared with intermittent bolus injections. Chronically instrumented preterm (0.7 gestation) fetal sheep received sham asphyxia or asphyxia induced by complete umbilical cord occlusion for 25\u00a0min. Six hours after asphyxia, fetuses received either a continuous infusion of rEPO (loading dose 2000\u00a0IU, infusion at 520\u00a0IU\/h) from 6 to 72\u00a0h post\u2010asphyxia or intravenous saline or 5000\u00a0IU rEPO, with repeated doses every 48\u00a0h for 5\u00a0days. Continuous infusion of rEPO did not improve EEG recovery, oligodendrocyte and neuronal survival at 1\u00a0week post\u2010asphyxia. By contrast, intermittent rEPO boluses were associated with impaired EEG recovery and bilateral cystic injury of temporal lobe intragyral white matter in 6\/8 fetuses. These studies demonstrate for the first time that initiation of intermittent rEPO boluses 6\u00a0h after HI, at a dose comparable with recent clinical trials, exacerbated neural injury. These data reinforce the importance of early initiation of many potential neuroprotective therapies.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp281269","type":"journal-article","created":{"date-parts":[[2021,5,25]],"date-time":"2021-05-25T09:17:04Z","timestamp":1621934224000},"page":"3593-3609","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Adverse neural effects of delayed, intermittent treatment with rEPO after asphyxia in preterm fetal sheep"],"prefix":"10.1113","volume":"599","author":[{"given":"Simerdeep K.","family":"Dhillon","sequence":"first","affiliation":[{"name":"Department of Physiology University of Auckland  Auckland New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guido","family":"Wassink","sequence":"additional","affiliation":[{"name":"Department of Physiology University of Auckland  Auckland New 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