Department of Physiology, University of Auckland, Auckland, New Zealand.
J Physiol. 2021 Jul;599(14):3593-3609. doi: 10.1113/JP281269. Epub 2021 Jun 18.
We have previously shown that high-dose constant infusion of recombinant human erythropoietin (rEPO) from 30 min to 72 h after asphyxia in preterm fetal sheep reduced histological injury and improved electrophysiological recovery. This study shows that a high-dose infusion of rEPO from 6 to 72 h after asphyxia did not improve EEG recovery, oligodendrocyte and neuronal survival at 1 week post-asphyxia. Of concern, intermittent rEPO boluses started 6 h after asphyxia were associated with impaired EEG recovery and bilateral cystic injury of temporal lobe intragyral white matter. 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.
Recombinant human erythropoietin (rEPO) is a promising treatment for hypoxic-ischaemic brain injury. Disappointingly, a large randomized controlled trial in preterm infants found that prophylactic, repeated high-dose rEPO boluses started within 24 h 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-ischaemia (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 min. Six hours after asphyxia, fetuses received either a continuous infusion of rEPO (loading dose 2000 IU, infusion at 520 IU/h) from 6 to 72 h post-asphyxia or intravenous saline or 5000 IU rEPO, with repeated doses every 48 h for 5 days. Continuous infusion of rEPO did not improve EEG recovery, oligodendrocyte and neuronal survival at 1 week post-asphyxia. 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 h 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.
我们之前已经表明，在早产胎羊窒息后 30 分钟至 72 小时内给予高剂量持续输注重组人促红细胞生成素（rEPO）可减轻组织学损伤并改善电生理恢复。这项研究表明，在窒息后 6 至 72 小时内给予高剂量 rEPO 输注并未改善电生理恢复、少突胶质细胞和神经元在窒息后 1 周的存活。值得关注的是，在窒息后 6 小时开始的间歇性 rEPO 推注与 EEG 恢复受损以及颞叶内回白质双侧囊性损伤有关。间歇性 rEPO 推注与显著增加的脑血管阻力和灌注不足有关，特别是在第一次剂量后，但不影响癫痫发作，提示灌注和脑活动之间不匹配。
重组人促红细胞生成素（rEPO）是一种有前途的治疗缺氧缺血性脑损伤的方法。令人失望的是，一项针对早产儿的大型随机对照试验发现，在出生后 24 小时内预防性、重复给予高剂量 rEPO 推注并不能改善神经发育结局。我们研究了在缺氧缺血（HI）后潜伏期末端开始持续输注 rEPO 是否可能改善结局，与间歇性推注相比。慢性仪器化的早产（0.7 孕周）胎羊接受假窒息或完全脐带结扎 25 分钟诱导的窒息。在窒息后 6 小时，胎儿接受持续输注 rEPO（负荷剂量 2000IU，输注速度为 520IU/h）从 6 至 72 小时 post-asphyxia 或静脉生理盐水或 5000IU rEPO，每 48 小时重复一次，共 5 天。持续输注 rEPO 并未改善窒息后 1 周时的脑电图恢复、少突胶质细胞和神经元存活。相比之下，间歇性 rEPO 推注与 6/8 只胎儿的 EEG 恢复受损以及颞叶内回白质双侧囊性损伤有关。这些研究首次证明，在 HI 后 6 小时开始间歇性 rEPO 推注，剂量与最近的临床试验相当，会加重神经损伤。这些数据强化了早期启动许多潜在神经保护疗法的重要性。
