Early antioxidant treatment and delayed hypothermia after hypoxia-ischemia have no additive neuroprotection in newborn pigs.
Early antioxidant treatment and delayed hypothermia after hypoxia-ischemia have no additive neuroprotection in newborn pigs.
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DOI：
10.1213/ane.0b013e31825d3600
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发表时间：
2012-09
影响因子：
5.7
通讯作者：
Koehler RC
中科院分区：
文献类型：
--
作者：
Ni X;Yang ZJ;Wang B;Carter EL;Larson AC;Martin LJ;Koehler RC
新生儿缺氧缺血性（HI）脑病中低温治疗的实施和临床疗效在一定程度上受到低温实施和设备获取延迟的限制。在 HI 仔猪模型中，壳核中一半的神经元在恢复 6 小时时已表现出缺血性细胞病理学。我们测试了这样的假设：在复苏 30 分钟时使用超氧化物歧化酶-过氧化氢酶模拟物 EUK-134 治疗，结合复苏后 4 小时实施一天的全身低温治疗，可以提供额外的神经元保护。麻醉仔猪经历 40 分钟的缺氧（10% 吸入氧），然后进行 7 分钟的气道阻塞和复苏。常温组体温维持在38.5℃，低温组维持在34℃。在恢复的第一天，所有组均接受机械通气、镇静并接受肌肉松弛剂。通过轮廓和体视细胞计数方法评估神经病理学。恢复 10 天时，用盐水载体治疗的常温组壳核中的神经元活力降低至假手术对照组值 (100±15%) 的 17±6%（±95% 置信区间）。静脉输注 EUK-134（恢复 30 分钟时 2.5 毫克/千克 + 恢复 4 小时前 1.25 毫克/千克/小时）并常温恢复导致壳核中 40±12% 的存活神经元。用盐水载体治疗然后延迟低温治疗导致部分保护（46±15%）。早期 EUK-134 治疗与延迟低温治疗相结合也产生了部分保护 (47±18%)，但并不显着高于 EUK-134 单一治疗（差异置信区间：-15% 至 29%）或延迟低温治疗（-16% 至 19%）。此外，在尾状核或旁矢状新皮质中没有检测到额外的神经保护作用，这些地方的神经元损失不太严重。我们得出的结论是，使用这种抗氧化剂进行早期治疗并不能显着增强延迟低温对保护高危新生儿中高度脆弱的神经元的治疗效果，可能是因为在施用 EUK-134 时基底神经节神经元已经在经历不可逆的细胞死亡信号传导，或者因为这种化合物和低温会减弱类似的损伤机制。
The implementation and clinical efficacy of hypothermia in neonatal hypoxic-ischemic (HI) encephalopathy are limited, in part, by the delay in instituting hypothermia and access to equipment. In a piglet model of HI, half of the neurons in putamen already showed ischemic cytopathology by 6 hours of recovery. We tested the hypothesis that treatment with the superoxide dismutase-catalase mimetic EUK-134 at 30 minutes of recovery provides additive neuronal protection when combined with one day of whole body hypothermia implemented 4 hours after resuscitation. Anesthetized piglets were subjected to 40 minutes of hypoxia (10% inspired oxygen) followed by 7 minutes of airway occlusion and resuscitation. Body temperature was maintained at 38.5°C in normothermic groups and at 34°C in hypothermic groups. All groups were mechanically ventilated, sedated, and received muscle relaxants during the first day of recovery. Neuropathology was assessed by profile and stereological cell counting methods. At 10 days of recovery, neuronal viability in putamen of a normothermic group treated with saline vehicle was reduced to 17±6% (±95% confidence interval) of the value in a sham-operated control group (100±15%). Intravenous infusion of EUK-134 (2.5 mg/kg at 30 minutes of recovery + 1.25 mg/kg/h until 4 hours of recovery) with normothermic recovery resulted in 40±12% viable neurons in putamen. Treatment with saline vehicle followed by delayed hypothermia resulted in partial protection (46±15%). Combining early EUK-134 treatment with delayed hypothermia also produced partial protection (47±18%) that was not significantly greater than single treatment with EUK-134 (confidence interval of difference: −15% to 29%) or delayed hypothermia (−16% to 19%). Furthermore, no additive neuroprotection was detected in caudate nucleus or parasagittal neocortex, where neuronal loss was less severe. We conclude that early treatment with this antioxidant does not substantially enhance the therapeutic benefit of delayed hypothermia in protecting highly vulnerable neurons in HI-insulted newborns, possibly because basal ganglia neurons are already undergoing irreversible cell death signaling by the time EUK-134 is administered or because this compound and hypothermia attenuate similar mechanisms of injury.