Nemeth J, Toth-Szuki V, Varga V, Kovacs V, Remzso G, Domoki F
Department of Physiology, University of Szeged, School of Medicine, Szeged, Hungary.
J Physiol Pharmacol. 2016 Oct;67(5):677-689.
Hypoxic-ischemic encephalopathy (HIE) is the major consequence of perinatal asphyxia (PA) in term neonates. Although the newborn piglet is an accepted large animal PA/HIE model, there is no consensus on PA-induction methodology to produce clinically relevant HIE. We aimed to create and to characterize a novel PA model faithfully reproducing all features of asphyxiation including severe hypercapnia resulting in HIE, and to test whether H is neuroprotective in this model. Piglets were anaesthetised, artificially ventilated, and intensively monitored (electroencephalography, core temperature, O saturation, arterial blood pressure and blood gases). Asphyxia (20 min) was induced by ventilation with a hypoxic-hypercapnic (6%O - 20%CO) gas mixture. Asphyxia-induced changes in the cortical microcirculation were assessed with laser-speckle contrast imaging and analysis. Asphyxia was followed by reventilation with air or air containing hydrogen (2.1%H, 4 hours). After 24 hours survival, the brains were harvested for neuropathology. Our PA model was characterized by the development of severe hypoxia (pO2 = 27 ± 4 mmHg), and combined acidosis (pH = 6.76 ± 0.04; pCO = 114 ± 11 mmHg; lactate = 12.12 ± 0.83 mmol/L), however, cortical ischemia did not develop during the stress. Severely depressed electroencephalography (EEG), and marked neuronal injury indicated the development of HIE. H was neuroprotective shown both by the enhanced recovery of EEG and by the significant preservation of neurons in the cerebral cortex, hippocampus, basal ganglia, and the thalamus. H2 appeared to reduce oxidative stress shown by attenuation of 8-hydroxy-2'-deoxyguanosine immunostaining. In summary, this new PA piglet model is able to induce moderate/severe HIE, and the efficacy of hydrogen post-treatment to preserve neuronal activity/function in this PA/HIE model suggests the feasibility of this safe and inexpensive approach in the treatment of asphyxiated babies.
缺氧缺血性脑病（HIE）是足月儿围产期窒息（PA）的主要后果。尽管新生仔猪是公认的大型动物PA/HIE模型，但对于产生临床相关HIE的PA诱导方法尚无共识。我们旨在创建并表征一种新型PA模型，该模型能忠实地再现窒息的所有特征，包括导致HIE的严重高碳酸血症，并测试氢气在该模型中是否具有神经保护作用。仔猪接受麻醉、人工通气并进行密切监测（脑电图、核心体温、血氧饱和度、动脉血压和血气）。通过用缺氧高碳酸血症（6%氧气 - 20%二氧化碳）混合气体通气诱导窒息（20分钟）。用激光散斑对比成像和分析评估窒息诱导的皮质微循环变化。窒息后用空气或含氢气（2.1%氢气，4小时）的空气进行再通气。存活24小时后，收获大脑进行神经病理学检查。我们的PA模型的特征是出现严重缺氧（动脉血氧分压 = 27 ± 4 mmHg）和混合性酸中毒（pH = 6.76 ± 0.04；动脉血二氧化碳分压 = 114 ± 11 mmHg；乳酸 = 12.12 ± 0.83 mmol/L），然而，在应激期间未发生皮质缺血。严重抑制的脑电图（EEG）和明显的神经元损伤表明HIE的发生。氢气通过增强EEG恢复以及显著保护大脑皮质、海马、基底神经节和丘脑的神经元显示出神经保护作用。氢气似乎通过减弱8-羟基-2'-脱氧鸟苷免疫染色显示的氧化应激。总之，这种新的PA仔猪模型能够诱导中度/重度HIE，并且氢气后处理在该PA/HIE模型中保护神经元活性/功能的功效表明这种安全且廉价的方法在治疗窒息婴儿方面具有可行性。
