In this study, we found that, compared with a TH group, our TH + H2 group showed (1) a lower HR with constant blood pressure, (2) a higher CBV and lower ScO2. These results indicate that combined H2 gas ventilation and TH might improve cerebral hemodynamics and oxygenation and thereby help to reduce brain injuries.
In previous animal studies, sheep and piglets with brain injuries showed increased cerebral blood flow (CBF) and CBV within 24 h after a HI insult (12–14). These cerebral hemodynamic changes could reflect a decrease in oxygen metabolism along with hyperemia due to secondary energy failure caused by impaired cerebral autoregulation. In the clinical setting, it has already been reported that HIE neonates with adverse outcomes exhibited increases in CBV or ScO2 from 6 to 24 h after birth (9, 15, 16). On the other hand, TH is likely to reduce CBF and CBV because it can induce a cooling-associated decrease in the cerebral metabolic rate (10, 17). Interestingly, it has been reported that fetal sheep with increased CBF during TH after a HI insult had a better outcome (18). In addition, we also reported that a greater decrease in CBV during TH after an insult was correlated with more suppressed neural activities (10).
To our knowledge, this is the first study to show that H2 gas improves cerebral hemodynamics and oxygenation during TH after a HI insult. TH is believed to protect against reperfusion injury via multiple mechanisms, including the suppression of free radicals, enzymes, and excitatory and inflammatory reactions (18, 19), in addition to the direct physical protection of membranes, similar to H2 gas (6). However, TH suppresses the cardiovascular system, unlike H2 gas. We speculated that H2 gas may be able to improve cerebral and cardiovascular systems under even TH conditions. Domoki et al suggested that H2 ventilation increased cerebrovascular reactivity to hypercapnia after insult in the piglet (20). In a rat model of global cerebral ischemia, inhalation of H2 gas palliated brain edema and blood-brain barrier disruption, reduced neuronal apoptosis, and improved neurological function (21). Reactive oxygen species (ROS) directly destroy lipids, proteins, and nucleic acids, damaging vascular endothelial cells and the basement membrane (22). Another study reported that H2 reduced hemorrhagic transformation in a focal cerebral ischemic/reperfusion rat model and that the reduction of oxidative agents might boost the survival of endothelial cells, neurons, and glial cells (23). In this study, we speculate that the reduction in potent ROS and the consequent decrease in brain edema may be responsible for the increase in CBV and lower ScO2. Furthermore, Hayashida et al reported that H2 gas inhalation can improve left ventricular function after the return of spontaneous circulation (ROSC) in the adult rat (24), and their results showing that their TH + H2 group had a lower HR than the TH group after ROSC is in the agreement with our results. Speculatively, H2 gas might improve cardiac function and thereby boost cardiac output, resulting in improvements in CBF and cerebral oxygen metabolism.
This study has some limitations. The mechanistic details of the H2-induced neuroprotection are still unclear but likely involve inhibition of oxidative injury and neuroinflammation. However, we have virtually no information on the mechanism underlying the H2-induced neuroprotection in this study. Accordingly, we will examine biomarkers related to multiple mechanisms, including the suppression of free radicals, enzymes, and excitatory and inflammatory reactions, in addition to the direct physical protection of membranes. HI injury represents a complex biological disturbance, which may lead to secondary energy failure and cell death by both necrosis and/or apoptosis.
We conclude that H2 gas ventilation combined with TH is associated with higher CBV and lower ScO2 after a HI insult versus TH alone and speculate that the CBV increase in the TH + H2 group reflects the ability of H2 gas to ameliorate the hemodynamic impairment induced by TH. This impact of H2 gas on cerebral hemodynamics and oxygen metabolism may provide a key to elucidating its neuroprotective mechanism.