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Neonatal hypoxic-ischemic encephalopathy (HIE) is a major cause of morbidity and mortality in newborns in both high- and low-income countries. The important determinants of its pathophysiology are neural cells and vascular components. In neonatal HIE, increased vascular permeability due to damage to the blood-brain barrier is associated with seizures and poor outcomes in both translational and clinical studies. In our previous studies, hydrogen gas (H 2 ) improved the neurological outcome of HIE and ameliorated the cell death. In this study, we used albumin immunohistochemistry to assess if H 2 inhalation effectively reduced the cerebral vascular leakage. Of 33 piglets subjected to a hypoxic-ischemic insult, 26 piglets were ultimately analyzed. After the insult, the piglets were grouped into normothermia (NT), H 2 ventilation (H 2 ), therapeutic hypothermia (TH), and H 2 combined with TH (H 2 -TH) groups. The ratio of albumin stained to unstained areas was analyzed and found to be lower in the H 2 group than in the other groups, although the difference was not statistically significant. In this study, H 2 therapy did not significantly improve albumin leakage despite the histological images suggesting signs of improvement. Further investigations are warranted to study the efficacy of H 2 gas for vascular leakage in neonatal HIE., (© 2023. The Author(s).)

We previously reported the neuroprotective potential of combined hydrogen (H 2 ) gas ventilation therapy and therapeutic hypothermia (TH) by assessing the short-term neurological outcomes and histological findings of 5-day neonatal hypoxic-ischemic (HI) encephalopathy piglets. However, the effects of H 2 gas on cerebral circulation and oxygen metabolism and on prognosis were unknown. Here, we used near-infrared time-resolved spectroscopy to compare combined H 2 gas ventilation and TH with TH alone. Piglets were divided into three groups: HI insult with normothermia (NT, n = 10), HI insult with hypothermia (TH, 33.5 ± 0.5 °C, n = 8), and HI insult with hypothermia plus H 2 ventilation (TH + H 2 , 2.1-2.7%, n = 8). H 2 ventilation and TH were administered and the cerebral blood volume (CBV) and cerebral hemoglobin oxygen saturation (ScO 2 ) were recorded for 24 h after the insult. CBV was significantly higher at 24 h after the insult in the TH + H 2 group than in the other groups. ScO 2 was significantly lower throughout the 24 h after the insult in the TH + H 2 group than in the NT group. In conclusion, combined H 2 gas ventilation and TH increased CBV and decreased ScO 2 , which may reflect elevated cerebral blood flow to meet greater oxygen demand for the surviving neurons, compared with TH alone., (© 2023. The Author(s).)

Perinatal hypoxic-ischemic brain injury of neonates remains a significant problem worldwide. During the resuscitation period, changes in cerebral hemoglobin oxygen saturation (ScO 2 ) have been identified by near-infrared spectroscopy (NIRS). However, in asphyxiated neonates, the relationship between these changes and brain injury is not known. Three-wavelength near-infrared time-resolved spectroscopy, an advanced technology for NIRS, allows for the estimation of ScO 2 and cerebral blood volume (CBV). Here, we studied changes in ScO 2 and CBV during the resuscitation period after hypoxic-ischemic insult and the relationship between these changes after insult and histopathological brain injuries on day 5 after insult using an asphyxiated piglet model. Of 36 newborn piglets subjected to hypoxic-ischemic insult, 29 were analyzed. ScO 2 and CBV were measured 0, 5, 10, 15, and 30 min after the insult. Brain tissue was histologically evaluated on day 5. ScO 2 and CBV increased immediately after the insult, reached a peak, and then maintained a consistent value. The increase in CBV 5 to 30 min after the insult was significantly correlated with histopathological injury scores. However, there was no correlation with ScO 2 . In conclusion, an increase in CBV within 30 min after hypoxic-ischemic insult reflects the histopathological brain injury on day 5 after insult in a piglet model., (© 2022. The Author(s).)

Neonatal hypoxic-ischemic encephalopathy is a notable cause of neonatal death and developmental disabilities. To achieve better outcomes, it is important in treatment strategy selection to categorize the degree of hypoxia ischemia and evaluate dose response. In an asphyxia piglet model with histopathological brain injuries that we previously developed, animals survived 5 days after insult and showed changes in cerebral blood volume (CBV) that reflected the severity of injuries. However, little is known about the relationship between changes in CBV during and after insult. In this study, an HI event was induced by varying the amount and timing of inspired oxygen in 20 anesthetized piglets. CBV was measured using near-infrared time-resolved spectroscopy before, during, and 6 h after insult. Change in CBV was calculated as the difference between the peak CBV value during insult and the value at the end of insult. The decrease in CBV during insult was found to correlate with the increase in CBV within 6 h after insult. Heart rate exhibited a similar tendency to CBV, but blood pressure did not. Because the decrement in CBV was larger in severe HI, the CBV increment immediately after insult is considered useful for assessing degree of HI insult.

Despite its poor outcomes, therapeutic hypothermia (TH) is the current standard treatment for neonatal hypoxic-ischaemic encephalopathy (HIE). In this study, due to its antioxidant, anti-inflammatory, and antiapoptotic properties, the effectiveness of molecular hydrogen (H 2 ) combined with TH was evaluated by means of neurological and histological assessments. Piglets were divided into three groups: hypoxic-ischaemic insult with normothermia (NT), insult with hypothermia (TH, 33.5 ± 0.5 °C), and insult with hypothermia with H 2 ventilation (TH-H 2 , 2.1-2.7%). H 2 ventilation and TH were administered for 24 h. After ventilator weaning, neurological assessment was performed every 6 h for 5 days. On day 5, the brains of the piglets were harvested for histopathological analysis. Regarding the neurological score, the piglets in the TH-H 2 group consistently had the highest score from day 2 to 5 and showed a significantly higher neurological score from day 3 compared with the NT group. Most piglets in the TH-H 2 group could walk at day 3 of recovery, whereas walking ability was delayed in the two other groups. The histological results revealed that TH-H 2 tended to improve the status of cortical gray matter and subcortical white matter, with a considerable reduction in cell death. In this study, the combination of TH and H 2 improved short-term neurological outcomes in neonatal hypoxic-ischaemic piglets.