Safety of intravenous administration of hydrogen-enriched fluid in patients with acute cerebral ischemia: Initial clinical studies

Most of the results regarding hydrogen (H2) therapy for acute cerebral ischemia are derived from in vitro studies and animal experiments, with only a few obtained from human trials with a limited number of subjects. Thus, there is a paucity of information regarding both the beneficial therapeutic effects as well as the side effects of H2 on acute cerebral ischemia in humans. We designed a pilot study to investigate single dose intravenous H2-administration in combination with edaravone, aiming to provide an initial estimate of the possible risks and benefits in select patients presenting with acute ischemic stroke. An open-label, prospective, non-randomized study of intravenous H2-administration was performed in 38 patients hospitalized for acute ischemic stroke. All patients received an H2-enriched intravenous solution in addition to edaravone immediately after the diagnosis of acute ischemic stroke. Acute stroke patients within 3 h of onset received intravenous tissue plasminogen activator (t-PA) (0.6 mg/kg) treatment, and patients receiving t-PA had to commence the administration of the H2-enriched intravenous solution and edaravone before or at the same time as the t-PA was infused. Complications were observed in 2 patients (5.3%), which consisted of diarrhea in 1 patient (2.6%) and cardiac failure in 1 patient (2.6%). No deterioration in laboratory tests, urinary tests, ECG, or chest X-ray radiograms occurred in any patient in this study. In all patients, the mean National Institutes of Health Stroke Scale (NIHSS) scores at baseline, and 7, 30, and 90 d after admission were 8.2 +/- 7.5, 5.6 +/- 7.1, 4.9 +/- 6.5, and 4.5 +/- 6.3, respectively. The early recanalization was identified in 4 of 11 patients (36.4%) who received intravenous t-PA administration. Hemorrhagic transformation was observed in 2 patients (18.2%). None of the patients in this study that were treated with t-PA developed symptomatic intracranial hemorrhage. Data from the current study indicate that an H2-enriched intravenous solution is safe for patients with acute cerebral infarction, including patients treated with t-PA.

Physiological effects of combination therapy of intracisternal infusion of magnesium sulfate solution and intravenous injection of hydrogen-enriched fluid in the rat

Combination therapy of intracisternal (ic) infusion of magnesium sulfate solution and intravenous (iv) injection of hydrogen-enriched fluid can provide protection against delayed ischemic neurological deficits after subarachnoid hemorrhage (SAH). However, the effects of this therapy on physiological parameters in vivo remain unclear. In this study, the effects of combination therapy were investigated on the physiological parameters of normal and experimental SAH model rats. SAH was induced by 0.1 mL autologous blood injection into the cisterna magna 24 hours prior to combination therapy. Male Sprague-Dawley rats received simultaneous ic infusion and iv injection as follows: control group, ic infusion of lactated Ringer solution and iv injection of glucose-electrolyte solution (SOLDEM1®); Mg group, ic infusion of magnesium sulfate solution and iv injection of SOLDEM1®; and Mg+H2 and SAH groups, ic infusion of magnesium sulfate solution and iv injection of hydrogen-enriched fluid. Blood gases, intracranial pressure, blood pressure, and rectal temperature were measured. The physiological values were all within normal ranges and no significant changes were found in all groups. No particular histological findings were observed. Combination therapy of ic infusion of magnesium and iv administration of hydrogen has no harmful effect on the physiological parameters of rats.

Hydrogen improves neurological function through attenuation of blood–brain barrier disruption in spontaneously hypertensive stroke-prone rats

Enhanced oxidative stress occurs in spontaneously hypertensive stroke-prone rats (SHRSP), and is important in blood-brain barrier (BBB) disruption. Hydrogen can exert potent protective cellular effects via reduction in oxidative stress in various diseases. The present study investigated whether long-term hydrogen treatment can improve neurological function outcome in the SHRSP model, and the effects of hydrogen on BBB function, especially the oxidative stress and the activity of matrix metalloproteinases (MMPs) in this model. Fifty-six animals were randomly assigned to 2 groups and treated as follows: SHRSP treated with hydrogen-rich water (HRW) (HRW group, n = 28); and SHRSP treated with regular water (control group, n = 28). The effect of HRW on overall survival and neurological function, and the effects of HRW on reactive oxygen species, BBB function, and MMP activities were examined. HRW treatment improved neurological function and tended to improve overall survival but without significant difference. The numbers of bleeds and infarcts were lower in the cortex and hippocampus in the HRW group. The HRW group exhibited a significantly lower number of 8-hydroxy-2′-deoxyguanosine-positive cells and vessels of extravasated albumin in the hippocampus compared with the control group. MMP-9 activity was reduced in the hippocampus in the HRW group compared with the control group. The present study suggests that ingestion of HRW can improve neurological function outcome in the SHRSP model. This beneficial effect may be due to attenuation of BBB disruption via reduction in reactive oxygen species and suppression of MMP-9 activity in the hippocampus.

Hydrogen does not Exert Neuroprotective Effects or Improve Functional Outcomes in Rats After Intracerebral Hemorrhage

Aim: Increasing evidence suggests that reactive oxygen species damage the blood-brain barrier and increase brain edema after intracerebral hemorrhage (ICH). Recently, strong clinical and experimental evidence has shown that hydrogen has potent protective cellular effects in various diseases. However, the effect of hydrogen on ICH remains unclear. The present study investigates whether hydrogen has neuroprotective effects and improves functional outcome in the rat ICH model. Material and methods: ICH model was generated by injecting 50 μl autologous tail artery blood stereotactically into the right caudate nucleus of Sprague-Dawley rats. Rats were randomly divided into four groups: sham, ICH/vehicle, ICH/hydrogen gas, and ICH/hydrogen-rich saline groups. Hydrogen treatment was performed for 3 days. The evaluation of functional outcome was done before, and at 24 and 72 hours after ICH. Hemorrhage volume, immunohistochemistry for 8-hydroxy-2′-deoxyguanosine (8-OHdG), and brain water content were evaluated at 72 hours after ICH. Results: Hydrogen administration reduced the expression of 8-OHdG in the brain, but did not attenuate brain water content or improve functional outcome, regardless of administration route. Conclusion: Hydrogen administration without surgery has no neuroprotective effect in the blood injection rat ICH model.

Hydrogen gas inhalation improves delayed brain injury by alleviating early brain injury after experimental subarachnoid hemorrhage

Molecular hydrogen (H2) protect neurons against reactive oxygen species and ameliorates early brain injury (EBI) after subarachnoid hemorrhage (SAH). This study investigated the effect of H2 on delayed brain injury (DBI) using the rat SAH + unilateral common carotid artery occlusion (UCCAO) model with the endovascular perforation method. 1.3% H2 gas (1.3% hydrogen premixed with 30% oxygen and balanced nitrogen) inhalation was performed on days 0 and 1, starting from anesthesia induction and continuing for 2 h on day 0, and starting from anesthesia induction and continuing for 30 min on day 1. EBI was assessed on the basis of brain edema, expression of S100 calcium-binding protein B (S100B), and phosphorylation of C-Jun N-terminal kinase on day 2, and neurological deficits on day 3. Reactive astrogliosis and severity of cerebral vasospasm (CV) were assessed on days 3 and 7. DBI was assessed on the basis of neurological deficits and neuronal cell death on day 7. EBI, reactive astrogliosis, and DBI were ameliorated in the H2 group compared with the control group. CV showed no significant improvement between the control and H2 groups. This study demonstrated that H2 gas inhalation ameliorated DBI by reducing EBI without improving CV in the rat SAH + UCCAO model.

Intravenous Hydrogen Therapy With Intracisternal Magnesium Sulfate Infusion in Severe Aneurysmal Subarachnoid Hemorrhage

Background and purpose: Poor-grade subarachnoid hemorrhage still has a poor prognosis. This randomized controlled clinical trial evaluated intracisternal magnesium sulfate infusion combined with intravenous hydrogen therapy in patients with poor-grade subarachnoid hemorrhage. Methods: Thirty-seven patients with poor-grade subarachnoid hemorrhage were randomized to Mg+H2, Mg, and control groups. Mg and Mg+H2 groups received intracisternal magnesium sulfate infusion (2.5 mmol/L) at 20 mL/h for 14 days. Mg+H2 group also received intravenous hydrogen-rich solution infusion for 14 days. Primary outcome measures were occurrence of delayed cerebral ischemia and cerebral vasospasm. Secondary outcome measures were modified Rankin Scale and Karnofsky performance status at 3 and 12 months, Barthel index at 12 months, and serum and cerebrospinal fluid malondialdehyde and neuron-specific enolase. Results: Serum neuron-specific enolase levels were significantly lower in the Mg+H2 group from days 3 to 14 than in the control group. Cerebrospinal fluid neuron-specific enolase levels were also significantly lower in the Mg+H2 group from days 3 to 7 than in the control group. Incidences of cerebral vasospasm and delayed cerebral ischemia were significantly higher in the control group than in other groups. Modified Rankin Scale and Karnofsky performance status did not significantly differ between the three groups at 3 months. Modified Rankin Scale scores 0 to 2 were more common in the Mg and Mg+H2 groups at 1 year. Barthel index was higher in the Mg+H2 group than in the control group. Conclusions: Intracisternal magnesium sulfate infusion started immediately after surgery reduces the incidence of cerebral vasospasm and delayed cerebral ischemia and improves clinical outcomes without complications in patients with poor-grade subarachnoid hemorrhage. Intracisternal magnesium sulfate infusion combined with intravenous hydrogen therapy decreases serum malondialdehyde and neuron-specific enolase and improves Barthel index, indicating hydrogen has additional effects. Registration: URL: https://www.umin.ac.jp/ctr/index.htm. Unique identifier: UMIN000014696.