Inhalation of hydrogen gas reduces infarct size in the rat model of myocardial ischemia-reperfusion injury

Inhalation of hydrogen (H(2)) gas has been demonstrated to limit the infarct volume of brain and liver by reducing ischemia-reperfusion injury in rodents. When translated into clinical practice, this therapy must be most frequently applied in the treatment of patients with acute myocardial infarction, since angioplastic recanalization of infarct-related occluded coronary artery is routinely performed. Therefore, we investigate whether H(2) gas confers cardioprotection against ischemia-reperfusion injury in rats. In isolated perfused hearts, H(2) gas enhances the recovery of left ventricular function following anoxia-reoxygenation. Inhaled H(2) gas is rapidly transported and can reach ‘at risk’ ischemic myocardium before coronary blood flow of the occluded infarct-related artery is reestablished. Inhalation of H(2) gas at incombustible levels during ischemia and reperfusion reduces infarct size without altering hemodynamic parameters, thereby preventing deleterious left ventricular remodeling. Thus, inhalation of H(2) gas is promising strategy to alleviate ischemia-reperfusion injury coincident with recanalization of coronary artery.

H2 gas improves functional outcome after cardiac arrest to an extent comparable to therapeutic hypothermia in a rat model

All clinical and biological manifestations related to postcardiac arrest (CA) syndrome are attributed to ischemia-reperfusion injury in various organs including brain and heart. Molecular hydrogen (H(2)) has potential as a novel antioxidant. This study tested the hypothesis that inhalation of H(2) gas starting at the beginning of cardiopulmonary resuscitation (CPR) could improve the outcome of CA. Ventricular fibrillation was induced by transcutaneous electrical epicardial stimulation in rats. After 5 minutes of the subsequent CA, rats were randomly assigned to 1 of 4 experimental groups at the beginning of CPR: mechanical ventilation (MV) with 2% N(2) and 98% O(2) under normothermia (37°C), the control group; MV with 2% H(2) and 98% O(2) under normothermia; MV with 2% N(2) and 98% O(2) under therapeutic hypothermia (TH), 33°C; and MV with 2% H(2) and 98% O(2) under TH. Mixed gas inhalation and TH continued until 2 hours after the return of spontaneous circulation (ROSC). H(2) gas inhalation yielded better improvement in survival and neurological deficit score (NDS) after ROSC to an extent comparable to TH. H(2) gas inhalation, but not TH, prevented a rise in left ventricular end-diastolic pressure and increase in serum IL-6 level after ROSC. The salutary impact of H(2) gas was at least partially attributed to the radical-scavenging effects of H(2) gas, because both 8-OHdG- and 4-HNE-positive cardiomyocytes were markedly suppressed by H(2) gas inhalation after ROSC. Inhalation of H(2) gas is a favorable strategy to mitigate mortality and functional outcome of post-CA syndrome in a rat model, either alone or in combination with TH.

Feasibility and Safety of Hydrogen Gas Inhalation for Post-Cardiac Arrest Syndrome – First-in-Human Pilot Study

Background: Hydrogen gas inhalation (HI) ameliorates cerebral and cardiac dysfunction in animal models of post-cardiac arrest syndrome (PCAS). HI for human patients with PCAS has never been studied.Methods and Results:Between January 2014 and January 2015, 21 of 107 patients with out-of-hospital cardiac arrest achieved spontaneous return of circulation. After excluding 16 patients with specific criteria, 5 patients underwent HI together with target temperature management (TTM). No undesirable effects attributable to HI were observed and 4 patients survived 90 days with a favorable neurological outcome. Conclusions: HI in combination with TTM is a feasible therapy for patients with PCAS.

Hydrogen gas inhalation inhibits progression to the ‘irreversible’ stage of shock after severe hemorrhage in rats

Background: Mortality of hemorrhagic shock primarily depends on whether or not the patients can endure the loss of circulating volume until radical treatment is applied. We investigated whether hydrogen (H2) gas inhalation would influence the tolerance to hemorrhagic shock and improve survival. Methods: Hemorrhagic shock was achieved by withdrawing blood until the mean arterial blood pressure reached 30-35 mm Hg. After 60 minutes of shock, the rats were resuscitated with a volume of normal saline equal to four times the volume of shed blood. The rats were assigned to either the H2 gas (1.3% H2, 26% O2, 72.7% N2)-treated group or the control gas (26% O2, 74% N2)-treated group. Inhalation of the specified gas mixture began at the initiation of blood withdrawal and continued for 2 hours after fluid resuscitation. Results: The survival rate at 6 hours after fluid resuscitation was 80% in H2 gas-treated rats and 30% in control gas-treated rats (p < 0.05). The volume of blood that was removed through a catheter to induce shock was significantly larger in the H2 gas-treated rats than in the control rats. Despite losing more blood, the increase in serum potassium levels was suppressed in the H2 gas-treated rats after 60 minutes of shock. Fluid resuscitation completely restored blood pressure in the H2 gas-treated rats, whereas it failed to fully restore the blood pressure in the control gas-treated rats. At 2 hours after fluid resuscitation, blood pressure remained in the normal range and metabolic acidosis was well compensated in the H2 gas-treated rats, whereas we observed decreased blood pressure and uncompensated metabolic acidosis and hyperkalemia in the surviving control gas-treated rats. Conclusions: H2 gas inhalation delays the progression to irreversible shock. Clinically, H2 gas inhalation is expected to stabilize the subject until curative treatment can be performed, thereby increasing the probability of survival after hemorrhagic shock.

The Effects of Hydrogen Gas Inhalation on Adverse Left Ventricular Remodeling After Percutaneous Coronary Intervention for ST-Elevated Myocardial Infarction – First Pilot Study in Humans

Background: Hydrogen gas inhalation (HI) reduced infarct size and mitigated adverse left ventricular (LV) remodeling in a rat model of acute myocardial infarction (AMI). We designed a prospective, open-label, rater-blinded clinical pilot study in patients experiencing ST-elevated MI (STEMI).Methods and Results:The 20 patients with an initial diagnosis of STEMI were assigned to either an HI group (1.3% H2with 26% oxygen) or a control group (26% oxygen). There were no HI-related severe adverse events. In the full analysis set, the cardiac salvage index as evaluated using cardiac magnetic resonance imaging at 7 days after primary percutaneous coronary intervention (PCI), showed no significant between-group difference (HI: 50.0±24.3%; control: 60.1±20.1%; P=0.43). However, the improvement from day 7 in the HI group was numerically greater than that in the control group in some of the surrogate outcomes at 6-month follow-up, including the LV stroke volume index (HI: 9.2±7.1 mL/m2; control: -1.4±7.2 mL/m2; P=0.03) and the LV ejection fraction (HI: 11.0%±9.3%; control: 1.7%±8.3%; P=0.11). Conclusions: The first clinical study has shown that HI during PCI is feasible and safe and may also promote LV reverse remodeling at 6 months after STEMI. The study was not powered to test efficacy and a further large-scale trial is warranted. (Clinical trials registration: UMIN00006825).