Hydrogen gas with extracorporeal cardiopulmonary resuscitation improves survival after prolonged cardiac arrest in rats

Abstract

Background Despite the benefits of extracorporeal cardiopulmonary resuscitation (ECPR) in cohorts of selected patients with cardiac arrest (CA), extracorporeal membrane oxygenation (ECMO) includes an artificial oxygenation membrane and circuits that contact the circulating blood and induce excessive oxidative stress and inflammatory responses, resulting in coagulopathy and endothelial cell damage. There is currently no pharmacological treatment that has been proven to improve outcomes after CA/ECPR. We aimed to test the hypothesis that administration of hydrogen gas (H2) combined with ECPR could improve outcomes after CA/ECPR in rats. Methods Rats were subjected to 20 min of asphyxial CA and were resuscitated by ECPR. Mechanical ventilation (MV) was initiated at the beginning of ECPR. Animals were randomly assigned to the placebo or H2 gas treatment groups. The supplement gas was administered with O2 through the ECMO membrane and MV. Survival time, electroencephalography (EEG), brain functional status, and brain tissue oxygenation were measured. Changes in the plasma levels of syndecan-1 (a marker of endothelial damage), multiple cytokines, chemokines, and metabolites were also evaluated. Results The survival rate at 4 h was 77.8% (7 out of 9) in the H2 group and 22.2% (2 out of 9) in the placebo group. The Kaplan–Meier analysis showed that H2 significantly improved the 4 h-survival endpoint (log-rank P = 0.025 vs. placebo). All animals treated with H2 regained EEG activity, whereas no recovery was observed in animals treated with placebo. H2 therapy markedly improved intra-resuscitation brain tissue oxygenation and prevented an increase in central venous pressure after ECPR. H2 attenuated an increase in syndecan-1 levels and enhanced an increase in interleukin-10, vascular endothelial growth factor, and leptin levels after ECPR. Metabolomics analysis identified significant changes at 2 h after CA/ECPR between the two groups, particularly in d-glutamine and d-glutamate metabolism. Conclusions H2 therapy improved mortality in highly lethal CA rats rescued by ECPR and helped recover brain electrical activity. The underlying mechanism might be linked to protective effects against endothelial damage. Further studies are warranted to elucidate the mechanisms responsible for the beneficial effects of H2 on ischemia–reperfusion injury in critically ill patients who require ECMO support.

Influence of oxygen concentration on the neuroprotective effect of hydrogen inhalation in a rat model of cardiac arrest

“…In line with previous animal studies, hydrogen inhalation alleviated post-CA brain injury and improved 96-h survival by its anti-oxidant and anti-apoptotic functions in the present study ( 10 , 13 , 14 , 16 , 18 , 19 ). Moreover, our study extended previous observation on the therapeutic mechanism of hydrogen and provided new evidence on confounding factors influencing its efficacy.…”

Rat model of asphyxia-induced cardiac arrest and resuscitation

“…Asphyxia cardiac arrest is usually induced by disconnecting the mechanical ventilator and clamping the tracheal tube, with or without vecuronium. In recent years, the ACA model has also been used for in vitro cardiopulmonary cerebral resuscitation studies ( Wollborn et al, 2019 ; Yin et al, 2021 ). It can accurately model the main causes of CA and death due to asphyxia, including post-CA changes in blood gases and pathophysiology of the heart, brain, kidney, and other tissues.…”

Molecular Hydrogen Neuroprotection in Post-Ischemic Neurodegeneration in the Form of Alzheimer’s Disease Proteinopathy: Underlying Mechanisms and Potential for Clinical Implementation—Fantasy or Reality?

“…It also prevented the increase in left ventricular end-diastolic pressure and the increase in serum IL-6 levels, and reduced mortality [ 31 , 79 , 80 ]. Hydrogen treatment increased the level of interleukin-10, vascular endothelial growth factor and leptin [ 81 ]. In addition, a reduction in mortality in rats after cardiac arrest and an effect on the restoration of the bioelectrical activity of the brain was noted [ 81 ].…”

“…Hydrogen treatment increased the level of interleukin-10, vascular endothelial growth factor and leptin [ 81 ]. In addition, a reduction in mortality in rats after cardiac arrest and an effect on the restoration of the bioelectrical activity of the brain was noted [ 81 ]. The survival rate at 4 h was 78% in the hydrogen group and 22% in the placebo group [ 81 ].…”

“…In addition, a reduction in mortality in rats after cardiac arrest and an effect on the restoration of the bioelectrical activity of the brain was noted [ 81 ]. The survival rate at 4 h was 78% in the hydrogen group and 22% in the placebo group [ 81 ]. In another global model of cerebral ischemia due to cardiac arrest in rats, increased survival and inhibition of autophagy were observed [ 82 ].…”