Hydrogen's Feasibility and Safety as a Therapy in ECPR

The purpose of this project is to test the feasibility and safety of inhaled hydrogen gas (H2) administration as a rescue therapy during cardiac arrest requiring extracorporeal cardiopulmonary resuscitation (ECPR, i.e. mechanical circulatory support). Each year, 500,000 patients in the US suffer a cardiac arrest and a growing number of them are resuscitated using ECPR. However, neurologic and renal injury remain important resulting comorbidities. The pathophysiology of these often-devastating injuries is ischemia (inadequacy of blood flow, at times compounded by hypoxemia) followed by an abrupt reperfusion (ECMO flow initiation). Among patients with congenital heart disease (CHD) receiving ECPR, 52% either die prior to discharge or suffer severe neurologic impairment. Diatomic hydrogen (H2) administration during and following ECPR may chemically reduce the toxic mediators that directly damage cellular structures and improve neurologically intact survival.

Preclinical data. Several groups have described that H2 inhalation decreases injury when administered following ischemic stroke, myocardial infarction, and cardiac arrest in rodents. Our group demonstrated that inhalation of 2.4% H2 for 24 hours following an experimental swine ischemia-reperfusion injury (as occurs in ECPR) improved neurologic scores, decreased seizures, diminished T2 white matter injury volume by 65%, and improved serum creatinine. Safety study in healthy participants. Under an investigator-initiated IND, we exposed 8 healthy adult participants to up to 72 hours of 2.4% H2 inhalation via high flow nasal cannula, finding no adverse effects on markers of hepatic, renal, cardiac or pulmonary function and no clinically significant symptoms reported. Having received a favorable pre-IND review from the FDA, we propose a two-center early phase study of H2 administration in patients with CHD receiving ECPR.

Study overview. We propose an early-phase randomized trial entitled the 'Hydrogen FAST Trial' (Hydrogen's Feasibility And Safety as a Therapeutic agent). The trial will have a 3-patient vanguard phase and 53 patients with CHD experiencing ECPR randomly assigned in a 3:2 (32/21) ratio to either usual care plus 2% H2 gas for 72 hours or to usual care. Patients will be recruited from two sites. We will primarily examine feasibility and safety (severe adverse events, independently adjudicated), as well as some indicators of efficacy.

Hypotheses. Primary feasibility endpoint: We hypothesize that H2 gas will be administered for a mean of \>90% of the first 72 consecutive post-arrest hours in patients so-assigned. Primary safety endpoint: We hypothesize that compared with patients receiving usual post-arrest care, patients receiving H2 will not exceed the treatment-related SAE rate of the usual care group by \>12.5% in the 30 days following randomization. Secondary feasibility endpoint: We hypothesize that H2 gas will be administered for a mean of \>90% of the first 72 consecutive hours post-H2 initiation in patients so-assigned.

• Survival to hospital discharge [Time frame: From date of randomization until the date of hospital discharge or date of death from any cause, whichever came first, assessed up to 12 months]
• ICU length of stay [Time frame: From date of randomization until the date of first ICU discharge or date of death from any cause, whichever came first, assessed up to 12 months]
• Hospital length of stay [Time frame: From date of randomization until the date of hospital discharge or date of death from any cause, whichever came first, assessed up to 12 months]
• Functional status score [Time frame: Calculated on admission to the hospital, at 24 h before cardiac arrest, at hospital discharge, and at 6 months post-randomization]
• Feasibility of hydrogen administration (secondary) [Time frame: 72 hours]