Background <p>Extracorporeal cardiopulmonary resuscitation (ECPR) improves survival for patients experiencing refractory cardiac arrest but is often associated with severe ischemia-reperfusion injury (IRI). Hydrogen gas (H₂) has demonstrated promising preclinical efficacy in reducing IRI. The Hydrogen-FAST trial investigates the feasibility and safety of inhaled hydrogen gas as an adjunctive therapy during ECPR in patients with congenital heart disease (CHD).</p> Methods <p>This phase 1 multicenter randomized controlled trial enrolls patients of any age undergoing ECPR due to refractory cardiac arrest associated with underlying cardiac morbidity. Due to the emergent nature of ECPR events, the trial leverages an Exception from Informed Consent enrollment process. Fifty-three participants will be randomized to standard care or standard care plus inhaled 2% H₂ gas delivered continuously for 72&#xa0;h via mechanical ventilator and extracorporeal membrane oxygenation (ECMO) circuit. Primary endpoints include feasibility, measured as the percentage of the first 72&#xa0;h post-arrest in which hydrogen is successfully administered, with feasibility defined as a mean percentage of ≥90%, and safety, evaluated through incidence rates of treatment-related serious adverse events (SAEs). Secondary endpoints examine clinical outcomes including survival to discharge, ICU length of stay, functional status at 6 months, neurologic function, and markers of ischemic injury.</p> Discussion <p>The Hydrogen-FAST trial will provide essential data on the feasibility and safety of H₂ administration during ECPR, informing larger efficacy studies and potential broader clinical use in critical care settings.</p> Trial registration <p>ClinicalTrials.gov NCT05574296. Registered on October 6, 2022. <a href="https://clinicaltrials.gov/study/NCT05574296">https://clinicaltrials.gov/study/NCT05574296</a>.</p>