Efficacy of inhaled hydrogen on neurological outcome following brain ischaemia during post-cardiac arrest care (HYBRID II): a multi-centre, randomised, double-blind, placebo-controlled trial

Background: Inhaled molecular hydrogen gas (H₂) has been shown to improve outcomes in animal models of cardiac arrest (CA). H₂ inhalation is safe and feasible in patients after CA. We investigated whether inhaled H₂ would improve outcomes after out-of-hospital CA (OHCA). Methods: HYBRID II is a prospective, multicentre, randomised, double-blind, placebo-controlled trial performed at 15 hospitals in Japan, between February 1, 2017, and September 30, 2021. Patients aged 20–80 years with coma following cardiogenic OHCA were randomly assigned (1:1) using blinded gas cylinders to receive supplementary oxygen with 2% H₂ or oxygen (control) for 18 h. The primary outcome was the proportion of patients with a 90-day Cerebral Performance Category (CPC) of 1 or 2 assessed in a full-analysis set. Secondary outcomes included the 90-day score on a modified Rankin scale (mRS) and survival. HYBRID II was registered with the University Hospital Medical Information Network (registration number: UMIN000019820) and re-registered with the Japan Registry for Clinical Trials (registration number: jRCTs031180352). Findings: The trial was terminated prematurely because of the restrictions imposed on enrolment during the COVID-19 pandemic. Between February 1, 2017, and September 30, 2021, 429 patients were screened for eligibility, of whom 73 were randomly assigned to H₂ (n = 39) or control (n = 34) groups. The primary outcome, i.e., a CPC of 1 or 2 at 90 days, was achieved in 22 (56%) and 13 (39%) patients in the H₂ and control groups (relative risk compared with the control group, 0.72; 95% CI, 0.46–1.13; P = 0.15), respectively. Regarding the secondary outcomes, median mRS was 1 (IQR: 0–5) and 5 (1–6) in the H₂ and control groups, respectively (P = 0.01). An mRS score of 0 was achieved in 18 (46%) and 7 (21%) patients in the H₂ and control groups, respectively (P = 0.03). The 90-day survival rate was 85% (33/39) and 61% (20/33) in the H₂ and control groups, respectively (P = 0.02). Interpretation: The increase in participants with good neurological outcomes following post-OHCA H₂ inhalation in a selected population of patients was not statistically significant. However, the secondary outcomes suggest that H₂ inhalation may increase 90-day survival without neurological deficits. Funding: Taiyo Nippon Sanso Corporation. Translation: For the Japanese translation of the abstract see Supplementary Materials section.