Respiratory-physiology modeling of therapeutic hydrogen inhalation: defining the fraction of inspired hydrogen (FiH2) and flow-rate requirements.

BACKGROUND: Molecular hydrogen (H2 gas) has emerged as a promising therapeutic agent with reported benefits across oxidative stress, inflammation, cardiovascular, and neurodegenerative conditions. Among administration routes, inhalation provides direct systemic delivery but has been hindered by a lack of individualization, methodological inconsistencies, misinterpretation of concentration, and safety concerns. We propose that fraction of inspired hydrogen (FiH2), defined at the airway opening rather than by source gas concentration (FH2) or flow rate, should be considered the standardized metric for dosing, akin to oxygen therapy. This directly links inspired H2 at the airway opening to resulting blood concentrations via Dalton’s and Henry’s laws, thereby enabling consistent dosing, interpretation of clinical data, and comparability across studies.

METHODS: A targeted analysis of experimental and clinical literature was used to identify H2 concentration ranges associated with minimum and optimal biological effects. Deterministic respiratory-physiology in silico modeling was then used to estimate the FiH2 during nasal cannula H2 administration under practical breathing conditions, accounting for minute ventilation, inspiratory flow dynamics, and duty cycle, and to derive H2 flow-rate requirements.

RESULTS: Evidence indicates that therapeutic effects typically require blood concentrations of ~2–10 µM, corresponding to ~1% FiH2; whereas optimal FiH2 remains elusive with trends favoring 2% over 4% in some settings and possibly the reverse in others. Use of H2 source gas exceeding 4% introduces intrinsic flammability risk that scales with flow rate, particularly if FiH2 exceeds 4%, and should be avoided. Modeling suggests that ~200–300 mL/min absolute hydrogen achieves ~1% FiH2 via nasal cannula in average adults, whereas higher flows (~600–1200 mL/min) may be required for 2–4% and may still fail to reach 1%. Thus, flow rate cannot reliably ensure a precise or therapeutic FiH2. In order to truly determine and provide minimum/optimal H2 concentrations, researchers must measure or estimate and report the specific FiH2 based on the provided equations.

CONCLUSIONS: FiH2 provides the only physiologically meaningful metric for hydrogen dosing because it determines airway partial pressure and tissue concentrations. Flow rate or device concentration alone cannot predict delivered FiH2. Standardizing FiH2 as the reported dosing metric will improve reproducibility, enable study comparisons, and personalized, safe dosing.