Physiological Responses to Acute Hypobaric and Normobaric Hypoxia: Differences in Maximal Exercise and Clinical Impact

Abstract

Ferrarini, Giovanni, Mattia Canevari, Valeria Azzini, Piergiuseppe Agostoni, Beatrice Pezzuto, and Carlo Vignati. Physiological responses to acute hypobaric and normobaric hypoxia: Differences in maximal exercise and clinical impact. High Alt Med Biol. 00:00–00, 2026.—Hypoxia, defined by inspired partial pressure of oxygen (PiO₂) <150 mmHg, has been extensively studied in conditions of both reduced barometric pressure (hypobaric hypoxia, HH) and reduced inspired fraction of oxygen (FiO₂) at sea level (normobaric hypoxia, NH). Traditionally considered interchangeable, mounting evidence indicates that HH and NH elicit distinct cardiovascular, ventilatory, and gas-exchange responses during physical effort, likely due to factors beyond PiO₂, including air density, alveolar gas composition, exercise modality, and the age and sex of the individual performing the effort. A thorough understanding of how different hypoxic modalities affect exercise responses provides fundamental insights into human physiology and pathophysiology under extreme conditions, with practical implications for sports medicine and athletic training, as well as for patients with pathologies potentially influenced by hypoxia dealing with high altitude. This narrative review synthesizes current evidence on the differential effects of HH and NH on exercise responses, with an emphasis on maximal exercise capacity and underlying the physiological mechanisms regarding cardiovascular function, ventilatory adaptation, and gas-exchange responses, also outlining the implications for athletes, clinical populations (heart failure, chronic obstructive pulmonary disease, pulmonary hypertension), and altitude medicine.