Exogenous ketosis attenuates acute mountain sickness and mitigates normobaric high-altitude hypoxemia

Acute mountain sickness (AMS) represents a considerable issue for individuals sojourning to high altitudes with systemic hypoxemia known to be intimately involved in its development. Based on recent evidence that ketone ester (KE) intake attenuates hypoxemia, we investigated whether exogenous ketosis might mitigate AMS development and identified underlying physiological mechanisms. Fourteen healthy, male participants were enrolled in two 29-h protocols (simulated altitude of 4,000-4,500 m) receiving either KE or a placebo (CON) at regular timepoints throughout the protocol in a randomized, crossover manner. Physiological responses were characterized after 15 min and 4 h in hypoxia, and the protocol was terminated prematurely upon development of severe AMS (Lake Louise Score ≥ 10). KE ingestion induced a consistent diurnal ketosis (d-β-hydroxybutyrate, [βHB] of ∼3 mM), whereas blood [βHB] remained low (<0.6 mM) in CON. Each participant tolerated the protocol equally long or longer (n = 6 or n = 8, respectively) in KE. Protocol duration increased by 32% on average with KE, and doubled upon KE for severe AMS-developing participants (n = 9). Relative to CON, KE induced a mild metabolic acidosis, hyperventilation, and relative sympathetic dominance. KE also inhibited the progressive hypoxemia that was observed between 15 min and 4 h in hypoxia in CON, while concomitantly increasing cerebral oxygenation and capillary Po₂ within this timeframe despite a KE-induced reduction in cerebral oxygen supply. These data indicate that exogenous ketosis attenuates AMS development. The key underlying mechanisms include improved arterial and cerebral oxygenation, in combination with lowered cerebral blood flow and oxygen delivery, and increased sympathetic dominance.NEW & NOTEWORTHY Ketone ester intake attenuated the development of acute mountain sickness at a simulated altitude of 4,000-4,500 m. This likely resulted from a mitigation of arterial and cerebral hypoxemia, reduced cerebral blood flow, and increased sympathetic drive.