Background 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 sought to investigate whether exogenous ketosis might mitigate AMS development and improve hypoxic tolerance.

Methods Fourteen healthy, male participants were enrolled in two 29h protocols (simulated altitude of 4,000-4,500m) receiving either KE or a placebo (CON) at regular timepoints throughout the protocol in a randomized, crossover manner. Select physiological responses were characterized after 15min and 4h in hypoxia, and the protocol was terminated prematurely upon development of severe AMS.

Results All participants tolerated the protocol equally long (n=6, of which n=5 completed the protocol in both conditions) or longer (n=8) in KE. Overall protocol duration increased by 32% on average with KE, and doubled for AMS-developing participants. KE consistently induced diurnal ketosis, a mild metabolic acidosis, hyperventilation, and relative sympathetic dominance. KE also fully negated the progressive hypoxemia that was observed between 15min and 4h in hypoxia in CON, while concomitantly increasing cerebral oxygenation and capillary pO2 within this timeframe. This coincided with a KE-induced reduction in cerebral oxygen supply, suggesting that KE reduced cerebral oxygen consumption under hypoxic conditions.

Conclusions These data indicate that exogenous ketosis improves hypoxic tolerance in humans and attenuates AMS development. The key underlying mechanisms include improved arterial and cerebral oxygenation, in combination with lowered cerebral blood flow and oxygen demand, and increased sympathetic dominance.

Summary Ketone ester intake attenuated the development of acute mountain sickness at a simulated altitude of 4,000-4,500m. This likely resulted from a mitigation of arterial and cerebral hypoxemia, reduced cerebral blood flow and increased sympathetic drive.

The authors have declared no competing interest.

ClinicalTrials.gov: NCT05588427

This study was funded by Fonds Wetenschappelijk Onderzoek (G073522N) Slovene Research Agency(N5-0247)

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