The effects of 2 days of intermittent exogenous ketosis at high altitude on baroreflex sensitivity and ventilation under hypoxic and hypercapnic conditions.

High-altitude (HA) exposure induces an integrated physiological response to mitigate hypoxemia. Exogenous ketosis at simulated HA was previously shown to accentuate sympathetic activation and attenuate pulse oxygen saturation ([Formula: see text]) decreases through hyperventilation. The aim of this study was to extend these findings by investigating the effects of intermittent exogenous ketosis (IEK) across 2 days at terrestrial HA (3,375 m) on baroreflex sensitivity, heart rate variability, and hypoxic/hypercapnic ventilatory responses. Thirty-four healthy active adults completed neutral, hypoxic, and hypercapnic (0.03 [Formula: see text]) exposures, each comprising 6 min of seated rest, once at sea level (SL) and once after 2 days at HA. Across the 2 days, participants intermittently ingested either ketone monoester supplements (IEK) or placebo (PLA). During each exposure, blood pressure, ventilation, [Formula: see text], and end-tidal CO pressure ([Formula: see text]) were continuously recorded, and arterialized capillary blood gas content was measured in the final 30 s. Baroreflex sensitivity and time-domain metrics of heart rate variability were reduced at HA ( = 0.006-0.043) but unaffected by group ( = 0.288-0.525). However, ventilation at HA under all three conditions was significantly higher in IEK compared with PLA (all < 0.001). In hypoxia, this induced a higher [Formula: see text] ( = 0.038) and capillary O pressure ( = 0.003). In hypercapnia, this induced a lower [Formula: see text] and capillary CO tension (both < 0.001). These results extend previous findings, suggesting that IEK enhances ventilation at terrestrial HA after 2 days of exposure, with this effect being independent from baroreflex sensitivity or heart rate variability changes. This study demonstrates that 2 days of intermittent exogenous ketosis at 3,375 m terrestrial altitude does not alter baroreflex sensitivity or heart rate variability but significantly increases pulmonary ventilation under neutral, hypoxic, and hypercapnic conditions, improving oxygenation and lowering carbon dioxide retention. These findings suggest that ketone supplementation may enhance ventilatory acclimatization to high altitude via metabolic acidosis-driven respiratory stimulation, offering a nonpharmacological alternative to typical interventions used to support acclimatization.