Ketone monoester intake alters ventilatory response but not cerebral blood flow at terrestrial high altitude
In a double‑blind, placebo‑controlled trial at 3,375 m, ingestion of a ketone monoester raised circulating β‑hydroxybutyrate, induced hyperventilation and lowered the ventilatory response to added CO₂, while middle‑cerebral‑artery blood flow and its CO₂ reactivity remained unchanged.
Study and findings
Thirty‑four healthy volunteers completed two experimental sessions: a normoxic baseline at sea level (no supplement) and a hypobaric hypoxic exposure after 20 h at 3,375 m, during which they received either ketone monoester (KE) or a taste‑matched placebo in a double‑blind fashion. Blood β‑hydroxybutyrate rose markedly after KE, accompanied by a modest acid‑base shift (lower pH, reduced arterial PCO₂ and bicarbonate). KE provoked a higher minute ventilation (V̇E) under ambient air, which translated into a reduced ventilatory response to incremental CO₂ (ΔV̇E/ΔPETCO₂) especially during the transition from baseline to 3 % CO₂. Cerebral blood flow, estimated by middle cerebral artery velocity, and its CO₂ reactivity (ΔMCAv/ΔPETCO₂) were not different between KE and placebo.
Clinical interpretation
The data indicate that acute KE ingestion can stimulate ventilation in hypoxic conditions, likely through a direct respiratory drive rather than through altered chemosensitivity to CO₂, as the blunted V̇E response was observed mainly during the baseline‑to‑low‑CO₂ transition. Importantly, despite the respiratory alkalosis and reduced arterial CO₂, cerebral perfusion metrics remained stable, suggesting that short‑term KE does not compromise cerebrovascular oxygen delivery at moderate altitude. For clinicians considering KE as a metabolic adjunct in high‑altitude exposure, the primary effect appears to be respiratory, with no evident impact on cerebral hemodynamics.
Limitations and open questions
The study examined only acute KE exposure in a relatively small, healthy cohort; longer‑term effects, dose‑response relationships, and responses in patients with cardiopulmonary disease remain unknown. Cerebral blood flow was inferred from transcranial Doppler velocity, which does not capture absolute perfusion or regional heterogeneity. The mechanisms linking KE to hyperventilation—whether central chemoreceptor modulation, peripheral metabolic signals, or acid‑base disturbances—were not resolved. Future randomized trials with larger, diverse populations and direct measurements of cerebral oxygenation are needed to clarify the physiological pathways and potential therapeutic relevance.
Source
Stalmans M et al. Ketone monoester intake affects the ventilatory response to O2 and CO2 in healthy individuals at high altitude. Am J Physiol Regul Integr Comp Physiol. 2026;310(4):R1234‑R1245.