Ketone monoester attenuates declines in cognitive performance and oxygen saturation during acute severe hypoxic exposure under resting conditions

Abstract

Exogenous ketone supplements are a potential augmentation strategy for cognitive resilience during acute hypoxic exposure due to their capacity to attenuate the decline in oxygen (O₂) availability, and by providing an alternative substrate for cerebral metabolism. Utilizing a single-blind randomized crossover design, 16 male military personnel (age, 25.3 ± 2.4 year, body mass, 86.2 ± 9.3 kg) performed tests of cognitive performance at rest in three environments: room air (baseline), normoxia (20 min; 0 m; 20.9% O₂) and hypoxia (20 min; 6096 m, 9.7% O₂) using a reduced O₂ breathing device (ROBD). (R)-3-Hydroxybutyl (R)-3-hydroxybutyrate (R-BD R-βHB) ketone monoester (KME; 650 mg/kg, split dose given at 30 min prior to each exposure) or taste-matched placebo (PLA) was ingested prior to normoxia and hypoxic exposure. Blood R-βHB and glucose concentrations, cognitive performance and O₂ saturation ( <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:msub><mml:mi>S</mml:mi> <mml:mrow><mml:mi>p</mml:mi> <mml:msub><mml:mi>O</mml:mi> <mml:mn>2</mml:mn></mml:msub> </mml:mrow> </mml:msub> <mml:annotation>${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$</mml:annotation></mml:semantics> </mml:math> ) were collected throughout. KME ingestion increased blood R-βHB concentration, which was rapid and sustained (>4 mM 30 min post; P < 0.001) and accompanied by lower blood glucose concentration (∼20 mg/dL; P < 0.01) compared to PLA. Declines in cognitive performance during hypoxic exposure, assessed as cognitive efficiency during a Defense Automated Neurobehavioral Assessment (DANA) code substitution task, were attenuated with KME leading to 6.8 (95% CL: 1.0, 12.6) more correct responses per minute compared to PLA (P = 0.018). The decline in <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:msub><mml:mi>S</mml:mi> <mml:mrow><mml:mi>p</mml:mi> <mml:msub><mml:mi>O</mml:mi> <mml:mn>2</mml:mn></mml:msub> </mml:mrow> </mml:msub> <mml:annotation>${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$</mml:annotation></mml:semantics> </mml:math> during hypoxic exposure was attenuated (6.40% <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:msub><mml:mi>S</mml:mi> <mml:mrow><mml:mi>p</mml:mi> <mml:msub><mml:mi>O</mml:mi> <mml:mn>2</mml:mn></mml:msub> </mml:mrow> </mml:msub> <mml:annotation>${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$</mml:annotation></mml:semantics> </mml:math> ; 95% CL: 0.04, 12.75; P = 0.049) in KME compared to PLA (KME, 76.8 ± 6.4% <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:msub><mml:mi>S</mml:mi> <mml:mrow><mml:mi>p</mml:mi> <mml:msub><mml:mi>O</mml:mi> <mml:mn>2</mml:mn></mml:msub> </mml:mrow> </mml:msub> <mml:annotation>${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$</mml:annotation></mml:semantics> </mml:math> ; PLA, 70.4 ± 7.4% <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:msub><mml:mi>S</mml:mi> <mml:mrow><mml:mi>p</mml:mi> <mml:msub><mml:mi>O</mml:mi> <mml:mn>2</mml:mn></mml:msub> </mml:mrow> </mml:msub> <mml:annotation>${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$</mml:annotation></mml:semantics> </mml:math> ). Acute ingestion of KME attenuated the decline in cognitive performance during acute severe hypoxic exposure, which coincided with attenuation of declines in O₂ saturation.