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Randomized Controlled Trial
. 2024 Oct;109(10):1672-1682.
doi: 10.1113/EP091794. Epub 2024 Aug 27.

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

Tyler S McClure  1   2 , Jeffrey Phillips  2 , Andrew P Koutnik  2   3 , Kody Coleman  2 , Ed Chappe  2 , Gary R Cutter  2 , Brendan Egan  1   2 , Todd Norell  2 , Brianna J Stubbs  4 , Marcas M Bamman  2 , Dawn Kernagis  2   5
Affiliations
Randomized Controlled Trial

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

Tyler S McClure et al. Exp Physiol. 2024 Oct.

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 ( S p O 2 ${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ) 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 S p O 2 ${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ during hypoxic exposure was attenuated (6.40% S p O 2 ${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ; 95% CL: 0.04, 12.75; P = 0.049) in KME compared to PLA (KME, 76.8 ± 6.4% S p O 2 ${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ; PLA, 70.4 ± 7.4% S p O 2 ${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ). Acute ingestion of KME attenuated the decline in cognitive performance during acute severe hypoxic exposure, which coincided with attenuation of declines in O2 saturation.

Keywords: code substitution; cognitive resilience; exogenous ketosis; β‐hydroxybutyrate.

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Conflict of interest statement

H.V.M.N. Inc. had no involvement in data collection, analysis or data interpretation. Tyler S. McClure, Jeffrey Phillips, Kody Coleman, Ed Chappe, Dawn Kernagis, Brendan Egan, and Marcas M. Bamman declare no conflicts of interest, and do not have any financial disclosures. Brianna J. Stubbs has stock and stock options in companies that produce ketone products (H.V.M.N. Inc., Juvenescence Ltd, BHB Therapeutics Ltd, Selah Ltd) and is an inventor on patents that relate to ketone bodies. Brianna J. Stubbs was an employee of H.V.M.N. Inc. at the time this study was conceived. Gary R. Cutter participates on Data and Safety Monitoring Boards for Applied Therapeutics, AI therapeutics, AMO Pharma, Astra‐Zeneca, Avexis Pharmaceuticals, Bristol Meyers Squibb/Celgene, CSL Behring, Horizon Pharmaceuticals, Immunic, Karuna Therapeutics, Kezar Life Sciences, Mapi Pharmaceuticals LTD, Merck, Mitsubishi Tanabe Pharma Holdings, Opko Biologics, Prothena Biosciences, Novartis, Regeneron, Sanofi‐Aventis, Reata Pharmaceuticals, Teva Pharmaceuticals, NHLBI (Protocol Review Committee), University of Texas Southwestern, University of Pennsylvania, and Visioneering Technologies, Inc. Gary R. Cutter participates as a consultant or Advisory Board member for Alexion, Antisense Therapeutics, Avotres, Biogen, Clene Nanomedicine, Clinical Trial Solutions LLC, Entelexo Biotherapeutics, Inc., Genzyme, Genentech, GW Pharmaceuticals, Hoya Corporation, Immunic, Immunosis Pty Ltd, Klein‐Buendel Incorporated, Linical, Merck/Serono, Novartis, Perception Neurosciences, Protalix Biotherapeutics, Regeneron, Roche, and SAB Biotherapeutics. Gary R. Cutter is President of Pythagoras, Inc. a private consulting company located in Birmingham, AL, USA. Andrew P. Koutnik is an inventor on patents related to ketone bodies (US11452704B2; US11596616B2) and on the Scientific Advisory Board for Simply Good Foods and Nutri.

Figures

FIGURE 1
FIGURE 1
Schematic illustration of the experimental design. This study investigated whether acute ingestion of R‐BD R‐βHB KME impacts cognitive performance and SpO2 at rest after exposure to rapid‐onset acute severe hypoxia.
FIGURE 2
FIGURE 2
Blood metabolites. Blood R‐β‐hydroxybutyrate (a) and glucose (b) at baseline, and before (Pre) and after (Post) normoxia and hypoxia after acute ingestion of an exogenous KME or non‐caloric taste matched PLA. n = 16. Data are means ± SD. T, time; C, condition (KME vs. PLA); T*C, time × condition interaction. **P < 0.01 and ***P < 0.001 for KME versus PLA. KME, ketone monoester; PLA, placebo.
FIGURE 3
FIGURE 3
Cognitive performance. DANA CSD cognitive efficiency (a), and DANA CSD correct reaction time (b) at baseline, and before (Pre) and after (Post) normoxia and hypoxia after acute ingestion of an exogenous KME or non‐caloric taste matched PLA. n = 16. Data are means ± SD. T, time; C, condition (KME vs. PLA); T*C, time × condition interaction. *P < 0.05 for KME versus PLA. CSD, code substitution delayed; DANA, Defense Automated Neurobehavioral Assessment; KME, ketone monoester; PLA, placebo.
FIGURE 4
FIGURE 4
Cardiorespiratory responses. Oxygen saturation (a) and heart rate (b) during hypoxic exposure reported in 5 min intervals after acute ingestion of an exogenous ketone monoester (KME) or non‐caloric taste matched placebo (PLA). n = 12. Data are means ± SD. T, time; C, condition (KME vs. PLA); T*C, time × condition interaction. *P < 0.05 for KME versus PLA. KME, ketone monoester; PLA, placebo.
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