Mechanistic Effect of Ketones on Cerebral Blood Flow (MEKC)

The Mechanistic Effect of Ketones on Cerebral Blood Flow and Cerebrovascular Function

Oral supplements containing exogenous ketones have recently become available and represent a novel tool for increasing plasma ketone bodies without the need for dietary restriction. Early evidence suggests that oral ketone supplements may enhance cerebral blood flow (CBF). However, a higher dose of a ketone monoester has been shown to slightly lower blood pH and reduce end-tidal CO2 (PetCO2) due to compensatory hyperventilation, which is accompanied by parallel reductions in CBF. Whether reductions in PetCO2 causes reductions in CBF is currently unknown.

The purpose of this study is to investigate the effect of manipulating PetCO2 at normocapnia (PetCO2 maintained at baseline) or poikilocapnia (no PetCO2 targeting; breathing room air), following the ingestion of a dose of a ketone monoester on CBF and cerebrovascular reactivity to CO2 in young adults.

Study Overview

• Status: Completed
• Conditions: Cerebral Blood Flow; Cerebrovascular Function
• Intervention / Treatment: Dietary supplement: Poikilocapnia; Dietary supplement: Normocapnia

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8S 4K1
      • McMaster University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Having a normal blood pressure (≤125/≤85 mmHg)
• Between the ages of 18 and 35

Exclusion Criteria:

• Individuals who are obese (body mass index > 30 kg/m^2)
• Individuals who smoke
• Individuals with respiratory illnesses
• A history of type 2 diabetes, hypoglycemia, or cardiovascular diseases (i.e. heart attack, stroke)
• Individuals currently following a ketogenic diet or taking ketone supplements
• Individuals with a history of concussion(s) with persistent symptoms
• Individuals participating in elite-level physical training (i.e. varsity athletics)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Sham Comparator: Poikilocapnia; Room air-breathing	Dietary supplement: Poikilocapnia; Following ingestion of 0.6 g β-OHB/kg body weight ketone monoester, participants will wear a specialized face mask and breathe room air for 60 min. The face mask will be attached to an automated gas-blender system; however, only room air will be delivered.
Experimental: Normocapnia; Breathing air mixture with slightly elevated CO2 to maintain PetCO2 to resting baseline levels	Dietary supplement: Normocapnia; Following ingestion of 0.6 g β-OHB/kg body weight ketone monoester, participants will be outfitted with a specialized face mask and breathe air with a slightly higher concentration of CO2 to maintain PetCO2 to resting baseline values for 60 min. Gas will be continuously delivered by an automated gas-blender system.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Resting cerebral blood flow (CBF)	Measured via duplex ultrasound of the internal carotid artery and vertebral artery	90-minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma beta-hydroxybutyrate area under the curve	Venous blood samples will be obtained via intravenous catheter	90-minutes
Blood pH	Venous blood samples will be obtained via intravenous catheter	90-minutes
End-tidal CO2	Breath-by-breath analysis performed via RespirAct (RespirAct, Thornhill Research, Toronto, ON, Canada).	90-minutes
Mean arterial pressure (MAP)	Automated blood pressure cuff measurements of brachial artery pressure in mmHg	90-minutes
Cerebrovascular Reactivity of the Internal Carotid and Middle Cerebral Artery as assessed by Duplex Ultrasound and Transcranial Doppler Ultrasound, respectively.	Automated gas-blender used to apply sequential gas delivery using an algorithm to target end-tidal CO2 at +3mmHg, +6mmHg, and +9mmHg above baseline, using five-minute step-wise stages. Simultaneously, changes in cerebral blood flow in the internal carotid artery and the middle cerebral artery will be assessed using duplex ultrasound and transcranial Doppler ultrasound, respectively. The final minute of each stage will be analyzed to characterize the slope of cerebrovascular reactivity to CO2 in the internal carotid artery and the middle cerebral artery.	90-minutes
Middle Cerebral Artery Blood Velocity	Measured via transcranial Doppler Ultrasound using a 2MHz probe	90-minutes

Collaborators and Investigators

• Sponsor: McMaster University
• Investigators: Principal Investigator: Jeremy J Walsh, PhD, McMaster University

Study record dates

Study Major Dates

• Study Start (Actual): January 19, 2024
• Primary Completion (Actual): May 30, 2024
• Study Completion (Actual): August 31, 2024

Study Registration Dates

• First Submitted: December 1, 2023
• First Submitted That Met QC Criteria: January 10, 2024
• First Posted (Actual): January 22, 2024

Study Record Updates

• Last Update Posted (Actual): April 23, 2025
• Last Update Submitted That Met QC Criteria: April 17, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: Cerebral Blood Flow; Cerebrovascular Function; Beta-hydroxybutyrate (β-OHB)
• Other Study ID Numbers: MEKC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The investigators will share individual patient data (de-identified) with researchers upon request.
• IPD Sharing Time Frame: Beginning 12 months and ending 36 months following article publication.
• IPD Sharing Access Criteria: Anyone who wishes to access the data.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No