Carbon Dioxide Challenge for Brain Blood Flow

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Washington University School of Medicine

Must not be taking: Stimulants, Antidepressants, Vasodilators

Disqualifiers: Lung disease, Heart failure, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

48 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this research study is to better understand how blood flow and metabolism are different between normal controls and patients with disease. The investigators will examine brain blood flow and metabolism using magnetic resonance imaging (MRI). The brain's blood vessels expand and constrict to regulate blood flow based on the brain's needs. The amount of expanding and contracting the blood vessels can do varies by age. The brain's blood flow changes in small ways during everyday activities, such as normal brain growth, exercise, or deep concentration. Significant illness or physiologic stress may increase the brain's metabolic demand or cause other bigger changes in blood flow. If blood vessels are not able to expand to give more blood flow when metabolic demand is high, the brain may not get all of the oxygen it needs. In less extreme circumstances, not having as much oxygen as it wants may cause the brain to grow and develop more slowly than it should. One way to test the ability of the blood vessels to expand is by measuring blood flow while breathing in carbon dioxide (CO2). CO2 causes blood vessels in the brain to dilate without increasing brain metabolism. The study team will use a special mask to control the amount of oxygen and carbon dioxide patients breath in so that we can study how their brain reacts to these changes. This device designed to simulate carbon dioxide levels achieved by a breath-hold and target the concentration of carbon dioxide in the blood in breathing patients. The device captures exhaled gas and provides an admixture of fresh gas and neutral/expired gas to target different carbon dioxide levels while maintaining a fixed oxygen level. The study team will obtain MRI images of the brain while the subjects are breathing air controlled by the device.

Will I have to stop taking my current medications?

The trial requires that you are not on stimulant medications, anti-depressant medications, or vasodilatory medications like sildenafil or verapamil. If you are taking these, you would need to stop before participating.

What data supports the effectiveness of the treatment Carbon Dioxide, CO2, Carbonic Anhydride for brain blood flow?

Research shows that carbonic anhydrase inhibitors, which affect carbon dioxide levels, can increase blood flow in the brain. For example, acetazolamide, a drug that inhibits carbonic anhydrase, significantly increased cerebral blood flow in studies with monkeys. ^{1 2 3 4 5}

Is carbon dioxide safe for use in brain blood flow studies?

Research shows that using carbon dioxide in brain blood flow studies is generally safe, as no adverse effects were reported in studies involving animals and humans. For example, a study on dogs using carbon dioxide for cerebral angiography found no negative effects, and another study on humans using a carbonic anhydrase inhibitor related to CO2 showed no harmful changes in blood pressure or breathing. ^{1 4 6 7 8}

How does the carbon dioxide treatment differ from other treatments for brain blood flow?

The carbon dioxide treatment is unique because it involves inhaling CO2 to increase blood flow in the brain without altering brain metabolism, unlike other treatments that may affect neural activity or oxygen consumption. ^{2 4 6 8 9}

Eligibility Criteria

This trial is for healthy adults over 18 or those with brain vascular issues, without a history of seizures, psychiatric conditions, or on certain medications like vasodilators. Participants must be able to undergo an MRI without sedation and not require daily headache prevention meds.

Inclusion Criteria

I sometimes have headaches but don't take daily medication for them.

I have not seen a psychiatrist nor taken antidepressants.

I am not taking any medication that widens my blood vessels.

Exclusion Criteria

I am unable to undergo rehabilitation therapy.

I cannot have an MRI due to a health condition, device, or metal in my body.

I have severe heart failure or lung disease with a resting breathing rate over 15 breaths per minute.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Respiratory Challenge

Participants undergo MRI imaging while breathing controlled air with varying CO2 levels to study brain blood flow and metabolism

1-2 weeks

1-2 visits (in-person)

Follow-up

Participants are monitored for any changes in brain blood flow and metabolism after the respiratory challenge

4 weeks

Treatment Details

Interventions

• Carbon Dioxide

Trial Overview The study tests how the brain's blood vessels respond to different levels of carbon dioxide and oxygen using a special mask during MRI imaging. It aims to understand blood flow and metabolism changes in normal individuals versus patients with disease.

Participant Groups

Group I: Healthy Adults Active Control 1 Intervention

Group II: Adults diagnosed with vascular pathology of the brain Active Control 1 Intervention

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

Findings from Research

Acetazolamide, a carbonic anhydrase inhibitor, significantly increased cerebral blood flow (CBF) by up to 75% within 25 minutes of intravenous injection in healthy humans, indicating its rapid vasodilatory effects on cerebral arterioles.

The drug did not affect ventilation or blood gas levels, suggesting that its vasodilatory action is independent of its role as a carbonic anhydrase inhibitor and occurs over a wide range of carbon dioxide levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute effects of acetazolamide on cerebral blood flow in man. Hauge, A., Nicolaysen, G., Thoresen, M.[2013]

In a study involving 14 dogs, the rapid injection of large quantities of carbon dioxide (CO2) into the arteries resulted in effective filling of the arteries and intracranial veins, as confirmed by advanced imaging techniques.

No adverse effects were observed during or after the procedure, with the dogs remaining neurologically normal for up to 6 months, suggesting that CO2 could be a safe and effective contrast agent for arterial and cerebrovascular imaging.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cerebral angiography with gaseous carbon dioxide CO2. Shifrin, EG., Plich, MB., Verstandig, AG., et al.[2016]

References

1. England pubmed.ncbi.nlm.nih.gov

Effects of a carbonic anhydrase inhibitor on cerebral blood flow in geriatric patients. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

The effect of acetazolamide on cerebral blood flow and oxygen utilization in the rhesus monkey. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

Middle cerebral artery flow velocity decreases and electroencephalogram (EEG) changes occur as acute hypercapnia reverses. [2018]

4. United States pubmed.ncbi.nlm.nih.gov

Searching for a truly "iso-metabolic" gas challenge in physiological MRI. [2018]

5. Austria pubmed.ncbi.nlm.nih.gov

Cerebral CO2 reactivity in severe head injury. A transcranial Doppler study. [2019]

6. England pubmed.ncbi.nlm.nih.gov

Acute effects of acetazolamide on cerebral blood flow in man. [2013]

7. Italy pubmed.ncbi.nlm.nih.gov

Cerebral angiography with gaseous carbon dioxide CO2. [2016]

8. England pubmed.ncbi.nlm.nih.gov

Mean carbon dioxide tension in the brain after carbonic anhydrase inhibition. [2019]

9. United States pubmed.ncbi.nlm.nih.gov

Time-dependent effects of prolonged hypercapnia on cerebrovascular parameters in dogs: acid-base chemistry. [2019]