Carbon Dioxide for Stroke in Children

(COMIC Trial)

Overseen By Kristin Guilliams, MD

Age: < 65

Sex: Any

Trial Phase: Academic

Sponsor: Washington University School of Medicine

Must not be taking: Vasodilators

Disqualifiers: Pregnancy, Epilepsy, Stroke, others

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

Compensation: Varies

Number of Visits: 3

350 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 change can influence brain development in the early decades of life. We 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 psychological 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 extreme circumstances, if the brain is unable to get enough oxygen for a long time, a stroke may occur. Sometimes small strokes occur without other noticeable changes and are only detectable on an MRI. These are sometimes called "silent strokes." 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 blood vessels to expand is by measuring blood flow while breathing in carbon dioxide. Carbon dioxide causes blood vessels in the brain to dilate without increasing brain metabolism. During this study participants may be asked to undergo a blood draw, MRI, and potential neuropsychological assessments. It is also possible that the study team will use a special mask to control the amount of carbon dioxide the participants breathe in so they don't breathe in too much.

Will I have to stop taking my current medications?

If you are taking vasodilatory medications like sildenafil or verapamil, you will need to stop taking them to participate in this trial. The protocol does not specify other medication restrictions.

What data supports the effectiveness of the treatment Carbon Dioxide for stroke in children?

Some studies suggest that carbon dioxide can improve blood flow to the brain, which might help in conditions like stroke. For example, research has shown that higher levels of carbon dioxide during anesthesia can lead to better recovery outcomes, indicating its potential to enhance brain function. ^{1 2 3 4 5}

Is carbon dioxide safe for use in medical procedures?

In a study with dogs, large amounts of carbon dioxide were injected into arteries, and no harmful effects were observed, suggesting it may be safe for use in certain medical procedures. ^{6 7 8 9 10}

How does the carbon dioxide treatment for stroke in children differ from other treatments?

The carbon dioxide treatment for stroke in children is unique because it involves inhaling carbon dioxide to increase cerebral blood flow, which is different from other treatments that may not focus on altering blood flow through gas inhalation. This approach leverages the vasodilatory effect of carbon dioxide to potentially improve brain oxygenation, which is not a standard method for treating strokes in children. ^{11 12 13 14 15}

Eligibility Criteria

This trial is for healthy individuals or those with sickle cell anemia, aged 3-50, who can have an MRI without sedation. It's not for pregnant women, people on certain blood flow medications, those with severe psychiatric conditions as determined by the study leader, a history of stroke or epilepsy.

Inclusion Criteria

I have sickle cell disease (Hb SS) or Sβ-thalassemia.

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

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

Exclusion Criteria

I have never had epilepsy.

No significant psychiatric history, defined as having a severe psychiatric diagnosis, per PI discretion

I have never had a stroke or brain blood vessel issues.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Participants undergo initial MRI scans and baseline neuropsychological assessments

1-2 weeks

1 visit (in-person)

Intervention

Participants may undergo MRI scans while breathing controlled amounts of carbon dioxide to assess cerebral blood flow and oxygen metabolism

4-6 weeks

2-3 visits (in-person)

Follow-up

Participants are monitored for changes in brain blood flow and metabolism over time

4 weeks

Treatment Details

Interventions

• Carbon Dioxide

Trial Overview The study tests how well brain blood vessels can handle increased demand by using carbon dioxide to dilate them during MRI scans. This helps understand oxygen metabolism and its impact on brain development and potential silent strokes in children.

Participant Groups

Group I: Healthy Controls Active Control 1 Intervention

Group II: Extracorporeal Membrane Oxygenation survivors Active Control 1 Intervention

Group III: Sickle Cell Anemia participants 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

A combined model using brain CT measurements (gray to white matter ratio and ambient cistern effacement) and blood pH analysis was highly effective in predicting neurological outcomes in children resuscitated from cardiac arrest, achieving an area under the curve (AUC) of 0.897.

The study found that the cutoff value for the gray to white matter ratio differed significantly by age, indicating that younger children (<4 years) have a different threshold (1.08) compared to older children (≥4 years, cutoff value: 1.18) for predicting poor neurological outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multimodal assessment using early brain CT and blood pH improve prediction of neurologic outcomes after pediatric cardiac arrest. Yang, D., Ha, SG., Ryoo, E., et al.[2020]

In a study of 60 female patients undergoing general anesthesia, those who received hypercarbic ventilation (higher CO2 levels) showed better recovery scores compared to those with normocarbic or hypocarbic ventilation, regardless of age.

Both younger and older patients experienced similar negative effects on recovery when subjected to hypocarbic ventilation, with some patients showing deterioration in recovery scores lasting up to 48 hours postoperatively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carbon dioxide homeostasis and recovery after general anaesthesia. Hovorka, J.[2019]

After pediatric cardiac arrest, there is significant variability in brain oxygen levels, with early and sustained hypoxia in the cortex and an initial increase in oxygen levels in the thalamus, indicating different responses in brain regions.

The study suggests that monitoring and targeting cortical oxygen levels could be crucial for improving neurological outcomes after cardiac arrest, especially since interventions like blood pressure augmentation had limited effects on cortical oxygenation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain tissue oxygen monitoring identifies cortical hypoxia and thalamic hyperoxia after experimental cardiac arrest in rats. Manole, MD., Kochanek, PM., Bayır, H., et al.[2021]

In a study of 9531 patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA), lower levels of carbon dioxide combining power (CO2CP) were linked to a higher risk of all-cause death and poor functional outcomes after 3 months and 1 year.

Patients in the lowest CO2CP quintile (21.1-23.3 mmol/L) had significantly worse outcomes compared to those in the fourth quintile, indicating that CO2CP may be an important prognostic marker in cerebrovascular disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CO2 combining power and outcomes in patients with acute ischaemic stroke or transient ischaemic attack. Wang, A., Tian, X., Gu, H., et al.[2022]

In a study involving 30 obese patients undergoing general anesthesia for bariatric surgery, ventilation with O2/CO2 improved cerebral tissue oxygenation index (TOI) and arterial oxygen pressure (PaO2) compared to O2/Air, indicating better oxygen delivery to the brain.

However, the study did not find a significant improvement in apnea tolerance, as the time until oxygen saturation dropped to critical levels was similar between the two ventilation methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

There is no evidence that carbon dioxide-enriched oxygen before apnea affects the time to arterial desaturation, but it might improve cerebral oxygenation in anesthetized obese patients: a single-blinded randomized crossover trial. Schmidt, MT., Studer, M., Kunz, A., et al.[2023]

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]

A 24-week treatment with acetazolamide (250 mg daily) significantly increased mean blood flow velocity in the middle cerebral artery of CADASIL patients, indicating improved cerebral blood flow.

The treatment also enhanced CO2-induced cerebrovascular reactivity, suggesting that acetazolamide may effectively improve cerebral hemodynamics in patients with this hereditary cerebrovascular disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acetazolamide improves cerebral hemodynamics in CADASIL. Huang, L., Yang, Q., Zhang, L., et al.[2016]

Carbonic anhydrase inhibitors (CAIs) are being explored as potential new treatments for ischemic stroke, which currently has limited pharmacological options, primarily tissue plasminogen activator (t-PA).

CAIs may help manage brain ischemia by regulating pH and metabolism, as they convert carbon dioxide into protons and bicarbonate, thus potentially offering protective mechanisms against the effects of reduced blood flow in the brain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of Carbonic Anhydrase in Cerebral Ischemia and Carbonic Anhydrase Inhibitors as Putative Protective Agents. Bulli, I., Dettori, I., Coppi, E., et al.[2021]

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]

In a study of 24 patients with chronic occlusive major cerebral artery disease, hypercapnia (inhalation of CO2) consistently increased regional cerebral blood flow (CBF) in nearly all patients, indicating preserved cerebrovascular reactivity in response to this stimulus.

Acetazolamide testing revealed that while some patients had preserved reactivity, others showed reduced or paradoxical responses, suggesting that acetazolamide may help identify patients with impaired vasomotor reactivity, but further research is needed to determine its clinical usefulness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dissociation of vasoreactivity to acetazolamide and hypercapnia. Comparative study in patients with chronic occlusive major cerebral artery disease. Kazumata, K., Tanaka, N., Ishikawa, T., et al.[2019]

In a study of 38 mechanically ventilated children with moderate to severe traumatic brain injury (TBI), it was found that younger children (under 2 years) had significantly lower carbon dioxide reactivity (CO2R) compared to older age groups, indicating age-related differences in brain response after injury.

Lower minimum CO2R values were linked to worse outcomes at discharge, suggesting that monitoring CO2R could be important for predicting recovery in children following TBI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Age-related carbon dioxide reactivity in children after moderate and severe traumatic brain injury. Maa, T., Yeates, KO., Moore-Clingenpeel, M., et al.[2017]

Acute stroke patients show significantly lower levels of carbon dioxide (CO2) compared to healthy controls, indicating a state of hypocapnia, based on a systematic review of 20 studies involving 660 participants.

The study also found that acute stroke is associated with reduced cerebral blood flow and impaired cerebral autoregulation, suggesting that monitoring CO2 levels could be important in managing acute stroke patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Do acute stroke patients develop hypocapnia? A systematic review and meta-analysis. Salinet, ASM., Minhas, JS., Panerai, RB., et al.[2020]

In a study involving 13 healthy children aged 3 months to 7 years, it was found that increasing levels of carbon dioxide (CO2) directly enhance cerebral blood flow velocity in the middle cerebral artery during anesthesia, indicating a significant physiological response.

The study utilized transcranial Doppler sonography without any complications, demonstrating a safe method to assess the effects of CO2 on cerebral circulation in pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcranial Doppler: response of cerebral blood-flow velocity to carbon dioxide in anaesthetized children. Pilato, MA., Bissonnette, B., Lerman, J.[2018]

In a study of 23 term neonates undergoing whole-body therapeutic hypothermia for neonatal hypoxic ischemic encephalopathy (HIE), severe neurodevelopmental outcomes were linked to high variability in arterial carbon dioxide tension (PaCO2) over the first 72 hours.

While there were no significant differences in mean PaCO2 levels between outcome groups, the group with severe outcomes exhibited a significantly higher standard deviation of PaCO2, suggesting that managing fluctuations in carbon dioxide levels could be a potential strategy to improve neurodevelopmental outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High blood carbon dioxide variability and adverse outcomes in neonatal hypoxic ischemic encephalopathy. Hansen, G., Al Shafouri, N., Narvey, M., et al.[2015]

Inhalation of carbogen (a mixture of oxygen and carbon dioxide) significantly increases cerebral blood flow (CBF) in healthy adults, while pure oxygen alone decreases CBF, suggesting that the addition of CO2 promotes vasodilation.

Both carbogen and oxygen effectively increase oxygen saturation in arterial blood (SaO2), indicating that carbogen may provide optimal oxygenation for healthy brain tissue by enhancing both CBF and SaO2.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improvement of brain tissue oxygenation by inhalation of carbogen. Ashkanian, M., Borghammer, P., Gjedde, A., et al.[2016]

References

1. Ireland pubmed.ncbi.nlm.nih.gov

Multimodal assessment using early brain CT and blood pH improve prediction of neurologic outcomes after pediatric cardiac arrest. [2020]

2. England pubmed.ncbi.nlm.nih.gov

Carbon dioxide homeostasis and recovery after general anaesthesia. [2019]

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

Brain tissue oxygen monitoring identifies cortical hypoxia and thalamic hyperoxia after experimental cardiac arrest in rats. [2021]

4. England pubmed.ncbi.nlm.nih.gov

CO2 combining power and outcomes in patients with acute ischaemic stroke or transient ischaemic attack. [2022]

5. England pubmed.ncbi.nlm.nih.gov

There is no evidence that carbon dioxide-enriched oxygen before apnea affects the time to arterial desaturation, but it might improve cerebral oxygenation in anesthetized obese patients: a single-blinded randomized crossover trial. [2023]

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

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

7. Netherlands pubmed.ncbi.nlm.nih.gov

Acetazolamide improves cerebral hemodynamics in CADASIL. [2016]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Role of Carbonic Anhydrase in Cerebral Ischemia and Carbonic Anhydrase Inhibitors as Putative Protective Agents. [2021]

9. Italy pubmed.ncbi.nlm.nih.gov

Cerebral angiography with gaseous carbon dioxide CO2. [2016]

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

Dissociation of vasoreactivity to acetazolamide and hypercapnia. Comparative study in patients with chronic occlusive major cerebral artery disease. [2019]

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

Age-related carbon dioxide reactivity in children after moderate and severe traumatic brain injury. [2017]

12. Netherlands pubmed.ncbi.nlm.nih.gov

Do acute stroke patients develop hypocapnia? A systematic review and meta-analysis. [2020]

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

Transcranial Doppler: response of cerebral blood-flow velocity to carbon dioxide in anaesthetized children. [2018]

14. England pubmed.ncbi.nlm.nih.gov

High blood carbon dioxide variability and adverse outcomes in neonatal hypoxic ischemic encephalopathy. [2015]

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

Improvement of brain tissue oxygenation by inhalation of carbogen. [2016]