Carbon Dioxide for Stroke in Children

(COMIC Trial)

Recruiting at 1 trial location

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how blood flow and metabolism in the brain influence its development in children and young adults. Researchers use carbon dioxide (CO2) to determine if blood vessels can widen and increase blood flow to meet the brain's needs. Participants may include healthy individuals, those with sickle cell anemia, or survivors of a heart-lung bypass treatment called ECMO. Ideal candidates can undergo an MRI without sedation and do not have significant psychiatric history, epilepsy, or a history of stroke. As an unphased study, this trial offers participants the chance to contribute to groundbreaking research that could enhance understanding of brain development.

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 prior data suggests that this method is safe for children?

Research has shown that using carbon dioxide to test how blood vessels in the brain expand is generally safe. Carbon dioxide helps these blood vessels widen without increasing brain activity, aiding in understanding how well blood flow adapts to different needs. When conducted carefully, it does not cause major side effects.

In other studies, researchers used controlled amounts of carbon dioxide to safely test brain function. The study team employs special equipment to ensure participants do not inhale excessive amounts, keeping carbon dioxide levels safe and comfortable during the test.

Overall, this method is well-tolerated under close monitoring, and similar studies have reported no serious side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about using carbon dioxide in treating strokes in children because it offers a unique approach compared to traditional methods like clot-busting drugs or mechanical thrombectomy. Unlike these standard treatments, which focus on removing or dissolving the clot, carbon dioxide might help by improving blood flow in the brain through vasodilation, potentially reducing damage. This novel mechanism could offer a safer and less invasive option, particularly beneficial for young patients.

What evidence suggests that carbon dioxide might be an effective treatment for stroke in children?

Studies have shown that carbon dioxide can increase blood flow in the brain by widening blood vessels. This is important because better blood flow helps the brain receive the oxygen it needs, especially during intense activity. This trial will use carbon dioxide to assess how well blood vessels can widen in different groups, including children who have had a stroke, healthy controls, extracorporeal membrane oxygenation survivors, and sickle cell anemia participants. Monitoring and managing blood flow is crucial for recovery and growth in children. Research suggests that using carbon dioxide in this way might provide insights into brain health and help researchers understand and prevent silent strokes, which are small strokes that occur without clear symptoms but can affect brain development. ^{1 3 6 7 8}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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 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 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]

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]

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 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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8219494/

Pediatric Stroke: Overview and Recent Updates - PMC In this review, we discuss the epidemiology of pediatric stroke, the diverse etiologies, presentation as well as both acute and preventative management.

2. mdpi.com mdpi.com/1422-0067/22/9/5029

Role of Carbonic Anhydrase in Cerebral Ischemia and ... CAIs, by regulating the volume of body fluids and thus brain water content, may therefore alleviate cerebral edema, which contributes to poor ...

3. pediatricstrokejournal.com pediatricstrokejournal.com/outcome-measures-in-pediatric-stroke-a-systematic-review/

Outcome Measures in Pediatric Stroke: A Systematic Review The purpose of this study was to systematically review the current literature for pediatric outcome measures, describe the studies using pediatric outcome ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11541810/

Association of cumulative oxygen and carbon dioxide ... Among 292 included children (median age 2.6 years (IQR 0.4–10.9)), 57 % survived to discharge and 48 % had favorable neurologic outcome (88 % of ...

5. researchgate.net researchgate.net/publication/351490186_Role_of_Carbonic_Anhydrase_in_Cerebral_Ischemia_and_Carbonic_Anhydrase_Inhibitors_as_Putative_Protective_Agents

Role of Carbonic Anhydrase in Cerebral Ischemia and ... The occlusion leads to a reduction of cerebral blood flow rate, a condition of hypoxia and. glucose deprivation (oxygen, ...

6. researchgate.net researchgate.net/publication/392523298_Annual_PM25_exposure_and_clinical_laboratory_and_stroke-risk_outcomes_in_pediatric_sickle_cell_disease

(PDF) Annual PM2.5 exposure and clinical, laboratory ... Importantly, the elevated stroke risk associated with PM2.5 exposure persisted, even among children receiving hydroxyurea therapy, highlighting ...

7. tandfonline.com tandfonline.com/doi/full/10.1080/14756366.2021.1907575

Protective effects of carbonic anhydrase inhibition in brain ... The occlusion leads to a reduction of cerebral blood flow rate, a condition of hypoxia and glucose deprivation (oxygen, glucose deprivation: OGD) and subsequent ...

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35636467/

Carbon dioxide rises beyond acceptable safety levels in ... Carbon dioxide rises beyond acceptable safety levels in children under nose and mouth covering: Results of an experimental measurement study in ...