Carbon Dioxide for Sickle Cell Anemia

Overseen By Kristin P 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: 2

120 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. SCA participants and healthy controls are age and sex-matched for comparison. Within the SCA cohort, children with infarcts may have thinner cortices than those without, reflecting a greater loss. 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 may vary by age. The brain's blood flow changes in small ways during everyday activities, such exercise, deep concentration, or normal brain growth. 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 a full oxygen supply may cause the brain to grow and develop more slowly than when it has a full supply. 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, cognitive assessments, and brief questionnaires. The study team will use a special mask to control the amount of carbon dioxide the participants breathe in.

Will I have to stop taking my current medications?

The trial requires that participants are not taking vasodilatory medications (drugs that widen blood vessels), such as sildenafil or verapamil. If you are on these medications, you may need to stop taking them to participate.

What data supports the effectiveness of the treatment Carbon Dioxide for sickle cell anemia?

Research suggests that increasing carbon dioxide levels in the blood might help reduce the sickling of red blood cells in sickle cell anemia, potentially offering some benefit by inhibiting the process that causes cells to sickle. ^{1 2 3 4 5}

How does carbon dioxide treatment differ from other treatments for sickle cell anemia?

Carbon dioxide treatment for sickle cell anemia is unique because it may help inhibit the sickling of red blood cells by increasing the blood's carbon dioxide levels, which affects hemoglobin's oxygen affinity and reduces cell sickling. This approach is different from standard treatments that typically focus on managing symptoms and preventing complications rather than altering the biochemical environment of red blood cells. ^{1 4 5 6 7}

Research Team

Kristin P Guilliams, MD

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

This trial is for children and young adults aged 4-21 with sickle cell anemia (SCA) or healthy individuals without significant psychiatric history, epilepsy, stroke, or cerebrovascular disease. Participants must be able to have an MRI scan without sedation and not be pregnant.

Inclusion Criteria

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

I am not taking any blood pressure-lowering medications like sildenafil or verapamil.

I am between 4 and 21 years old.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Participants undergo initial MRI scans, blood draw, and cognitive assessments

1-2 weeks

1 visit (in-person)

Cerebrovascular Reactivity Testing

Participants undergo MRI to measure blood flow changes in response to carbon dioxide

15 minutes

1 visit (in-person)

Follow-up

Participants are monitored for changes in brain volume and cortical thickness over time

3 years

Treatment Details

Interventions

• Carbon Dioxide

Trial Overview The study tests how breathing in carbon dioxide affects blood flow in the brain using MRI scans. It aims to understand blood vessel function related to oxygen delivery during normal activities and stress in SCA patients compared to healthy controls.

Participant Groups

Group I: Sickle Cell Anemia Active Control 1 Intervention

Group II: Healthy Control Active Control 1 Intervention

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

National Institute of Neurological Disorders and Stroke (NINDS)

Collaborator

Trials

1,403

Recruited

655,000+

Findings from Research

In a study involving sickle cell disease patients, administering carbon monoxide at concentrations of 1000-2000 ppm led to a significant prolongation of red blood cell survival, indicating a potential positive effect on the properties of sickle cells.

Despite these promising results, the authors do not recommend carbon monoxide as a treatment for sickle cell disease at this time, but suggest that further controlled trials could be beneficial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of carbon monoxide on red cell life span in sickle cell disease. Beutler, E.[2021]

The quality of life for patients with sickle cell disease has significantly improved in developed countries over the last 20 years due to various preventive measures and treatments.

Individualized therapy is becoming more important, as genetic studies are helping to link specific genetic variations to treatment responses, which could enhance efficacy and reduce side effects for sickle cell patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The genomics of new drugs in sickle cell disease. Makis, AC., Hatzimichael, EC., Stebbing, J.[2018]

A semiautomated extracorporeal treatment using cyanate for four patients with sickle cell anemia resulted in significant hemoglobin carbamylation without serious toxicity, indicating a safer method of administration compared to systemic delivery.

Two out of four patients showed a hematologic response, suggesting potential efficacy of this treatment approach, but further research is needed to fully assess its effectiveness in managing sickle cell anemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preliminary studies of continuous extracorporeal carbamylation in the treatment of sickle cell anemia. Balcerzak, SP., Grever, MR., Sing, DE., et al.[2007]

A study involving 21 Nigerians with homozygous sickle-cell disease found that their ventilatory response to carbon dioxide is similar to that of healthy individuals, indicating normal sensitivity to carbon dioxide levels.

The research utilized a rebreathing technique to measure this response, suggesting that sickle-cell patients can effectively regulate their breathing in response to carbon dioxide, which is important for their respiratory health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ventilatory response to carbon dioxide in patients with homozygous sickle-cell disease. Elegbeleye, OO., Akinsete, FI., Afonja, AO., et al.[2019]

In sickle cell anemia (SS), increasing levels of carbon dioxide (PCO2) can inhibit the sickling of red blood cells, particularly at higher pH levels, suggesting a potential therapeutic role for managing PCO2 in patients.

The study found that SS blood exhibits unique responses to changes in PCO2, including increased oxygen affinity and significant differences in the Bohr effect compared to normal blood (AA), indicating that CO2 levels can significantly impact respiratory functions and red blood cell properties in sickle cell disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of carbon dioxide and pH variations in vitro on blood respiratory functions, red blood cell volume, transmembrane pH gradients, and sickling in sickle cell anemia. Ueda, Y., Bookchin, RM.[2014]

Inhibition of carbonic anhydrase (CA) activity using acetazolamide (AZ) significantly affects hemoglobin's (Hb) affinity for oxygen, as shown by changes in the oxygen partial pressure at 50% saturation (P(50)) in human blood.

The study found that the effects of CA inhibition on Hb-oxygen affinity were temporary and diminished after 4 hours of tonometry, suggesting that CA plays a crucial role in regulating oxygen transport by influencing CO(2) movement between air and liquid compartments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regulation of hemoglobin affinity for oxygen by carbonic anhydrase. Gai, X., Taki, K., Kato, H., et al.[2013]

In a study involving eight patients with sickle cell anemia, extracorporeal carbamylation of red blood cells led to significant improvements in hematologic parameters, including an increase in hemoglobin levels from 6.4 to 9.1 g/100 ml and a 65% reduction in irreversibly sickled erythrocytes over three months.

The treatment also resulted in an 80% decrease in the frequency of severe painful crises, with spontaneous crises virtually disappearing, indicating a promising therapeutic effect without noted toxic side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematologic and clinical responses in patients with sickle cell anemia after chronic extracorporeal red cell carbamylation. Deiderich, DA., Trueworthy, RC., Gill, P., et al.[2018]

References

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

The effect of carbon monoxide on red cell life span in sickle cell disease. [2021]

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

The genomics of new drugs in sickle cell disease. [2018]

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

Preliminary studies of continuous extracorporeal carbamylation in the treatment of sickle cell anemia. [2007]

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

Ventilatory response to carbon dioxide in patients with homozygous sickle-cell disease. [2019]

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

Effects of carbon dioxide and pH variations in vitro on blood respiratory functions, red blood cell volume, transmembrane pH gradients, and sickling in sickle cell anemia. [2014]

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

Regulation of hemoglobin affinity for oxygen by carbonic anhydrase. [2013]

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

Hematologic and clinical responses in patients with sickle cell anemia after chronic extracorporeal red cell carbamylation. [2018]