CO2 Rebreathing for Orthostatic Hypotension

Overseen By Tanya Siddiqui, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of Calgary

Must not be taking: Autonomic medications

Disqualifiers: Heart failure, Pulmonary disease, Dementia, others

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

Compensation: Varies

Number of Visits: 1

28 Participants Needed

Trial Summary

What is the purpose of this trial?

Neurogenic orthostatic hypotension (nOH) is a chronic condition associated with increased cardiovascular risk and reduced quality of life. On standing, patients with nOH experience a large reduction in blood pressure (BP; at least ≥20/10mmHg, but often much more), which is often accompanied by debilitating symptoms and syncope. A previous study (unpublished) showed that hypercapnia significantly increases standing BP in patients with nOH. Human bodies naturally produce and exhale CO2. Rebreathe devices offer a simple, cost-effective technology to increase arterial CO2. In brief, rebreathe devices work by capturing expired CO2, which is then re-inhaled. The net effect is a transient increase in CO2. A CO2 rebreathing device may offer a novel hemodynamic therapy for patients with nOH. This is a pilot, proof-of-concept study to evaluate a CO2 rebreather to improve blood pressure and orthostatic tolerance in patients with nOH. The hypothesis is that a rebreather will increase CO2 sufficiently enough to improve BP in patients with nOH. Male and female patients (n=28) will be asked to complete two randomized 70° head-up tilt (HUT) tests breathing either room air or using a CO2 rebreather. Hemodynamics (BP, heart rate, stroke volume, brain blood flow) and orthostatic symptoms will be assessed throughout. Breath-by-breath data will include O2, CO2, respiration rate and tidal volume. The primary outcome measure will be the magnitude of the BP response (ΔBP = HUT - Supine) during Room Air vs. Hypercapnia. The primary outcome will be compared between room air and hypercapnia using a paired t-test.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it excludes those on medical therapies or medications that could interfere with testing of autonomic function. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the CO2 ReHaler treatment for orthostatic hypotension?

The research on the rebreathing method shows that it can increase carbon dioxide levels in the body, which might help with conditions like orthostatic hypotension (a drop in blood pressure when standing up). However, the study focused on sensorineural deafness and did not recommend this method for that condition, so its effectiveness for orthostatic hypotension is not directly supported by the available data. ^{1 2 3 4 5}

How does the CO2 ReHaler treatment for orthostatic hypotension differ from other treatments?

The CO2 ReHaler is unique because it involves breathing in carbon dioxide (CO2) to help manage orthostatic hypotension, which is a condition where blood pressure drops when standing up. This treatment works by affecting the body's chemoreceptors, which help regulate cardiovascular responses, potentially improving tolerance to orthostatic stress, unlike traditional treatments that may focus on medication or lifestyle changes. ^{1 6 7 8 9}

Research Team

Satish R Raj, MD

Principal Investigator

University of Calgary

Eligibility Criteria

This trial is for adults over 18 with neurogenic orthostatic hypotension (nOH), who don't smoke and can travel to the University of Calgary. It's not for those with severe heart or lung issues, other illnesses affecting autonomic function, substance abuse problems, pregnant or breastfeeding women, or anyone on medications that could affect test results.

Inclusion Criteria

People who do not smoke.

I am either male or female.

Able and willing to provide informed consent

Exclusion Criteria

I do not have conditions like dementia, substance abuse, or major organ disease that could affect my study participation.

I am not on medications that affect nerve function tests.

I cannot climb stairs without feeling short of breath due to heart or lung problems.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Study Day

Participants undergo instrumentation and complete two randomized 70° head-up tilt (HUT) tests breathing either room air or using a CO2 rebreather.

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after the study day procedures

4 weeks

Treatment Details

Interventions

• CO2 ReHaler

Trial Overview The study tests a CO2 rebreather device as a potential treatment for nOH by having participants use it during a head-up tilt test. The goal is to see if re-inhaling CO2 can help improve their blood pressure when they stand up.

Participant Groups

Group I: CO2 Rebreathing Experimental Treatment 1 Intervention

Participants will breathe with the rebreather in the supine position until CO2 levels increase between 5-10mmHg. Once CO2 levels are increased, participants will be tilted upright, and will continue to breathe with the rebreather during a 5-min HUT test

Group II: Room Air Active Control 1 Intervention

Participants will breathe room air in the supine position and during a 5-min HUT test

Who Is Running the Clinical Trial?

University of Calgary

Lead Sponsor

Trials

827

Recruited

902,000+

Findings from Research

In a study involving 11 healthy subjects, a rebreathing device successfully raised end-tidal carbon dioxide levels, but the increase was variable and not as high as levels achieved with 5% carbon dioxide inhalation.

The device caused a significant drop in end-tidal oxygen levels in one subject, indicating potential safety concerns, leading to the conclusion that this method is not recommended for treating sudden or fluctuating sensorineural deafness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhalation of carbon dioxide mixtures for sensorineural deafness. Evaluation of a rebreathing method. Freeman, P., Salamonsen, RF., Mainland, JF.[2019]

In a multicenter trial involving 326 patients with acute respiratory distress syndrome (ARDS), intravenous salbutamol treatment was associated with increased 28-day mortality, with 34% of patients in the salbutamol group dying compared to 23% in the placebo group.

Due to safety concerns and the lack of benefit, the trial was stopped early, indicating that salbutamol is unlikely to be a safe or effective treatment for ARDS, and further studies on beta-agonists in this context are not recommended.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beta-Agonist Lung injury TrIal-2 (BALTI-2): a multicentre, randomised, double-blind, placebo-controlled trial and economic evaluation of intravenous infusion of salbutamol versus placebo in patients with acute respiratory distress syndrome. Gates, S., Perkins, GD., Lamb, SE., et al.[2022]

In a study involving 20 preterm infants, using non-valved aerosol spacers for delivering albuterol resulted in significantly greater reductions in respiratory system resistance compared to using spacers with a non-rebreathing valve, indicating better efficacy of the treatment.

The use of non-valved spacers was also associated with increased heart rate and lower carbon dioxide levels, suggesting potential safety concerns that warrant consideration when delivering aerosol therapies to small infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aerosol delivery to non-ventilated infants by metered dose inhaler: should a valved spacer be used? Fok, TF., Lam, K., Chan, CK., et al.[2019]

In a study of 43 patients with acute brain damage, many showed abnormally low responsiveness to rising CO2 levels, indicating potential issues with their ventilatory control.

Unlike patients with chronic brain damage, this group did not exhibit increased responsiveness to CO2, suggesting that the nature of brain damage significantly affects respiratory responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Response of ventilation and of intracranial pressure during rebreathing of carbon dioxide in patients with acute brain damage. North, JB., Jennett, S.[2019]

The Beta Agonist Lung Injury Trial (BALTI-2) is a large-scale clinical trial involving 1,334 patients across approximately fifty UK ICUs, designed to assess whether intravenous salbutamol can improve survival rates in patients with acute respiratory distress syndrome (ARDS).

The primary outcome of the trial is 28-day mortality, with secondary outcomes including ICU and hospital mortality, ventilator-free days, and quality of life assessments at six and twelve months, ensuring a comprehensive evaluation of salbutamol's efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beta Agonist Lung Injury TrIal-2 (BALTI-2) trial protocol: a randomised, double-blind, placebo-controlled of intravenous infusion of salbutamol in the acute respiratory distress syndrome. Perkins, GD., Gates, S., Lamb, SE., et al.[2021]

In a study involving 7 subjects, it was found that the ventilatory response to changes in CO2 levels was significantly greater when the subjects were in an upright position (tilt) compared to when they were lying down (supine), indicating heightened sensitivity during orthostasis.

These findings suggest that the interaction between respiratory control and cardiovascular stability is crucial in understanding orthostatic intolerance, highlighting the need for further research into how breathing responses may contribute to this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of ventilatory sensitivity to carbon dioxide changes during orthostasis. Richardson, L., Topor, Z., Bhakta, D., et al.[2013]

Breathing 5% carbon dioxide (CO2) improved tolerance to orthostatic stress in nine young adults, suggesting that hypercapnia may enhance cardiovascular regulation during challenges like lower body negative pressure (LBNP).

Under hypercapnic conditions, participants experienced increased heart rate and delayed presyncopal symptoms, indicating a potential protective effect on cerebral blood flow, despite a reduction in stroke volume.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of breathing 5% CO2 on human cardiovascular responses and tolerance to orthostatic stress. Howden, R., Lightfoot, JT., Brown, SJ., et al.[2013]

A trial involving a healthy young volunteer demonstrated that induced syncope led to severe hyperventilation and periodic breathing, with hyperventilation rates reaching 57 L/min.

This hyperventilation caused a significant reduction in cerebral blood flow velocity by approximately 65%, highlighting the impact of respiratory changes on brain blood supply even without systemic hypotension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Profound hyperventilation and development of periodic breathing during exceptional orthostatic stress in a 21-year-old man. Donnelly, J., Lucas, SJ., Thomas, KN., et al.[2011]

Both nonpharmacologic and pharmacologic treatments can effectively reduce symptoms of orthostatic hypotension, with new strategies emerging based on recent insights into the condition's underlying mechanisms.

Patients with severe autonomic failure may benefit significantly from simple interventions like drinking water, which can trigger a strong blood pressure response, highlighting the importance of personalized treatment approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New trends in the treatment of orthostatic hypotension. Jordan, J.[2019]

References

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

Inhalation of carbon dioxide mixtures for sensorineural deafness. Evaluation of a rebreathing method. [2019]

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

Beta-Agonist Lung injury TrIal-2 (BALTI-2): a multicentre, randomised, double-blind, placebo-controlled trial and economic evaluation of intravenous infusion of salbutamol versus placebo in patients with acute respiratory distress syndrome. [2022]

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

Aerosol delivery to non-ventilated infants by metered dose inhaler: should a valved spacer be used? [2019]

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

Response of ventilation and of intracranial pressure during rebreathing of carbon dioxide in patients with acute brain damage. [2019]

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

Beta Agonist Lung Injury TrIal-2 (BALTI-2) trial protocol: a randomised, double-blind, placebo-controlled of intravenous infusion of salbutamol in the acute respiratory distress syndrome. [2021]

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

Assessment of ventilatory sensitivity to carbon dioxide changes during orthostasis. [2013]

7. England pubmed.ncbi.nlm.nih.gov

The effects of breathing 5% CO2 on human cardiovascular responses and tolerance to orthostatic stress. [2013]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Profound hyperventilation and development of periodic breathing during exceptional orthostatic stress in a 21-year-old man. [2011]

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

New trends in the treatment of orthostatic hypotension. [2019]