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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new device that might help people with neurogenic orthostatic hypotension (nOH), a condition where standing causes a significant drop in blood pressure, leading to dizziness or fainting. The device, called a CO2 rebreather (or CO2 ReHaler), helps increase carbon dioxide levels, which may improve blood pressure when standing. Participants will breathe normally and then use the device to assess its effectiveness. People with a doctor-diagnosed nOH who don't smoke and can visit the University of Calgary might be suitable for this trial. As an unphased trial, this study offers a unique opportunity to contribute to innovative research that could enhance treatment options for nOH.

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 prior data suggests that this CO2 rebreathing device is safe for patients with neurogenic orthostatic hypotension?

Research shows that increasing carbon dioxide (CO2) intake can raise blood pressure in people with neurogenic orthostatic hypotension (nOH). This condition causes a significant drop in blood pressure upon standing, leading to symptoms like dizziness or fainting. The CO2 ReHaler captures exhaled CO2 and allows users to inhale it again, potentially improving blood pressure when standing.

Although specific safety data for CO2 therapy in nOH is lacking, past studies with healthy individuals have shown that small increases in inhaled CO2 are generally safe. This suggests the CO2 ReHaler could be safe for people with nOH, but further research is necessary to confirm this.

This trial is a pilot study, exploring the treatment’s effects and side effects. Pilot studies often assess treatment tolerance before larger studies are conducted. While the treatment shows promise, potential participants should understand that it remains experimental. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about the CO2 ReHaler because it offers a novel approach to managing orthostatic hypotension. Unlike traditional treatments that often rely on medications to increase blood pressure, the CO2 ReHaler uses controlled CO2 rebreathing to elevate CO2 levels in the blood. This technique may enhance blood circulation and stabilize blood pressure when a person stands up. By focusing on a non-pharmacological method, the CO2 ReHaler has the potential to reduce side effects associated with drugs and provide a quick-acting solution to prevent dizzy spells and fainting episodes.

What evidence suggests that the CO2 ReHaler is effective for neurogenic orthostatic hypotension?

Research has shown that higher carbon dioxide (CO2) levels can raise blood pressure in people with neurogenic orthostatic hypotension (nOH). In past studies, patients with nOH experienced improved blood pressure when standing after inhaling more CO2. CO2 helps maintain steady blood pressure when standing, reducing symptoms like dizziness or fainting. In this trial, participants in the CO2 Rebreathing arm will use a CO2 rebreathing device, which allows them to inhale the CO2 they exhale, temporarily increasing CO2 levels. This simple method might help manage the blood pressure drop associated with nOH, offering a promising option for those affected by this condition. ^{3 4 6 7 8}

Who Is on the Research Team?

Satish R Raj, MD

Principal Investigator

University of Calgary

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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 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]

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]

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]

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]

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]

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 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]

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Current blood pressure therapies lack effcacy and have serious side effects. In healthy people, increased inspired CO 2 increases blood pressure ...