Orthostatic HypotensionNCT05295810
Hypercapnia in Orthostatic Hypotension
A study testing Sequential Gas Delivery in people with Orthostatic Hypotension and Neurogenic Orthostatic Hypotension, run by University of Calgary at 1 site in Canada.
Trial summary
The Autonomic (or "automatic") Nervous System (ANS) regulates internal processes, including control of heart rate and blood pressure (BP). When someone stands, and gravity tries to pull blood away from the brain, the ANS works to maintain BP and brain blood flow. Read more about this study
- Who is it for?
- Ages 18 to 100 yearsHealthy volunteers can take part
- Conditions the study is for
- Orthostatic Hypotension, Neurogenic Orthostatic Hypotension
- What is being tested?
- Sequential Gas Delivery
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 80 participants
- Where
- 1 siteCanada
- Study dates
- 1 Mar 2022to 31 May 2030
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 100 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Age ≥18 years
- Male and Female
- Non - smokers.
- Able and willing to provide informed consent.
- Ability to travel to Libin Cardiovascular Institute Autonomic Testing Lab at the University of Calgary, Calgary, AB.
Who cannot join
- Medical therapies or medications which could interfere with testing of autonomic function
- Participants with somatization or severe anxiety symptoms will be excluded
- Pregnant or breast-feeding females
- Inability to tolerate mask for the duration of the study
- Subjects who require portable oxygen at rest or with exercise
- Subjects with chronic heart failure or severe pulmonary disease who are unable to climb one flight of stairs due to shortness of breath.
- Presence of failure of other organ systems or systemic illness that can affect autonomic function or the participant's ability to cooperate. These include: dementia, alcohol and/or drug abuse, cerebrovascular disease, kidney or liver disease, surgical procedures where the nerves of the sympathetic nervous system have been cut.
- Other factors which in the investigator's opinion would prevent the participant from completing the protocol, including poor compliance during previous studies.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Rasha Hamzeh, RN contact
Canada1 site, 1 recruiting
- Recruiting
University of Calgary
Calgary, Alberta
Satish R Raj, MD, 403-210-6152, autonomic.research@ucalgary.ca
Robert S Sheldon, MD, PhD, 403-220-8191, autonomic.research@ucalgary.ca
About this study
Official title: Investigating Hypercapnia to Treat Neurogenic Orthostatic Hypotension
The Autonomic (or "automatic") Nervous System (ANS) regulates internal processes, including control of heart rate and blood pressure (BP). When someone stands, and gravity tries to pull blood away from the brain, the ANS works to maintain BP and brain blood flow. Neurogenic Orthostatic Hypotension (NOH) occurs when our "fight-or-flight" part ("sympathetic") of the ANS fails. BP can drop a lot when upright, reducing blood flow and oxygen delivery to the brain, and this can cause symptoms of light-headedness, nausea, and fainting.
One solution to help counter the effects of NOH may be to increase sympathetic activity by breathing higher levels of carbon dioxide. In healthy volunteers, small increases in the amount of inhaled carbon dioxide has been shown to increase BP in the upright position, and this improves symptoms!
The objectives of the current study are to apply carbon dioxide in patients with NOH and healthy controls to: (a) evaluate the effects of breathing carbon dioxide on BP and brain blood flow, and (b) determine if a device that increases carbon dioxide while standing will work as a new therapy
Read the detailed description
BACKGROUND: Regulation of tissue blood supply to vital organs such as the brain and heart is met in large part by local adjustment of the microvasculature (autoregulation) and autonomic nervous system control of the cardiovascular system. Neurogenic Orthostatic Hypotension (NOH) is a key example of when these systems fail. Patients experience a significant and persistent blood pressure (BP) drop (≥20/10 mmHg) in the upright position, resulting in cerebral hypoperfusion and symptoms of light-headedness, nausea, pre-syncope and even syncope. NOH and impaired cerebrovascular perfusion occur due to failure of the baroreflex to appropriately increase sympathetic outflow.
A novel solution to counter the acute effects of NOH is to transiently increase sympathetic activity by stimulating the peripheral and central respiratory chemoreceptors with elevated Fractional Inspired (Fi)CO2. In healthy volunteers, elevated FiCO2 improves orthostatic tolerance and BP control during rapid postural transitions. Additionally, few have considered sex-difference effects on the chemoreflex-autonomic relationship. Existing evidence demonstrates an augmented sympathetic response to chemoreflex stimulation in postmenopausal women with observed vasoconstriction and increased BPs. These data indicate females may respond better to hypercapnia as a novel therapeutic intervention for NOH. Unfortunately, it may also highlight a predisposition for cardiovascular risk associated with supine hypertension.
To better understand the mechanistic underpinnings of NOH in males and females, and to explore the use of elevated FiCO2 to treat it, researchers need a better way to monitor sympathetic activity and cerebrovascular perfusion. Functional Optical Coherence Tomography (fOCT) of the retinal and choroid vascular beds of the eye (an out crop of the brain) was recently developed in Calgary to allow physiological monitoring of these essential variables. In summary, elevated FiCO2 levels (hypercapnia) appear to improve BP responses to standing and orthostatic tolerance and may constitute an attractive therapy for NOH patients.
This is a proof-of-concept study to evaluate hypercapnia as a novel therapeutic intervention to improve blood pressure and orthostatic tolerance in male and female patients with NOH. In addition, the investigators will aim to evaluate functional OCT as an advance, non-invasive tool to measure sympathetic and metabolic cerebrovascular control.
OBJECTIVES: The aims of the current proposal are to apply hypercapnia during fOCT monitoring in male and female patients with NOH and healthy controls to: (a) evaluate and compare the effects of hypercapnia on cardiovascular and cerebrovascular responses to better understand basic chemoreflex and baroreflex physiology in male and female patients with NOH, (b) determine if a device that transiently increases FiCO2 in response to postural changes will have efficacy as a non-drug therapeutic and (c) evaluate fOCT as a novel advanced tool to measure sympathetic and metabolic components of cerebral autoregulation in patients with autonomic failure.
METHODS: Male and female NOH patients (n=40) will be recruited from the Calgary Autonomic Clinic, along with sex and age-matched controls from the community. Participants will complete five Active Stand Tests during which they will be asked to target different end-tidal (ET) CO2 levels. OCT images will be captured throughout each test. Participants will complete the following breathing protocol during an active stand test: a) breathing normal room air (ETCO2 free to fluctuate), b) ETCO2 clamped at baseline, c) ETCO2 clamped at +5mmHg, d) ETCO2 clamped at +10mmHg, e) ETCO2 clamped at +10mmHg with ETO2 clamped at 50mmHg. Target ETCO2 levels will be achieved through a computerized gas delivery system. A rebreathing task to elicit hypercapnia and hypoxia (low oxygen) will be performed last. Each condition will be followed by a minimum 10-minute recovery period to ensure ETCO2 normalization. Hemodynamics (BP, HR and stroke volume) and orthostatic symptoms will be assessed throughout. Breath-by-breath data will include ETO2, ETCO2, respiration rate, tidal volume, and minute ventilation. OCT image analyses in the seated and standing position will measure choroid and retinal (surrogates for peripheral sympathetic activity and metabolic cerebral autoregulation, respectively) perfusion densities.
- Being tested
- Sequential Gas Delivery
- Medical subject headings
- Hypotension, Orthostatic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Sequential Gas DeliveryDrug
Sequential Gas Delivery will be controlled using the RespirAct™ system (Thornhill Research Inc., Toronto, Canada)
| Study group | Role | What they receive |
|---|---|---|
| Room Air | No intervention | All participants will complete an active stand breathing room air with CO2 free to fluctuate |
| +0mmHg CO2 Clamped at baseline | Experimental | All participants will complete an active stand with their CO2 held constant at baseline Receives: Drug: Sequential Gas Delivery |
| +5mmHg CO2 | Experimental | All participants will complete an active stand breathing +5mmHg of CO2 relative to baseline Receives: Drug: Sequential Gas Delivery |
| +10mmHg | Experimental | All participants will complete an active stand breathing +10mmHg of CO2 relative to baseline Receives: Drug: Sequential Gas Delivery |
| +10mmHg CO2 + 50mmHg O2 | Experimental | All participants will complete an active stand breathing +10mmHg of CO2 relative to baseline and 50mmHg of O2 Receives: Drug: Sequential Gas Delivery |
What is being measured
The primary outcome is the main question the study is designed to answer.
Δ Blood Pressure (BP)
Magnitude of ΔBP (Stand-Sit) breathing room air vs +10mmHg of CO2
Measured: The ΔBP (stand-sit) calculated as the average BP in the final minute of sitting and the average BP between minute 3 and 5 of stand will be compared between room air and +10mmHg of CO2
Secondary outcomes (11)
Δ Blood Pressure (BP)
Magnitude of ΔBP (Stand-Sit) breathing room air vs 0 mmHg of CO2
Measured: The ΔBP (stand-sit) calculated as the average BP in the final minute of sitting and the average BP between minute 3 and 5 of stand will be compared between room air and 0 mmHg of CO2
Δ Blood Pressure (BP)
Magnitude of ΔBP (Stand-Sit) breathing room air vs +5mmHg of CO2
Measured: The ΔBP (stand-sit) calculated as the average BP in the final minute of sitting and the average BP between minute 3 and 5 of stand will be compared between room air and +5mmHg of CO2
Δ Blood Pressure (BP)
Magnitude of ΔBP (Stand-Sit) breathing room air vs +10mmHgCO2/50mmHg O2
Measured: The ΔBP (stand-sit) calculated as the average BP in the final minute of sitting and the average BP between minute 3 and 5 of stand will be compared between room air and +10mmHgCO2/50mmHg O2
Δ Vanderbilt Orthostatic Symptom Score [Range: 0 (absent) to 10 (worst)]
Magnitude of Δ Vanderbilt Orthostatic Symptom Score (Stand-Sit) breathing room air vs +10mmHg of CO2
Measured: The Δ Vanderbilt Orthostatic Symptom Score (symptoms at the 5th minute of stand - symptoms at the 5th minute of sit) will be compared between room air and +10mmHg of CO2
Δ Vanderbilt Orthostatic Symptom Score [Range: 0 (absent) to 10 (worst)]
Magnitude of Δ Vanderbilt Orthostatic Symptom Score (Stand-Sit) breathing room air vs 0 mmHg of CO2
Measured: The Δ Vanderbilt Orthostatic Symptom Score (symptoms at the 5th minute of stand - symptoms at the 5th minute of sit) will be compared between room air and 0 mmHg of CO2
Δ Vanderbilt Orthostatic Symptom Score [Range: 0 (absent) to 10 (worst)]
Magnitude of Δ Vanderbilt Orthostatic Symptom Score (Stand-Sit) breathing room air vs +5mmHg of CO2
Measured: The Δ Vanderbilt Orthostatic Symptom Score (symptoms at the 5th minute of stand - symptoms at the 5th minute of sit) will be compared between room air and +5mmHg of CO2
Δ Vanderbilt Orthostatic Symptom Score [Range: 0 (absent) to 10 (worst)]
Magnitude of Δ Vanderbilt Orthostatic Symptom Score (Stand-Sit) breathing room air vs +10mmHgCO2/50mmHg O2
Measured: The Δ Vanderbilt Orthostatic Symptom Score (symptoms at the 5th minute of stand - symptoms at the 5th minute of sit) will be compared between room air and +10mmHgCO2/50mmHg O2
Δ Cerebral Blood Flow Velocity (CBFv)
Magnitude of ΔCBFv (Stand-Sit) breathing room air vs +10mmHg of CO2
Measured: The ΔCBFv (stand-sit) calculated as the average CBFv in the final minute of sitting and the average CBFv between minute 3 and 5 of stand will be compared between room air and +10mmHg of CO2
Δ Cerebral Blood Flow Velocity (CBFv)
Magnitude of ΔCBFv (Stand-Sit) breathing room air vs 0 mmHg of CO2
Measured: The ΔCBFv (stand-sit) calculated as the average CBFv in the final minute of sitting and the average CBFv between minute 3 and 5 of stand will be compared between room air and 0 mmHg of CO2
Δ Cerebral Blood Flow Velocity (CBFv)
Magnitude of ΔCBFv (Stand-Sit) breathing room air vs +5mmHg of CO2
Measured: The ΔCBFv (stand-sit) calculated as the average CBFv in the final minute of sitting and the average CBFv between minute 3 and 5 of stand will be compared between room air and +5mmHg of CO2
Δ Cerebral Blood Flow Velocity (CBFv)
Magnitude of ΔCBFv (Stand-Sit) breathing room air vs +10mmHgCO2/50mmHg O2
Measured: The ΔCBFv (stand-sit) calculated as the average CBFv in the final minute of sitting and the average CBFv between minute 3 and 5 of stand will be compared between room air and +10mmHgCO2/50mmHg O2
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Mar 2022
- Study start1 Mar 2022
- Primary completion31 Dec 2029 (estimated)
- Study completion31 May 2030 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (7)Papers the sponsor has linked to this study.
- Other trials for Orthostatic HypotensionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Male and female NOH patients (n=40) will be recruited from the Calgary Autonomic Clinic, along with sex and age-matched controls from the community. Participants will complete five Active Stand Tests during which they will be asked to target different end-tidal (ET) CO2 levels. Participants will complete the following breathing protocol during an active stand test: 1. Breathing normal room air (ETCO2 free to fluctuate), 2. ETCO2 clamped at baseline, 3. ETCO2 clamped at +5mmHg, 4. ETCO2 clamped at +10mmHg, 5. ETCO2 clamped at +10mmHg with ETO2 clamped at 50mmHg.
- Masking
- None (open label)
- Enrolment
- 80 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Calgary
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Dr. Satish Raj, University of Calgary
- Investigators
- Satish R Raj, MD, Principal investigator, University of Calgary
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05295810
- Sponsor's protocol ID
- REB20-1322
- Status last verified
- Apr 2026
- First submitted
- 7 Mar 2022
- Last updated
- 5 May 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Freeman R, Wieling W, Axelrod FB, Benditt DG, Benarroch E, Biaggioni I, Cheshire WP, Chelimsky T, Cortelli P, Gibbons CH, Goldstein DS, Hainsworth R, Hilz MJ, Jacob G, Kaufmann H, Jordan J, Lipsitz LA, Levine BD, Low PA, Mathias C, Raj SR, Robertson D, Sandroni P, Schatz I, Schondorff R, Stewart JM, van Dijk JG. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin Auton Res. 2011 Apr;21(2):69-72. doi: 10.1007/s10286-011-0119-5. No abstract available.
PubMed 21431947Freeman R, Abuzinadah AR, Gibbons C, Jones P, Miglis MG, Sinn DI. Orthostatic Hypotension: JACC State-of-the-Art Review. J Am Coll Cardiol. 2018 Sep 11;72(11):1294-1309. doi: 10.1016/j.jacc.2018.05.079.
PubMed 30190008Morgan BJ, Crabtree DC, Palta M, Skatrud JB. Combined hypoxia and hypercapnia evokes long-lasting sympathetic activation in humans. J Appl Physiol (1985). 1995 Jul;79(1):205-13. doi: 10.1152/jappl.1995.79.1.205.
PubMed 7559221Schultz HD, Li YL, Ding Y. Arterial chemoreceptors and sympathetic nerve activity: implications for hypertension and heart failure. Hypertension. 2007 Jul;50(1):6-13. doi: 10.1161/HYPERTENSIONAHA.106.076083. Epub 2007 May 14. No abstract available.
PubMed 17502495Shoemaker JK, O'Leary DD, Hughson RL. PET(CO(2)) inversely affects MSNA response to orthostatic stress. Am J Physiol Heart Circ Physiol. 2001 Sep;281(3):H1040-6. doi: 10.1152/ajpheart.2001.281.3.H1040.
PubMed 11514269Howden R, Lightfoot JT, Brown SJ, Swaine IL. The effects of breathing 5% CO2 on human cardiovascular responses and tolerance to orthostatic stress. Exp Physiol. 2004 Jul;89(4):465-71. doi: 10.1113/expphysiol.2004.027250. Epub 2004 May 6.
PubMed 15131068Baker JR, Ranada SI, Incognito AV, Sheldon RS, Morillo CA, Wilson RJA, Phillips AA, Raj SR. Elevating blood pressure in neurogenic orthostatic hypotension: Investigating the efficacy and tolerability of rebreathing therapy. Auton Neurosci. 2026 Apr;264:103400. doi: 10.1016/j.autneu.2026.103400. Epub 2026 Feb 20.
PubMed 41734601
Study at a glance
From the registry record, last updated by the sponsor on 5 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Investigating Hypercapnia to Treat Neurogenic Orthostatic Hypotension
- ClinicalTrials.gov ID
- NCT05295810
- Acronym / sponsor ID
- REB20-1322
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 80 participants (estimated)
- Lead sponsor
- University of CalgaryUniversity, hospital or other
- Study start
- 1 Mar 2022 (actual)
- Primary completion
- 31 Dec 2029 (estimated)
- Study completion
- 31 May 2030 (estimated)
- First posted
- 25 Mar 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The Autonomic (or "automatic") Nervous System (ANS) regulates internal processes, including control of heart rate and blood pressure (BP). When someone stands, and gravity tries to pull blood away from the brain, the ANS works to maintain BP and brain blood flow. Neurogenic Orthostatic Hypotension (NOH) occurs when our "fight-or-flight" part ("sympathetic") of the ANS fails. BP can drop a lot when upright, reducing blood flow and oxygen delivery to the brain, and this can cause symptoms of light-headedness, nausea, and fainting.
One solution to help counter the effects of NOH may be to increase sympathetic activity by breathing higher levels of carbon dioxide. In healthy volunteers, small increases in the amount of inhaled carbon dioxide has been shown to increase BP in the upright position, and this improves symptoms!
The objectives of the current study are to apply carbon dioxide in patients with NOH and healthy controls to: (a) evaluate the effects of breathing carbon dioxide on BP and brain blood flow, and (b) determine if a device that increases carbon dioxide while standing will work as a new therapy
Detailed description
BACKGROUND: Regulation of tissue blood supply to vital organs such as the brain and heart is met in large part by local adjustment of the microvasculature (autoregulation) and autonomic nervous system control of the cardiovascular system. Neurogenic Orthostatic Hypotension (NOH) is a key example of when these systems fail. Patients experience a significant and persistent blood pressure (BP) drop (≥20/10 mmHg) in the upright position, resulting in cerebral hypoperfusion and symptoms of light-headedness, nausea, pre-syncope and even syncope. NOH and impaired cerebrovascular perfusion occur due to failure of the baroreflex to appropriately increase sympathetic outflow.
A novel solution to counter the acute effects of NOH is to transiently increase sympathetic activity by stimulating the peripheral and central respiratory chemoreceptors with elevated Fractional Inspired (Fi)CO2. In healthy volunteers, elevated FiCO2 improves orthostatic tolerance and BP control during rapid postural transitions. Additionally, few have considered sex-difference effects on the chemoreflex-autonomic relationship. Existing evidence demonstrates an augmented sympathetic response to chemoreflex stimulation in postmenopausal women with observed vasoconstriction and increased BPs. These data indicate females may respond better to hypercapnia as a novel therapeutic intervention for NOH. Unfortunately, it may also highlight a predisposition for cardiovascular risk associated with supine hypertension.
To better understand the mechanistic underpinnings of NOH in males and females, and to explore the use of elevated FiCO2 to treat it, researchers need a better way to monitor sympathetic activity and cerebrovascular perfusion. Functional Optical Coherence Tomography (fOCT) of the retinal and choroid vascular beds of the eye (an out crop of the brain) was recently developed in Calgary to allow physiological monitoring of these essential variables. In summary, elevated FiCO2 levels (hypercapnia) appear to improve BP responses to standing and orthostatic tolerance and may constitute an attractive therapy for NOH patients.
This is a proof-of-concept study to evaluate hypercapnia as a novel therapeutic intervention to improve blood pressure and orthostatic tolerance in male and female patients with NOH. In addition, the investigators will aim to evaluate functional OCT as an advance, non-invasive tool to measure sympathetic and metabolic cerebrovascular control.
OBJECTIVES: The aims of the current proposal are to apply hypercapnia during fOCT monitoring in male and female patients with NOH and healthy controls to: (a) evaluate and compare the effects of hypercapnia on cardiovascular and cerebrovascular responses to better understand basic chemoreflex and baroreflex physiology in male and female patients with NOH, (b) determine if a device that transiently increases FiCO2 in response to postural changes will have efficacy as a non-drug therapeutic and (c) evaluate fOCT as a novel advanced tool to measure sympathetic and metabolic components of cerebral autoregulation in patients with autonomic failure.
METHODS: Male and female NOH patients (n=40) will be recruited from the Calgary Autonomic Clinic, along with sex and age-matched controls from the community. Participants will complete five Active Stand Tests during which they will be asked to target different end-tidal (ET) CO2 levels. OCT images will be captured throughout each test. Participants will complete the following breathing protocol during an active stand test: a) breathing normal room air (ETCO2 free to fluctuate), b) ETCO2 clamped at baseline, c) ETCO2 clamped at +5mmHg, d) ETCO2 clamped at +10mmHg, e) ETCO2 clamped at +10mmHg with ETO2 clamped at 50mmHg. Target ETCO2 levels will be achieved through a computerized gas delivery system. A rebreathing task to elicit hypercapnia and hypoxia (low oxygen) will be performed last. Each condition will be followed by a minimum 10-minute recovery period to ensure ETCO2 normalization. Hemodynamics (BP, HR and stroke volume) and orthostatic symptoms will be assessed throughout. Breath-by-breath data will include ETO2, ETCO2, respiration rate, tidal volume, and minute ventilation. OCT image analyses in the seated and standing position will measure choroid and retinal (surrogates for peripheral sympathetic activity and metabolic cerebral autoregulation, respectively) perfusion densities.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 5
- Model description
- Male and female NOH patients (n=40) will be recruited from the Calgary Autonomic Clinic, along with sex and age-matched controls from the community. Participants will complete five Active Stand Tests during which they will be asked to target different end-tidal (ET) CO2 levels. Participants will complete the following breathing protocol during an active stand test: 1. Breathing normal room air (ETCO2 free to fluctuate), 2. ETCO2 clamped at baseline, 3. ETCO2 clamped at +5mmHg, 4. ETCO2 clamped at +10mmHg, 5. ETCO2 clamped at +10mmHg with ETO2 clamped at 50mmHg.
| Arm | Type | Receives |
|---|---|---|
| Room Air | No intervention | –All participants will complete an active stand breathing room air with CO2 free to fluctuate |
| +0mmHg CO2 Clamped at baseline | Experimental | Drug: Sequential Gas DeliveryAll participants will complete an active stand with their CO2 held constant at baseline |
| +5mmHg CO2 | Experimental | Drug: Sequential Gas DeliveryAll participants will complete an active stand breathing +5mmHg of CO2 relative to baseline |
| +10mmHg | Experimental | Drug: Sequential Gas DeliveryAll participants will complete an active stand breathing +10mmHg of CO2 relative to baseline |
| +10mmHg CO2 + 50mmHg O2 | Experimental | Drug: Sequential Gas DeliveryAll participants will complete an active stand breathing +10mmHg of CO2 relative to baseline and 50mmHg of O2 |
Who may qualify
- Ages
- 18 to 100 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Age ≥18 years
- Male and Female
- Non - smokers.
- Able and willing to provide informed consent.
- Ability to travel to Libin Cardiovascular Institute Autonomic Testing Lab at the University of Calgary, Calgary, AB.
Key exclusion criteria (8 listed)
- Medical therapies or medications which could interfere with testing of autonomic function
- Participants with somatization or severe anxiety symptoms will be excluded
- Pregnant or breast-feeding females
- Inability to tolerate mask for the duration of the study
- Subjects who require portable oxygen at rest or with exercise
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Sequential Gas DeliverySequential Gas Delivery will be controlled using the RespirAct™ system (Thornhill Research Inc., Toronto, Canada) | Drug | +0mmHg CO2 Clamped at baseline, +10mmHg, +10mmHg CO2 + 50mmHg O2, +5mmHg CO2 |
Primary outcome
Δ Blood Pressure (BP)
Time frame: The ΔBP (stand-sit) calculated as the average BP in the final minute of sitting and the average BP between minute 3 and 5 of stand will be compared between room air and +10mmHg of CO2
Magnitude of ΔBP (Stand-Sit) breathing room air vs +10mmHg of CO2
11 secondary outcomes
Δ Blood Pressure (BP)
Time frame: The ΔBP (stand-sit) calculated as the average BP in the final minute of sitting and the average BP between minute 3 and 5 of stand will be compared between room air and 0 mmHg of CO2
Δ Blood Pressure (BP)
Time frame: The ΔBP (stand-sit) calculated as the average BP in the final minute of sitting and the average BP between minute 3 and 5 of stand will be compared between room air and +5mmHg of CO2
Δ Blood Pressure (BP)
Time frame: The ΔBP (stand-sit) calculated as the average BP in the final minute of sitting and the average BP between minute 3 and 5 of stand will be compared between room air and +10mmHgCO2/50mmHg O2
Δ Vanderbilt Orthostatic Symptom Score [Range: 0 (absent) to 10 (worst)]
Time frame: The Δ Vanderbilt Orthostatic Symptom Score (symptoms at the 5th minute of stand - symptoms at the 5th minute of sit) will be compared between room air and +10mmHg of CO2
Δ Vanderbilt Orthostatic Symptom Score [Range: 0 (absent) to 10 (worst)]
Time frame: The Δ Vanderbilt Orthostatic Symptom Score (symptoms at the 5th minute of stand - symptoms at the 5th minute of sit) will be compared between room air and 0 mmHg of CO2
Δ Vanderbilt Orthostatic Symptom Score [Range: 0 (absent) to 10 (worst)]
Time frame: The Δ Vanderbilt Orthostatic Symptom Score (symptoms at the 5th minute of stand - symptoms at the 5th minute of sit) will be compared between room air and +5mmHg of CO2
Δ Vanderbilt Orthostatic Symptom Score [Range: 0 (absent) to 10 (worst)]
Time frame: The Δ Vanderbilt Orthostatic Symptom Score (symptoms at the 5th minute of stand - symptoms at the 5th minute of sit) will be compared between room air and +10mmHgCO2/50mmHg O2
Δ Cerebral Blood Flow Velocity (CBFv)
Time frame: The ΔCBFv (stand-sit) calculated as the average CBFv in the final minute of sitting and the average CBFv between minute 3 and 5 of stand will be compared between room air and +10mmHg of CO2
Δ Cerebral Blood Flow Velocity (CBFv)
Time frame: The ΔCBFv (stand-sit) calculated as the average CBFv in the final minute of sitting and the average CBFv between minute 3 and 5 of stand will be compared between room air and 0 mmHg of CO2
Δ Cerebral Blood Flow Velocity (CBFv)
Time frame: The ΔCBFv (stand-sit) calculated as the average CBFv in the final minute of sitting and the average CBFv between minute 3 and 5 of stand will be compared between room air and +5mmHg of CO2
Δ Cerebral Blood Flow Velocity (CBFv)
Time frame: The ΔCBFv (stand-sit) calculated as the average CBFv in the final minute of sitting and the average CBFv between minute 3 and 5 of stand will be compared between room air and +10mmHgCO2/50mmHg O2
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 May 2026.
- Background: PubMed 21431947Freeman R, Wieling W, Axelrod FB, Benditt DG, Benarroch E, Biaggioni I, Cheshire WP, Chelimsky T, Cortelli P, Gibbons CH, Goldstein DS, Hainsworth R, Hilz MJ, Jacob G, Kaufmann H, Jordan J, Lipsitz LA, Levine BD, Low PA, Mathias C, Raj SR, Robertson D, Sandroni P, Schatz I, Schondorff R, Stewart JM, van Dijk JG. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin Auton Res. 2011 Apr;21(2):69-72. doi: 10.1007/s10286-011-0119-5. No abstract available.
- Background: PubMed 30190008Freeman R, Abuzinadah AR, Gibbons C, Jones P, Miglis MG, Sinn DI. Orthostatic Hypotension: JACC State-of-the-Art Review. J Am Coll Cardiol. 2018 Sep 11;72(11):1294-1309. doi: 10.1016/j.jacc.2018.05.079.
- Background: PubMed 7559221Morgan BJ, Crabtree DC, Palta M, Skatrud JB. Combined hypoxia and hypercapnia evokes long-lasting sympathetic activation in humans. J Appl Physiol (1985). 1995 Jul;79(1):205-13. doi: 10.1152/jappl.1995.79.1.205.
- Background: PubMed 17502495Schultz HD, Li YL, Ding Y. Arterial chemoreceptors and sympathetic nerve activity: implications for hypertension and heart failure. Hypertension. 2007 Jul;50(1):6-13. doi: 10.1161/HYPERTENSIONAHA.106.076083. Epub 2007 May 14. No abstract available.
- Background: PubMed 11514269Shoemaker JK, O'Leary DD, Hughson RL. PET(CO(2)) inversely affects MSNA response to orthostatic stress. Am J Physiol Heart Circ Physiol. 2001 Sep;281(3):H1040-6. doi: 10.1152/ajpheart.2001.281.3.H1040.
- Background: PubMed 15131068Howden R, Lightfoot JT, Brown SJ, Swaine IL. The effects of breathing 5% CO2 on human cardiovascular responses and tolerance to orthostatic stress. Exp Physiol. 2004 Jul;89(4):465-71. doi: 10.1113/expphysiol.2004.027250. Epub 2004 May 6.
- Derived from this study: PubMed 41734601Baker JR, Ranada SI, Incognito AV, Sheldon RS, Morillo CA, Wilson RJA, Phillips AA, Raj SR. Elevating blood pressure in neurogenic orthostatic hypotension: Investigating the efficacy and tolerability of rebreathing therapy. Auton Neurosci. 2026 Apr;264:103400. doi: 10.1016/j.autneu.2026.103400. Epub 2026 Feb 20.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Rasha Hamzeh, RN contact
Satish R Raj, MD principal investigator
University of Calgary
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Sequential Gas Delivery in people with Orthostatic Hypotension and Neurogenic Orthostatic Hypotension, run by University of Calgary at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 5 May 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Jacquie Baker, PhD (4032103819, jacquie.baker@ucalgary.ca), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Δ Blood Pressure (BP) (time frame: The ΔBP (stand-sit) calculated as the average BP in the final minute of sitting and the average BP between minute 3 and 5 of stand will be compared between room air and +10mmHg of CO2). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05295810, which also lists 7 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 May 2026.