Hypercapnia in Orthostatic Hypotension

NCT05295810 | Recruiting

• 1 other identifier: REB20-1322
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

Brief 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. 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

Conditions

Orthostatic Hypotension; Neurogenic Orthostatic Hypotension

Outcome Measures

Primary Outcomes (1)

• Δ Blood Pressure (BP)

  Magnitude of ΔBP (Stand-Sit) breathing room air vs +10mmHg of CO2

  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)

  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)

  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)

  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)]

  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)]

  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

Study Arms (5)

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

Drug: Sequential Gas Delivery

+5mmHg CO2

EXPERIMENTAL

All participants will complete an active stand breathing +5mmHg of CO2 relative to baseline

Drug: Sequential Gas Delivery

+10mmHg

EXPERIMENTAL

All participants will complete an active stand breathing +10mmHg of CO2 relative to baseline

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

Drug: Sequential Gas Delivery

Interventions

Sequential Gas Delivery DRUG

Sequential Gas Delivery will be controlled using the RespirAct™ system (Thornhill Research Inc., Toronto, Canada)

+0mmHg CO2 Clamped at baseline; +10mmHg; +10mmHg CO2 + 50mmHg O2; +5mmHg CO2

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Calgary: lead

Study Sites (1)

University of Calgary

Calgary, Alberta, Canada

RECRUITING

Related Publications (7)

• 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.

  PMID: 21431947 BACKGROUND

• Freeman 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.

  PMID: 30190008 BACKGROUND

• Morgan 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.

  PMID: 7559221 BACKGROUND

• Schultz 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.

  PMID: 17502495 BACKGROUND

• Shoemaker 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.

  PMID: 11514269 BACKGROUND

• Howden 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.

  PMID: 15131068 BACKGROUND

• Baker 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.

  PMID: 41734601 DERIVED

MeSH Terms

Conditions

Hypotension, Orthostatic

Condition Hierarchy (Ancestors)

Orthostatic Intolerance; Primary Dysautonomias; Autonomic Nervous System Diseases; Nervous System Diseases; Hypotension; Vascular Diseases; Cardiovascular Diseases

Study Officials

• Satish R Raj, MD

  University of Calgary

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jacquie Baker, PhD

CONTACT

4032103819; jacquie.baker@ucalgary.ca

Rasha Hamzeh, RN

CONTACT

autonomic.research@ucalgary.ca

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: All participants will be fitted with a face mask connected to a tube supplied with gas from the RespirAct™ system. The participants will not be informed about the concentration of gases during each active stand test. After the study completion they will be informed about the order of interventions.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: 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.

Study Record Dates

• First Submitted: March 7, 2022
• First Posted: March 25, 2022
• Study Start: March 1, 2022
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): May 31, 2030
• Last Updated: May 5, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)