CO2 Rebreathing in nOH: A Proof-of-Concept Pilot Study

CO2 Rebreathing to Increase Blood Pressure in Neurogenic Orthostatic Hypotension: A Proof-of-Concept Pilot Study

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 A previous study (unpublished) showed that hypercapnia significantly increases standing BP in patients with nOH.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.

BACKGROUND: 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. nOH affects the elderly and patients with neurodegenerative diseases (e.g., Parkinson's disease, multiple system atrophy), neuropathies (e.g., diabetes), and neural injury (e.g., spinal cord injury). In healthy controls, hypercapnia (i.e., high CO2) increases in sympathetic nerve activity and BP. Hypercapnia significantly increases supine and seated BP in patients with nOH, and 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. OBJECTIVE: 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 study hypothesis is that a rebreather will increase CO2 sufficiently enough to improve BP in patients with nOH. METHODS: Male and female patients (n=28) will be recruited from the Calgary Autonomic Investigation and Management Clinic. STUDY PROCEDURE Informed Consent: The informed consent will be sent by email to the patients in advance. The investigators will give each patient a chance to ask questions about the protocol and have these questions answered to their satisfaction. Written informed consent will be documented prior to engaging in study-related procedures. Holding Pre-Existing Medications: Participants will be asked to hold their clinical medications on the day of the study testing, if possible, but this will not be mandatory. The investigators will make note of the medications used by each participant at the time of the study. Study Day: Participants will be instrumented at least 2h post-prandial on an empty bladder. Participants will be asked to abstain from alcohol, caffeine, and exercise for a period of 12 hours prior to testing. Participants will be allowed to drink water on the morning of study. Upon lab arrival, a description of the study will be given and written informed consent will be attained if the individual chooses to participate in the study. A member of the research team will ask participants about current medications and other disorders they many have as part of the study inclusion/exclusion criteria. The investigators will also review all other inclusion/exclusion criteria for the study. All study equipment will be introduced to the participant, and then the investigators will begin to prepare for the study. Participants will be asked to lie supine on the tilt table during instrumentation. Following instrumentation, the study will begin with a 10-minute baseline in the supine position. During this period, the investigators will track blood pressure, heart rate, brain blood flow velocity, fluid shifts, and respiratory pattern using the following equipment: Finger and arm blood pressure cuffs Skin electrodes to measure heart rate and fluid shifts A Transcranial Doppler (TCD) which will use a band around the head, with an ultrasound-like probe at the left and/or right temple Pulse oximeter on the finger to measure oxygen saturation Participants will be fitted with a mouthpiece to breathing into. The mouthpiece will be connected to a breathing bag that will capture the CO2 exhaled. The mouthpiece will also be connected to a tube that will measure respiratory rate, respiratory depth, CO2 and O2. Following instrumentation, participants will complete up to two 70° head-up tilt (HUT) tests while breathing either normal room air or while breathing with the rebreather. Each HUT will last a maximum of 5 minutes, and when participants are not upright, the participants will be in the supine position. Participants will be asked to breathe with the rebreather until the measured CO2 increases between 5-10mmHg. Once CO2 is increased, HUT will begin. Participants will continue to breathe with the rebreather until the end of HUT. The two HUT tests will be randomized and will consist of: HUT with Room Air HUT with ETCO2 levels increased 5-10mmHg above normal levels 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.

Male and female NOH patients (n=28) will be recruited from the Calgary Autonomic Clinic. Participants will complete the following two randomized head-up tilt tests (HUT): Room Air: Participants will breathe room air while supine and during a 5-min HUT test CO2 rebreathing: 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

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

The ReHaler captures expired CO2, which is then re-inhaled. The net effect is a transient increase in CO2.

The ΔBP (HUT-Supine) calculated as the average BP in the final two minutes of supine baseline and the average BP between minute 3 and 5 of HUT will be compared between room air and CO2 rebreathe

The Δ Vanderbilt Orthostatic Symptom Score (symptoms at the 5th minute of HUT - symptoms at the 5th minute of supine rest) will be compared between room air vs CO2 rebreathe

The ΔCBFv (HUT-Supine) calculated as the average CBFv in the final two minutes of supine baseline and the average CBFv between minute 3 and 5 of HUT will be compared between room air and CO2 rebreathe

Inclusion Criteria: Age ≥18 years Male and Female Physician diagnosis of Neurogenic Orthostatic Hypotension 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. Exclusion Criteria: Medical therapies or medications which could interfere with testing of autonomic function Pregnant or breast-feeding females 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.

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