Hypercapnia in Orthostatic Hypotension

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.

• Δ Blood Pressure (BP) [Срок оценки: 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) [Срок оценки: 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) [Срок оценки: 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)] [Срок оценки: 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)] [Срок оценки: 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)] [Срок оценки: 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)] [Срок оценки: 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) [Срок оценки: 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) [Срок оценки: 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) [Срок оценки: 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) [Срок оценки: 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]