The Effect of Inhaled Nitric Oxide on Dyspnea and Exercise Tolerance in COPD
The Effect of Inhaled Nitric Oxide on Dyspnea and Exercise Tolerance in COPD
Chronic Obstructive Pulmonary Disease (COPD) is a lung disorder commonly caused by smoking,
 which makes breathing more difficult. When COPD patients exercise, they are not efficient
 breathers and this leads to serious breathing difficulties, which often causes these patients
 to stop exercise at low intensities. Even though patients with a mild form of COPD have
 relatively well preserved lung function, they still have inefficient breathing during
 exercise. The investigators think that these patients have problems exchanging fresh gas
 (i.e., oxygen) into the blood stream because of poor lung blood vessel function. The
 investigators will test whether inhaled medications, specifically nitric oxide, can improve
 lung blood vessel function and decrease breathing difficulties during exercise. With this
 research, the investigators will understand more about breathing efficiency and lung blood
 vessel function in patients with COPD, and find out whether improving lung blood vessel
 function helps COPD patients breathe easier and exercise longer. Understanding the reasons
 behind the feeling of difficult breathing may lead to more effective therapy and improved
 quality of life in COPD patients.
Chronic Obstructive Pulmonary Disease (COPD) is a respiratory disorder typically caused by
 smoking and is characterized by airway obstruction. Exertional dyspnea (perceived
 breathlessness) is a hallmark of COPD regardless of severity and is the primary reason for
 exercise intolerance even in patients with mild COPD (defined using spirometric criteria as a
 forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <0.70 and a FEV1 ≥ 80%).
 Dyspnea in COPD has been shown to profoundly reduce patient quality of life, physical
 activity, and impair patients' ability to complete day-to-day tasks. Previous work in mild
 COPD has demonstrated that exertional dyspnea is the result of increased work of breathing
 during exercise, and that this increased work of breathing comes from: 1) an exaggerated
 ventilatory response to exercise (i.e. increased minute ventilation relative to carbon
 dioxide production, V̇E/V̇CO2), and 2) airflow limitation (i.e. expiratory flow limitation
 and resulting dynamic hyperinflation). A great deal of work has focused on improving airflow
 limitation in COPD; however, very little has been done to understand and treat the
 exaggerated ventilatory response to exercise in COPD.

 Several previous studies in COPD have consistently shown an elevated ventilatory response
 (i.e. greater V̇E/V̇CO2) during exercise. The elevated V̇E/V̇CO2 response to exercise appears
 to be clinically important, as it independently predicts mortality in COPD and indicates that
 physiological abnormalities beyond airflow obstruction are important in determining disease
 severity, dyspnea, and risk of death. This increased V̇E/V̇CO2 in COPD appears to be
 secondary to increased deadspace ventilation(i.e. sections of the lung with ventilation, but
 no perfusion), and this increased deadspace ventilation results in a compensatory increase in
 total minute ventilation (i.e. increased V̇E/V̇CO2) to maintain effective alveolar
 ventilation and arterial blood gas homeostasis.

 The underlying mechanism(s) for the increased deadspace ventilation and V̇E/V̇CO2 during
 exercise in mild to moderate COPD is currently unclear; however, pulmonary microvascular
 abnormalities and hypoperfusion of pulmonary capillaries are potential pathophysiologic
 mechanisms. Mild to moderate COPD patients have reduced pulmonary microvascular blood flow in
 nonemphysematous lung regions, which has led researchers to conclude that the low pulmonary
 perfusion in an intact pulmonary vascular bed is likely the result of pulmonary vascular
 dysfunction. Ventilation-perfusion (V̇A/Q̇) data in mild and moderate COPD shows substantial
 V̇A/Q̇ inequality at rest, with the V̇A/Q̇ distribution skewed towards regions of high
 V̇A/Q̇, which is indicative of increased deadspace. Consistent with this capillary
 hypoperfusion hypothesis, our recent work has shown a blunted pulmonary capillary blood
 volume response to exercise in mild COPD, when compared to age- and height-matched
 non-smoking controls. Importantly, the low pulmonary capillary blood volume was associated
 with increased V̇E/V̇CO2 during exercise, suggesting that low pulmonary perfusion (i.e.
 reduced pulmonary capillary blood volume) leads to increased deadspace.

 Inhaled nitric oxide (NO) is commonly used to test for pulmonary vasodilatory responses in
 patients with pulmonary arterial hypertension (PAH), as it increases NO bioavailability and
 improves pulmonary vascular function. Previous work in PAH and heart failure (HF) patients
 has shown that standard doses (20-40 parts per million (ppm)) of inhaled NO can reduce
 pulmonary vascular resistance and increase peak oxygen consumption (V̇O2peak). If inhaled NO
 can reduce vascular dysfunction and increase perfusion in mild and moderate COPD, this would
 result in a reduction in V̇E/V̇CO2 and improved exercise tolerance.

 STUDY PURPOSE

 Purpose: To examine the effect of inhaled NO on exercise capacity (V̇O2peak) ventilation and
 dyspnea in in patents with COPD.

 Hypothesis: Inhaled NO will improve exercise capacity, secondary to reduced V̇E/V̇CO2 and
 dyspnea, in mild and moderate COPD, while no change will be observed in healthy controls and
 severe COPD.

 Study Design: Randomized double-blind cross-over design.

 All participants will have a pulmonary function and cardiopulmonary exercise test. The study
 procedure is briefly outlined below and is further outlined in the attached University
 Hospital Foundation Grant.

 Study Protocol: Seven sessions will be completed over a 3-week period in the following order:

 Day 1) Participant enrollment, medical history, standard pulmonary function (PFT) and
 cardiopulmonary exercise test (CPET).

 Days 2 & 3) Randomly-ordered experimental CPETs while either breathing room air or inhaled
 nitric oxide (room air with 40 ppm NO).

 Days 4 & 5) Randomly-ordered constant load exercise tests, at 75% peak power output, while
 either breathing room air or inhaled nitric oxide (room air with 40 ppm NO).

 Day 6) Ultrasonography doppler measurements will be completed to determine pulmonary arterial
 systolic pressure (at rest and during exercise) while breathing room air or inhaled nitric
 oxide. Doppler measurements of systemic vascular endothelial function will be measured at
 rest while breathing room air. To enhance doppler signal during the cardiac ultrasound,
 agitated saline contrast will be used. A small sample of venous blood will be taken to
 analyze inflammatory levels. Additionally, participants will breathe into a small tube so
 that expelled saliva can be analyzed to determine airway inflammation.

 Day 7) Prospective quantitative computed tomography (CT) imaging will be completed to obtain
 lung density, heterogeneity, tissue, vascular and airway measurements.

 Each visit will take approximately 3 hours. The total time duration for each participant will
 be approximately 21 hours.
Inclusion Criteria - COPD Patients:

 -  No significant cardiovascular disease.

 -  No significant metabolic disease

 -  No significant neuromuscular disease

 -  Participants will range from 18-85 years old

 Inclusion Criteria - Control Patients:

 -  Age- and sex-matched to COPD patients

 -  Normal lung function

 -  Minimal smoking history

 -  No previous diagnosis of COPD

 -  Participants will range from 18-85 years old

 Exclusion Criteria:

 -  Individuals with significant cardiovascular, metabolic, neuromuscular or any other
 disease

 -  Individual with musculoskeletal injuries

 -  Individuals currently on oral steroids (i.e. prednisone), phosphodiesterase type 5
 (PDE5) inhibitors or supplemental O2 therapy