The Effect of Inhaled Nitric Oxide on Dyspnea and Exercise Tolerance in COPD
Condition: Dyspnea
MeSH terms: Dyspnea
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Nitric Oxide; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Inhaled nitric oxide, which consists of breathing medical grade air (21% O2) with 40 parts per million of nitric oxide.; Inhaled placebo, which consists of breathing medical grade air (21% O2).
Other intervention name(s): Inhaled Nitric Oxide; Medical Grade Room Air
Intervention MeSH terms: Nitric Oxide
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Randomized double-blind cross-over design
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Treatment