BACKGROUND. Interstitial Lung Disease (ILD) is a respiratory disorder characterized by chronic
inflammation and fibrosis of the lung parenchyma. Exertional dyspnea (perceived
breathlessness) is a hallmark of ILD regardless of severity and is the primary reason for the
observed exercise intolerance, typically observed in this population. Dyspnea in ILD has been
shown to profoundly reduce quality of life, physical activity, and impair the ability of
participants with ILD to complete day-to-day tasks. Previous work in ILD 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 growing body of work has focused on respiratory mechanics in ILD; however,
very little has been done to understand and treat the exaggerated ventilatory response to
exercise in ILD.
Several previous studies in ILD have consistently shown an elevated ventilatory response
(i.e. greater V̇E/V̇CO2) during exercise. This increased V̇E/V̇CO2 in ILD 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 ILD is currently unclear;
however, pulmonary microvascular abnormalities and hypoperfusion of pulmonary capillaries are
potential pathophysiologic mechanisms. Individuals with ILD have a reduced pulmonary
capillary blood volume and, in more severe ILD, present with pulmonary vascular dysfunction
and are prone to developing exercise-induced pulmonary arterial hypertension. It is likely
that the pulmonary vascular dysfunction, in ILD, may impair pulmonary capillary perfusion,
leading to ventilation (V̇A) -perfusion (Q̇) inequality (specifically, areas of high, V̇A/Q̇,
which is indicative of increased deadspace), however this has not yet been examined. Inhaled
nitric oxide (NO) is commonly used to test for pulmonary vasodilatory responses in
individuals with pulmonary arterial hypertension (PAH), as it increases NO bioavailability
and improves pulmonary vascular function. Previous work in PAH and heart failure (HF) 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 ILD, this would result in a reduction in
V̇E/V̇CO2 and dyspnea, and improved exercise tolerance.
STUDY PURPOSE. Purpose: To examine the effect of inhaled NO on exercise capacity (V̇O2peak), ventilation and
dyspnea in ILD.
Hypothesis: Inhaled NO will improve exercise capacity, secondary to reduced V̇E/V̇CO2 and
dyspnea, in individuals with ILD.
Study Design: Randomized double-blind cross-over design.
Study Protocol:
Six 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) Resting and
exercise trials while breathing room air or inhaled nitric oxide with ultrasonography doppler
measurements to determine pulmonary arterial systolic pressure. Each visit will take
approximately 3 hours.
On Day 1, participants will complete the informed consent procedure, fill out a medical
history questionnaire and be screened for exercise using the physical activity readiness
questionnaire. Study participants will undergo lung function and cardiopulmonary exercise
testing on the same day. The participants will be spending approximately three hours in the
laboratory on this testing day.
On days 2 & 3 (one day per week in 2 consecutive weeks; order randomized), the participants
will breathe the placebo, which is medical grade air (room air) or room air titrated with 40
parts per million of nitric oxide and have blood flow/cardiac output and expired gas
evaluated, and time to exhaustion determined in a standard incremental cardiopulmonary
exercise test.
On day 2, the participant will lie supine and be rested for 5 minutes. Resting blood pressure
will be determined using manual auscultation. Resting cardiac output will be evaluated using
noninvasive impedance cardiography (PhysioflowTM) and oxygen saturation estimated with pulse
oximetry. Ventilation will be measured from expired gas analysis. Following these
measurements, the subject will begin to breathe medical grade room air. Following a 20 minute
wash-in period, ventilation, cardiac output and oxygen saturation recordings will be
repeated. Participants will then perform a standard cardiopulmonary exercise test while
continuing to breathe the medical grade room air. The participants will be spending
approximately three hours in the laboratory on this testing day.
Day 3 will be identical to day 2 except, in the place of medical grade room air, participants
will breathe room air with 40 parts per million of nitric oxide.
On days 4 & 5 (one day per week in 2 consecutive weeks; order randomized), the participants
will breathe the placebo, which is medical grade air (room air) or room air titrated with 40
parts per million of nitric oxide and have blood flow/cardiac output and expired gas
evaluated, and time to exhaustion determined in a standard constant work rate cardiopulmonary
exercise test. Measurement procedures will be identical to days 2 & 3.
On day 6, the participants will complete resting and sub-maximal exercise trials while
breathing placebo or iNO, with ultrasonography Doppler measurements to determine pulmonary
arterial systolic pressure.
The participant will lie supine and be rested for 5 minutes. Resting blood pressure will be
determined using manual auscultation and pulmonary arterial pressure by echocardiography.
Resting cardiac output will be evaluated using impedance cardiography (PhysioflowTM) and
oxygen saturation estimated with pulse oximetry. Ventilation will be measured from expired
gas analysis. Following these measurements, the subject will begin to breathe either placebo
or iNO. Upon completion of resting measurements, participants will complete 5-minutes of
sub-maximal exercise at 40 Watts in each experimental conditions. All resting measurements
will be repeated during exercise. At least 10-minute recover will be given between conditions
to ensure washout of NO and restoration of baseline oxygen saturation.
Intervention. Inhaled Nitric Oxide Intervention: Inhaled NO is a selective pulmonary vasodilator and has
been shown to improve blood flow to well-ventilated lung areas (i.e. improve V̇A/Q̇ matching)
in conditions with elevated vascular tone. Inhaled NO has been previously shown to lower
pulmonary artery pressure during exercise in individuals with severe lung disease, while not
affecting systemic blood pressure. It is important to note that a selective pulmonary
vasodilator will be used instead of an intravenously infused vasodilator (e.g. prostacyclin)
to avoid systemic vasodilation, severe arterial hypotension and syncope. Consistent with
previous work, a standard 40 ppm dose of inhaled NO will be administered using a
non-rebreathing circuit.
Statistical analysis and Interpretation: A 2-way repeated measures ANOVA will be used to
evaluate the changes in V̇E/V̇CO2, dyspnea and exercise capacity (V̇O2peak) with inhaled NO
during exercise. Type of intervention (room air vs.#46;inhaled NO), and time-point (baseline and
during exercise) will be used as fixed factors in the statistical analysis. Should inhaled NO
reduce V̇E/V̇CO2 and dyspnea, and improve exercise capacity in ILD, these results would
indicate that pulmonary vascular dysfunction contributes to exercise intolerance as well as
the potentiated ventilatory and dyspnea response to exercise in participants with ILD.
