Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic interstitial lung disease
characterized by bi-basilar sub-pleural honeycombing, septal thickening, and traction
bronchiectasis. Patients with IPF, even in mild cases, have a reduced exercise capacity which
is strongly associated with exertional breathlessness (dyspnea). Our previous work in IPF has
shown that dyspnea during exercise is associated with increased inspiratory neural drive
(IND) compared with healthy controls. High IND, in turn, is related to a combination of 1)
reduced ventilatory efficiency (i.e. increased ventilation relative to carbon dioxide
production (V̇E/V̇CO2)); 2) abnormal dynamic breathing mechanics (blunted tidal volume (VT)
and critically low inspiratory reserve volume (IRV)), especially in more advanced disease,
and; 3) impaired pulmonary gas-exchange (i.e. diffusion limitation and arterial hypoxemia).
Preliminary work from our laboratory in patients with IPF but only mild restriction (total
lung capacity (TLC) >70% predicted) demonstrated elevated IND and dyspnea during exercise,
when compared to healthy age- and sex-matched controls. The increased IND appeared to be
largely the result of the excess ventilation (high V̇E/V̇CO2), as dynamic respiratory
mechanics (VT and operating lung volumes) during exercise were similar to healthy controls,
when accounting for ventilation. Importantly, these patients showed only minor decreases in
arterial O2 saturation. These data suggest that patients with mild forms of IPF have
significant exertional dyspnea, secondary to reduced ventilatory efficiency (high V̇E/V̇CO2),
although the exact mechanisms of elevated V̇E/V̇CO2 in mild IPF remains unclear.
Increased chemosensitivity has been linked to elevated V̇E/V̇CO2 in cardiopulmonary diseases.
It is reasonable to postulate that persistent V̇A/Q̇ mismatch with elevated total
physiological dead space and possible sympathetic over-excitation may alter central medullary
chemoreceptor characteristics in patients with IPF, at least partially explaining elevated
exercise V̇E/V̇CO2. Pulmonary microvascular abnormalities may also be a key contributor to
the increased dead space and V̇E/V̇CO2 during exercise in IPF. Patients with IPF and mild
mechanical restriction have relatively preserved gas transfer between the alveoli and
capillaries, even in fibrotic lung regions with interstitial thickening. This suggests that
regional capillary hypoperfusion in IPF with mild restriction, despite a relatively preserved
alveolar-capillary interface, may lead to V̇A/Q̇ mismatch (specifically an increased
proportion of high V̇A/Q̇ lung units), which would increase total physiologic dead space and
V̇E/V̇CO2. The relative contribution of increased chemosensitivity and/or pulmonary
microvascular abnormalities to elevated exercise V̇E/V̇CO2 in patients mild IPF has not been
determined and are the primary focus of this study.
Treatment options for dyspnea management in IPF are limited. Recent work from the INSTAGE
trial showed that a combination of nintedanib (anti-fibrotic) and sildenafil (pulmonary
vasodilator) showed minimal improvement in dyspnea. However, improvements in physical
activity and gas-exchange in patients with IPF following 8-week treatment of inhaled nitric
oxide (iNO), a selective pulmonary vasodilator have been demonstrated in other, more recent
studies. Since patients with mild forms of IPF are thought to have a relatively intact
capillary bed but a relatively high physiological dead space due to attenuation of regional
pulmonary perfusion, inhaled selective vasodilation may be more beneficial than in advanced
disease with fixed microvascular destruction. This is supported by recent work demonstrating
a reduced V̇E/V̇CO2 (reflecting a decrease in physiological dead space) and dyspnea during
exercise in patients with mild chronic obstructive pulmonary disease with minimal or no
emphysema. Importantly, arterial O2 saturation was normal throughout exercise and unaffected
by iNO, which suggests no deleterious effects of iNO on overall gas-exchange. The reduction
in V̇E/V̇CO2 during exercise with iNO suggests that iNO increases pulmonary microvascular
perfusion heterogeneity, leading to improved V̇A/Q̇ matching, reduced dead space and
therefore a lower ventilation for a given metabolic demand.
As an exploratory outcome, we will determine whether iNO improves V̇A/Q̇ and reduces dead
space and attendant dyspnea, in patients with IPF and mild mechanical restriction. Moreover,
this would clearly establish if partially reversible vascular dysfunction contributes to
V̇A/Q̇ mismatch, elevated V̇E/V̇CO2, inspiratory neural drive and dyspnea exists in
non-hypoxemic patients with IPF and minimal mechanical abnormalities.
Rationale: It has been well established that patients with advanced IPF have mechanical and
pulmonary gas exchange abnormalities which require compensatory increases in inspiratory
neural drive and an exaggerated ventilatory response to exercise with consequent increase in
activity-related dyspnea. However, very little work has been done to understand mechanisms of
exertional dyspnea in patients IPF in whom restrictive mechanics and hypoxemia are not
prominent. The proposed work has the potential to not only provide important physiological
insight into the underlying mechanisms for increased V̇E/V̇CO2 and inspiratory neural drive,
but also to examine therapeutic avenues to improve ventilatory efficiency, dyspnea, exercise
capacity and ultimately quality of life in patients with IPF.