Effects of inhaled nitric oxide at rest and during exercise in idiopathic pulmonary fibrosis

Abstract

Patients with idiopathic pulmonary fibrosis (IPF) usually develop hypoxemia and pulmonary hypertension when exercising. To what extent endothelium-derived vasodilating agents modify these changes is unknown. The study was aimed to investigate in patients with IPF whether exercise induces changes in plasma levels of endothelium-derived signaling mediators, and to assess the acute effects of inhaled nitric oxide (NO) on pulmonary hemodynamics and gas exchange, at rest and during exercise. We evaluated seven patients with IPF (6 men/1 woman; 57 ± 11 yr; forced vital capacity, 60 ± 13% predicted; carbon monoxide diffusing capacity, 52 ± 10% predicted). Levels of endothelin, 6-keto-prostaglandin-F1α, thromboxane B2, and nitrates were measured at rest and during submaximal exercise. Pulmonary hemodynamics and gas exchange, including ventilation-perfusion relationships, were assessed breathing ambient air and 40 ppm NO, both at rest and during submaximal exercise. The concentration of thromboxane B2 increased during exercise ( P = 0.046), whereas levels of other mediators did not change. The change in 6-keto-prostaglandin-F1α correlated with that of mean pulmonary arterial pressure ( r = 0.94; P < 0.005). Inhaled NO reduced mean pulmonary arterial pressure at rest (−4.6 ± 2.1 mmHg) and during exercise (−11.7 ± 7.1 mmHg) ( P = 0.001 and P = 0.004, respectively), without altering arterial oxygenation or ventilation-perfusion distributions in any of the study conditions. Alveolar-to-capillary oxygen diffusion limitation, which accounted for the decrease of arterial Po2 during exercise, was not modified by NO administration. We conclude that, in IPF, some endothelium-derived signaling molecules may modulate the development of pulmonary hypertension during exercise, and that the administration of inhaled NO reduces pulmonary vascular resistance without disturbing gas exchange.

Physiology of the lung in idiopathic pulmonary fibrosis

“…At exercise, V′/Q′ and shunt accounted for 60% of PA-aO 2 and diffusion limitation for 40% [62]. These data are consistent with a more recent MIGET study [76]. It is not known whether exaggerated decreases in central venous oxygen tension contribute to hypoxaemia in IPF at rest.…”

“…Increases in mPAP are observed in IPF patients during exercise at 60% of the maximal workload, while PVR does not decrease as observed in normal subjects [62]. In favour of the early onset of vascular damage in IPF, mPAP increased from 20 mmHg to 40 mmHg in seven patients with mild-to-moderate IPF [76]. The increase in oxygen diffusion impairment at exercise, documented by MIGET, is consistent with decrease of the alveolar-capillary contact time subsequent to the increase in cardiac output, most probably indicating reduced recruitment of the lung vasculature in IPF [62].…”

“…It is unclear whether these associations reflect a causative relationship between the alteration of pulmonary haemodynamics and exertional limitation in IPF patients without severe PH. In seven patients with IPF (mean FVC 60% pred, DLCO 52% pred), two of whom had mPAP slightly over 25 mmHg at rest, the inhalation of nitric oxide during submaximal exercise reduced the increase in mPAP and reduced PVR, but did not increase cardiac output or PaO 2 and did not reduce VD/VT [76]. However, a 12-week course of oral sildenafil, which potentiates the effect of endogenous nitric oxide, yielded clinically significant benefits in terms of dyspnoea and quality of life in patients with advanced IPF [126].…”

“…A right ventricle to left ventricle diameter ratio >1 is associated with a 5.4 increase in the HR for mortality in IPF [90], while moderate-to-severe right ventricle dysfunction, identified by tricuspid annular plane systolic excursion <1.6 cm, is associated with a 7.5 increase, suggesting that echocardiography may indeed have a role for the identification of IPF patients with clinically significant pulmonary vascular impairment [90]. HRCT measurements of the diameter of the pulmonary artery do not accurately indicate PH in IPF, possibly due to the confounding effect of reduced pleural pressure causing the dilation of cavitary intrathoracic organs [76]. Noninvasive measurements of pulmonary blood flow using rebreathing of sulfur hexafluoride may be an interesting tool for the exploration of haemodynamic limitation in IPF [77].…”

Pulmonary vascular and cardiac impairment in interstitial lung disease

“…Conventional vasodilators such as calcium channel blockers are not recommended because of their interference with hypoxic vasoconstriction, which diverts pulmonary blood flow from more seriously to less seriously affected lung segments and lack of efficacy after long-term use [2]. Sufficient evidence is lacking on the long-term use of vasodilators such as inhaled prostanoids or nitric oxide that may preferentially access the better ventilated/oxygenated areas of the fibrotic lung due to their advantageous mode of distribution [70,71]. However, a 16-week monotherapy trial with inhaled iloprost was associated with improvement in baseline PVR, mPAP and activity in some patients with sarcoidosis-associated pulmonary hypertension [72].…”