Elsevier

The Lancet

Volume 360, Issue 9337, 21 September 2002, Pages 895-900
The Lancet

Articles
Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial

https://doi.org/10.1016/S0140-6736(02)11024-5Get rights and content

Summary

Background

Lung fibrosis can be complicated by pulmonary hypertension, limiting exercise tolerance and life expectancy. Furthermore, vasodilators might cause deterioration in gas exchange. Our aim was to compare acute effects of sildenafil, nitric oxide, and epoprostenol in individuals with pulmonary hypertension secondary to lung fibrosis.

Methods

We did a randomised controlled, open-label trial, in 16 individuals admitted to our hospital with pulmonary hypertension secondary to lung fibrosis. After inhalation of nitric oxide (10–20 ppm), we assigned patients to either maximum tolerated dose of intravenous epoprostenol (mean 8·0 ng/kg per min; n=8) or oral sildenafil (50 mg; n=8). Our primary objective was to assess pulmonary vasodilative potency (decrease in pulmonary vascular resistance index) of sildenafil by comparison with inhaled nitric oxide and infused epoprostenol. Analyses were by intention to treat.

Findings

Pulmonary vascular resistance index was reduced by nitric oxide (−21·9%, 95% Cl −14·1 to −36·2), epoprostenol (−36·9%, −24·4 to −59·6), and sildenafil (−32·5%, −10·2 to −54·1). However, ratio of pulmonary to systemic vascular resistance decreased only in individuals who received nitric oxide and sildenafil. Baseline measurement of multiple-inert-gas elimination showed right-to-left shunt flow (4·8%, 0·0−28·2) and little perfusion of low ventilation(V)/perfusion(Q) areas (0·1%, 0·0−13·0). Prostacyclin increased V/Q mismatch (shunt 16·8%, 10·8−35·9; low V/Q 3·8%, 0·0−13·0) and decreased arterial oxygenation. By contrast, nitric oxide (4·5%, 0·0−18·0; 0·0%, 0·0−17·3) and sildenafil (3·3%, 0·0−11·3; 0·0%, 0·0−12·4) maintained V/Q matching, with raised arterial partial pressure of oxygen (14·3 mm Hg, −1·7 to 31·3) noted for sildenafil. We recorded no adverse events.

Interpretation

Sildenafil causes preferential pulmonary vasodilation and improves gas exchange in patients with severe lung fibrosis and secondary pulmonary hypertension.

Introduction

Lung fibrosis is often associated with pulmonary hypertension, which can be a major cause of morbidity and mortality.1 In individuals with primary pulmonary hypertension, intravenous epoprostenol acts as a potent pulmonary vasodilator, which improves exercise tolerance and survival after long-term infusion.2 However, in the presence of interstitial lung disease, systemic administration of vasodilators can increase blood flow to poorly-ventilated or non-ventilated areas of the lung by interfering with the physiological hypoxic vasoconstrictor mechanism, thereby worsening pre-existent ventilation/perfusion mismatch and shunt flow.3, 4, 5 This effect causes a fall in concentration of arterial oxygen, reducing the small ventilatory reserve of these patients.

Inhalation of a vasorelaxant, to achieve selective pulmonary vasodilation and to redistribute blood flow to the well ventilated areas of the lung, can circumvent these problems, as shown with gaseous nitric oxide and aerosolised prostanoids in individuals with adult respiratory distress syndrome (ARDS).6, 7 Long-term inhalation of nitric oxide and daily aerosolisation with the long-acting epoprostenol analogue iloprost have been suggested as new treatments for primary pulmonary hypertension.8, 9, 10, 11 In secondary pulmonary hypertension associated with lung fibrosis, inhaled iloprost decreases pulmonary vascular resistance to the same degree as intravenous prostacyclin, but does not increase shunt flow, as noted during prostanoid infusion.5

Continuous inhalation strategies present practical difficulties, and an approach that combines easy oral administration with selective (preferential lung over systemic vasodilation) and supraselective (vasodilation in well ventilated, but not in non-ventilated, lung areas) pulmonary vasorelaxation is required. Our aim was to assess the efficacy of the phosphodiesterase type 5 inhibitor sildenafil, as a treatment for severely ill patients with lung fibrosis and pulmonary hypertension, whose gas exchange abnormalities are characterised by predominant shunt flow. We postulate that sildenafil does not act as a non-specific vasodilator, but amplifies local vasoregulatory mechanisms still maintained in the diseased lung.

Section snippets

Patients

We enrolled patients admitted to the medical clinic of University Hospital, Giessen, Germany, between December, 2000, and October, 2001. We included individuals with lung fibrosis, diagnosed according to the American Thoracic Society and European Respiratory Society guidelines,12 and severe pulmonary hypertension (mean pulmonary arterial pressure >35 mm Hg). We excluded patients with pulmonary venous hypertension—ie, pulmonary arterial wedge pressure >15 mm Hg—and underlying lung diseases other

Results

figure 1 shows the trial profile. We enrolled 16 patients (ten women, six men), whose underlying diseases were idiopathic pulmonary fibrosis (seven), CREST syndrome (three), systemic sclerosis (two), silicosis (two), and extrinsic allergic alveolitis (two).12

Table 1 shows baseline haemodynamic and gas exchange variables of patients. The median vital capacity of all patients was 55·0% and the median carbon monoxide diffusion capacity was 24·5%, both indicative of lung fibrosis. Of the 16

Discussion

Our findings indicate that sildenafil causes pulmonary vasodilation in patients with lung fibrosis and pulmonary hypertension, with the overall potency corresponding to that of intravenous epoprostenol. Furthermore, by contrast with infused epoprostenol, sildenafil showed selectivity for well ventilated areas of the lung, resulting in an improvement rather than a deterioration in gas exchange.

All participants had severe lung fibrosis, with a reduction of vital capacity and carbon monoxide

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