ArticlesSildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial
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
References (26)
New treatments for pulmonary fibrosis?
Lancet
(1999)- et al.
Aerosolised prostacyclin in adult respiratory distress syndrome
Lancet
(1993) - et al.
Pulsed delivery of inhaled nitric oxide to patients with primary pulmonary hypertension: an ambulatory delivery system and initial clinical tests
Chest
(1996) - et al.
A comparison of the acute hemodynamic effects of inhaled nitric oxide and aerosolized iloprost in primary pulmonary hypertension
J Am Coll Cardiol
(2000) - et al.
Atrial natriuretic peptide in severe primary and nonprimary pulmonary hypertension: response to iloprost inhalation
J Am Coll Cardiol
(2001) - et al.
Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model
Am J Respir Crit Care Med
(2001) - et al.
A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension
N Engl J Med
(1996) - et al.
Effect of pulmonary hypertension on gas exchange
Eur Respir J
(1993) - et al.
Inhaled prostacyclin and iloprost in severe pulmonary hypertension secondary to lung fibrosis
Am J Respir Crit Care Med
(1999) - et al.
Inhaled nitric oxide for the adult respiratory distress syndrome
N Engl J Med
(1993)
Aerosolized prostacyclin and iloprost in severe pulmonary hypertension
Ann Intern Med
Inhaled iloprost to treat severe pulmonary hypertension: an uncontrolled trial
Ann Intern Med
Long-term treatment of primary pulmonary hypertension with aerosolized iloprost, a prostacyclin analogue
N Engl J Med
Cited by (677)
Comprehensive review of potential drugs with anti-pulmonary fibrosis properties
2024, Biomedicine and PharmacotherapySildenafil in endotoxin-induced pulmonary hypertension: an experimental study
2023, Brazilian Journal of Anesthesiology (English Edition)French practical guidelines for the diagnosis and management of idiopathic pulmonary fibrosis – 2021 update. Full-length version
2023, Respiratory Medicine and ResearchFrench practical guidelines for the diagnosis and management of IPF – 2021 update, full version
2022, Revue des Maladies RespiratoiresUse of sildenafil in patients with severe COVID-19 pneumonitis
2022, British Journal of Anaesthesia