Pulmonary Hypertension Clinical Trial
Official title:
The Effect of Sildenafil on Diffusion Capacity Measurements in Patients With Pulmonary Hypertension and Parenchymal Lung Disease
The purpose of this study was to investigate the acute effects of sildenafil on diffusion
capacity, a commonly performed pulmonary function test, which is used to assess the lungs'
gas exchange capability.
This study does not assess safety or efficacy of the drug. The study does not have clinical
end points. The variables studied are diffusion capacity and 6 minute walk after a single
dose of sildenafil.
This study has been completed.
Sildenafil is a cyclic GMP selective phosphodiesterase type 5 inhibitor approved for use by
the FDA in patients with pulmonary arterial hypertension. There has been recent interest in
the use of the drug in patients with diffuse parenchymal lung diseases. This is largely
based on sildenafil's salutary effects observed in small studies (Collard et al.
897-99;Ghofrani et al. 895-900;Collard et al. 897-99) and the frequent coexistence of
pulmonary hypertension in these patients (Nathan et al. 657-63). In eight patients with
pulmonary fibrosis and pulmonary hypertension, sildenafil reduced pulmonary artery pressure
and improved shunt fraction as determined by multiple inert gas elimination technique
(Ghofrani et al. 895-900;Nathan et al. 657-63). Collard et al demonstrated a 49 meter
improvement in 6 minute walk distance in 11 patients with idiopathic pulmonary fibrosis and
pulmonary hypertension after 3 months of therapy with sildenafil.
Main theoretical concern with the use of pulmonary arterial vasodilator therapy has been
worsening of ventilation perfusion matching due to release of hypoxic vasoconstriction. Such
a phenomenon is well recognized during prostacyclin infusion(Ghofrani et al.
895-900;Walmrath et al. 1084-92). Inhaled route seems to circumvent this side effect by
preferentially delivering the drug to the alveoli with high V/Q ratios and augmenting blood
flow to these regions (Ghofrani et al. 895-900;Walmrath et al. 1084-92). In the only study
to address possible effect of systemically administered sildenafil on gas exchange, Ghofrani
et al observed improvement in V/Q matching in eight patients using the multiple inert gas
elimination technique (MIGET). The authors postulated an enhancement of local defense
mechanisms against hypoxia i.e. increased nitric oxide availability to hypoxic alveoli
despite oral route of administration(Ghofrani et al. 895-900). In a recent study of 14
normal subjects, oral sildenafil did not effect DLCO measurements at rest, after exercise
and under hypoxic conditions(Snyder et al. 421-30).
Diffusion capacity of the lung for carbon monoxide (DLCO) is the clinically available method
of assessing gas exchange for practitioners. It is frequently used as a tool for serial
monitoring of diffuse parenchymal lung disease. American Thoracic Society has endorsed its
use in the assessment of patients with idiopathic interstitial pneumonias(American Thoracic
Society/European Respiratory Society International Multidisciplinary Consensus
Classification of the Idiopathic Interstitial Pneumonias . This Joint Statement of the
American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by
the ATS Board of Directors, June 2001 and by The ERS Executive Committee, June 2001
277-304).
The aim of our study was to delineate the effects of orally administered sildenafil on
diffusion capacity (absolute value). The significance of this information was twofold.
First, it would be helpful clinically to determine the contribution of a pulmonary
vasodilator to the change in DLCO to separate this effect from a true clinical change.
Second, sildenafil's effect on gas exchange may lead to modifications in therapy such as
changes in oxygen flow delivered to patients.
This is not a study that measures clinical outcome or safety of sildenafil. A single dose
was administered and effect on diffusion capacity and 6 minute walk were assessed compared
to baseline. While we would caution clinicians for rare exceptions to these findings, we
believe our data exclude a significant confounding effect in interpretation of diffusion
capacity in patients with parenchymal lung disease who are treated for pulmonary
hypertension with oral sildenafil. Whether this conclusion holds true at higher doses of
sildenafil and in patients with vasodilator response may offer further venues for research.
We were asked to retrospectively register the study at the request of BMC Pulmonary Medicine
Journal Editorial Office prior to publication.
;
Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Diagnostic
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