Sildenafil improves hemodynamic parameters in COPD—an investigation of six patients

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Abstract

Pulmonary hypertension (PH) is an important predictor of mortality in chronic obstructive pulmonary disease (COPD). The phosphodiesterase 5 inhibitor sildenafil has been demonstrated to reduce pulmonary arterial pressure (PAP) in different diseases. We wanted to investigate the effect of sildenafil on hemodynamic parameters and the 6-min walk test (6 MWT) in six patients with severe COPD and echocardiographically estimated PH. A 6 MWT was performed and hemodynamic parameters were measured by right heart catheterization before and 1 and 12 h after injection of 50 mg sildenafil intravenously. A 3-months period of peroral sildenafil therapy 50 mg twice daily followed and finally hemodynamic parameters and a 6 MWT were repeated. Intravenously applied sildenafil could be demonstrated to reduce PAP and pulmonary vasculature resistance (PVR) significantly. And after 3 months of oral sildenafil, the mean PAP has decreased from 30.2±5.5 mmHg (range: 24–39 mmHg) to 24.6±4.2 mmHg (range: 20–30 mmHg) (p=0.01). The PVR has decreased from 401±108 dyn s cm−5 (range: 266–558 dyn s cm−5) to 264±52 dyn s cm−5 (range: 204–333 dyn s cm−5) (p<0.05). Physical conditions improved: the 6-min walk distance increased from 351±49 to 433±52 m. In conclusion, in six patients suffering from severe COPD we could demonstrate significantly improved hemodynamic parameters after 50 mg sildenafil intravenous application. And after 3 months of oral sildenafil, walking distance in the 6 MWT increased significantly as well as hemodynamic parameters in the five patients who had accepted a second right heart catheterization.

Introduction

Chronic obstructive pulmonary disease (COPD) is at number 6 in a list of causes of mortality. Apart from smoking cessation and long-term oxygen therapy in some special patients, no approach or agent affects the rate of decline in lung function and progression of the disease in the long time course [1], [2].

Pulmonary hypertension (PH) is the single strongest marker of survival in COPD much stronger than any lung function parameter [3], [4]. According to the agreements of the venice conference, PH in COPD belongs to group 3 comprising of patients with PH in chronic respiratory disease [5]. These patients PH is probably due to structural changes caused by hypoxemia. Additionally, the lesions of pulmonary endothelium by cigarette-smoke products have also been postulated an important initial event in the natural history of PH in COPD [6]. And the severity of PH in hypoxemic patients with COPD appears to be determined by polymorphism in the 5-HTT gene [7].

PH in patients with COPD is almost never as severe as in patients suffering from idiopathic pulmonary arterial hypertension with pulmonary arterial pressures (PAPs) sometimes reaching systemic pressure [8], [9]. In stable severe COPD, mean PAP (mPAP) is between 20 and 35 mmHg in 87% of the patients [10]; but during exercise or during an acute ecacerbation of the disease, mPAP increases remarkably [11]. The impact of the increased mPAP on the course of the disease is not fully understood, but the higher the PAP, the shorter the life expectancy [6]. The average change of mPAP in COPD patients with PH was 0.5–0.6 mmHg/year and may even slow down by long-time oxygen therapy (LTOT) [12].

The phosphodiesterase 5 inhibitor sildenafil is able to reduce pulmonary vasculature resistance (PVR) in different forms of precapillary PH—systemic sclerosis [13], [14], HIV [15], thromboembolic disease [16] and idiopathic pulmonary arterial hypertension [17], [18].

An effect of sildenafil on the PAP in COPD has not been published, yet.

Section snippets

Methods

The ethic committee of the Ruhr University of Bochum approved the protocol and all patients signed informed consent before participating in the study.

Inclusion criteria: Men and women, age 40–80 years suffering from severe COPD (FEV1<50% of predicted), who were smokers or ex-smokers with a history of at least 30 packyears, and an echocardiographically demonstrated tricuspid regurgitation with an estimated pulmonary arterial systolic pressure >40 mmHg.

Exclusion criteria: Patients taking

Sildenafil i.v.

Tolerability: The intravenously applied sildenafil was tolerated very well. The patients did not even notice nasal congestion or flush side effects frequently complained about after oral sildenafil. As a side effect, the systemic vascular resistance decreased slightly.

Hemodynamic parameters (6 patients): One hour after 50 mg of sildenafil was injected, the mPAP has decreased from 29.5±5.2 to 22.3±4.5 mmHg (p<0.001) (Fig. 1). The PVR has decreased from 373±118 to 219±61 by 42% (p<0.05). The SVR

Discussion

There is not much experience with intravenously applied sildenafil. It has been successfully used in a catheter laboratory in children with congenital heart disease [20]. We injected sildenafil in two fractions: after the first 12.5 mg bolus a second bolus of 37.5 mg was applied 20 min later. None of the six study patients suffering from severe COPD with PH noticed any side effect. They did not even notice nasal congestion or flush side effects frequently complained about after oral sildenafil.

Acknowledgment

Sildenafil was supplied by Pfizer, Sandwich, UK.

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