Sildenafil improves hemodynamic parameters in COPD—an investigation of six patients
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 () (Fig. 1). The PVR has decreased from 373±118 to 219±61 by 42% (). 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.
References (28)
- et al.
Prospects for new drugs for chronic obstructive pulmonary disease
Lancet
(2004) Management of severe COPD
Lancet
(2004)- et al.
Significance of pulmonary artery pressure in emphysema patients with mild-to-moderate hypoxemia
Respir Med
(2003) - et al.
Pulmonary hemodynamics in advanced COPD candidates for lung volume reduction surgery or lung transplantation
Chest
(2005) - et al.
Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial
Lancet
(2002) - et al.
Hemodynamic response to sildenafil, nitric oxide, and iloprost in primary pulmonary hypertension
Chest
(2004) - et al.
Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. International COPD Study Group
Lancet
(1998) - et al.
Measuring functional status in chronic lung disease: conclusions from a randomized control trial
Respir Med
(1991) - et al.
Benefits of a multidisciplinary pulmonary rehabilitation program. Improvements are independent of lung function
Chest
(1991) - et al.
Prognostic value of pulmonary artery hypertension in chronic obstructive pulmonary disease
Thorax
(1981)
Pulmonary hypertension in chronic obstructive pulmonary disease
Eur Respir J
Polymorphism of the serotonin transporter gene and pulmonary hypertension in chronic obstructive pulmonary disease
Circulation
Patterns of cardiovascular dysfunction in chronic obstructive lung disease
N Engl J Med
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2012, Annales d'EndocrinologieCitation Excerpt :For example, Prostacyclin and Bosentan have been evaluated in placebo-controlled studies and a decrease in arterial oxygenation was reported [7,8]. In two studies, Sildenafil did improve exercise and hemodynamic tolerance but no assessment of gas exchange was performed [33–35] whereas, more recently, a worsening in arterial oxygenation was reported in a prospective study including 20 patients [9]. In conclusion, we hereby show, for the first time in humans, that a 3-month DHEA treatment of PH-COPD patients improves both their clinical and hemodynamics status with an excellent overall as well as respiratory tolerance.