Pulmonary Pharmacology & Therapeutics 19 (2006) 386–390 Sildenafil improves hemodynamic parameters in COPD—an S. Alp, M. Skrygan, W.E. Schmidt, A. Bastianà Department of Internal Medicine 1, St. Josef Hospital, University Hospital of the Ruhr-Universita¨t Bochum, Germany Received 13 July 2005; received in revised form 13 September 2005; accepted 26 September 2005 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. Wewanted to investigate the effect of sildenafil on hemodynamic parameters and the 6-min walk test (6 MWT) in six patients with severeCOPD and echocardiographically estimated PH. A 6 MWT was performed and hemodynamic parameters were measured by right heartcatheterization before and 1 and 12 h after injection of 50 mg sildenafil intravenously. A 3-months period of peroral sildenafil therapy50 mg twice daily followed and finally hemodynamic parameters and a 6 MWT were repeated. Intravenously applied sildenafil could bedemonstrated to reduce PAP and pulmonary vasculature resistance (PVR) significantly. And after 3 months of oral sildenafil, the meanPAP has decreased from 30.275.5 mmHg (range: 24–39 mmHg) to 24.674.2 mmHg (range: 20–30 mmHg) (p ¼ 0:01). The PVR hasdecreased from 4017108 dyn s cmÀ5 (range: 266–558 dyn s cmÀ5) to 264752 dyn s cmÀ5 (range: 204–333 dyn s cmÀ5) (po0:05). Physicalconditions improved: the 6-min walk distance increased from 351749 to 433752 m. In conclusion, in six patients suffering from severeCOPD we could demonstrate significantly improved hemodynamic parameters after 50 mg sildenafil intravenous application. And after 3months of oral sildenafil, walking distance in the 6 MWT increased significantly as well as hemodynamic parameters in the five patientswho had accepted a second right heart catheterization.
r 2005 Elsevier Ltd. All rights reserved.
Keywords: COPD; Pulmonary hypertension; Phosphodiesterase inhibitor; Sildenafil disease These patients PH is probably due to structuralchanges caused by hypoxemia. Additionally, the lesions of Chronic obstructive pulmonary disease (COPD) is at pulmonary endothelium by cigarette-smoke products have number 6 in a list of causes of mortality. Apart from also been postulated an important initial event in the smoking cessation and long-term oxygen therapy in some natural history of PH in COPD And the severity of PH special patients, no approach or agent affects the rate of in hypoxemic patients with COPD appears to be deter- decline in lung function and progression of the disease in mined by polymorphism in the 5-HTT gene .
PH in patients with COPD is almost never as severe as in Pulmonary hypertension (PH) is the single strongest patients suffering from idiopathic pulmonary arterial marker of survival in COPD much stronger than any lung hypertension with pulmonary arterial pressures (PAPs) function parameter According to the agreements of sometimes reaching systemic pressure . In stable severe the venice conference, PH in COPD belongs to group 3 COPD, mean PAP (mPAP) is between 20 and 35 mmHg in comprising of patients with PH in chronic respiratory 87% of the patients ; but during exercise or during anacute ecacerbation of the disease, mPAP increases remark-ably . The impact of the increased mPAP on the course of the disease is not fully understood, but the higher the Corresponding author. Augusta-Kranken-Anstalten, Bergstr. 26, PAP, the shorter the life expectancy The average 44791 Bochum, Germany. Tel.: +49 234 517 2017.
E-mail address: [email protected] (A. Bastian).
change of mPAP in COPD patients with PH was 1094-5539/$ - see front matter r 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.pupt.2005.09.006 S. Alp et al. / Pulmonary Pharmacology & Therapeutics 19 (2006) 386–390 0.5–0.6 mmHg/year and may even slow down by long-time Study design: After all measurements were performed, 50 mg of sildenafil was applied intravenously (first a bolus The phosphodiesterase 5 inhibitor sildenafil is able to of 12.5 mg followed by 37.5 mg after 20 min). Hemody- reduce pulmonary vasculature resistance (PVR) in different namic measurements were repeated after 1 and 12 h to forms of precapillary PH—systemic sclerosis HIV control effectiveness of the medication.
thromboembolic disease and idiopathic pulmon- For the following 3 months, each patient received sildenafil 50 mg po twice daily before a final right heart An effect of sildenafil on the PAP in COPD has not been catheterization and a 6 MWT was repeated. In one patient, this final investigations was performed 3 weeks earlierbecause he had to undergo abdominal surgery. In anotherpatient, the final investigation had to be postponed for 4 weeks because the patient suffered from a mild exacerba-tion of the COPD just 4 days before the scheduled The ethic committee of the Ruhr University of Bochum time point. One patient denied control right heart 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 (FEV1o50% of predicted), who were smokers or ex-smokers with a history of at least30 packyears, and an echocardiographically demonstrated tricuspid regurgitation with an estimated pulmonaryarterial systolic pressure 440 mmHg.
Tolerability: The intravenously applied sildenafil was Exclusion criteria: Patients taking aminophyllines, pa- tolerated very well. The patients did not even notice nasal congestion or flush side effects frequently complained Patients: Six patients were included; 4 men and 2 women; about after oral sildenafil. As a side effect, the systemic aged 45–64. All were cigarette smokers or ex-smokers with vascular resistance decreased slightly.
35–52 packyears. All had a long-term history of COPD Hemodynamic parameters (6 patients): One hour after with an FEV 1 of 16–48% of predicted and signs of PH in 50 mg of sildenafil was injected, the mPAP has decreased echocardiography. A change of medication was notallowed during the study period and the 4 weeks prior.
All patients received inhalative therapy: all took a long-acting parasympathicolytic and four patients took long-acting sympathomimetics, additionally. Three patients received oral steroids and two were on LTOT. Indisaccordance with the protocol, prednisolon medicationwas reduced in two patients from 10 to 5 mg. All patientswere well without signs of exacerbation of the COPD by the time of inclusion into the study and the 4 weeks prior.
Measurements: 6-min walk test (6 MWT): The 6 MWT was carried out 2 times with a break of at least 1 h on a27 m even floor with vocal support from the investigator according to the ATS guidelines The distance achievedon the second walk was taken.
Right heart catheterization: The right heart catheteriza- tion was performed in an intensive care unit. The PA mean PAP (mPAP) [mmHg]
catheter (Baxter) was inserted and the patient was leftalone or with a relative for 60 min to relax from the stressof the insertion of the catheter. Central venous pressure (CVP), right ventricular pressure, PAP, and pulmonarywedge pressure (Pw) were measured. Cardiac output (CO)was detected by thermodilution. Blood pressure was taken meanÀPw)/CO] Â 80 (dyn s cmÀ5) as well as systemic vasculature resistance: SVR ¼ [(RRmeanÀCVP)/CO] Â 80 Fig. 1. The mPAPs (mean pulmonary arterial pressures) were detected in six patients with severe COPD. mPAP decreased from 29.575.2 to Statistics: To measure significance of changes, we used 22.374.5 mmHg 1 h after 50 mg of sildenafil was injected (po0:001); after the Student’s T-test for paired data.
12 h, the mPAP was 23.675.6 mmHg (po0:005).
S. Alp et al. / Pulmonary Pharmacology & Therapeutics 19 (2006) 386–390 from 29.575.2 to 22.374.5 mmHg (po0:001) The PVR has decreased from 3737118 to 219761 by 42%(po0:05). The SVR was down by 20%.
Twelve hours after 50 mg of sildenafil was injected, the mPAPs has decreased from the initial 29.575.2 to23.675.6 mmHg (po0:005) The PVR hasdecreased from 3737118 to 266767 by 30% (p ¼ 0:05).
The SVR was unchanged (À2%).
Tolerability: Sildenafil p.o. was tolerated very well.
Hemodynamic parameters (5 patients): The mPAP was PVR [dyn·s·cm
30.275.5 mmHg (range: 24–39 mmHg) before sildenafil and was 24.674.2 mmHg (range: 20–30 mmHg) at the endof the 3-months therapy (p ¼ 0:01) ( The PVR decreased from 4017108 dyn s cmÀ5 (range: 266–558 dyn s cmÀ5) before the medication had started to264752 dyn s cmÀ5 (range: 204–333 dyn s cmÀ5) at the endof the study period (po0:05) The PVR hasdecreased by 35%. The SVR was unchanged.
Six-minute walk test (6 patients): The distance of the 6 MWT increased from 351749 m (range: 270–405 m) to Fig. 3. In five patients with severe COPD who accepted a second right 433752 m (range: 386–525 m) after the therapy (po0:05) heart catheterization after 3 months of oral sildenafil, the pulmonary vasculature resistance (PVR) has decreased from 4017108 dyn s cmÀ5(range: 266–558 dyn s cmÀ5) before the medication to 264752 dyn s cmÀ5(range: 204–333 dyn s cmÀ5) at the end of the 3-months study period(po0:05).
mPAP [mmHg]
6-minutes-walk distance [m]
Fig. 2. At the end of the 3-months peroral sildenafil therapy, the mPAP Fig. 4. In all six patients, the distance of the 6-min walk test increased. It (mean pulmonary arterial pressure) has decreased from 30.275.5 mmHg improved from 351749 m (range: 270–405 m) before the start of sildenafil medication to 433752 m (range: 386–525 m) at the end of the 3-months S. Alp et al. / Pulmonary Pharmacology & Therapeutics 19 (2006) 386–390 controlled study to prove sildenafil therapy on qualityof life parameters as well as survival in COPD patients There is not much experience with intravenously applied sildenafil. It has been successfully used in a catheterlaboratory in children with congenital heart disease .
We injected sildenafil in two fractions: after the first12.5 mg bolus a second bolus of 37.5 mg was applied 20 min Sildenafil was supplied by Pfizer, Sandwich, UK.
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