Articles
3 August 2004

Sildenafil Increased Exercise Capacity during Hypoxia at Low Altitudes and at Mount Everest Base Camp: A Randomized, Double-Blind, Placebo-Controlled Crossover Trial

Publication: Annals of Internal Medicine
Volume 141, Number 3

Abstract

Background:

Alveolar hypoxia causes pulmonary hypertension and enhanced right ventricular afterload, which may impair exercise tolerance. The phosphodiesterase-5 inhibitor sildenafil has been reported to cause pulmonary vasodilatation.

Objective:

To investigate the effects of sildenafil on exercise capacity under conditions of hypoxic pulmonary hypertension.

Design:

Randomized, double-blind, placebo-controlled crossover study.

Setting:

University Hospital Giessen, Giessen, Germany, and the base camp on Mount Everest.

Participants:

14 healthy mountaineers and trekkers.

Measurements:

Systolic pulmonary artery pressure, cardiac output, and peripheral arterial oxygen saturation at rest and during assessment of maximum exercise capacity on cycle ergometry 1) while breathing a hypoxic gas mixture with 10% fraction of inspired oxygen at low altitude (Giessen) and 2) at high altitude (the Mount Everest base camp).

Intervention:

Oral sildenafil, 50 mg, or placebo.

Results:

At low altitude, acute hypoxia reduced arterial oxygen saturation to 72.0% (95% CI, 66.5% to 77.5%) at rest and 60.8% (CI, 56.0% to 64.5%) at maximum exercise capacity. Systolic pulmonary artery pressure increased from 30.5 mm Hg (CI, 26.0 to 35.0 mm Hg) at rest to 42.9 mm Hg (CI, 35.6 to 53.5 mm Hg) during exercise in participants taking placebo. Sildenafil, 50 mg, significantly increased arterial oxygen saturation during exercise (P = 0.005) and reduced systolic pulmonary artery pressure at rest (P < 0.001) and during exercise (P = 0.031). Of note, sildenafil increased maximum workload (172.5 W [CI, 147.5 to 200.0 W]) vs. 130.6 W [CI, 108.8 to 150.0 W]); P < 0.001) and maximum cardiac output (P < 0.001) compared with placebo. At high altitude, sildenafil had no effect on arterial oxygen saturation at rest and during exercise compared with placebo. However, sildenafil reduced systolic pulmonary artery pressure at rest (P = 0.003) and during exercise (P = 0.021) and increased maximum workload (P = 0.002) and cardiac output (P = 0.015). At high altitude, sildenafil exacerbated existing headache in 2 participants.

Limitations:

The study did not examine the effects of sildenafil on normoxic exercise tolerance.

Conclusions:

Sildenafil reduces hypoxic pulmonary hypertension at rest and during exercise while maintaining gas exchange and systemic blood pressure. To the authors' knowledge, sildenafil is the first drug shown to increase exercise capacity during severe hypoxia both at sea level and at high altitude.

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Buddha Basnyat 24 August 2004
An ethical issue?

The recent study by Ghofrani et al published in the Annals was indeed a technical and logistic tour de force. However if they did obtain permission from the Nepal Health Research Council ( NHRC), they did not think it important enough to mention this in the text of their article.

Clearly involving the NHRC would have meant more paper work, but this step would have enabled some young Nepali researher ( as the NHRC rule mandates this) to be involved with the fascinating set of experiments performed by the authors of the study in the Mount Everest region of Nepal.

If the authors had done this,this study would also have been a moral tour de force. Interestingly I reckon it would be impossible for a Nepali team to arrive with ethical clearance from Nepal and carry out studies of this nature in Germany.

Conflict of Interest:

None declared

Anil Pandit 26 August 2004
Sildenafil has no clinical benefit of increasing exercise capacity at Mount Everest Base Camp

The study has beyond doubt proved that seldenafil enhanced exercise capacity at low altitude when person is exposed to acute normobaric hypoxia. To say, sildenafil also increased exercise capacity during hypobaric hypoxia at Mount Everest Base Camp is over exaggeration. Increased in exercise capacity in placebo vs sildenafil group in the Base camp is statistically but not clinically significant (12%)[1}.

Headache is a common and deemed cardinal symptom of acute mountain sickness. It's good to know that with long term sildenafil intake up to 150 mg per day has no incidence of headache. But, trekkers and mountaineers who go to high altitude is basically for recreational purpose and their stay is short-term. So, it wouldn't be wrong to say sildenafil has potential of masking effect on symptoms of acute mountain sickness making sildenafil dangerous choice for mountaineers and hikers willing to take sildenafil as performance-enhancing drug. As early recognition and immediate descent is key to management of acute mountain sickness.

1. Ghofrani HA, Reichenberger F, Kohstall MG, Mrosek EH, Seeger T, Olschewski H, et al. Sildenafil increased exercise capacity during hypoxia at low altitudes and at Mount Everest base camp. A randomized, double- blind, placebo-controlled crossover trial. Ann Intern Med. 2004;141:169-77

Conflict of Interest:

None declared

Information & Authors

Information

Published In

cover image Annals of Internal Medicine
Annals of Internal Medicine
Volume 141Number 33 August 2004
Pages: 169 - 177

History

Published online: 3 August 2004
Published in issue: 3 August 2004

Keywords

Authors

Affiliations

Hossein A. Ghofrani, MD
From University Hospital Giessen and Justus-Liebig University, Giessen, Germany.
Frank Reichenberger, MD
From University Hospital Giessen and Justus-Liebig University, Giessen, Germany.
Markus G. Kohstall, MD
From University Hospital Giessen and Justus-Liebig University, Giessen, Germany.
Eike H. Mrosek, MD
From University Hospital Giessen and Justus-Liebig University, Giessen, Germany.
Timon Seeger, MD
From University Hospital Giessen and Justus-Liebig University, Giessen, Germany.
Horst Olschewski, MD
From University Hospital Giessen and Justus-Liebig University, Giessen, Germany.
Werner Seeger, MD
From University Hospital Giessen and Justus-Liebig University, Giessen, Germany.
Friedrich Grimminger, PhD, MD
From University Hospital Giessen and Justus-Liebig University, Giessen, Germany.
Acknowledgments: The authors thank the numerous porters and Sherpas who made this study possible, in particular Sherpa Pemba, who organized the logistics of the ascent. They also thank Peter Becker, MD, for his tireless medical support during the expedition and Siemens Medical Solutions USA, Inc., for providing 2 portable echocardiography devices. Finally, they thank Michael Yeager for editing the manuscript.
Grant Support: By the German Research Foundation (Sonderforschungsbereich 547) and in part by an unrestricted independent research grant from Pfizer GmbH, Karlsruhe, Germany.
Disclosures: Grants received: H.A. Ghofrani (Pfizer Ltd., ALTANA Pharma AG, Schering AG), W. Seeger (Schering AG, Pfizer Ltd., ALTANA Pharma AG, Lung Rx, Myogen), F. Grimminger (ALTANA Pharma AG, Bayer AG, Pfizer Ltd.); Grants pending: H.A. Ghofrani (Eli Lilly and Co.), F. Grimminger (Eli Lilly and Co.).
Corresponding Author: Friedrich Grimminger, PhD, MD, Department of Internal Medicine, Klinikstrasse 36, 35392 Giessen, Germany; e-mail, [email protected].
Current Author Addresses: Drs. Ghofrani, Reichenberger, Kohstall, Mrosek, T. Seeger, Olschewski, W. Seeger, and Grimminger: Department of Internal Medicine, Klinikstrasse 36, 35392 Giessen, Germany.
Author Contributions: Conception and design: H.A. Ghofrani, F. Reichenberger, M.G. Kohstall, E.H. Mrosek, W. Seeger, F. Grimminger.
Analysis and interpretation of the data: H.A. Ghofrani, F. Reichenberger, M.G. Kohstall, E.H. Mrosek, T. Seeger, H. Olschewski, W. Seeger, F. Grimminger.
Drafting of the article: H.A. Ghofrani, H. Olschewski, W. Seeger, F. Grimminger.
Critical revision of the article for important intellectual content: H.A. Ghofrani, F. Reichenberger, M.G. Kohstall, E.H. Mrosek, T. Seeger, H. Olschewski, W. Seeger, F. Grimminger.
Final approval of the article: H.A. Ghofrani, M.G. Kohstall, E.H. Mrosek, T. Seeger, H. Olschewski, W. Seeger, F. Grimminger.
Provision of study materials or patients: H.A. Ghofrani, E.H. Mrosek, W. Seeger, F. Grimminger.
Statistical expertise: H.A. Ghofrani, H. Olschewski, W. Seeger, F. Grimminger.
Obtaining of funding: H.A. Ghofrani, W. Seeger, F. Grimminger.
Administrative, technical, or logistic support: H.A. Ghofrani, F. Reichenberger, E.H. Mrosek, H. Olschewski, W. Seeger, F. Grimminger.
Collection and assembly of data: H.A. Ghofrani, F. Reichenberger, M.G. Kohstall, E.H. Mrosek, T. Seeger, W. Seeger, F. Grimminger.

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Hossein A. Ghofrani, Frank Reichenberger, Markus G. Kohstall, et al. Sildenafil Increased Exercise Capacity during Hypoxia at Low Altitudes and at Mount Everest Base Camp: A Randomized, Double-Blind, Placebo-Controlled Crossover Trial. Ann Intern Med.2004;141:169-177. [Epub 3 August 2004]. doi:10.7326/0003-4819-141-3-200408030-00005

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