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

Hossein A. Ghofrani, MD; Frank Reichenberger, MD; Markus G. Kohstall, MD; Eike H. Mrosek, MD; Timon Seeger, MD; Horst Olschewski, MD; Werner Seeger, MD; and Friedrich Grimminger, PhD, MD
[+] Article and Author Information

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.

Potential Financial Conflicts of Interest: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.).

Requests for Single Reprints: Friedrich Grimminger, PhD, MD, Department of Internal Medicine, Klinikstrasse 36, 35392 Giessen, Germany; e-mail, ardeschir.ghofrani@innere.med.uni-giessen.de.

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.


Ann Intern Med. 2004;141(3):169-177. doi:10.7326/0003-4819-141-3-200408030-00005
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Hypoxic pulmonary vasoconstriction is a fundamental physiologic mechanism, optimizing perfusion–ventilation matching in periods of regional hypoventilation of the lung (19). However, during global alveolar hypoxia, whether due to lung disease or environmental conditions such as high altitude, this mechanism results in pulmonary hypertension and enhanced right-heart load. These effects were consistently reproduced in the healthy volunteers in our study, who developed substantial pulmonary hypertension both under experimental hypoxia at sea level and at high altitude in the Mount Everest base camp. Moreover, a marked further increase in pulmonary hypertension was noted during hypoxic exercise in participants taking placebo; median systolic pulmonary artery pressure was 42.9 mm Hg at low altitude and 33.6 mm Hg at high altitude. Of note, this pulmonary hypertensive response was observed in persons not previously characterized as sensitive to pulmonary edema at high altitudes. This finding is consistent with the notion that exercise enhances even moderate forms of pulmonary hypertension (20). The Doppler echocardiographic technique used to assess systolic pulmonary artery pressure in our study has been extensively evaluated in different types of pulmonary hypertension and is closely correlated with right-heart catheterization in healthy participants (2123).

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Figures

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Figure 1.
Flow of participants through the study.
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Figure 2.
Experimental setting at Mount Everest base camp.

The high-altitude laboratory was equipped with 2 sets of devices for performing exercise testing and assessing pulmonary hemodynamics. The Khumbu Glacier and Mount Nuptse are in the background. A volunteer is seated on the cycle ergometer, and the investigator is performing echocardiography. The device for noninvasive measurement of cardiac output is on the left.

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Figure 3.
Impact of sildenafil on exercise capacity during hypoxic challenge at low and high altitudes.

Maximum exercise levels were assessed at low altitude in Giessen and at the base camp on Mount Everest. At Giessen, participants underwent exercise testing under normoxic conditions at baseline and during hypoxic challenge after receiving placebo or sildenafil in a crossover design on day 1 and day 2. Each group (placebo first and sildenafil first) included 7 participants. Exercise testing was also performed on day 1 and day 2 at the base camp. The placebo-first group had 7 participants, and the sildenafil-first group had 6 participants. Data points represent medians; error bars represent 95% CIs.

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Comments

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An ethical issue?
Posted on August 24, 2004
Buddha Basnyat
Himalayan Rescue Association
Conflict of Interest: None Declared

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

Sildenafil has no clinical benefit of increasing exercise capacity at Mount Everest Base Camp
Posted on August 26, 2004
Anil Pandit
Patan Hospital, GPO 252, Kathmandu, Nepal
Conflict of Interest: None Declared

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

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Summary for Patients

Sildenafil Increases Exercise Capacity in Low-Oxygen Settings

The summary below is from the full report titled “Sildenafil Increased Exercise Capacity during Hypoxia at Low Altitudes and at Mount Everest Base Camp. A Randomized, Double-Blind, Placebo-Controlled Crossover Trial.” It is in the 3 August 2004 issue of Annals of Internal Medicine (volume 141, pages 169-177). The authors are H.A. Ghofrani, F. Reichenberger, M.G. Kohstall, E.H. Mrosek, T. Seeger, H. Olschewski, W. Seeger, and F. Grimminger.

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