Sildenafil Increased Exercise Capacity during Hypoxia at Low Altitudes and at Mount Everest Base Camp

A Randomized, Double-Blind, Placebo-Controlled Crossover Trial

  1. Hossein A. Ghofrani, MD;
  2. Frank Reichenberger, MD;
  3. Markus G. Kohstall, MD;
  4. Eike H. Mrosek, MD;
  5. Timon Seeger, MD;
  6. Horst Olschewski, MD;
  7. Werner Seeger, MD; and
  8. Friedrich Grimminger, PhD, MD
  1. From University Hospital Giessen and Justus-Liebig University, Giessen, Germany.

    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.

    Article and Author Information

    • 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{at}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.

    Responses to this article

    • Sildenafil has no clinical benefit of increasing exercise capacity at Mount Everest Base Camp
      • Anil Pandit
      Ann Intern Med published online October 26, 2009
    • An ethical issue?
      • Buddha Basnyat and
      • Kathmandu, Nepal
      Ann Intern Med published online October 26, 2009

    Summary for Patients

    • Summaries for Patients:Sildenafil Increases Exercise Capacity in Low-Oxygen Settings Ann Intern Med August 3, 2004 141:I-12
    « Previous | Next Article »Table of Contents

    This Article

    1. Ann Intern Med August 3, 2004 vol. 141 no. 3 169-177
    1. » Abstract
    2. Figures
    3. Full Text
    4. Full Text (PDF)
      1. Summary for Patients

    Current Issue

    1. November 3, 2009, 151 (9)
    1. Alert me to current issues