Salmeterol for the prevention of high-altitude pulmonary edema

N Engl J Med. 2002 May 23;346(21):1631-6. doi: 10.1056/NEJMoa013183.


Background: Pulmonary edema results from a persistent imbalance between forces that drive water into the air space and the physiologic mechanisms that remove it. Among the latter, the absorption of liquid driven by active alveolar transepithelial sodium transport has an important role; a defect of this mechanism may predispose patients to pulmonary edema. Beta-adrenergic agonists up-regulate the clearance of alveolar fluid and attenuate pulmonary edema in animal models.

Methods: In a double-blind, randomized, placebo-controlled study, we assessed the effects of prophylactic inhalation of the beta-adrenergic agonist salmeterol on the incidence of pulmonary edema during exposure to high altitudes (4559 m, reached in less than 22 hours) in 37 subjects who were susceptible to high-altitude pulmonary edema. We also measured the nasal transepithelial potential difference, a marker of the transepithelial sodium and water transport in the distal airways, in 33 mountaineers who were prone to high-altitude pulmonary edema and 33 mountaineers who were resistant to this condition.

Results: Prophylactic inhalation of salmeterol decreased the incidence of high-altitude pulmonary edema in susceptible subjects by more than 50 percent, from 74 percent with placebo to 33 percent (P=0.02). The nasal potential-difference value under low-altitude conditions was more than 30 percent lower in the subjects who were susceptible to high-altitude pulmonary edema than in those who were not susceptible (P<0.001).

Conclusions: Prophylactic inhalation of a beta-adrenergic agonist reduces the risk of high-altitude pulmonary edema. Sodium-dependent absorption of liquid from the airways may be defective in patients who are susceptible to high-altitude pulmonary edema. These findings support the concept that sodium-driven clearance of alveolar fluid may have a pathogenic role in pulmonary edema in humans and therefore represent an appropriate target for therapy.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Adrenergic beta-Agonists / pharmacology
  • Adrenergic beta-Agonists / therapeutic use*
  • Adult
  • Albuterol / analogs & derivatives*
  • Albuterol / pharmacology
  • Albuterol / therapeutic use*
  • Altitude Sickness / complications*
  • Altitude Sickness / prevention & control
  • Biological Transport, Active
  • Double-Blind Method
  • Epithelium / drug effects
  • Epithelium / metabolism
  • Female
  • Humans
  • Hypertension, Pulmonary / metabolism
  • Hypoxia / complications
  • Hypoxia / prevention & control
  • Male
  • Membrane Potentials / drug effects
  • Middle Aged
  • Nasal Mucosa / metabolism
  • Pulmonary Alveoli / drug effects
  • Pulmonary Alveoli / metabolism
  • Pulmonary Edema / etiology
  • Pulmonary Edema / metabolism
  • Pulmonary Edema / prevention & control*
  • Salmeterol Xinafoate
  • Sodium / metabolism


  • Adrenergic beta-Agonists
  • Salmeterol Xinafoate
  • Sodium
  • Albuterol