High-Altitude Pulmonary Edema

High-altitude pulmonary edema (HAPE) is an uncommon form of pulmonary edema that occurs in healthy individuals within a few days of arrival at altitudes above 2,500–3,000 m. The crucial pathophysiology is an excessive hypoxia-mediated rise in pulmonary vascular resistance (PVR) or hypoxic pulmonary vasoconstriction (HPV) leading to increased microvascular hydrostatic pressures despite normal left atrial pressure. The resultant hydrostatic stress can cause both dynamic changes in the permeability of the alveolar capillary barrier and mechanical damage leading to leakage of large proteins and erythrocytes into the alveolar space in the absence of inflammation. Bronchoalveolar lavage (BAL) and pulmonary artery (PA) and microvascular pressure measurements in humans confirm that high capillary pressure induces a high-permeability non-inflammatory-type lung edema; a concept termed “capillary stress failure.” Measurements of endothelin and nitric oxide (NO) in exhaled air, NO metabolites in BAL fluid, and NO-dependent endothelial function in the systemic circulation all point to reduced NO availability and increased endothelin in hypoxia as a major cause of the excessive hypoxic PA pressure rise in HAPE-susceptible individuals. Other hypoxia-dependent differences in ventilatory control, sympathetic nervous system activation, endothelial function, and alveolar epithelial sodium and water reabsorption likely contribute additionally to the phenotype of HAPE susceptibility. Recent studies using magnetic resonance imaging in humans strongly suggest nonuniform regional hypoxic arteriolar vasoconstriction as an explanation for how HPV occurring predominantly at the arteriolar level can cause leakage. This compelling but not yet fully proven mechanism predicts that in areas of high blood flow due to lesser vasoconstriction edema will develop owing to pressures that exceed the structural and dynamic capacity of the alveolar capillary barrier to maintain normal alveolar fluid balance. Numerous strategies aimed at lowering HPV and possibly enhancing active alveolar fluid reabsorption are effective in preventing and treating HAPE. Much has been learned about HAPE in the past four decades such that what was once a mysterious alpine malady is now a well-characterized and preventable lung disease. This chapter will relate the history, pathophysiology, and treatment of HAPE, using it not only to illuminate the condition, but also for the broader lessons it offers in understanding pulmonary vascular regulation and lung fluid balance.