How HAPE Happens
How HAPE Happens
Abstracts & Commentary
Synopsis: Recent studies suggest that high-altitude pulmonary edema (HAPE) is not primarily an inflammatory process, but that it might result from alterations in the sodium-driven clearance of alveolar fluid. In addition to gradual ascent, prophylactic salmeterol might be effective in travelers who are predisposed to HAPE.
Sources: Swenson ER, et al. Pathogenesis of high-altitude pulmonary edema: Inflammation is not an etiologic factor. JAMA. 2002;287:2228-2235; Sartori C, et al. Salmeterol for the prevention of high-altitude pulmonary edema. N Engl J Med. 2002;346:1631-1636.
To determine whether inflammatory changes are important in the pathogenesis of high-altitude pulmonary edema (HAPE), Swenson and colleagues studied 10 subjects who had previously had HAPE and 6 similar alpinists who had not suffered from HAPE. Pulmonary artery pressure determinations and bronchoalveolar lavage (BAL) sampling were done at 490 m elevation prior to ascent and then again at 4559 m elevation before or at the onset of HAPE. HAPE-susceptible climbers had higher pulmonary artery pressures at altitude than did their HAPE-resistant counterparts. BAL fluid in HAPE-sensitive climbers had higher quantities of red blood cells and plasma-derived proteins than in HAPE-resistant subjects, but concentrations of white blood cells and inflammatory cytokines were similar in the 2 groups. Swenson et al concluded that inflammation is not a primary etiologic factor in HAPE but that HAPE is a form of hydrostatic pulmonary edema with altered alveolar-capillary permeability.
Sartori and associates studied similar mountaineers at the same Swiss site. In 33 HAPE-susceptible subjects, HAPE occurred more commonly with placebo (14 of 19, 74%) than with prophylactic salmeterol (6 of 18, 33%, P = 0.02). Understanding that beta-adrenergic agonists such as salmeterol affect sodium transport and the clearance of alveolar fluid, the nasal transepithelial difference (a marker for transepithelial sodium and water transport in distal airways) was found to be 30% lower (P < 0.001) in 33 HAPE-sensitive climbers than in 33 HAPE-resistant climbers. While providing evidence that alteration in the sodium-driven clearance of alveolar fluid might be important in the pathogenesis of HAPE, Sartori et al also provided initial evidence that salmeterol might be useful in preventing HAPE in hikers and climbers susceptible to this condition.
Comment by Philip r. Fisher, MD, DTM&H
High-altitude recreation is increasingly accessible to adventurous individuals. In fact, on a single day (May 16, 2002), 54 individuals successfully reached the summit of Mt. Everest.1 (In 1953, Tenzing Norgay and Sir Edmund Hillary reached Everest’s summit for the first time.) Tenzing’s grandson and Hillary’s son were both among the dozens of people climbing Everest.
As travel medicine practitioners know, however, one need not climb Everest to suffer physical effects of high altitude. Acute mountain sickness (AMS) is a problem for 25% of travelers visiting destinations between 2000 and 3000 m above sea level and for more than 50% of people traveling to sites higher than 3000 meters.2 Gradual ascent, acetazolamide, and, in selected cases, dexamethasone provide effective prophylaxis in AMS-susceptible individuals.2 Treatment is by descent. High altitude cerebral edema (HACE) and HAPE are less common but can be fatal. Prevention of these serious complications has until now been limited to gradual ascent. Even in HAPE-susceptible travelers, gradual ascent can be preventive.3 Treatment of symptomatic travelers with HAPE and/or HACE involves rapid descent, oxygen, dexamethasone (for HACE), and nifedipine (for HAPE).2
During the 4 decades since HAPE was characterized, there has been uncertainty as to the pathogenesis of this disorder. While pulmonary pressures and alveolar-capillary leaking seemed primary, there has also been concern that inflammation might play a key role in the pathogenesis of HAPE. This notion was supported by the finding that children with respiratory infections are more likely to develop HAPE4 and by the suggestion that inflammatory mediators are increased in HAPE. The careful (and fairly aggressive interventional) study of Swenson et al provides compelling evidence that inflammation is not a major factor in leading to or initially mediating the development of HAPE. Previous findings of signs of inflammation in the alveolar fluid of patients suffering from HAPE were probably due to a later secondary result of HAPE rather than to a primary etiologic factor.5
Since inflammation does not seem to mediate HAPE, what might be the feature of susceptible travelers that prompts the development of life-threatening pulmonary edema at altitude? Sartori et al provide good evidence that the clearance of alveolar fluid is, at baseline, defective in HAPE-susceptible individuals. Perhaps the relative hypoxia seen at high altitude leads to increased pulmonary arterial pressures and increased alveolar-capillary leaking.6 Many climbers can clear this increased leak, especially if given time during a gradual ascent and a gradual adaptation to increasing altitudes. Travelers with limited or defective alveolar clearance are much less likely to adequately handle the increased hydrostatic fluid shifts and can develop significant pulmonary edema. While the predisposing variation in salt and fluid equilibrium might not be amenable to full correction, it does appear that the added time and adaptation afforded by a gradual ascent allow the lungs to tolerate temporarily increased alveolar fluids. Even in HAPE-susceptible travelers who must reascend to high altitude, salmeterol now seems to offer promise as an additionally effective means of preventing HAPE.
References
1. Gurubacharya B. Not lonely at the top: Mount Everest has a record day. The Associated Press. May 16, 2002.
2. Weiss EA. Medical considerations for wilderness and adventure travelers. Med Clin North Am. 1999;83: 885-902.
3. Litch JA, Bishop RA. Reascent following resolution of high altitude pulmonary edema. High Alt Med Biol. 2001;2:53-55.
4. Durmowicz AG, et al. Inflammatory processes may predispose children to high-altitude pulmonary edema. J Pediatr. 1997;130:838-840.
5. Hackett P, Rennie D. High-altitude pulmonary edema (editorial). JAMA. 2002;287:2275-2278.
6. Voelkel NF. High-altitude pulmonary edema (perspective). N Engl J Med. 2002;346:1606-1607.
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