High‐Altitude Pulmonary Edema

Abstract

High-altitude pulmonary edema (HAPE), a not uncommon form of acute altitude illness, can occur within days of ascent above 2500 to 3000 m. Although life-threatening, it is avoidable by slow ascent to permit acclimatization or with drug prophylaxis. The critical pathophysiology is an excessive rise in pulmonary vascular resistance or hypoxic pulmonary vasoconstriction (HPV) leading to increased microvascular pressures. The resultant hydrostatic stress causes dynamic changes in the permeability of the alveolar capillary barrier and mechanical injurious damage leading to leakage of large proteins and erythrocytes into the alveolar space in the absence of inflammation. Bronchoalveolar lavage and hemodynamic pressure measurements in humans confirm that elevated capillary pressure induces a high-permeability noninflammatory lung edema. Reduced nitric oxide availability and increased endothelin in hypoxia are the major determinants of excessive HPV in HAPE-susceptible individuals. Other hypoxia-dependent differences in ventilatory control, sympathetic nervous system activation, endothelial function, and alveolar epithelial active fluid reabsorption likely contribute additionally to HAPE susceptibility. Recent studies strongly suggest nonuniform regional hypoxic arteriolar vasoconstriction as an explanation for how HPV occurring predominantly at the arteriolar level causes leakage. In areas of high blood flow due to lesser HPV, edema develops due to pressures that exceed the dynamic and structural capacity of the alveolar capillary barrier to maintain normal fluid balance. This article will review the pathophysiology of the vasculature, alveolar epithelium, innervation, immune response, and genetics of the lung at high altitude, as well as therapeutic and prophylactic strategies to reduce the morbidity and mortality of HAPE.

Obesity as a Conditioning Factor for High-Altitude Diseases

“…However, the two major theories for the cause of HAPE, exacerbated pulmonary hypertension and/or capillary alterations due to inflammatory mediators [43,44], are in line with some pathophysiological effects seen in obese patients regardless of whether or not they are at high altitude. In fact, it has been observed that obese individuals present an obesity-hypoventilation syndrome (OHS) accompanied by sleep disturbances, resulting in deep nocturnal oxygen desaturation and periodic apneic breathing [41,45] even at moderate elevations.…”

“…In addition, obese patients experience an increased inflammatory state, with the presence of inflammation mediators where increased levels of interleukin 6 have been described, along with other cytokines [48]. The above conditions are at the core of the current understanding of HAPE pathophysiology [44]. Therefore, the above mentioned factors are highly suggestive of a link between not only obesity and AMS but also between obesity and the development of HAPE.…”

Cardiovascular Adaptation to High-Altitude Hypoxia

“…This enhanced hydrostatic stress causes dynamic changes in the permeability of the alveolar capillary barrier and induces a highpermeability noninflammatory lung edema. Previous report indicated that decreased nitric oxide release and enhanced endothelin levels following acute high-altitude exposure may be the major determinants of exaggerated hypoxic pulmonary vasoconstriction in HAPE-susceptible individuals [25]. In addition, other hypoxia-mediated changes of sympathetic nervous activity, endothelial function, and altered levels of other vasoactive mediators such as endothelin and angiotensin II may also contribute additionally to HAPE susceptibility.…”

Of Deep Waters and Thin Air

“…To date, 3 not mutually exclusive explanations have been put forward: (1) HAPE may initially arise from a subset of capillaries that branch off directly from the larger arteries and, thus, are unprotected when pulmonary artery pressures increases 17 ; (2) capillary pressures may rise because of concomitant pulmonary venoconstriction 18 ; and (3) heterogeneous vasoconstriction may result in uneven distribution of perfusion and local areas of high flow and pressure. 3 These concepts not only illustrate that drawing conclusions on local microhemodynamics from macrohemodynamic measurements can be problematic, but they also stress the potential role of pulmonary vasoconstriction in lung edema formation. A closer look at the data by Moon and colleagues may suggest a similar element of vasoconstriction in SIPE: Despite lower CO values, the transpulmonary pressure gradient (ie, the difference between mPAP and PAWP) tended to be higher in SIPE-susceptible subjects than in controls during both the dunk and subsequent submersed exercise.…”

“…Interestingly, SIPE shares common features with another form of pulmonary edema that is caused by strenuous exercise in an evolutionary nonphysiological habitat, namely high-altitude pulmonary edema (HAPE): Both SIPE and HAPE typically affect young healthy individuals, are triggered by strenuous exercise in a cold environment, resolve spontaneously after return to physiological conditions, yet will recur on reexposure in prone individuals. 2,3 At the pathological level, edema fluid in both SIPE and HAPE patients contains considerable amounts of red blood cells and high-molecular-weight proteins in the absence of markedly elevated inflammatory markers. 4,5 The pathophysiology of both diseases has long puzzled the field and hampered the development of effective counterstrategies, because their features tend to evade the traditional classification of pulmonary edema.…”