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High‐Altitude Pulmonary Edema

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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. Published 2012. Compr Physiol 2:2753‐2773, 2012.

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Figure 1. Figure 1.

Chest radiograph with bronchoalveolar lavage fluid aliquots (first and fifth) from a representative subject with early high‐altitude pulmonary edema. The radiograph shows interstitial and alveolar infiltrates and the lavage performed after the x‐ray was taken shows mild alveolar hemorrhage .

Figure 2. Figure 2.

Pulmonary artery pressure (PAP) in high‐altitude pulmonary edema (HAPE)‐susceptible individuals (continuous lines and filled symbols) and in nonsusceptible controls (dashed lines and open symbols) during exposure to normobaric hypoxia (left) and before and during exercise on a bicycle ergometer (right). The highest PAP recordings during exercise (75‐150 W) are shown .

Figure 3. Figure 3.

Mean pulmonary artery pressure (Ppa) and pulmonary capillary pressure (Pcap) in 14 controls and in 16 high‐altitude edema susceptible (HAPE‐s) subjects at high altitude. HAPE‐s is further divided in those who developed HAPE (HAPE) and those who did not develop HAPE (non‐HAPE). Bars indicate the mean values in each group. *P < 0.05, **P < 0.01 versus control, †P < 0.01 versus non‐HAPE .

Figure 4. Figure 4.

(A) Exhaled nitric oxide (NO) after 40 h at 4559 m in individuals developing high‐altitude edema susceptible (HAPE) (left) and in individuals not developing HAPE (HAPE‐R) despite identical exposure to high altitude . (B) Exhaled NO in individuals with (HAPE‐S) and without susceptibility (HAPE‐R) to HAPE after 4 h of exposure to hypoxia (FIO2 = 0.12) at low altitude (elevation 100 m) .

Figure 5. Figure 5.

Individual bronchoalveolar lavage (BAL) red blood cell count and albumin concentrations plotted against pulmonary artery systolic pressures at high altitude (4559 m). Acronyms: BAL, bronchoalveolar lavage; HAPE, high‐altitude pulmonary edema. The vertical lines denote a threshold systolic pulmonary artery (PA) pressure (> 60 mmHg) above which red blood cell (A) appear in the BAL fluid in contrast to the lower pressure (35 mmHg) at which albumin leakage occurs (B). The open circles in the lower left of both panels show the normal values for these at low altitude. The correlation coefficients are given for the best‐fit curves of the values at high altitude (P < 0.05 for both curves) .

Figure 6. Figure 6.

Schematic sequence of events in the progression of edema with pulmonary artery pressure rise in high‐altitude pulmonary edema (HAPE) from dynamic changes in alveolar capillary barrier permeability to mechanical injury.



Figure 1.

Chest radiograph with bronchoalveolar lavage fluid aliquots (first and fifth) from a representative subject with early high‐altitude pulmonary edema. The radiograph shows interstitial and alveolar infiltrates and the lavage performed after the x‐ray was taken shows mild alveolar hemorrhage .



Figure 2.

Pulmonary artery pressure (PAP) in high‐altitude pulmonary edema (HAPE)‐susceptible individuals (continuous lines and filled symbols) and in nonsusceptible controls (dashed lines and open symbols) during exposure to normobaric hypoxia (left) and before and during exercise on a bicycle ergometer (right). The highest PAP recordings during exercise (75‐150 W) are shown .



Figure 3.

Mean pulmonary artery pressure (Ppa) and pulmonary capillary pressure (Pcap) in 14 controls and in 16 high‐altitude edema susceptible (HAPE‐s) subjects at high altitude. HAPE‐s is further divided in those who developed HAPE (HAPE) and those who did not develop HAPE (non‐HAPE). Bars indicate the mean values in each group. *P < 0.05, **P < 0.01 versus control, †P < 0.01 versus non‐HAPE .



Figure 4.

(A) Exhaled nitric oxide (NO) after 40 h at 4559 m in individuals developing high‐altitude edema susceptible (HAPE) (left) and in individuals not developing HAPE (HAPE‐R) despite identical exposure to high altitude . (B) Exhaled NO in individuals with (HAPE‐S) and without susceptibility (HAPE‐R) to HAPE after 4 h of exposure to hypoxia (FIO2 = 0.12) at low altitude (elevation 100 m) .



Figure 5.

Individual bronchoalveolar lavage (BAL) red blood cell count and albumin concentrations plotted against pulmonary artery systolic pressures at high altitude (4559 m). Acronyms: BAL, bronchoalveolar lavage; HAPE, high‐altitude pulmonary edema. The vertical lines denote a threshold systolic pulmonary artery (PA) pressure (> 60 mmHg) above which red blood cell (A) appear in the BAL fluid in contrast to the lower pressure (35 mmHg) at which albumin leakage occurs (B). The open circles in the lower left of both panels show the normal values for these at low altitude. The correlation coefficients are given for the best‐fit curves of the values at high altitude (P < 0.05 for both curves) .



Figure 6.

Schematic sequence of events in the progression of edema with pulmonary artery pressure rise in high‐altitude pulmonary edema (HAPE) from dynamic changes in alveolar capillary barrier permeability to mechanical injury.

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Erik R. Swenson, Peter Bärtsch. High‐Altitude Pulmonary Edema. Compr Physiol 2012, 2: 2753-2773. doi: 10.1002/cphy.c100029