Journal of Applied Physiology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

J Appl Physiol 98: 1101-1110, 2005; doi:10.1152/japplphysiol.01167.2004
8750-7587/05 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (56)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bärtsch, P.
Right arrow Articles by Swenson, E. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bärtsch, P.
Right arrow Articles by Swenson, E. R.

INVITED REVIEW

HIGHLIGHTED TOPICS
Pulmonary Circulation and Hypoxia

Physiological aspects of high-altitude pulmonary edema

Peter Bärtsch,1 Heimo Mairbäurl,1 Marco Maggiorini,2 and Erik R. Swenson3

1Division of Sports Medicine, Department of Internal Medicine, Medical University Hospital, Heidelberg, Germany; and 2Department of Cardiology, Medical Clinic, Zurich, Switzerland; and 3Veterans Affairs Puget Sound Health Care System, Seattle, Washington


   ABSTRACT
TOP
 ABSTRACT
CLINICAL PICTURE
 CHARACTERISTICS OF SUSCEPTIBLE...
 MECHANISMS ACCOUNTING FOR...
 HAPE IS A HYDROSTATIC...
 MECHANISMS ACCOUNTING FOR...
 NATURE OF THE LEAK...
 ADDITIONAL CONTRIBUTING FACTORS
 PHYSIOLOGICAL ASPECTS OF HAPE...
 REFERENCES
 
High-altitude pulmonary edema (HAPE) develops in rapidly ascending nonacclimatized healthy individuals at altitudes above 3,000 m. An excessive rise in pulmonary artery pressure (PAP) preceding edema formation is the crucial pathophysiological factor because drugs that lower PAP prevent HAPE. Measurements of nitric oxide (NO) in exhaled air, of nitrites and nitrates in bronchoalveolar lavage (BAL) fluid, and forearm NO-dependent endothelial function all point to a reduced NO availability in hypoxia as a major cause of the excessive hypoxic PAP rise in HAPE-susceptible individuals. Studies using right heart catheterization or BAL in incipient HAPE have demonstrated that edema is caused by an increased microvascular hydrostatic pressure in the presence of normal left atrial pressure, resulting in leakage of large-molecular-weight proteins and erythrocytes across the alveolarcapillary barrier in the absence of any evidence of inflammation. These studies confirm in humans that high capillary pressure induces a high-permeability-type lung edema in the absence of inflammation, a concept first introduced under the term "stress failure." Recent studies using microspheres in swine and magnetic resonance imaging in humans strongly support the concept and primacy of nonuniform hypoxic arteriolar vasoconstriction to explain how hypoxic pulmonary vasoconstriction occurring predominantly at the arteriolar level can cause leakage. This compelling but as yet unproven mechanism predicts that edema occurs in areas of high blood flow due to lesser vasoconstriction. The combination of high flow at higher pressure results in pressures, which exceed the structural and dynamic capacity of the alveolar capillary barrier to maintain normal alveolar fluid balance.

pulmonary artery pressure; hypoxic pulmonary vasoconstriction; nitric oxide; inflammation; alveolar fluid clearance; pathophysiology; review


   CLINICAL PICTURE
TOP
 ABSTRACT
 CLINICAL PICTURE
CHARACTERISTICS OF SUSCEPTIBLE...
 MECHANISMS ACCOUNTING FOR...
 HAPE IS A HYDROSTATIC...
 MECHANISMS ACCOUNTING FOR...
 NATURE OF THE LEAK...
 ADDITIONAL CONTRIBUTING FACTORS
 PHYSIOLOGICAL ASPECTS OF HAPE...
 REFERENCES
 
High-altitude pulmonary edema (HAPE) is noncardiogenic pulmonary edema that usually occurs at altitudes above 3,000 m in rapidly ascending nonacclimatized individuals within the first 2–5 days after arrival. It may also occur in high-altitude dwellers who return from sojourns at low altitude. The first medical description of HAPE was published in Peru and recognized the latter form, also called reentry HAPE, as a pulmonary edema associated with electrographic signs of right ventricular overload (67). The first cases of HAPE in unacclimatized lowlanders climbing to high altitude were reported from the Rocky Mountains (53). The two forms very probably share the same pathophysiology.

The reader is referred to other reviews (9, 41, 96, 97) for an extensive presentation of the clinical picture. In this review, we point out some particular characteristics that might elucidate the underlying pathophysiology and are revealed by classical and newly evolving pathophysiological concepts.

The prevalence of HAPE depends on the degree of susceptibility, the rate of ascent, and the final altitude. At an altitude of 4,500 m, the prevalence may vary depending on the rate of ascent between 0.2 and 6% in an unselected population (13) and at 5,500 m between 2 and 15% (40, 100). Mountaineers who develop HAPE at altitudes between 3,000 and 4,500 m have a 60% recurrence rate when ascending rapidly to these altitudes (13). On the other hand, susceptible mountaineers can ascend up to 7,000 m without developing HAPE when ascent rate is slow, with an average gain of altitude of 300–350 m/day above 2,000 m (9). Even more astonishing is the fact that a mountaineer who develops HAPE and descends to recover can reascend to even higher altitudes a few days after recovery without developing HAPE again (66). There is most likely no complete "resistance" to HAPE. Episodes of HAPE in experienced, successful high-altitude climbers demonstrate that most likely everyone can get HAPE when ascending fast and high enough (9). It is also important to note that the setting in which HAPE occurs usually involves heavy and prolonged exercise and that there seems to be a male predominance (55).

Chest X-ray and computerized tomography (CT) scans in early HAPE show a patchy peripheral distribution of edema as shown in Fig. 1. The radiographic appearance of HAPE is more homogenous and diffuse in advanced cases and during recovery (112, 113). Moreover, in patients who had two episodes of HAPE, the similarity of the radiographic appearance between the two periods was random, suggesting that structural abnormalities do not account for edema location (112), except in those with congenital unilateral absence of a pulmonary artery, in whom the edema always occurs in the contralateral lung (39).



View larger version (96K):
[in this window]
[in a new window]
  		Fig. 1. A: radiograph of a 37-yr-old male mountaineer with high-altitude pulmonary edema (HAPE) that shows a patchy to confluent distribution of edema, predominantly on the right side. B: computerized tomography scan of 27-yr-old mountaineer with recurrent HAPE showing patchy distribution of edema.

 
Autopsies reveal distended pulmonary arteries and diffuse pulmonary edema with bloody foamy fluid present in the airways but no evidence of left ventricular failure (7, 77). In addition, hyaline membranes were found in most cases and arteriolar thrombi, pulmonary hemorrhages, or infarcts were often present.


   CHARACTERISTICS OF SUSCEPTIBLE INDIVIDUALS
TOP
 ABSTRACT
 CLINICAL PICTURE
 CHARACTERISTICS OF SUSCEPTIBLE...
MECHANISMS ACCOUNTING FOR...
 HAPE IS A HYDROSTATIC...
 MECHANISMS ACCOUNTING FOR...
 NATURE OF THE LEAK...
 ADDITIONAL CONTRIBUTING FACTORS
 PHYSIOLOGICAL ASPECTS OF HAPE...
 REFERENCES
 
It is well known that individuals who develop HAPE at altitudes of 4,000 m show an abnormal increase in pulmonary artery pressure (PAP) during brief or prolonged hypoxic exposure (38, 54, 110). Interestingly, they also have a greater PAP rise during exercise in normoxia (Fig. 2) (34, 38, 61), pointing to a constitutionally generalized hyperreactivity of the pulmonary circulation. Furthermore, most HAPE-susceptible individuals have a low hypoxic ventilatory response (HVR) (42, 47, 72), which leads to a low alveolar PO2 and thus a greater stimulus to HPV at any given altitude. The hypothesis that polymorphisms of the tyrosine hydroxylase gene leading to decreased peripheral chemoreceptor dopamine synthesis might be associated with blunted HVR and susceptibility to HAPE could not be confirmed in Japanese mountaineers (45). Evidence in support of reduced peripheral chemosensitivity to hypoxia contributing to greater HPV comes from studies where carotid body resection and/or denervation of the lung increases HPV at a constant alveolar PO2 (24, 118). HAPE-susceptible individuals also have 10–15% lower lung volumes (34, 101, 110), which may contribute to increased PAP in hypoxia or exercise by causing greater alveolar hypoxia. Also lower lung volumes may cause greater pulmonary vascular resistance by virtue of a smaller vascular bed and less vascular recruitability as shown by diminished increases in diffusing capacity with exercise compared with HAPE-resistant individuals (101).



View larger version (23K):
[in this window]
[in a new window]
  		Fig. 2. Pulmonary artery pressure (PAP) in HAPE-susceptible individuals (solid 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). Highest PAP recordings during exercise (75–150 W) are shown. FIO2, fraction of inspired O2. Data from Ref. 38. *P < 0.005 compared with preexercise values within groups and with postexercise values between groups.

 

   MECHANISMS ACCOUNTING FOR ENHANCED HPV
TOP
 ABSTRACT
 CLINICAL PICTURE
 CHARACTERISTICS OF SUSCEPTIBLE...
 MECHANISMS ACCOUNTING FOR...
HAPE IS A HYDROSTATIC...
 MECHANISMS ACCOUNTING FOR...
 NATURE OF THE LEAK...
 ADDITIONAL CONTRIBUTING FACTORS
 PHYSIOLOGICAL ASPECTS OF HAPE...
 REFERENCES
 
Decreased nitric oxide (NO) concentrations in exhaled air were found in HAPE-susceptible individuals during a 4-h hypoxic exposure at low altitude (20) and during the development of HAPE at high altitude (Fig. 3) (29). Furthermore, concentrations of nitrate and nitrite in bronchoalveolar lavage fluid were lower in mountaineers who developed HAPE compared with controls (105), and inhalation of 15–40 ppm NO lowered PAP and improved gas exchange in subjects with HAPE to values measured in controls (5, 95). A recent investigation of our collaborative study group in Heidelberg demonstrates an impaired endothelium-dependent vasodilator response to acetylcholine in hypoxia measured by forearm venous occlusion plethysmography in HAPE-susceptible vs. nonsusceptible controls (19a). Taken together, these data suggest that hypoxia impairs endothelial function in HAPE-susceptible individuals and results in decreased bioavailability of NO and its second messenger cGMP, which is likely to contribute to the enhanced hypoxic pulmonary vasoconstriction in HAPE. Furthermore, our observation that susceptibility to HAPE is associated with an abnormal rise of PAP to exercise in normoxia (38, 61) might be explained by an impaired endothelial NO release in response to increased blood flow in the pulmonary circulation. In accordance with this concept, the phosphodiesterase-5 inhibitors sildenafil or tadalafil, which increase the cGMP in lung tissue by inhibition of its degradation, lower PAP and improve exercise capacity at high altitude (36, 87)and prevent HAPE (68).



View larger version (16K):
[in this window]
[in a new window]
  		Fig. 3. Left: exhaled nitric oxide (NO) after 40 h at 4,559 m in individuals developing HAPE and in individuals not developing HAPE (HAPE-R) despite identical exposure to high altitude (29). Right: exhaled NO in HAPE-susceptible subjects (HAPE-S) and HAPE-R individuals after 4 h of exposure to hypoxia (FIO2 = 0.12) at low altitude (elevation 100 m) (20). n, No. of subjects.

 
In addition, the latter study demonstrated that 2 x 8 mg dexamethasone daily starting 2 days before ascending lowers PAP as much as tadalafil and prevents HAPE equally effectively (68). This is a rather unexpected finding considering the observations that HAPE developed in individuals during or shortly after treatment of AMS by dexamethasone (17; and Schoene, personal communication). Lowering PAP by dexamethasone is compatible with reduced NO availability in HAPE in hypoxia because dexamethasone can activate endothelial NO synthase by a nontranscriptional mechanism (43) and block hypoxia-induced endothelial dysfunction in organ-cultured pulmonary arteries by increasing endothelial NO synthase (eNOS) expression (76). The observation that HAPE may develop in individuals despite receiving dexamethasone (17) for treatment of AMS suggests that new gene transcription-mediated protein expression is critical for prevention of HAPE and may require days rather than hours to be fully realized. In addition, other actions of dexamethasone could also contribute to its preventive effect in HAPE. By increasing surfactant phospholipid and protein secretion into the alveolar lining fluid of adult animals (120, 121), dexamethasone will reduce surface tension and microvascular transmural pressure (3). This mechanism may explain the reduction in vascular permeability in hypoxic mice treated with dexamethasone in whom no changes in PAP were reported (102). Enhanced alveolar sodium (and water) reabsorption mediated by corticosteroid-induced upregulation of alveolar epithelial apical membrane sodium channel activity and basolateral membrane Na+-K+-ATPase activity is another highly relevant action of dexamethasone (73). Both mechanisms could indirectly contribute to a lowering of PAP by improving ventilation and/or gas exchange, thus improving alveolar and arterial PO2. Lastly, given the results with dexamethasone, it may be fruitful to explore whether HAPE susceptibility has any link to polymorphisms in the glucocorticoid receptor that influence cardiovascular and metabolic control (27).

The concept of an endothelium predisposed to greater vasoconstriction is also supported by the fact that in the Japanese population, HAPE is positively associated with two eNOS gene polymorphisms (G894T-variant and 27-base pair variable numbers of tandem repeats), which are associated with vascular diseases such as essential hypertension and coronary heart disease (28). However, an investigation in Caucasians equivalent to the Japanese study did not find an association between susceptibility to HAPE and a number of eNOS polymorphisms, including the G894T variant (114). Ethnic or environmental differences or different linkage disequilibrium in Japanese and Caucasians could account for the discrepant results.

The observation that inhaled NO did not completely normalize PAP in HAPE-susceptible individuals, but did so in those resistant to HAPE (5, 16), indicates that impaired NO synthesis cannot fully account for the excessive pulmonary vascular reactivity in HAPE-prone subjects. It is likely that additional factors, such as increased sympathetic activity or other vasoconstrictors such as angiotensin II (15), endothelin (93), or arachadonic acid metabolites (98) contribute to the increased PAP in HAPE-susceptible subjects. Microneurography in HAPE subjects demonstrates increased skeletal muscle sympathetic activity during hypoxia at low altitudes and before HAPE at high altitudes (30). In accordance with these findings, increased plasma and/or urinary levels of norepinephrine, compared with controls, were found to precede (15) and accompany (15, 62) HAPE. Both animal and human data (75, 108) support the notion that increased sympathetic activity contributes to the greater HPV. In this fashion HAPE may bear some resemblance to neurogenic pulmonary edema (65). Whether activation of the renin-aldosterone-angiotensin system in HAPE (15) can be attributed to increased sympathetic activity or a genetically determined response is not clear. The insertion-deletion polymorphism of the angiotensin-converting enzyme is not associated with susceptibility to HAPE in Caucasian (26) and Japanese (52) mountaineers or in Indian soldiers (64), whereas the G1517T variant of the angiotensin receptor (AT1R) gene, a polymorphism of unknown functional significance, is associated with HAPE susceptibility in Japan (52).

In summary, individuals with susceptibility to HAPE are characterized by an excessive rise in PAP in hypoxia, which can in part be attributed to a decreased bioavailability of NO. Increased sympathetic activity and vasoconstrictors such as endothelin and possibly arachadonic acid metabolites may also contribute to a greater hypoxic pulmonary vascular response. It is not, however, clear whether a greater sympathetic and vasoconstrictor response in HAPE-susceptible individuals vs. controls is simply caused by more severe hypoxemia or whether it indicates an exaggerated response to hypoxia. Arterial PO2 is often already significantly lower in HAPE-susceptible vs. nonsusceptible individuals early during exposure in hypoxia (59).


   HAPE IS A HYDROSTATIC EDEMA
TOP
 ABSTRACT
 CLINICAL PICTURE
 CHARACTERISTICS OF SUSCEPTIBLE...
 MECHANISMS ACCOUNTING FOR...
 HAPE IS A HYDROSTATIC...
MECHANISMS ACCOUNTING FOR...
 NATURE OF THE LEAK...
 ADDITIONAL CONTRIBUTING FACTORS
 PHYSIOLOGICAL ASPECTS OF HAPE...
 REFERENCES
 
Two studies performed recently at the Capanna Regina Margherita (4,559 m) in HAPE-susceptible individuals demonstrate that HAPE is caused by a noninflammatory, hydrostatic leak. Right heart catheterization showed that the abnormal rise in PAP in individuals developing HAPE is accompanied, as shown in Fig. 4, by capillary pressure increased to 20–25 mmHg (69). Thus capillary pressure exceeds a threshold value for edema formation (17–24 mmHg) established in dog models of lung edema (48). Bronchoalveolar lavage (BAL) performed within 1 day of ascent to 4,559 m reveals elevated red blood cell counts and serum-derived protein concentration in BAL fluid (Table 1), both in subjects with HAPE and in those who develop HAPE within the next 24 h (105). There was, however, no increase in alveolar macrophages, neutrophils, or the concentration of various proinflammatory mediators [interleukin (IL)-1, tumor necrosis factor-{alpha}, IL-8, thromboxane, prostaglandin E2 and leukotriene B4 (LTB4)] at high altitude, and there was no difference between individuals resistant and susceptible to HAPE in these parameters. These data indicate that there is a partial disruption of the alveolar capillary barrier that is not caused by an inflammatory process.



View larger version (17K):
[in this window]
[in a new window]
  		Fig. 4. Mean pulmonary artery pressure (Ppa) and pulmonary capillary pressure (Pcap) in 14 controls and in 16 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 vs. control, {dagger}P < 0.01 vs. non-HAPE. Data from Ref. 69.

 

View this table:
[in this window]
[in a new window]
  		Table 1. Bronchoalveolar lavage in HAPE: differential cell count and protein concentrations

 
BAL in more advanced HAPE (and sometimes many days after onset) showed in some, but not all cases, elevated proinflammatory cytokines, LTB4, and increased granulocytes (63, 98). Furthermore, urinary leukotriene E4 excretion was increased in patients with HAPE reporting to clinics in the Rocky Mountains (60). These observations suggest that inflammation may occur as a consequence of alveolar edema and microvascular disruption, which may then secondarily enhance capillary permeability.


   MECHANISMS ACCOUNTING FOR INCREASED CAPILLARY PRESSURE
TOP
 ABSTRACT
 CLINICAL PICTURE
 CHARACTERISTICS OF SUSCEPTIBLE...
 MECHANISMS ACCOUNTING FOR...
 HAPE IS A HYDROSTATIC...
 MECHANISMS ACCOUNTING FOR...
NATURE OF THE LEAK...
 ADDITIONAL CONTRIBUTING FACTORS
 PHYSIOLOGICAL ASPECTS OF HAPE...
 REFERENCES
 
As pointed out above, HAPE-susceptible individuals exhibit an abnormal heightened PAP response when exposed to hypoxia (38, 54, 110). Furthermore, the excessive rise in PAP precedes HAPE (14). Cardiac catheterization of untreated cases of HAPE at high altitude revealed mean pulmonary artery pressures of 60 (range 33–117 mmHg) (6, 56, 69, 83), whereas pulmonary wedge pressures were normal. Estimations of systolic PAP by echocardiography revealed values between 50 and 80 mmHg for subjects with HAPE and 30 and 50 mmHg for healthy controls (14, 79, 95, 105). Furthermore, drugs such as nifedipine (14) and tadalafil (68), which lower PAP, prevent HAPE, and are effective for treatment (79). Because capillary pressure is also elevated in HAPE, the question arises how hypoxic constriction of arterioles can lead to edema. Three mechanisms have been suggested: transarteriolar leakage, irregular vasoconstriction with regional overperfusion, and hypoxic venoconstriction.

There is evidence in hypoxic animal experiments using the double-occlusion technique (44, 89) that the small arterioles are exposed to high pressure and that they are the site of transvascular leakage in the presence of markedly increased PAP in hypoxia (117). Pulmonary veins also contract in response to hypoxia (86, 122), increasing the resistance downstream of the fluid filtration region. Both mechanisms, alone or in combination, however, cannot explain the patchy radiographic appearance of early HAPE as it appears on chest radiographs or CT scans, unless we postulate in addition regional heterogeneity of hypoxic pulmonary vasoconstriction.

If vasoconstriction in hypoxia is inhomogeneous, HAPE could be the consequence of uneven distribution of blood flow. High flow in areas with low vasoconstriction would lead to increased capillary pressure due to venous resistance as demonstrated in animal experiments by Younes et al. (119) and a longitudinal pressure drop across these vessels insufficient to lower the tension below the threshold of 17–24 mmHg at the point of entry into the alveolar microvasculature (48). This concept of increased capillary pressure by a high blood flow was postulated by Visscher (109) first and adapted to HAPE by Hultgren (57). Recent investigations, which demonstrate that hypoxic pulmonary vasoconstriction is uneven, give substantial support to the concept of regional overperfusion. With the use of microspheres, it was shown that the spatial heterogeneity of the pulmonary perfusion in pigs increases with hypoxia (46). Furthermore, a study using magnetic resonance imaging found larger blood flow heterogeneity in hypoxia in HAPE-susceptible individuals vs. nonsusceptible controls (49).

In summary, these most recent investigations provide evidence for the concept that a high blood flow accounts for the increased capillary pressure because it exceeds the capacity of dilation of the capillary-venous side (119). Pulmonary edema due to high blood flow can occur in nonoccluded areas in pulmonary embolism (58), following thromboendarterectomy (74), and it contributes to pulmonary edema during vigorous exercise in highly trained athletes (21, 50) or racehorses (115) that can sustain a very high cardiac output. It is quite likely that the increase in pulmonary blood flow on exercise in HAPE-susceptible individuals will raise pulmonary capillary pressure more and provoke more edema formation.

Uneven HPV might be attributed to uneven distribution of arterial smooth muscle cells. This hypothesis could account for the fact that slow ascent does not lead to HAPE even in susceptible individuals and for the observation that HAPE only occurs during the first 5 days after acute exposure to a given altitude. In both situations, rapid remodeling and generalized muscular hypertrophy of pulmonary arterioles could lead to a more even distribution of blood flow. This may contribute to persistent excessive pulmonary hypertension and lead over some weeks to months to congestive right heart failure termed "sub-acute mountain sickness" as described in Han infants in Tibet (103) and in Indian soldiers stationed at altitudes between 5,000 and 6,000 m (4).


   NATURE OF THE LEAK IN HAPE
TOP
 ABSTRACT
 CLINICAL PICTURE
 CHARACTERISTICS OF SUSCEPTIBLE...
 MECHANISMS ACCOUNTING FOR...
 HAPE IS A HYDROSTATIC...
 MECHANISMS ACCOUNTING FOR...
 NATURE OF THE LEAK...
ADDITIONAL CONTRIBUTING FACTORS
 PHYSIOLOGICAL ASPECTS OF HAPE...
 REFERENCES
 
Measurements of capillary pressure (69) and analysis of BAL fluid (105) in early HAPE indicate that hydrostatic stress can lead to a permeability-type edema with high protein concentration in the absence of inflammation. This concept was first advanced in left-sided congestive heart failure (106) and extended to HAPE by West et al. (116), who coined the structural engineering term "stress failure" and went on to describe its basis in excessive stress on the collagen and other supporting extracellular matrix elements of the alveolar capillary barrier. West and colleagues (115) showed in rabbit lungs that a rapid exposure of the pulmonary microcirculation to transvascular pressures of 40–60 cmH2O (30–44 mmHg) within 1 min is a hydraulic stress that exceeds the load-bearing limits of the membrane collagen network and results in ruptures of the basement membrane and thus the alveolar-capillary barrier. We hesitate to use the term "stress failure" that is linked to these structural changes to account for the permeability changes observed in early HAPE with only moderate capillary pressure elevation at rest and with mild-moderate exercise. Although capillary pressure may rise considerably higher during the exercise of ascending, our subjects showed no signs of pulmonary edema after arrival and abstained from exercise during the following 12–36 h, during which time HAPE developed (105). In addition to the difference regarding magnitude and mode of exposure of the pulmonary microcirculation to increased pressure, there are some observations in early HAPE that point to substantial differences between the model of stress failure and nascent HAPE. LTB4 is elevated in edema fluid in animal models of stress failure (107) as well as in lavage fluid of elite cyclists with alveolar hemorrhage (50) and in advanced cases of HAPE (63, 98), although this is not the case in early HAPE. LTB4 elevation may be a marker of most extreme stress that accompanies large and abrupt pressure elevation. Furthermore, we found no increase of markers of in vivo fibrin or thrombin formation and normal levels of {beta}-thromboglobulin, a marker of platelet activation, in early HAPE (10, 12). If exposure of basement membranes and rupture of tissue occur, we would expect to find such activation, which occurs in very severe, advanced HAPE (11, 18).

These observations suggest that the leak in early HAPE might be caused by nontraumatic, dynamic, pressure-sensitive opening/stretching of pores, fenestrae, or increased transcellular vesicular flux, which allows plasma components to access the interstitial and then the alveolar spaces without overt damage to the barrier. Transcellular movements of plasma and its constituents via pressure-sensitive and pressure-induced continuous vesicular channels have been described in the systemic circulation (32, 78). Vesical formation might be induced by active signaling initiated by the state of stretch on collagen and its attachments to the cell. The nature of this signaling may entail changes in intracellular calcium or cAMP concentrations, as the work of Parker and colleagues (80–82) and Adamson et al. (1) indicate. Parker et al. suggested that dynamic modulation of the vascular barrier in response to pressure changes may serve as a mechanism to release transient increases in pressure to preserve the basement membrane and collagen network so that the barrier function can rapidly be reestablished. Although the exact nature of its leak is not known, HAPE is another example of a pulmonary edema that demonstrates that the old paradigm according to which hydrostatic stress can only lead to ultrafiltration of protein-poor fluid is too simplistic. This has also been shown for cardiogenic pulmonary edema (99) as well as in a rabbit model of cardiogenic edema (8).


   ADDITIONAL CONTRIBUTING FACTORS
TOP
 ABSTRACT
 CLINICAL PICTURE
 CHARACTERISTICS OF SUSCEPTIBLE...
 MECHANISMS ACCOUNTING FOR...
 HAPE IS A HYDROSTATIC...
 MECHANISMS ACCOUNTING FOR...
 NATURE OF THE LEAK...
 ADDITIONAL CONTRIBUTING FACTORS
PHYSIOLOGICAL ASPECTS OF HAPE...
 REFERENCES
 
Exercise.   Increasing cardiac output several-fold over baseline contributes to edema formation by increasing capillary pressure in overperfused areas and may even worsen the regional heterogeneity of blood flow. Furthermore, the greater increase of PAP in HAPE-susceptible individuals may impair left ventricular filling because of a ventricular septal shift shown by Ritter et al. (88) and to possible mild left ventricular stiffness arising from decreased cardiac lymph clearance to the right heart (25). Diastolic dysfunction due to pulmonary hypertension likely explains the significantly greater wedge pressure increase in HAPE-susceptible individuals compared with nonsusceptible controls during exercise in hypoxia (34), whereas at rest, wedge pressure is normal in untreated HAPE (69). In many cases of HAPE, particularly at lower elevations, exercise may be the essential component of the setting that leads to pulmonary edema.

Alveolar fluid clearance.   A further mechanism that may contribute to the pathophysiology of HAPE is a diminished capacity for alveolar fluid reabsorption. The major processes that mediate water and sodium reabsorption across alveolar epithelial cells are indicated in Fig. 5A. Results obtained in cultured alveolar epithelial cells and hypoxia-exposed rats show that hypoxia 1) inhibits activity and expression of various Na transporters, the most important being apical membrane epithelial Na channels and the basolateral membrane Na+-K+-ATPase (84, 85), 2) decreases transepithelial alveolar Na transport (70), and 3) decreases the reabsorption of fluid instilled into the lung (Fig. 5B) (111). Taken together, these findings suggest that impaired clearance of fluid filtered into the alveoli may be involved in the pathophysiology of HAPE.



View larger version (21K):
[in this window]
[in a new window]
  		Fig. 5. Alveolar fluid balance. A: removal of alveolar fluid is driven by the active reabsorption of Na+ that enters the cell via Na channels and Na-coupled transport (Na/X) and is extruded by Na+-K+-ATPases. Thus active Na reabsorption generates the osmotic gradient for the reabsorption of water. B: hypoxia inhibits the reabsorption of fluid instilled into lungs of hypoxia-exposed rats, which is fully explained by inhibition of amiloride-sensitive pathways (mostly Na channels). *P < 0.05 vs. control values in normoxia. Modified from Vivona et al. (111).

 
Alveolar epithelial sodium and fluid transport can be stimulated by {beta}2-receptor agonists (for review, see Ref. 73). In addition, a recent field study shows successful prevention (~40–50% reduction) of HAPE with high-dose inhalation of the {beta}2-agonist salmeterol (90). It should be noted, however, that this drug also lowers PAP as shown by the same authors (92), tightens cell-to-cell contacts (80), and increases NO production (2) as well as the ventilatory response to hypoxia (104). Any or all of these {beta}-agonist-mediated effects could account for the protection afforded by salmeterol, independent of stimulation of Na reabsorption.

The nasal epithelium contains Na transporters similar to those of alveolar epithelium and is sometimes used as an in vivo model to obtain information on what might transpire at the experimentally inaccessible human alveolar epithelium. In accordance with the results obtained on alveolar cells, it has been found that nasal epithelial Na transport is also inhibited by hypoxia (71, 91). On the basis of decreased transepithelial nasal potentials in HAPE-susceptible individuals even at low altitude (71, 90), Sartori et al. (90) suggested that a decreased capacity of epithelial Na reabsorption might predispose to HAPE. However, because environmental factors and nasal dryness stimulate secretion (22) and might therefore affect nasal potential measurements (71), but not Na reabsorption by alveolar epithelium, it is unclear to what extent this parameter is predictive of altered alveolar Na transport. Nevertheless, experimental evidence in support of this hypothesis comes from genetically engineered mice partially deficient in the apical (alveolar facing) epithelial sodium channel, which show greater accumulation of lung water in hypoxia (94) and hyperoxia (33).

It is important to note that, during ascent, the rate of filtration into the interstitial space and the alveoli increases slowly as PAP increases with exercise and increasing degree of hypoxia. Genetically or constitutionally reduced alveolar Na transport capacity in combination with hypoxic inhibition of Na transport might blunt the removal of alveolar fluid, causing greater fluid accumulation and hypoxemia. In contrast, a high capacity of alveolar Na transport, with or without pharmacological stimulation, might limit alveolar flooding (51). It is obvious, however, that reabsorption can only be effective when the alveolar barrier is greatly intact and the rate of fluid transudation is modest so that the rate of reabsorption can be higher than leakage, a prerequisite not granted in situations when microvascular pressures are high and proteins and erythrocytes escape easily into the alveolar space (105).

Because HAPE can be fully prevented by decreasing PAP, more specific drugs that solely target alveolar epithelial Na and water reabsorption are required to establish, on a quantitative basis, the role of active alveolar fluid reabsorption in the pathophysiology of HAPE.

Inflammation.   It is conceivable that the pressure required for transvascular leakage decreases when the integrity of the alveolar capillary barrier is weakened. Thus any inflammatory process of the respiratory tract that extends to the alveolar space would facilitate edema formation at lower capillary pressures. Indeed, increased fluid accumulation during hypoxic exposure after priming by endotoxin or viruses in animals (23) and the association of previous viral infections (predominantly of the upper respiratory tract) with HAPE in children (31) support this concept. Under conditions of increased permeability, HAPE may also occur in individuals with normal hypoxic pulmonary vascular response or in susceptible individuals at lower altitudes around 2,000 m (35).

Reduction in cross-sectional area of the pulmonary capillaries.   Any reduction in the capillary bed should enhance edema formation because of reduced reserve capacity and thus higher resistance to increased flow. Examples are pulmonary edema at low altitude after pulmonary embolism in nonoccluded lung areas (58). Minor, unrecognized pulmonary embolism may explain a HAPE-like presentation at moderate altitudes (35) or unexpected HAPE in nonsusceptible individuals at high altitude (P. Bärtsch, E. Grünig, and E. Mayer, unpublished observations). Furthermore, unilateral absence of a main pulmonary artery is a known factor for HAPE at altitudes around 2,000 m (39).


   PHYSIOLOGICAL ASPECTS OF HAPE AND QUESTIONS FOR FURTHER RESEARCH
TOP
 ABSTRACT
 CLINICAL PICTURE
 CHARACTERISTICS OF SUSCEPTIBLE...
 MECHANISMS ACCOUNTING FOR...
 HAPE IS A HYDROSTATIC...
 MECHANISMS ACCOUNTING FOR...
 NATURE OF THE LEAK...
 ADDITIONAL CONTRIBUTING FACTORS
 PHYSIOLOGICAL ASPECTS OF HAPE...
REFERENCES
 
HAPE is now well established as the consequence of hypoxic pulmonary vasoconstriction (HPV) and sufficient transmission of high PAP and blood flow to portions of the pulmonary capillary bed, most likely due to regional unevenness in HPV. Although strong HPV is a characteristic shared by most individuals who develop HAPE, there probably can be no absolute resistance to HAPE, even in "nonsusceptible" individuals if altitude gained and ascent rate are high enough. HPV is thought to be an adaptive physiological mechanism that serves two purposes. In utero, combined with a patent ductus arteriosus, it directs venous blood flow to the arterial circulation and away from the nonventilated non-gas-exchanging lung. After birth, it enhances ventilation-perfusion matching and, particularly with regional lung disease, it helps to preserve oxygenation of arterial blood by diverting blood flow away from poorly ventilated hypoxic areas. HPV, however, becomes detrimental when the whole lung or large portions of it are exposed to hypoxia, especially in those individuals who have a particularly vigorous HPV. Acute exposure predisposes them to HAPE and prolonged exposure to right heart overload, resulting in congestive right heart failure, a syndrome also called subacute mountain sickness. Invasive measurements of PAP in Tibetans, the population that is genetically best adapted to high altitude demonstrate that evolution has selected against and virtually abolished HPV (37), possibly by a greater production of NO (19). These findings suggest that HPV has no vital significance even in utero and that it reduces the high-altitude tolerance of populations living at low altitude.

The fluid leak in humans with HAPE (and in animal models) supports the concept proposed by West et al. (115) that increased pulmonary capillary pressure can lead to a permeability-type edema in the absence of inflammation and challenges the classical paradigm that hydrostatic stress can only lead to ultrafiltration of protein-poor fluid. The same pathophysiology of capillary leak at high pressure and flow (overperfusion edema) exceeding local mechanisms of fluid absorption and clearance that is central to HAPE is also relevant to other forms of pulmonary edema at low altitude, including maximal exercise in highly trained humans or horses, pulmonary embolism, reperfusion lung injuries (thromboendarterectomy and acute graft dysfunction of the new transplanted lung), and neurogenic pulmonary edema. The study of HAPE has taught us much about the physiology of the lung and pulmonary vasculature, and it is hoped that successful strategies for HAPE prevention and treatment may find broader clinical application in pulmonary edema of other etiologies.

Despite considerable recent advances in our understanding of the mechanisms that account for HAPE, there remain many hypotheses to be challenged or questions to be answered, such as the relation between susceptibility to HAPE and subacute mountain sickness, the remodeling of the pulmonary circulation in newcomers to high altitude, or the genetic basis of susceptibility. We need to examine the significance of fluid clearance from the alveoli for the pathogenesis of HAPE, ideally with drugs that have no other actions except stimulation of sodium reabsorption, to more fully characterize the leak of the alveolocapillary barrier and to elucidate the mechanisms by which dexamethasone prevents HAPE, including whether inhaled glucocorticoids may be sufficient.


   FOOTNOTES
 

Address for reprint requests and other correspondence: P. Bärtsch, Dept. of Internal Medicine VII, Div. of Sports Medicine, Medical Univ. Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany (E-mail: peter_bartsch{at}med.uni-heidelberg.de)


   REFERENCES
TOP
 ABSTRACT
 CLINICAL PICTURE
 CHARACTERISTICS OF SUSCEPTIBLE...
 MECHANISMS ACCOUNTING FOR...
 HAPE IS A HYDROSTATIC...
 MECHANISMS ACCOUNTING FOR...
 NATURE OF THE LEAK...
 ADDITIONAL CONTRIBUTING FACTORS
 PHYSIOLOGICAL ASPECTS OF HAPE...
 REFERENCES
 

  1. Adamson RH, Liu B, Fry GN, Rubin L, and Curry FE. Microvascular permeability and number of tight junctions are modulated by cAMP. Am J Physiol Heart Circ Physiol 274: H1885–H1894, 1998.[Abstract/Free Full Text]
  2. Adding LC, Agvald P, Artlich A, Persson MG, and Gustafson LE. Beta-adrenoceptor agonist stimulation of pulmonary nitric oxide production in the rabbit. Br J Pharmacol 126: 833–839, 1999.[CrossRef][Web of Science][Medline]
  3. Albert RK, Lakshminarayan S, Hildebrandt J, Kirk W, and Butler J. Increased surface tension favors pulmonary edema formation in anesthetized dogs' lungs. J Clin Invest 63: 1015–1018, 1979.[Web of Science][Medline]
  4. Anand IS, Malhotra RM, Chandrashekhar Y, Bali HK, Chauhan SS, Jindal SK, Bhandari RK, and Wahi PL. Adult subacute mountain sickness—a syndrome of congestive heart failure in man at very high altitude. Lancet 335: 561–565, 1990.[CrossRef][Web of Science][Medline]
  5. Anand IS, Prasad BAK, Chugh SS, Rao KRM, Cornfield DN, Milla CE, Singh N, Singh S, and Selvamurthy W. Effects of inhaled nitric oxide and oxygen in high-altitude pulmonary edema. Circulation 98: 2441–2445, 1998.[Abstract/Free Full Text]
  6. Antezana G, Leguia G, Morales Guzman A, Coudert J, and Spielvogel H. Hemodynamic study of high altitude pulmonary edema (12,200 ft). In: High Altitude Physiology and Medicine, edited by Brendel W and Zink RA. New York: Springer Verlag, p. 232–241, 1982.
  7. Arias-Stella J and Kruger H. Pathology of high altitude pulmonary edema. Arch Pathol 76: 147–157, 1963.[Web of Science][Medline]
  8. Bachofen H, Schürch S, and Weibel ER. Experimental hydrostatic pulmonary edema in rabbit lungs: barrier lesions. Am Rev Respir Dis 147: 997–1004, 1993.[Web of Science][Medline]
  9. Bärtsch P. High altitude pulmonary edema. Med Sci Sports Exerc 31: S23–S27, 1999.
  10. Bärtsch P, Haeberli A, Franciolli M, Kruithof EKO, and Straub PW. Coagulation and fibrinolysis in acute mountain sickness and beginning pulmonary edema. J Appl Physiol 66: 2136–2144, 1989.[Abstract/Free Full Text]
  11. Bärtsch P, Haeberli A, Nanzer A, Lämmle B, Vock P, Oelz O, and Straub PW. High altitude pulmonary edema: blood coagulation. In: Hypoxia and Molecular Medicine, edited by Sutton JR, Houston CS, and Coates G. Burlington, VT: Queen City Printers, 1993, p. 252–258.
  12. Bärtsch P, Lämmle B, Huber I, Haeberli A, Vock P, Oelz O, and Straub PW. Contact phase of blood coagulation is not activated in edema of high altitude. J Appl Physiol 67: 1336–1340, 1989.[Abstract/Free Full Text]
  13. Bärtsch P, Maggiorini M, Mairbäurl H, Vock P, and Swenson E. Pulmonary extravascular fluid accumulation in climbers (Letter). Lancet 360: 571, 2002.[Medline]
  14. Bärtsch P, Maggiorini M, Ritter M, Noti C, Vock P, and Oelz O. Prevention of high-altitude pulmonary edema by nifedipine. N Engl J Med 325: 1284–1289, 1991.[Abstract]
  15. Bärtsch P, Shaw S, Franciolli M, Gnädinger MP, and Weidmann P. Atrial natriuretic peptide in acute mountain sickness. J Appl Physiol 65: 1929–1937, 1988.[Abstract/Free Full Text]
  16. Bärtsch P, Swenson ER, and Maggiorini M. Update: high altitude pulmonary edema. In: Hypoxia: From Genes to the Bedside, edited by Roach RC. New York: Kluwer Academic/Plenum, 2001, p. 89–106.
  17. Bärtsch P, Vock P, and Franciolli M. High altitude pulmonary edema after successful treatment of acute mountain sickness with dexamethasone. Wilderness Med 1: 162–164, 1990.
  18. Bärtsch P, Waber U, Haeberli A, Maggiorini M, Kriemler S, Oelz O, and Straub WP. Enhanced fibrin formation in high-altitude pulmonary edema. J Appl Physiol 63: 752–757, 1987.[Abstract/Free Full Text]
  19. Beall CM, Laskowski D, Strohl KP, Soria R, Villena M, Vargas E, Alarcon AM, Gonzales C, and Erzurum SC. Pulmonary nitric oxide in mountain dwellers. Nature 414: 411–412, 2001.[CrossRef][Medline]
  20. Berger M, Hesse C, Dehnert C, Siedler H, Kleinbongard P, Gharini P, Bardenheuer H, Kelm M, Bärtsch P, and Haefeli W. Hypoxia impairs endothelial function in individuals susceptible to high-altitude pulmonary oedema (HAPE): the missing link in the pathogenesis of HAPE (Abstract)? High Alt Med Biol. In press.
  21. Busch T, Bärtsch P, Pappert D, Grünig E, Elser H, Falke KJ, and Swenson ER. Hypoxia decreases exhaled nitric oxide in mountaineers susceptible to high altitude pulmonary edema. Am J Respir Crit Care Med 163: 368–373, 2001.[Abstract/Free Full Text]
  22. Caillaud C, Serre-Cousiné O, Anselme F, Capdevilla X, and Préfaut C. Computerized tomography and pulmonary diffusing capacity in highly trained athletes after performing a triathlon. J Appl Physiol 79: 1226–1232, 1995.[Abstract/Free Full Text]
  23. Canning BJ. Neurology of allergic inflammation and rhinitis. Curr Allergy Asthma Rep 2: 210–215, 2002.[Medline]
  24. Carpenter TD, Reeves JT, and Durmowicz AG. Viral respiratory infection increases susceptibility of young rats to hypoxia-induced pulmonary edema. J Appl Physiol 84: 1048–1054, 1998.[Abstract/Free Full Text]
  25. Chapleau MW, Wilson LB, Gregory TJ, and Levitzky MG. Chemoreceptor stimulation interferes with regional hypoxic pulmonary vasoconstriction. Respir Physiol 71: 185–200, 1988.[CrossRef][Web of Science][Medline]
  26. Davis KL, Mehlhorn U, Laine GA, and Allen SJ. Myocardial edema, left ventricular function, and pulmonary hypertension. J Appl Physiol 78: 132–137, 1995.[Abstract/Free Full Text]
  27. Dehnert C, Weymann J, Montgomery HE, Woods D, Maggiorini M, Scherrer U, Gibbs JSR, and Bärtsch P. No association between high-altitude tolerance and the ACE I/D gene polymorphism. Med Sci Sports Exerc 34: 1928–1933, 2002.
  28. DeRijk RH, Schaaf M, and de Kloet ER. Glucocorticoid receptor variants: clinical implications. J Steroid Biochem Mol Biol 81: 103–122, 2002.[CrossRef][Web of Science][Medline]
  29. Droma Y, Hanaoka M, Ota M, Katsuyama Y, Koizumi T, Fujimoto K, Kobayashi T, and Kubo K. Positive association of the endothelial nitric oxide synthase gene polymorphisms with high-altitude pulmonary edema. Circulation 106: 826–830, 2002.[Abstract/Free Full Text]
  30. Duplain H, Sartori C, Lepori M, Egli M, Allemann Y, Nicod P, and Scherrer U. Exhaled nitric oxide in high-altitude pulmonary edema: role in the regulation of pulmonary vascular tone and evidence for a role against inflammation. Am J Respir Crit Care Med 162: 221–224, 2000.[Abstract/Free Full Text]
  31. Duplain H, Vollenweider L, Delabays A, Nicod P, Bärtsch P, and Scherrer U. Augmented sympathetic activation during short-term hypoxia and high-altitude exposure in subjects susceptible to high-altitude pulmonary edema. Circulation 99: 1713–1718, 1999.[Abstract/Free Full Text]
  32. Durmowicz AG, Nooordeweir E, Nicholas R, and Reeves JT. Inflammatory processes may predispose children to develop high altitude pulmonary edema. J Pediatr 130: 838–840, 1997.[Web of Science][Medline]
  33. Dvorak AM and Feng D. The vesiculo-vacuolar organelle (VVO): a new endothelial cell permeability organelle. J Histochem Cytochem 49: 419–431, 2001.[Abstract/Free Full Text]
  34. Egli M, Duplain H, Lepori M, Cook S, Nicod P, Hummler E, Sartori C, and Scherrer U. Defective respiratory amiloride sensitive sodium transport predisposes to pulmonary oedema and delays its resolution in mice. J Physiol 560: 857–865, 2004.[Abstract/Free Full Text]
  35. Eldridge MW, Podolsky A, Richardson RS, Johnson DH, Knight DR, Johnson EC, Hopkins SR, Michimata H, Grassi B, Feiner J, Kurdak SS, Bickler PE, Wagner PD, and Severinghaus JW. Pulmonary hemodynamic response to exercise in subjects with prior high-altitude pulmonary edema. J Appl Physiol 81: 911–921, 1996.[Abstract/Free Full Text]
  36. Gabry AL, Ledoux X, Mozziconacci M, and Martin C. High-altitude pulmonary edema at moderate altitude (<2,400 m; 7,870 feet). Chest 123: 49–53, 2003.[CrossRef][Web of Science][Medline]
  37. Ghofrani HA, Reichenberger F, Kohstall MG, Mrosek EH, Seeger T, Olschewski H, Seeger W, and Grimminger F. Sildenafil increased exercise capacity during hypoxia at low altitudes and at Mount Everest Base Camp. Ann Intern Med 141: 169–177, 2004.[Abstract/Free Full Text]
  38. Groves BM, Droma T, Sutton JR, McCullough RG, McCullough RE, Zhuang J, Rapmund G, Sun S, Janes G, and Moore LG. Minimal hypoxic pulmonary hypertension in normal Tibetans at 3,658 m. J Appl Physiol 74: 312–318, 1993.[Abstract/Free Full Text]
  39. Grünig E, Mereles D, Hildebrandt W, Swenson ER, Kübler W, Kuecherer H, and Bärtsch P. Stress Doppler echocardiography for identification of susceptibility to high altitude pulmonary edema. J Am Coll Cardiol 35: 980–987, 2000.[Abstract/Free Full Text]
  40. Hackett PH, Creagh CE, Grover RF, Honigman B, Houston CS, Reeves JT, Sophocles AM, and van Hardenbroek M. High altitude pulmonary edema in persons without the right pulmonary artery. N Engl J Med 302: 1070–1073, 1980.[Web of Science][Medline]
  41. Hackett PH, Rennie D, and Levine HD. The incidence, importance, and prophylaxis of acute mountain sickness. Lancet II: 1149–1154, 1976.
  42. Hackett PH and Roach RC. High-altitude illness. N Engl J Med 345: 107–114, 2001.[Free Full Text]
  43. Hackett PH, Roach RC, Schoene RB, Harrison GL, and Mills WJ. Abnormal control of ventilation in high-altitude pulmonary edema. J Appl Physiol 64: 1268–1272, 1988.[Abstract/Free Full Text]
  44. Hafezi-Moghadam A, Simoncini T, Yang Z, Limbourt FP, Plumier JC, Rebdamen MC, Hsieh CM, Chui DS, Thomas KL, Prorock A, Laubach VE, Moskowitz MA, French BA, Ley K, and Liao JK. Acute cardiovascular protective effects of corticosteroids are mediated by non-transcriptional activation of endothelial nitric oxide synthase. Nat Med 8: 473–479, 2002.[CrossRef][Web of Science][Medline]
  45. Hakim TS and Kelly S. Occlusion pressures vs. micropipette pressures in the pulmonary circulation. J Appl Physiol 67: 1277–1285, 1989.[Abstract/Free Full Text]
  46. Hanaoka M, Droma Y, Hotta J, Matsuzawa Y, Kobayashi T, Kubo K, and Ota M. Polymorphisms of the tyrosine hydroxylase gene in subjects susceptible to high-altitude pulmonary edema. Chest 123: 54–58, 2003.[Medline]
  47. Hlastala MP, Lamm WJE, Karp A, Polissar NL, Starr IR, and Glenny RW. Spatial distribution of hypoxic pulmonary vasoconstriction in the supine pig. J Appl Physiol 96: 1589–1599, 2004.[Abstract/Free Full Text]
  48. Hohenhaus E, Paul A, McCullough RE, Kücherer H, and Bärtsch P. Ventilatory and pulmonary vascular response to hypoxia and susceptibility to high altitude pulmonary oedema. Eur Respir J 8: 1825–1833, 1995.[Abstract]
  49. Homik LA, Bshouty RB, Light RB, and Younes M. Effect of alveolar hypoxia on pulmonary fluid filtration in in situ dog lungs. J Appl Physiol 65: 46–52, 1988.[Abstract/Free Full Text]
  50. Hopkins SR, Garg J, Bolar DS, Balouch J, and Levin DL. Pulmonary blood flow heterogeneity during hypoxia and high altitude pulmonary edema. Am J Respir Crit Care Med doi:10.1164/rccm.200406-707OC. 2004.
  51. Hopkins SR, Schoene RB, Henderson WR, Spragg RG, Martin TR, and West JB. Intense exercise impairs the integrity of the pulmonary blood-gas barrier in elite athletes. Am J Respir Crit Care Med 155: 1090–1094, 1997.[Abstract]
  52. Höschele S and Mairbäurl H. Alveolar flooding at high altitude: failure of reabsorption? News Physiol Sci 18: 55–59, 2003.[Abstract/Free Full Text]
  53. Hotta J, Hanaoka M, Droma Y, Katsuyama M, Ota M, and Kobayashi T. Polymorphisms of renin-angiotensin system genes with high-altitude pulmonary edema in Japanese subjects. Chest 126: 825–830, 2004.[Medline]
  54. Houston CS. Acute pulmonary edema of high altitude. N Engl J Med 263: 478–480, 1960.[Web of Science][Medline]
  55. Hultgren HN, Grover RF, and Hartley LH. Abnormal circulatory responses to high altitude in subjects with a previous history of high-altitude pulmonary edema. Circulation 44: 759–770, 1971.[Abstract/Free Full Text]
  56. Hultgren HN, Honigman B, Theis K, and Nicholas D. High-altitude pulmonary edema at a ski resort. West J Med 164: 222–227, 1996.[Web of Science][Medline]
  57. Hultgren HN, Lopez CE, Lundberg E, and Miller H. Physiologic studies of pulmonary edema at high altitude. Circulation 29: 393–408, 1964.[Abstract/Free Full Text]
  58. Hultgren NH. High altitude pulmonary edema. In: Lung Water Solute Exchange, edited by Staub NC. New York: Dekker, p. 437–464, 1978.
  59. Hyers TM, Fowler AA, and Wicks AB. Focal pulmonary edema after massive pulmonary embolism. Am Rev Respir Dis 123: 232–233, 1981.[Web of Science][Medline]
  60. Hyers TM, Scoggin CH, Will DH, Grover RF, and Reeves JT. Accentuated hypoxemia at high altitude in subjects susceptible to high-altitude pulmonary edema. J Appl Physiol 46: 41–46, 1979.[Web of Science][Medline]
  61. Kaminsky DA, Jones K, Schoene RB, and Voelkel NF. Urinary leuktriene E (4) levels in high-altitude pulmonary edema: a possible role for inflammation. Chest 110: 939–945, 1996.[Medline]
  62. Kawashima A, Kubo K, Kobayashi T, and Sekiguchi M. Hemodynamic responses to acute hypoxia, hypobaria, and exercise in subjects susceptible to high-altitude pulmonary edema. J Appl Physiol 67: 1982–1989, 1989.[Abstract/Free Full Text]
  63. Koyama S, Kobayashi T, Kubo K, Fukushima M, Yoshimura K, and Shibamoto TKS. The increased sympathoadrenal activity in patients with high altitude pulmonary edema is centrally mediated. Jpn J Med 27: 10–16, 1988.[Medline]
  64. Kubo K, Hanaoka M, Yamaguchi S, Hayano T, Hayasaka M, Koizumi T, Fujimoto K, Kobayashi T, and Honda T. Cytokines in bronchoalveolar lavage fluid in patients with high altitude pulmonary oedema at moderate altitude in Japan. Thorax 51: 739–742, 1996.[Abstract/Free Full Text]
  65. Kumar R, Pasha Q, Kann AP, and Gupta V. Renin angiotensin aldosterone system and ACE I/D gene polymorphism in high altitude pulmonary edema. Aviat Space Environ Med 75: 981–983, 2004.[Medline]
  66. Lear GH. Neurogenic pulmonary oedema. Acta Paediatr Scand 79: 1131–1133, 1990.[Web of Science][Medline]
  67. Litch JA and Bishop RA. Reascent following resolution of high altitude pulmonary edema (HAPE) (Case Report). High Alt Med Biol 2: 53–55, 2001.[CrossRef][Medline]
  68. Lizarraga L. Soroche agudo: Edema agudo del pulmón. An Fac Med (San Marco, Lima) 38: 244–274, 1955.
  69. Maggiorini M, Brunner-La Rocca HP, Bärtsch P, Fischler MT, Böhm Bloch KE, and Mairbäurl H. Dexamethasone and tadalafil prophylaxis prevents both excessive pulmonary constriction and high altitude pulmonary edema in susceptible subjects (Abstract). Eur Respir J 24: 110s, 2004.
  70. Maggiorini M, Mélot C, Pierre S, Pfeiffer F, Greve I, Sartori C, Lepori M, Hauser M, Scherrer U, and Naeije R. High-altitude pulmonary edema is initially caused by an increase in capillary pressure. Circulation 103: 2078–2083, 2001.[Abstract/Free Full Text]
  71. Mairbäurl H, Mayer K, Kim KJ, Borok Z, Bärtsch P, and Crandall ED. Hypoxia decreases active Na transport across primary rat alveolar epithelial cell monolayers. Am J Physiol Lung Cell Mol Physiol 282: L659–L665, 2002.[Abstract/Free Full Text]
  72. Mairbäurl H, Weymann J, Möhrlein A, Swenson ER, Maggiorini M, Gibbs JSR, and Bärtsch P. Nasal epithelium potential difference at high altitude (4,559 m). Am J Respir Crit Care Med 167: 862–867, 2003.[Abstract/Free Full Text]
  73. Matsuzawa Y, Fujimoto K, Kobayashi T, Namushi NR, Harada K, Kohno H, Fukushima M, and Kusama S. Blunted hypoxic ventilatory drive in subjects susceptible to high-altitude pulmonary edema. J Appl Physiol 66: 1152–1157, 1989.[Abstract/Free Full Text]
  74. Matthay MA, Clerici C, and Saumon C. Active fluid clearance from distal airspaces. J Appl Physiol 93: 1533–1541, 2002.[Abstract/Free Full Text]
  75. Miller WT, Osiason AW, Langlotz CP, and Palevsky HI. Reperfusion edema after thromboendarterectomy: radiographic patterns of disease. J Thorac Imaging 13: 178–183, 1998.[Web of Science][Medline]
  76. Ming Z and Wang DX. Sympathetic innervation of pulmonary circulation ant its role in hypoxic pulmonary vasoconstriction. J Tongji Med Univ 9: 153–159, 1989.[Medline]
  77. Murata T, Hori M, Sakamoto K, Karaki H, and Ozaki H. Dexamethasone blocks hypoxia-induced endothelial dysfunction in organ-cultured pulmonary arteries. Am J Respir Crit Care Med 170: 647–655, 2004.[Abstract/Free Full Text]
  78. Nayak NC, Roy S, and Narayanan TK. Pathologic features of altitude sickness. Am J Pathol 45: 381–391, 1964.[Web of Science][Medline]
  79. Neal CR and Michel CC. Openings in frog microvascular endothelium induced by high intravascular pressures. J Physiol 492: 39–52, 1996.[Abstract/Free Full Text]
  80. Oelz O, Ritter M, Jenni R, Maggiorini M, Waber U, Vock P, and Bärtsch P. Nifedipine for high altitude pulmonary oedema. Lancet 2: 1241–1244, 1989.[Web of Science][Medline]
  81. Parker JC and Ivey CL. Isoproterenol attenuates high vascular pressure-induced permeability increases in isolated rat lungs. J Appl Physiol 83: 1962–1967, 1997.[Abstract/Free Full Text]
  82. Parker JC, Ivey CL, and Tucker JA. Gadolinium prevents high airway pressure-induced permeability increases in isolated rat lungs. J Appl Physiol 84: 1113–1118, 1998.[Abstract/Free Full Text]
  83. Parker JC and Yoshikawa S. Vascular segmental permeabilities at high peak inflation pressure in isolated rat lungs. Am J Physiol Lung Cell Mol Physiol 283: L1203–L1209, 2002.[Abstract/Free Full Text]
  84. Penaloza D and Sime F. Circulatory dynamics during high altitude pulmonary edema. Am J Cardiol 23: 369–378, 1969.[CrossRef][Web of Science][Medline]
  85. Pham I, Uchida T, Planes C, Ware LB, Kaner R, Matthay MA, and Clerici C. Hypoxia upregulates VEGF expression in alveolar epithelial cells in vitro and in vivo. Am J Physiol Lung Cell Mol Physiol 283: L1133–L1142, 2002.[Abstract/Free Full Text]
  86. Planes C, Escoubet B, Blot-Chabaud M, Friedlander G, Farman N, and Clerici C. Hypoxia downregulates expression and activity of epithelial sodium channels in rat alveolar epithelial cells. Am J Respir Cell Mol Biol 17: 508–518, 1997.[Abstract/Free Full Text]
  87. Raj JU and Chen P. Micropuncture measurement of microvascular pressures in isolated lamb lungs during hypoxia. Circ Res 59: 398–404, 1986.[Abstract/Free Full Text]
  88. Richalet JP, Gratadour P, Robach P, Pham I, Déchaux M, Joncquiert-Latarjet A, Mollard P, Brugniaux J, and Cornolo J. Sildenafil inhibits the altitude-induced hypoxemia and pulmonary hypertension. Am J Resp Crit Care Med doi:10.1164/rccm.200406–804OC: 2004.
  89. Ritter M, Jenni R, Maggiorini M, Grimm J, and Oelz O. Abnormal left ventricular diastolic filling patterns in acute hypoxic pulmonary hypertension at high altitude. Am J Noninvas Cardiol 7: 33–38, 1993.
  90. Rock P, Patterson GA, Permutt S, and Sylvester JT. Nature and distribution of vascular resistance in hypoxic pig lungs. J Appl Physiol 59: 1891–1901, 1985.[Abstract/Free Full Text]
  91. Sartori C, Allemann Y, Duplain H, Lepori M, Egli M, Lipp E, Hutter D, Turini P, Hugli O, Cook S, Nicod P, and Scherrer U. Salmeterol for the prevention of high-altitude pulmonary edema. N Engl J Med 346: 1631–1636, 2002.[Abstract/Free Full Text]
  92. Sartori C, Duplain H, Lepori M, Egli M, Maggiorini M, Nicod P, and Scherrer U. High altitude impairs nasal transepithelial sodium transport in HAPE-prone subjects. Eur Respir J 23: 916–920, 2004.[Abstract/Free Full Text]
  93. Sartori C, Lipp E, Duplain H, Egli M, Hutter D, Allemann Y, Nicod P, and Scherrer U. Prevention of high altitude pulmonary edema by beta-adrenergic stimulation of the alveolar transepithelial sodium transport (Abstract). Am Respir Crit Care Med 161: A415, 2000.
  94. Sartori C, Vollenweider L, Löffler BM, Delabays A, Nicod P, Bärtsch P, and Scherrer U. Exaggerated endothelin release in high-altitude pulmonary edema. Circulation 99: 2665–2668, 1999.[Abstract/Free Full Text]
  95. Scherrer U, Sartori C, Lepori M, Allemann Y, Duplain H, Trueb L, and Nicod P. High-altitude pulmonary edema: from exaggerated pulmonary hypertension to a defect in transepithelial sodium transport. Adv Exp Med Biol 474: 93–107, 1999.[Web of Science][Medline]
  96. Scherrer U, Vollenweider L, Delabays A, Savcic M, Eichenberger U, Kleger GR, Firkrle A, Ballmer P, Nicod P, and Bärtsch P. Inhaled nitric oxide for high-altitude pulmonary edema. N Engl J Med 334: 624–629, 1996.[Abstract/Free Full Text]
  97. Schoene RB. Unraveling the mechanism of high altitude pulmonary edema. High Alt Med Biol 5: 125–135, 2004.[CrossRef][Medline]
  98. Schoene RB, Swenson ER, and Hultgren HN. High-altitude pulmonary edema. In: High Altitude—An Exploration of Human Adaptation, edited by Hornbein TF and Schoene R. New York: Dekker, 2001, p. 777–814.
  99. Schoene RB, Swenson ER, Pizzo CJ, Hackett PH, Roach RC, Mills WJ, Henderson WR, and Martin TR. The lung at high altitude: bronchoalveolar lavage in acute mountain sickness and pulmonary edema. J Appl Physiol 64: 2605–2613, 1988.[Abstract/Free Full Text]
  100. Schütte H, Lohmeyer J, Rosseau S, Ziegler S, Siebert C, Kielisch H, Pralle H, Grimminger F, Morr H, and Seeger W. Bronchoalveolar and systemic cytokine profiles in patients with ARDS, severe pneumonia and cardiogenic pulmonary oedema. Eur Respir J 9: 1858–1867, 1996.[Abstract]
  101. Singh I and Roy SB. High altitude pulmonary edema: clinical, hemodynamic, and pathologic studies. In: Biomedicine of High Terrestrial Elevation Problems. Washington, DC: US Army Research and Development Command, 1969, p. 108–120.
  102. Steinacker JM, Tobias E, Menold E, Rei{beta}necker S, Hohenhaus E, Liu Y, Lehmann M, Bärtsch P, and Swenson ER. Lung diffusing capacity and exercise in subjects with previous high altitude pulmonary edema. Eur Respir J 11: 643–650, 1998.[Abstract]
  103. Stelzner TJ, O'Brien RF, Sato K, and Weil JV. Hypoxia-induced increases in pulmonary transvascular protein escape in rats; modulation by glucocorticoids. J Clin Invest 82: 1840–1847, 1988.[Web of Science][Medline]
  104. Sui GJ, Liu YH, Cheng XS, Anand IS, Harris E, Harris P, and Heath D. Subacute infantile mountain sickness. J Pathol 155: 161–170, 1988.[CrossRef][Web of Science][Medline]
  105. Swenson ER and Maggiorini M. Salmeterol for the prevention of high-altitude pulmonary edema. N Engl J Med 347: 1284, 2002.
  106. Swenson ER, Maggiorini M, Mongovin S, Gibbs JSR, Greve I, Mairbäurl H, and Bärtsch P. Pathogenesis of high-altitude pulmonary edema: inflammation is not an etiologic factor. JAMA 287: 2228–2235, 2002.[Abstract/Free Full Text]
  107. Szidon JP, Pietra GG, and Fishman AP. The alveolar-capillary membrane and pulmonary edema. N Engl J Med 286: 1200–1204, 1972.[Web of Science][Medline]
  108. Tsukimoto K, Yoshimura N, Ichioka M, Tojo N, Miyazato I, Marumo F, Mathieu-Costello O, and West JB. Protein, cell, and LTB4 concentrations of lung edema fluid produced by high capillary pressures in rabbit. J Appl Physiol 76: 321–327, 1994.[Abstract/Free Full Text]
  109. van Heerden PV, Cameron PD, Karanovic A, and Goodman MA. Orthodeoxia—an uncommon presentation following bilateral sympathectomy. Anaesth Intensive Care 31: 581–583, 2003.[Web of Science][Medline]
  110. Visscher MB. The Discussant. Pulmonary edema at high altitude (panel discussion). Med Thorac 19: 326–327, 1962.
  111. Viswanathan R, Jain SK, Subramanian S, Subramanian TAV, Dua GL, and Giri J. Pulmonary edema of high altitude II. Clinical, aerohemodynamic, and biochemical studies in a group with history of pulmonary edema of high altitude. Am Rev Respir Dis 100: 334–341, 1969.[Web of Science][Medline]
  112. Vivona ML, Matthay M, Chabaud MB, Friedlander G, and Clerici C. Hypoxia reduces alveolar epithelial sodium and fluid transport in rats: reversal by beta-adrenergic agonist treatment. Am J Respir Cell Mol Biol 25: 554–561, 2001.[Abstract/Free Full Text]
  113. Vock P, Brutsche MH, Nanzer A, and Bartsch P. Variable radiomorphologic data of high altitude pulmonary edema—features from 60 patients. Chest 100: 1306–1311, 1991.[CrossRef][Web of Science][Medline]
  114. Vock P, Fretz C, Franciolli M, and Bärtsch P. High-altitude pulmonary edema: findings at high-altitude chest radiography and physical examination. Radiology 170: 661–666, 1989.[Abstract/Free Full Text]
  115. Weiss J, Haefeli WE, Gasse C, Hoffmann MM, Weyman J, Gibbs S, Mansmann U, and Bärtsch P. Lack of evidence for association of high altitude pulmonary edema and polymorphisms of the NO pathway. High Alt Med Biol 4: 355–366, 2003.[CrossRef][Medline]
  116. West JB, Mathieu-Costello O, Jones JH, Birks EK, Logemann RB, Pascoe JR, and Tyler WS. Stress failure of pulmonary capillaries in racehorses with exercise-induced pulmonary hemorrhage. J Appl Physiol 75: 1097–1109, 1993.[Abstract/Free Full Text]
  117. West JB, Tsukimoto K, Mathieu-Costello O, and Prediletto R. Stress failure in pulmonary capillaries. J Appl Physiol 70: 1731–1742, 1991.[Abstract/Free Full Text]
  118. Whayne TF Jr and Severinghaus JW. Experimental hypoxic pulmonary edema in the rat. J Appl Physiol 25: 729–732, 1968.[Free Full Text]
  119. Wilson LB and Levitzky MG. Chemoreflex blunting of hypoxic pulmonary vasoconstriction is vagally mediated. J Appl Physiol 66: 782–791, 1989.[Abstract/Free Full Text]
  120. Younes M, Bshouty Z, and Ali J. Longitudinal distribution of pulmonary vascular resistance with very high pulmonary flow. J Appl Physiol 62: 344–358, 1987.[Abstract/Free Full Text]
  121. Young SL, Ho YS, and Silbajoris RA. Surfactant apoprotein in adult rat lung compartments is increased by dexamethasone. Am J Physiol Lung Cell Mol Physiol 260: L161–L167, 1991.[Abstract/Free Full Text]
  122. Young SL and Silbajoris R. Dexamethasone increases adult rat lung surfactant lipids. J Appl Physiol 60: 1665–1672, 1986.[Abstract/Free Full Text]
  123. Zhao Y, Packer CS, and Rhoades RA. Pulmonary vein contracts in response to hypoxia. Am J Physiol Lung Cell Mol Physiol 265: L87–L92, 1993.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 JAMAHome page
T. G. Smith, N. P. Talbot, C. Privat, M. Rivera-Ch, A. H. Nickol, P. J. Ratcliffe, K. L. Dorrington, F. Leon-Velarde, and P. A. Robbins
Effects of Iron Supplementation and Depletion on Hypoxic Pulmonary Hypertension: Two Randomized Controlled Trials
JAMA, October 7, 2009; 302(13): 1444 - 1450.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
S. X. L. Zhang, J. J. Miller, D. B. Stolz, L. D. Serpero, W. Zhao, D. Gozal, and Y. Wang
Type I Epithelial Cells Are the Main Target of Whole-Body Hypoxic Preconditioning in the Lung
Am. J. Respir. Cell Mol. Biol., March 1, 2009; 40(3): 332 - 339.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
D. M. Bailey, K. A. Evans, P. E. James, J. McEneny, I. S. Young, L. Fall, M. Gutowski, E. Kewley, J. M. McCord, K. Moller, et al.
Altered free radical metabolism in acute mountain sickness: implications for dynamic cerebral autoregulation and blood-brain barrier function
J. Physiol., January 1, 2009; 587(1): 73 - 85.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
A. M. Luks, R. J. Johnson, and E. R. Swenson
Chronic Kidney Disease at High Altitude
J. Am. Soc. Nephrol., December 1, 2008; 19(12): 2262 - 2271.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
S. Kriemler, C. Jansen, A. Linka, A. Kessel-Schaefer, M. Zehnder, T. Schurmann, M. Kohler, K. Bloch, and H. P. Brunner-La Rocca
Higher pulmonary artery pressure in children than in adults upon fast ascent to high altitude
Eur. Respir. J., September 1, 2008; 32(3): 664 - 669.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
S. Sarada, P. Himadri, C. Mishra, P. Geetali, M. S. Ram, and G. Ilavazhagan
Role of Oxidative Stress and NFkB in Hypoxia-Induced Pulmonary Edema
Experimental Biology and Medicine, September 1, 2008; 233(9): 1088 - 1098.
[Abstract] [Full Text] [PDF]

Home page
 ChestHome page
R. B. Schoene
Illnesses at High Altitude
Chest, August 1, 2008; 134(2): 402 - 416.
[Abstract] [Full Text] [PDF]

Home page
 Poult. Sci.Home page
A. P. Gomez, M. J. Moreno, R. M. Baldrich, and A. Hernandez
Endothelin-1 Molecular Ribonucleic Acid Expression in Pulmonary Hypertensive and Nonhypertensive Chickens
Poult. Sci., July 1, 2008; 87(7): 1395 - 1401.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
G. Zhou, L. A. Dada, and J. I. Sznajder
Regulation of alveolar epithelial function by hypoxia
Eur. Respir. J., May 1, 2008; 31(5): 1107 - 1113.
[Abstract] [Full Text] [PDF]

Home page
 ChestHome page
A. M. Luks and E. R. Swenson
Medication and Dosage Considerations in the Prophylaxis and Treatment of High-Altitude Illness
Chest, March 1, 2008; 133(3): 744 - 755.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
S. R. Hopkins, A. Kleinsasser, S. Bernard, A. Loeckinger, E. Falor, B. Neradilek, N. L. Polissar, and M. P. Hlastala
Hypoxia has a greater effect than exercise on the redistribution of pulmonary blood flow in swine
J Appl Physiol, December 1, 2007; 103(6): 2112 - 2119.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
P. Bartsch and J. S. R. Gibbs
Effect of Altitude on the Heart and the Lungs
Circulation, November 6, 2007; 116(19): 2191 - 2202.
[Full Text] [PDF]

Home page
 Poult. Sci.Home page
A. P. Gomez, M. J. Moreno, A. Iglesias, P. X. Coral, and A. Hernandez
Endothelin 1, its Endothelin Type A Receptor, Connective Tissue Growth Factor, Platelet-Derived Growth Factor, and Adrenomedullin Expression in Lungs of Pulmonary Hypertensive and Nonhypertensive Chickens
Poult. Sci., May 1, 2007; 86(5): 909 - 916.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
A. M. Luks and E. R. Swenson
Travel to high altitude with pre-existing lung disease
Eur. Respir. J., April 1, 2007; 29(4): 770 - 792.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
L. A. Shimoda, T. Luke, J. T. Sylvester, H.-W. Shih, A. Jain, and E. R. Swenson
Inhibition of hypoxia-induced calcium responses in pulmonary arterial smooth muscle by acetazolamide is independent of carbonic anhydrase inhibition
Am J Physiol Lung Cell Mol Physiol, April 1, 2007; 292(4): L1002 - L1012.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
L. J. Teppema, G. M. Balanos, C. D. Steinback, A. D. Brown, G. E. Foster, H. J. Duff, R. Leigh, and M. J. Poulin
Effects of Acetazolamide on Ventilatory, Cerebrovascular, and Pulmonary Vascular Responses to Hypoxia
Am. J. Respir. Crit. Care Med., February 1, 2007; 175(3): 277 - 281.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
E. M. Snyder, K. C. Beck, M. L. Hulsebus, J. F. Breen, E. A. Hoffman, and B. D. Johnson
Short-term hypoxic exposure at rest and during exercise reduces lung water in healthy humans
J Appl Physiol, December 1, 2006; 101(6): 1623 - 1632.
[Abstract] [Full Text] [PDF]

Home page
 ANN INTERN MEDHome page
E. R. Swenson
Hypoxic lung whiteout: further clearing but more questions from on high.
Ann Intern Med, October 3, 2006; 145(7): 550 - 552.
[Full Text] [PDF]

Home page
 Cardiovasc ResHome page
E. K. Weir and A. Olschewski
Role of ion channels in acute and chronic responses of the pulmonary vasculature to hypoxia
Cardiovasc Res, September 1, 2006; 71(4): 630 - 641.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
M. Dehler, E. Zessin, P. Bartsch, and H. Mairbaurl
Hypoxia causes permeability oedema in the constant-pressure perfused rat lung.
Eur. Respir. J., March 1, 2006; 27(3): 600 - 606.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
T. Lehmann, H. Mairbaurl, B. Pleisch, M. Maggiorini, P. Bartsch, and W. H. Reinhart
Platelet count and function at high altitude and in high-altitude pulmonary edema
J Appl Physiol, February 1, 2006; 100(2): 690 - 694.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (56)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bärtsch, P.
Right arrow Articles by Swenson, E. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bärtsch, P.
Right arrow Articles by Swenson, E. R.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2005 by the American Physiological Society.