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Abstract

High-altitude pulmonary edema (HAPE) is a life-threatening noncardiogenic form of pulmonary edema (PE) that afflicts susceptible persons after rapid ascent to high altitude above 2500 m. Its pathogenesis is related to increased sympathetic tone, exaggerated hypoxic pulmonary vasoconstriction, uneven hypoxic pulmonary vasoconstriction with overperfusion of some regions of the pulmonary vascular bed, increased pulmonary capillary pressure, stress failure of pulmonary capillaries, and alveolar fluid leak across capillary endothelium resulting in interstitial and alveolar edema. Prevention of HAPE is most effectively achieved by gradual ascent with time for acclimatization, although recent small studies have highlighted a number of pharmacologic options. Inhaled salmeterol prevents HAPE presumably by increasing alveolar fluid clearance, the phosphodiesterase-5 inhibitor tadalafil works by acting as a pulmonary vasodilator, and dexamethasone seems to prevent HAPE by stabilizing the capillary endothelium, along with other potential effects. These investigations have yet to be validated in widespread clinical practice. Nifedipine, which prevents HAPE via its effects as a pulmonary vasodilator, has a longer history of clinical use. The most effective and reliable treatment of established HAPE is immediate descent and/or adequate flow supplemental oxygen to maintain arterial saturation above 90%, accompanied by rest from strenuous physical activity. Use of a portable hyperbaric chamber is an effective temporizing measure, and nifedipine may be used for treatment of HAPE, although only as an adjunct to descent and/or supplemental oxygen if these methods of treatment are not immediately available to a person with HAPE.

Keywords

altitude illness pulmonary edema high altitude mountaineering HAPE

Introduction and clinical description

High-altitude pulmonary edema (HAPE) is a life-threatening noncardiogenic form of pulmonary edema (PE) that develops in nonacclimatized persons after rapid ascent to altitudes above 2000 to 3000 m. HAPE is primarily a pulmonary disorder, whereas acute mountain sickness (AMS) and the much less frequent high-altitude cerebral edema, are neurologic disorders. First described in the English language medical literature in 1960 by Houston¹ and Hultgren,² HAPE is characterized by cough, progressive dyspnea with exertion, and decreased exercise tolerance, generally developing within 2 to 4 days after arrival at high altitude. The cough typically begins as a dry cough that progresses to a cough productive of pink, frothy sputum, rarely producing frank blood.³ Symptoms of AMS, including headache and nausea, may accompany HAPE, but 50% of persons with HAPE experience no AMS symptoms.⁴ On physical examination, persons with HAPE have tachycardia, tachypnea, low-grade fever, and inspiratory crackles on lung auscultation, which are typically bilateral but may be unilateral in early HAPE, often heard in the right middle lobe.⁴ The latter diagnostic finding is not particularly specific for early HAPE, because focal crackles may be heard in the absence of any high-altitude illness after ascent to high altitude.^5,6 As HAPE progresses, crackles may become diffuse. On chest radiography, HAPE is characterized by patchy bilateral alveolar infiltrates that may be unilateral in the right hemithorax in early HAPE.⁶ A retrospective review of 60 cases of severe HAPE (requiring hospitalization) found more homogeneous, confluent infiltrates in the late stage of the disease, suggesting progression from its initial patchy distribution with increasing severity (Figure 1).⁷ HAPE is characterized by increased pulmonary artery (PA) pressure with a normal cardiac output and pulmonary capillary wedge pressure. HAPE-related hypoxemia is variable, with a mean arterial oxygen saturation of 74% observed in one study at a ski resort at 2928 m (normal average saturation at that altitude is approximately 92%) (Table 1).^3,4

Figure 1

Panel A, Chest radiograph of a 15-year-old male with high-altitude pulmonary edema after helicopter evacuation from an altitude of 11 000 feet (3353 m) to 4500 feet (1372 m). The chest radiograph shows dense bilateral patchy alveolar infiltrative change and normal cardiac and mediastinal width. Panel B, Chest radiograph from the same patient after 1 day of treatment with supplemental oxygen delivered by nasal cannula at a flow rate of 4 L/min. The chest radiograph shows improvement in bilateral infiltrates.

Table 1

Hemodynamic and gas exchange parameters in 14 patients with high-altitude pulmonary edema at 3600 m before and after treatment with supplemental oxygen^*95

Risk factors and susceptibility

Factors that increase the incidence of HAPE include a prior history of HAPE,⁸ faster rates of ascent, higher altitudes, male sex,^4,9 cold ambient temperatures,^9,10 preexisting respiratory infection,¹¹ and intense exercise.¹² Most HAPE-susceptible persons (at least 1 prior episode of HAPE) can travel to high altitude on subsequent trips without developing HAPE if they ascend at a gradual rate to allow time for acclimatization once above 2000 m.¹³ As demonstrated in children by Durmowicz and colleagues¹¹ and anecdotally observed in adults, preexisting respiratory tract infection is a risk factor for the development of HAPE, presumably due to the alteration of vascular permeability by inflammatory mediators. Priming with endotoxin and preexisting viral respiratory infection has been found to increase pulmonary vascular permeability and protein content in edema fluid of rats exposed to high altitude, further supporting this theory.^14,15

Evidence also exists for an association between a predisposition to HAPE and the HLA-DR6 and HLA-DQ4 alleles, suggesting an immunogenetic susceptibility to HAPE.¹⁶ Because these studies were conducted in the somewhat restricted gene pool of entirely Japanese individuals, more comprehensive investigation of this intriguing possibility is warranted.¹⁷

Preexisting conditions or anatomic abnormalities that lead to increased pulmonary blood flow or intravascular pressure may predispose to HAPE, even at altitudes less than 2500 m. These include primary pulmonary hypertension,¹⁸ congenital absence of one pulmonary artery (PA),¹⁹ or intracardiac shunt. The latter includes left-to-right shunts, such as atrial septal defect,²⁰ ventricular septal defect,²¹ and the more well-studied patent foramen ovale (PFO).²² It has been theorized that, as a result of rising pulmonary vascular resistance (PVR) during hypoxic pulmonary vasoconstriction (HPV), a PFO may reverse direction and begin shunting blood from the right to left heart, further exacerbating hypoxemia.²³ This effect has been demonstrated in HAPE-prone persons at high altitude, and the presence of a PFO has been found to be 4 times more frequent in HAPE-susceptible individuals. The size of the PFO directly correlates to the degree of arterial hypoxemia, with a trend toward increased risk of developing HAPE in those with large PFOs.²² Considering these findings, cases of HAPE that occur at low to moderate altitude certainly warrant investigation into a preexisting cardiopulmonary abnormality, and these patients should seek consultation with a physician knowledgeable in high-altitude illness before traveling to such altitudes.

Although particular genetic, anatomic, or pathologic characteristics may increase the risk of HAPE in certain individuals, complete resistance may not exist. Several authors have postulated that any person may develop HAPE if the ascent rate is fast enough to a high enough altitude.¹³ This assertion is based on studies that show subclinical increased extravascular lung water in the majority of persons who ascend to high altitude.^24,25

Long-term inhabitants of high-altitude regions constitute a special group at risk for HAPE because of “reentry HAPE” that may occur upon reascent after a sojourn at low altitude.^2,26 Children appear to be more susceptible to this condition.²⁶

Pathophysiology

HAPE is characterized by exaggerated HPV^27,28 and high-permeability noncardiogenic PE.^29,30 HAPE is caused by stress failure of pulmonary capillaries^31,32 in focal areas of the pulmonary circulation due to increased pulmonary capillary transmural pressures³³ and resultant permeability edema, leading to alveolar flooding and progressive hypoxemia (Figure 2). The exaggerated hypoxia-induced pulmonary hypertension in HAPE-susceptible individuals may be accompanied by blunted HPV, thereby worsening hypoxemia.³⁴^–36

Figure 2

Proposed pathogenesis of high-altitude pulmonary edema.

The etiology of the abnormal increase in PA pressure in HAPE-prone persons is likely multifactorial, involving augmented sympathetic activity,³⁷ increased levels of endothelin-1,³⁸ and decreased availability of nitric oxide (NO).^30,39,40 It is readily apparent that vigorous exercise and cold ambient temperatures in mountainous areas can contribute to an increase in sympathetic activity.⁴¹ In HAPE-susceptible persons, this increase in sympathetic activation is exaggerated in response to hypoxia at both low and high altitude and is directly correlated to the increase in PA pressure.³⁷ The concept of a sympathetic contribution to the pulmonary hypertension of HAPE is supported by the efficacy of alpha-blockade by phentolamine infusion in decreasing PA pressure in subjects with HAPE, more than other vasodilators without antiadrenergic properties.⁴² Levels of endothelin-1, a potent endothelium-derived pulmonary vasoconstrictor, directly correlate with increased PA pressure in HAPE-susceptible persons at high altitude, with levels 33% higher than those in persons without a history of HAPE.³⁸ More recent data indicate that antagonism of endothelin-1 with bosentan decreases PA pressures in healthy volunteers at high altitude.⁴³

As a mediator of exaggerated HPV, decreased NO availability may play a major role in the susceptibility to and development of HAPE and is thus a potential target for prevention and/or treatment. At high altitude, HAPE-prone individuals demonstrate significantly reduced levels of exhaled NO with an associated increase in PA pressure.^39,40 Additionally, bronchoalveolar lavage fluid in HAPE-susceptible persons at high altitude held reduced concentrations of nitrates and nitrites.⁴⁴ Berger and colleagues recently implicated impairment of the NO-mediated vasodilator pathway, demonstrating that HAPE-prone persons exposed to normobaric hypoxia had a decreased systemic endothelium-dependent vasodilator response to intra-arterial acetylcholine.⁴⁵ Several factors may contribute to the decreased bioavailability of NO, including downregulation or defect of endogenous NO synthase (eNOS), inhibition of eNOS by l-arginine analogs, reduction of substrate for eNOS, and a possible increase in the breakdown of NO.⁴⁵ A study in Japanese mountaineers found that HAPE susceptibility is associated with a higher frequency of 2 eNOS gene polymorphisms.⁴⁶ Although these mutations arise in parts of the eNOS gene whose effect on functional enzymatic activity is yet unknown, this finding supports the role of NO-mediated endothelial dysfunction and raises the possibility of another immunogenetic predisposition to HAPE. The role of NO in the pathogenesis of HAPE has been further supported by the fact that phosphodiesterase-5 inhibitors are effective in increasing cyclic guanosine monophosphate (cGMP)-mediated pulmonary vasodilation, consequently reducing altitude-induced pulmonary hypertension and improving exercise tolerance and arterial hypoxemia.^47,48

Studies of bronchoalveolar lavage fluid demonstrate mild pulmonary hemorrhage and transvascular leak of proteins into the alveolar spaces in early HAPE, without elevation of cytokines and other inflammatory mediators.^44,49 Maggiorini and coworkers have demonstrated that increased pulmonary capillary pressure is an initiating factor in the development of HAPE, presumably resulting in injury to the capillaries and a high-permeability edema. These investigators found an altitude-induced increase in mean pulmonary capillary pressure to 19 mm Hg in HAPE-susceptible persons, compared with a mean of 13 mm Hg in controls, after rapid ascent to 4559 m. Furthermore, a capillary pressure of 19 mm Hg appears to be a threshold for the development of HAPE, because only individuals with pressures exceeding this value went on to develop HAPE during the study.³³ The development of increased permeability edema in the setting of elevated pulmonary capillary pressures seems to result from structural alterations in the barrier formed by the alveolar epithelium and capillary endothelium, proposed by West and colleagues as “pulmonary capillary stress failure.”³¹ This concept describes the traumatic breakdown of the basement membrane and pulmonary capillary endothelium resulting from excessive intravascular pressures.^32,50 Indeed, upon ultrastructural examination of pulmonary capillaries in thoroughbred racehorses, stress failure has been demonstrated in the setting of overt pulmonary hemorrhage as a result of extreme exercise.⁵¹ Increased levels of proteins and erythrocytes have also been observed in the bronchoalveolar lavage fluid of elite athletes after intense exercise.⁵² However, the activation of platelets and coagulation factors that would be expected to stem from exposure of the basement membrane in this model of stress failure only occurs in very advanced cases of HAPE.⁵³

Another mechanism for the alveolar fluid leak in HAPE may be a transient pressure-induced increase in the transvascular transport of fluid, erythrocytes, and proteins, without overt injury to the underlying structure. This may be mediated by the intercellular passage of fluid and proteins by relaxation of tight junctions or perhaps an increase in transcellular fluid flux via pores, fenestrae, and/or vesicular channels.⁴⁴ Indeed, studies in isolated rabbit lungs verify that hydrostatic edema with capillary pressures of 14 to 29 mm Hg is associated with numerous disruptions of the alveolar epithelial layers, with a relatively intact endothelial barrier.⁵⁴ Notably, in frogs with intravascular pressures high enough to rupture capillaries, more than 80% of the pressure-induced wall openings passed through endothelial cells, with the basement membrane remaining intact.⁵⁵ In both frogs⁵⁵ and rabbits,⁵⁶ these transcellular channels readily close when intravascular pressure is reduced to normal. These findings bear a conceptual similarity to the rapid reversibility of HAPE, which can even allow some afflicted persons to reascend to altitude after only a few days of descent and rest. From this evidence, we may conclude that as intravascular pulmonary capillary pressure increases in HAPE, dynamic changes are triggered in the structural permeability of the blood-gas barrier, allowing alveolar flooding to occur.

One question that remains a point of contention in the pathogenesis of HAPE is the etiology of increased capillary pressures that lead to PE. A commonly accepted theory is that the process of HPV is unevenly distributed in the pulmonary arteriolar bed, resulting in overperfusion of some regions of microvasculature that are not protected from high intravascular pressures by upstream vasoconstriction.²⁷ The role of increased pulmonary blood flow as an etiologic factor is supported by case reports in which the absence of the right pulmonary artery leads to the development of HAPE limited to the left lung after ascent to moderate altitudes.^19,57 In a HAPE-susceptible individual who experiences an abnormal increase in PA pressure upon rapid ascent to high altitude, this results in portions of the pulmonary capillary bed being subjected to increased hydrostatic pressures that may cause stress failure. First proposed by Hultgren,⁵⁸ the concept of “uneven HPV” has been demonstrated in microsphere studies by nonuniform spatial distribution of HPV in pigs and cephalization of pulmonary perfusion in HAPE-susceptible individuals.^59,60 Recent investigations using magnetic resonance imaging perfusion scanning reveal increased heterogeneity of pulmonary blood flow after hypoxic challenge in persons prone to HAPE,^61,62 who also demonstrate an exaggerated exercise-induced increase in ventilation-perfusion mismatch.²⁵ These findings support the idea that, in susceptible persons, the hypoxia of high altitude causes an augmented and more unevenly distributed pulmonary vasoconstrictor response, which in turn may lead to regional overperfusion of pulmonary capillaries, transient structural changes in the permeability barrier, and resultant interstitial and alveolar edema.

An area of further interest in the pathophysiology of HAPE is the possible role of impaired alveolar sodium and fluid clearance as a permissive factor in the development of alveolar flooding. Studies in rat lungs demonstrate that hypoxia downregulates the expression and activity of sodium channels and Na⁺, K⁺-ATPase, as well as decreases apical sodium influx via amiloride-sensitive channels.⁶³ ^–66 Furthermore, mice with a targeted lesion in the gene coding for the alpha-subunit of the amiloride-sensitive sodium channel have significantly decreased alveolar transepithelial fluid clearance and higher risk of developing PE.⁶⁷ There are also data to suggest that impaired alveolar fluid clearance may contribute to the pathogenesis of HAPE in humans.⁶⁸

Prevention

Gradual ascent remains the best method for prevention of HAPE and other high-altitude illnesses, with the recommended ascent rate of 300 to 350 m per day at altitudes above 2500 m.¹³ These refer to sleeping altitudes, and an extra day of acclimatization should be added for every 600 to 1200 m above 2500 m. Although this strategy is optimal, pharmacologic prophylaxis is recommended as adjunctive therapy for persons with a prior history of HAPE and for those who must ascend more than 3000 m in a 24-hour period, as in some rescue situations.⁶⁹

With regard to prophylactic methods, inhibition of altitude-induced pulmonary hypertension has been the mainstay in pharmacologic prevention of HAPE. Nifedipine (30 mg extended release form orally once or twice daily), a calcium-channel blocker, has long been a recommended prophylactic agent, based on a single randomized double-blinded clinical trial. In HAPE-susceptible individuals, it mitigated the increase in PA pressure, reduced the incidence of HAPE, and improved gas exchange upon rapid ascent to 4559 m.⁸

As potent pulmonary vasodilators via the NO/cGMP pathway, phosphodiesterase-5 inhibitors have been recently scrutinized as a prophylactic measure for HAPE. A 1-time dose of sildenafil (50 mg per oral [PO]) improves cardiac output and exercise capacity and mitigates the increase in PA pressure in healthy persons exposed to normobaric hypoxic challenge and ascent to 5400 m.⁴⁷ In a more recent study, sildenafil (40 mg PO 3 times daily) given to healthy subjects for several days after arrival to high altitude improved gas exchange and attenuated altitude-induced pulmonary hypertension without significant effects on systemic blood pressure.⁴⁸ Although neither of the sildenafil studies examined HAPE incidence, Maggiorini and colleagues demonstrated that prophylactic use of the phosphodiesterase-5 inhibitor tadalafil (10 mg PO twice daily, started 1 day prior to ascent) reduces the risk of developing HAPE by 65% in HAPE-prone individuals.⁷⁰ However, although tadalafil effectively relieved the altitude-induced increase in PA pressure, 2 of 10 individuals in the tadalafil group were incapacitated by severe headache after rapid ascent to 4559 m, which may reflect drug effect and/or worsening of AMS symptoms.

Maggiorini et al also compared dexamethasone (8 mg PO twice daily, started 1 day prior to ascent) with tadalafil in the prevention of HAPE in susceptible individuals. Dexamethasone, commonly used for both treatment and prevention of AMS, was predictably superior in preventing AMS (50% reduction) and decreasing AMS symptom severity. Surprisingly, dexamethasone, with a 78% reduction in HAPE incidence, was superior to tadalafil in the prevention of HAPE, reduction of PA pressure, and improvement of hypoxemia.⁷⁰ It appears that in order to protect against the development of HAPE, dexamethasone should be administered 1 day before ascent, because HAPE has occurred in persons who were given dexamethasone for treatment of AMS after ascent.⁷¹ The mechanism by which dexamethasone prevents HAPE remains unclear. Maggiorini et al observed a significantly lower heart rate in the dexamethasone group of the above study, suggesting that it may contribute to protection from HAPE by attenuating sympathetic activation.⁷⁰ In animal studies, dexamethasone has been shown to increase expression and activity of eNOS, as well as cGMP concentration, which supports its possible role as a pulmonary vasodilator.^72,73 Dexamethasone may also reduce transvascular fluid transport by “tightening” the pulmonary capillary endothelium.⁷⁴ Another suggested mechanism is a dexamethasone-mediated increase in alveolar fluid clearance by increased expression of epithelial sodium channels and augmented activity of Na⁺, K⁺-ATPase.^75,76

Intriguing findings by Sartori and colleagues that prophylactic inhalation of the beta-adrenergic agonist salmeterol (125 μg twice daily) reduces the risk of HAPE by 50% in HAPE-prone persons support the role of impaired alveolar fluid resorption in the pathogenesis of HAPE.⁶⁸ Data show that beta agonists enhance transepithelial sodium and fluid transport during hypoxia and mechanical lung injury in animal studies^64,77 and decrease extravascular lung water in humans with acute lung injury.⁷⁸ Although salmeterol may prevent HAPE by increasing fluid uptake through epithelial sodium channels and thus inhibiting alveolar flooding, it may also contribute via additional mechanisms, including tightening of endothelial intercellular junctions and the production of pulmonary NO.^79,80

An area of budding interest in the prevention of HAPE is the effect of the carbonic anhydrase inhibitor acetazolamide, which, like dexamethasone, is already an accepted drug for prophylaxis and treatment of AMS. Berg and coworkers have shown its efficacy in preventing HAPE-like alveolar protein leak in rats exposed to hypobaric hypoxia, likely via mitigation of HPV.⁸¹ In humans with no history of HAPE, Teppema et al demonstrated that acetazolamide (250 mg PO 3 times daily for 3 days prior to hypoxic challenge) decreases normoxic PVR and blunts the pulmonary vasoconstrictor response to hypoxia.⁸² Other animal studies have verified acetazolamide's attenuation of HPV, which seems to be independent of carbonic anhydrase inhibition or effects on the NO vasodilation pathway but rather mediated by relaxation of the pulmonary vascular musculature.⁸³ ^–86 The applicability of these conclusions to the prevention of HAPE is yet unknown, but these recent findings warrant further study of acetazolamide as another drug that may provide dual prophylaxis against both AMS and HAPE.

For the prevention of HAPE in all individuals, we emphasize that gradual ascent is the optimal strategy (Table 2). However, we recommend oral nifedipine as adjunctive pharmacologic prophylaxis in those with a history of HAPE. With few significant adverse effects other than reflex tachycardia, it has withstood the test of time for protection from HAPE. Inhaled salmeterol is another optional adjunct for HAPE prevention, because it is logistically convenient and has only minor side effects due to increased beta-adrenergic tone. Cautious use of phosphodiesterase-5 inhibitors may be an acceptable alternative for selected individuals who have already been observed to tolerate these drugs without ill effects, because they may worsen symptoms of AMS, including headache. The finding of dexamethasone as an effective agent in the prevention of HAPE is intriguing, as are the preliminary studies with acetazolamide. Both drugs may prevent AMS and HAPE, 2 disorders that have traditionally required prophylaxis with separate agents (acetazolamide or dexamethasone for AMS and nifedipine for HAPE), because nifedipine does not confer protection from AMS.⁸⁷ The concept of one drug working to prevent both AMS and HAPE is of particular relevance to those persons with a history of HAPE who continue to pursue high-altitude endeavors on a frequent basis. However, because the use of dexamethasone is known to be associated with insomnia, euphoria, hyperglycemia, and adrenal suppression, it is not recommended as the initial choice for pharmacologic prevention of HAPE, except in rescue operations in which unacclimatized persons are deposited at high altitude, when it will also provide prophylaxis against AMS and high-altitude cerebral edema. Acetazolamide has not been studied as a preventive measure for HAPE in humans but warrants further study in this role, because it may prove useful for dual prophylaxis of AMS and HAPE.

Table 2

Prevention of high-altitude pulmonary edema

Treatment

The most reliable treatment for HAPE is immediate descent (at least 500 to 1000 m), supplemental oxygen, or both. Supplemental oxygen and rest while remaining at high altitude are sufficient treatment for mild to moderate HAPE in persons without preexisting cardiopulmonary disease, and it is a common method of treatment for destination tourists who develop HAPE at high-altitude ski resorts.^88,89 Oxygen should be provided at a high enough fraction of inspired oxygen to achieve an arterial oxygen saturation of greater than 90%. If oxygen is not available and descent is unsafe or impossible, a portable hyperbaric chamber can simulate a descent of 1500 m or more and is a good temporizing measure before definitive therapy is possible with descent to a lower altitude.^90,91 Optimal therapy includes ensuring passive descent and keeping the patient warm, which will minimize any additional exercise- or cold-induced sympathetic contribution to the condition.

If none of the above methods is feasible for someone suffering from HAPE, adjunctive pharmacologic therapy may be considered, focusing primarily on reduction of PA pressure with vasodilators. Nifedipine (10 mg sublingually, then 20 to 30 mg PO extended release every 12 hours) can be considered but should not be regarded as a substitute for descent or oxygen. In a limited study of individuals with mild HAPE, Oelz and coworkers demonstrated that nifedipine decreased systolic PA pressure (by 50%), narrowed the alveolar-arterial oxygen gradient, and led to improving radiographic scores as PE cleared, although without a significant improvement in arterial oxygenation.^92,93

Hackett and colleagues compared several vasodilators as treatment for HAPE, finding that nifedipine (10 mg sublingually) reduced mean PA pressure and PVR by about 30%, with improved oxygenation and slight decreases in mean arterial blood pressure.⁴² Intravenous hydralazine (10 to 20 mg) behaved similarly, albeit with corresponding decreases in systemic blood pressure and heart rate. Interestingly, phentolamine infusion (1 mg/min for 10 minutes, then 0.5 mg/min for 20 minutes) induced significantly greater decreases in PA pressure and PVR, proving itself superior to nifedipine, hydralazine, or even oxygen. Phentolamine did, however, cause a 12.5 mm Hg drop in mean arterial pressure. When oxygen was added to phentolamine, the investigators observed a further reduction of 10 to 15% in PA pressure.

Nitric oxide, a pulmonary vasodilator already implicated in the pathogenesis of HAPE, has also been studied as a pharmacologic therapy for established HAPE. Scherrer and colleagues found that inhaled NO (40 ppm) markedly decreased systolic PA pressure and improved arterial oxygenation in individuals with HAPE and was also found to redistribute pulmonary blood flow to nonedematous regions of lung in these patients without significant effects on systemic blood pressure, minute ventilation, or end-tidal carbon dioxide.⁹⁴ More recently, Anand et al investigated the use of inhaled NO (15 ppm) with or without oxygen in patients with severe HAPE at a field hospital. The authors demonstrated similar effects of NO or oxygen alone on PA pressure and arterial oxygenation, with NO significantly more effective at decreasing PVR. When NO was combined with supplemental oxygen in participants with HAPE, the reduction in PA pressure and PVR, as well as the increase in oxygenation, was greater than with either gas alone. These additive effects of oxygen and inhaled NO on pulmonary hemodynamics and gas exchange are likely due to improvement in ventilation-perfusion matching in patients with HAPE.⁹⁵

Some researchers have investigated the use of expiratory positive airway pressure, which has been demonstrated to improve gas exchange in persons with HAPE, albeit transiently.⁹⁶ However, expiratory positive airway pressure, like inhaled NO, may present logistical difficulties in isolated mountain areas or hospitals at destination ski resorts where HAPE frequently occurs. Given the efficacy of inhaled beta agonists in the prevention of HAPE, as well as their convenience and minimal side effects, there may be a role for these agents in the treatment of HAPE, but this requires further study. For practical purposes, we recommend descent, supplemental oxygen, or both as the primary methods of HAPE treatment, using all other modalities of treatment, including pharmacotherapy, as adjunctive or temporizing measures (Table 3).

Table 3

Treatment of high-altitude pulmonary edema

Although drugs may act as adjuncts to definitive therapy for HAPE, there is no abundant evidence for their efficacy and they may not always be readily available to a person who develops HAPE in the mountains. In our experience, treatment of HAPE with descent or supplemental oxygen to achieve an arterial oxygen saturation of 90% results in relief of symptoms and, given adequate time, resolution of PE and gas exchange abnormalities.

References

Houston

Acute pulmonary edema of high altitude. N Engl J Med 1960; 263, 478–480.

Hultgren

Spickard

Medical experiences in Peru. Stanford Med Bull 1960; 18, 76–95.

Hackett

Roach

High-altitude medicine. In: Auerbach

ed. Wilderness Medicine . 5th ed. St. Louis, MO: Mosby, 2007, 2–36.

Hultgren

Honigman

Theis

Nicholas

High-altitude pulmonary edema at a ski resort. West J Med 1996; 164, 222–227.

Grissom

High-altitude diseases (HACE/HAPE). In: Fein

Kamholz

Ost

eds. Respiratory Emergencies , London: Hodder Arnold, 2006, 253–267.

Vock

Fretz

Franciolli

Bartsch

High-altitude pulmonary edema: findings at high-altitude chest radiography and physical examination. Radiology 1989; 170(3 Pt 1), 661–666.

Vock

Brutsche

Nanzer

Bartsch

Variable radiomorphologic data of high altitude pulmonary edema: features from 60 patients. Chest 1991; 100, 1306–1311.

Bärtsch

Maggiorini

Ritter

Noti

Vock

Oelz

Prevention of high-altitude pulmonary edema by nifedipine. N Engl J Med 1991; 325, 1284–1289.

Sophocles

High-altitude pulmonary edema in Vail, Colorado, 1975–1982. West J Med 1986; 144, 569–573.

10.

Reeves

Wagner

Zafren

Honigman

Schoene

Seasonal variation in barometric pressure and temperature in Summit County: effect on altitude illness. In: Sutton

Houston

Coates

eds. Hypoxia and Molecular Medicine , Burlington, VT: Charles S Houston, 1993, 275–281.

11.

Durmowicz

Noordeweir

Nicholas

Reeves

Inflammatory processes may predispose children to high-altitude pulmonary edema. J Pediatr 1997; 130, 838–840.

12.

Grissom CK. High altitude illness prevention and treatment. In: Braunwald E, ed. Harrison's Internal Medicine Online. Update 12/8/2006. The McGraw-Hill Companies, AccessMedicine. Available at: http://www.accessmedicine.com. Accessed June 22, 2007..

13.

Bärtsch

High altitude pulmonary edema. Med Sci Sports Exerc 1999; 31(suppl 1), S23–S27.

14.

Carpenter

Reeves

Durmowicz

Viral respiratory infection increases susceptibility of young rats to hypoxia-induced pulmonary edema. J Appl Physiol 1998; 84, 1048–1054.

15.

Ono

Westcott

Chang

Voelkel

Endotoxin priming followed by high altitude causes pulmonary edema in rats. J Appl Physiol 1993; 74, 1534–1542.

16.

Hanaoka

Kubo

Yamazaki

et al. Association of high-altitude pulmonary edema with the major histocompatibility complex. Circulation 1998; 97, 1124–1128.

17.

Arnett

High-altitude pulmonary edema: an immunogenetically mediated disease?. Circulation 1998; 97, 1111–1113.

18.

Naeije

De Backer

Vachiery

J-L

De Vuyst

High-altitude pulmonary edema with primary pulmonary hypertension. Chest 1996; 110, 286–289.

19.

Hackett

Creagh

Grover

et al. High-altitude pulmonary edema in persons without the right pulmonary artery. N Engl J Med 1980; 302, 1070–1073.

20.

Khoury

Hawes

Atrial septal defect associated with pulmonary hypertension in children living at high altitude. J Pediatr 1967; 70, 432–435.

21.

Willerson

Baggett

Jr Thomas

Goldblatt

Ventricular septal defect with altitude-dependent pulmonary hypertension. N Engl J Med 1971; 285, 157–158.

22.

Allemann

Hutter

Lipp

et al. Patent foramen ovale and high-altitude pulmonary edema. JAMA 2006; 296, 2954–2958.

23.

Levine

Grayburn

Voyles

Greene

Roach

Hackett

Intracardiac shunting across a patent foramen ovale may exacerbate hypoxemia in high-altitude pulmonary edema. Ann Intern Med 1991; 114, 569–570.

24.

Cremona

Asnaghi

Baderna

et al. Pulmonary extravascular fluid accumulation in recreational climbers: a prospective study. Lancet 2002; 359, 303–309.

25.

Podolsky

Eldridge

Richardson

et al. Exercise-induced VA/Q inequality in subjects with prior high-altitude pulmonary edema. J Appl Physiol 1996; 81, 922–932.

26.

Scoggin

Hyers

Reeves

Grover

High-altitude pulmonary edema in the children and young adults of Leadville, Colorado. N Engl J Med 1977; 297, 1269–1272.

27.

Hultgren

Grover

Hartley

Abnormal circulatory responses to high altitude in subjects with a previous history of high-altitude pulmonary edema. Circulation 1971; 44, 759–770.

28.

Kawashima

Kubo

Kobayashi

Sekiguchi

Hemodynamic responses to acute hypoxia, hypobaria, and exercise in subjects susceptible to high-altitude pulmonary edema. J Appl Physiol 1989; 67, 1982–1989.

29.

Schoene

Hackett

Henderson

et al. High-altitude pulmonary edema: characteristics of lung lavage fluid. JAMA 1986; 256, 63–69.

30.

Schoene

Swenson

Pizzo

et al. The lung at high altitude: bronchoalveolar lavage in acute mountain sickness and pulmonary edema. J Appl Physiol 1988; 64, 2605–2613.

31.

West

Mathieu-Costello

High altitude pulmonary edema is caused by stress failure of pulmonary capillaries. Int J Sports Med 1992; 13(suppl 1), S54–S58.

32.

West

Colice

Lee

et al. Pathogenesis of high-altitude pulmonary oedema: direct evidence of stress failure of pulmonary capillaries. Eur Respir J 1995; 8, 523–529.

33.

Maggiorini

Melot

Pierre

et al. High-altitude pulmonary edema is initially caused by an increase in capillary pressure. Circulation 2001; 103, 2078–2083.

34.

Hackett

Roach

Schoene

Harrison

Mills

Abnormal control of ventilation in high-altitude pulmonary edema. J Appl Physiol 1988; 64, 1268–1272.

35.

Matsuzawa

Fujimoto

Kobayashi

et al. Blunted hypoxic ventilatory drive in subjects susceptible to high-altitude pulmonary edema. J Appl Physiol 1989; 66, 1152–1157.

36.

Hohenhaus

Paul

McCullough

Kucherer

Bartsch

Ventilatory and pulmonary vascular response to hypoxia and susceptibility to high altitude pulmonary oedema. Eur Respir J 1995; 8, 1825–1833.

37.

Duplain

Vollenweider

Delabays

Nicod

Bartsch

Scherrer

Augmented sympathetic activation during short-term hypoxia and high-altitude exposure in subjects susceptible to high-altitude pulmonary edema. Circulation 1999; 99, 1713–1718.

38.

Sartori

Vollenweider

Loffler

et al. Exaggerated endothelin release in high-altitude pulmonary edema. Circulation 1999; 99, 2665–2668.

39.

Busch

Bartsch

Pappert

et al. Hypoxia decreases exhaled nitric oxide in mountaineers susceptible to high-altitude pulmonary edema. Am J Respir Crit Care Med 2001; 163, 368–373.

40.

Duplain

Sartori

Lepori

et al. 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 2000; 162, 221–224.

41.

Rintamaki

Human responses to cold. Alaska Med 2007; 49(suppl 2), 29–31.

42.

Hackett

Roach

Hartig

Greene

Levine

The effect of vasodilators on pulmonary hemodynamics in high altitude pulmonary edema: a comparison. Int J Sports Med 1992; 13(suppl 1), S68–S71.

43.

Modesti

Vanni

Morabito

et al. Role of endothelin-1 in exposure to high altitude: acute mountain sickness and endothelin-1 (ACME-1) study. Circulation 2006; 114, 1410–1416.

44.

Swenson

Maggiorini

Mongovin

et al. Pathogenesis of high-altitude pulmonary edema: inflammation is not an etiologic factor. JAMA 2002; 287, 2228–2235.

45.

Berger

Hesse

Dehnert

et al. Hypoxia impairs systemic endothelial function in individuals prone to high-altitude pulmonary edema. Am J Respir Crit Care Med 2005; 172, 763–767.

46.

Droma

Hanaoka

Ota

et al. Positive association of the endothelial nitric oxide synthase gene polymorphisms with high-altitude pulmonary edema. Circulation 2002; 106, 826–830.

47.

Ghofrani

Reichenberger

Kohstall

et al. Sildenafil increased exercise capacity during hypoxia at low altitudes and at Mount Everest base camp: a randomized, double-blind, placebo-controlled crossover trial. Ann Intern Med 2004; 141, 169–177.

48.

Richalet

Gratadour

Robach

et al. Sildenafil inhibits altitude-induced hypoxemia and pulmonary hypertension. Am J Respir Crit Care Med 2005; 171, 275–281.

49.

Grissom

Albertine

Elstad

Alveolar haemorrhage in a case of high altitude pulmonary oedema. Thorax 2000; 55, 167–169.

50.

West

Invited review: pulmonary capillary stress failure. J Appl Physiol 2000; 89, 2483–2489 discussion 2497.

51.

West

Mathieu-Costello

Jones

et al. Stress failure of pulmonary capillaries in racehorses with exercise-induced pulmonary hemorrhage. J Appl Physiol 1993; 75, 1097–1109.

52.

Hopkins

Schoene

Henderson

Spragg

Martin

West

Intense exercise impairs the integrity of the pulmonary blood-gas barrier in elite athletes. Am J Respir Crit Care Med 1997; 155, 1090–1094.

53.

Bärtsch

Waber

Haeberli

et al. Enhanced fibrin formation in high-altitude pulmonary edema. J Appl Physiol 1987; 63, 752–757.

54.

Bachofen

Schurch

Weibel

Experimental hydrostatic pulmonary edema in rabbit lungs: barrier lesions. Am Rev Respir Dis 1993; 147, 997–1004.

55.

Neal

Michel

Openings in frog microvascular endothelium induced by high intravascular pressures. J Physiol 1996; 492, 39–52 (part 1).

56.

Elliott

Tsukimoto

Prediletto

Mathieu-Costello

West

Short-term reversibility of ultrastructural changes in pulmonary capillaries caused by stress failure. J Appl Physiol 1992; 73, 1150–1158.

57.

Rios

Driscoll

McNamara

High-altitude pulmonary edema with absent right pulmonary artery. Pediatrics 1985; 75, 314–317.

58.

Hultgren

High altitude pulmonary edema. In: Staub

ed. Lung Water and Solute Exchange , New York, NY: Marcel Dekker, 1978, 437–469.

59.

Hlastala

Lamm

Karp

Polissar

Starr

Glenny

Spatial distribution of hypoxic pulmonary vasoconstriction in the supine pig. J Appl Physiol 2004; 96, 1589–1599.

60.

Hanaoka

Tanaka

et al. Hypoxia-induced pulmonary blood redistribution in subjects with a history of high-altitude pulmonary edema. Circulation 2000; 101, 1418–1422.

61.

Hopkins

Garg

Bolar

Balouch

Levin

Pulmonary blood flow heterogeneity during hypoxia and high-altitude pulmonary edema. Am J Respir Crit Care Med 2005; 171, 83–87.

62.

Dehnert

Risse

Ley

et al. Magnetic resonance imaging of uneven pulmonary perfusion in hypoxia in humans. Am J Respir Crit Care Med 2006; 174, 1132–1138.

63.

Planes

Escoubet

Blot-Chabaud

Friedlander

Farman

Clerici

Hypoxia downregulates expression and activity of epithelial sodium channels in rat alveolar epithelial cells. Am J Respir Cell Mol Biol 1997; 17, 508–518.

64.

Vivona

Matthay

Chabaud

Friedlander

Clerici

Hypoxia reduces alveolar epithelial sodium and fluid transport in rats: reversal by beta-adrenergic agonist treatment. Am J Respir Cell Mol Biol 2001; 25, 554–561.

65.

Mairbäurl

Mayer

Kim

Borok

Bärtsch

Crandall

Hypoxia decreases active Na transport across primary rat alveolar epithelial cell monolayers. Am J Physiol Lung Cell Mol Physiol 2002; 282, L659–L665.

66.

Mairbäurl

Schwobel

Hoschele

et al. Altered ion transporter expression in bronchial epithelium in mountaineers with high-altitude pulmonary edema. J Appl Physiol 2003; 95, 1843–1850.

67.

Egli

Duplain

Lepori

et al. Defective respiratory amiloride-sensitive sodium transport predisposes to pulmonary oedema and delays its resolution in mice. J Physiol 2004; 560(part 3), 857–865.

68.

Sartori

Allemann

Duplain

et al. Salmeterol for the prevention of high-altitude pulmonary edema. N Engl J Med 2002; 346, 1631–1636.

69.

Hackett

Roach

High-altitude illness. N Engl J Med 2001; 345, 107–114.

70.

Maggiorini

Brunner-La Rocca

Peth

et al. Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema: a randomized trial. Ann Intern Med 2006; 145, 497–506.

71.

Bärtsch

Vock

Franciolli

High altitude pulmonary edema after successful treatment of acute mountain sickness with dexamethasone. J Wilderness Med 1990; 1, 162–164.

72.

Murata

Hori

Sakamoto

Karaki

Ozaki

Dexamethasone blocks hypoxia-induced endothelial dysfunction in organ-cultured pulmonary arteries. Am J Respir Crit Care Med 2004; 170, 647–655.

73.

Asoh

Kumai

Murano

Kobayashi

Koitabashi

Effect of antenatal dexamethasone treatment on Ca2+-dependent nitric oxide synthase activity in rat lung. Pediatr Res 2000; 48, 91–95.

74.

Stelzner

O’Brien

Sato

Weil

Hypoxia-induced increases in pulmonary transvascular protein escape in rats. Modulation by glucocorticoids. J Clin Invest 1988; 82, 1840–1847.

75.

Noda

Suzuki

Tsubochi

et al. Single dexamethasone injection increases alveolar fluid clearance in adult rats. Crit Care Med 2003; 31, 1183–1189.

76.

Guney

Schuler

Ott

et al. Dexamethasone prevents transport inhibition by hypoxia in rat lung and alveolar epithelial cells by stimulating activity and expression of Na+-K+-ATPase and epithelial Na+ channels. Am J Physiol Lung Cell Mol Physiol 2007; 293, L1332–L1338.

77.

Saldias

Lecuona

Comellas

Ridge

Rutschman

Sznajder

Beta-adrenergic stimulation restores rat lung ability to clear edema in ventilator-associated lung injury. Am J Respir Crit Care Med 2000; 162, 282–287.

78.

Perkins

McAuley

Thickett

Gao

The beta-agonist lung injury trial (BALTI): a randomized placebo-controlled clinical trial. Am J Respir Crit Care Med 2006; 173, 281–287.

79.

Parker

Ivey

Isoproterenol attenuates high vascular pressure-induced permeability increases in isolated rat lungs. J Appl Physiol 1997; 83, 1962–1967.

80.

Adding

Agvald

Artlich

Persson

Gustafson

Beta-adrenoceptor agonist stimulation of pulmonary nitric oxide production in the rabbit. Br J Pharmacol 1999; 126, 833–839.

81.

Berg

Ramanathan

Swenson

Inhibitors of hypoxic pulmonary vasoconstriction prevent high-altitude pulmonary edema in rats. Wilderness Environ Med 2004; 15, 32–37.

82.

Teppema

Balanos

Steinback

et al. Effects of acetazolamide on ventilatory, cerebrovascular, and pulmonary vascular responses to hypoxia. Am J Respir Crit Care Med 2007; 175, 277–281.

83.

Höhne

Pickerodt

Francis

Boemke

Swenson

Pulmonary vasodilation by acetazolamide during hypoxia is unrelated to carbonic anhydrase inhibition. Am J Physiol Lung Cell Mol Physiol 2007; 292, L178–L184.

84.

Höhne

Krebs

Seiferheld

Boemke

Kaczmarczyk

Swenson

Acetazolamide prevents hypoxic pulmonary vasoconstriction in conscious dogs. J Appl Physiol 2004; 97, 515–521.

85.

Deem

Hedges

Kerr

Swenson

Acetazolamide reduces hypoxic pulmonary vasoconstriction in isolated perfused rabbit lungs. Respir Physiol 2000; 123, 109–119.

86.

Shimoda

Luke

Sylvester

Shih

Jain

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 2007; 292, L1002–L1012.

87.

Hohenhaus

Niroomand

Goerre

Vock

Oelz

Bartsch

Nifedipine does not prevent acute mountain sickness. Am J Respir Crit Care Med 1994; 150, 857–860.

88.

Marticorena

Hultgren

Evaluation of therapeutic methods in high altitude pulmonary edema. Am J Cardiol 1979; 43, 307–312.

89.

Zafren

Reeves

Schoene

Treatment of high-altitude pulmonary edema by bed rest and supplemental oxygen. Wilderness Environ Med 1996; 7, 127–132.

90.

Bärtsch

Treatment of high altitude diseases without drugs. Int J Sports Med 1992; 13(suppl 1), S71–S74.

91.

Freeman

Shalit

Stroh

Use of the Gamow bag by EMT-Basic park rangers for treatment of high-altitude pulmonary edema and high-altitude cerebral edema. Wilderness Environ Med 2004; 15, 198–201.

92.

Oelz

Maggiorini

Ritter

et al. Nifedipine for high altitude pulmonary oedema. Lancet 1989; 2, 1241–1244.

93.

Oelz

Noti

Ritter

Jenni

Bärtsch

Nifedipine for high altitude pulmonary oedema. Lancet 1991; 337, 556.

94.

Scherrer

Vollenweider

Delabays

et al. Inhaled nitric oxide for high-altitude pulmonary edema. N Engl J Med 1996; 334, 624–629.

95.

Anand

Prasad

Chugh

et al. Effects of inhaled nitric oxide and oxygen in high-altitude pulmonary edema. Circulation 1998; 98, 2441–2445.

96.

Schoene

Roach

Hackett

Harrison

Mills

High altitude pulmonary edema and exercise at 4,400 meters on Mount McKinley: effect of expiratory positive airway pressure. Chest 1985; 87, 330–333.

Update on High-Altitude Pulmonary Edema: Pathogenesis,Prevention,and Treatment

Abstract

Keywords

Introduction and clinical description

Risk factors and susceptibility

Pathophysiology

Prevention

Treatment

References