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Recent Advances in Chest Medicine |

Illnesses at High Altitude* FREE TO VIEW

Robert B. Schoene, MD
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*From the Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA.

Correspondence to: Robert B. Schoene, MD, Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Diego, 200 W Arbor Dr, 9th Floor, Suite 901, Mail Code 8, La Jolla, CA 92103; e-mail: rschoene@ucsd.edu



Chest. 2008;134(2):402-416. doi:10.1378/chest.07-0561
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High-altitude illnesses have profound consequences on the health of many unsuspecting and otherwise healthy individuals who sojourn to high altitude for recreation and work. The clinical manifestations of high-altitude illnesses are secondary to the extravasation of fluid from the intravascular to extravascular space, especially in the brain and lungs. The most common of these illnesses, which can present as low as 2,000 m, is acute mountain sickness, which is usually self-limited but can progress to the more severe and potentially fatal entities of high-altitude cerebral edema and high-altitude pulmonary edema. This article will briefly review normal adaptation to high altitude and then more extensive reviews of the clinical presentations, prevention, and treatments of these potentially fatal conditions. Research on the mechanisms of these conditions will also be reviewed. A better understanding of these disorders by practitioners will lead to improved prevention and rational treatment for the increasing number of people visiting high-altitude areas around the globe. There will not be space for writing about high-altitude residents, medical conditions in low-altitude residents going to high altitude, or training for athletes at high altitude. These topics deserve another article.

Figures in this Article

Interest in human travel to and habitation of high-altitude regions has expanded over the last few decades. With improved transportation, access to moderate (2,000 to 4,000 m) and even very high altitude (> 5,000 m) is very easy. Both work and recreation have stimulated this flurry of travel. Thus, there has been increased interest in both the acute adaptation of these sojourners as well as the chronic adaptation of the nearly 150 million people of the world who have lived in these sometimes remote geographic areas > 2,500 m for many centuries. Furthermore, the effect of physical training at moderate altitude has generated an intense interest by athletes who are looking for means to improve their performances in competitive environments at low altitude.

This review will limit itself to those unwary, healthy individuals who travel to high altitude and the illnesses that they incur if they ascend too rapidly and do not allow time for acclimatization. Review of exciting new research should provide the clinician with a better understanding of more common conditions encountered at high altitudes. More exhaustive treatises of the large topic of high altitude12 and a review of high-altitude illness3 are referred to these works.

The journey of oxygen from the air to the blood to the tissues and mitochondria is often called the oxygen cascade. This popular term underestimates the complex, interactive process that takes place as the body attempts to optimize the availability of oxygen at the cellular level. There are two important facts to remember: (1) each step along the way has its own time course, and (2) there is a great deal of variability in this time course and the magnitude of these processes between individuals. This heterogeneity plays an important role in determining the time required for overall acclimatization that influences physical performance, as well as susceptibility to high-altitude illnesses.

On ascent to high altitude, there is an immediate increase in alveolar ventilation (hypoxic ventilatory response [HVR]), which is perpetrated by the peripheral chemosensor, the carotid body, which over the next 2 weeks or so at the same altitude increases its sensitivity to the hypoxemia that results in an even greater increase in ventilation. This process is called ventilatory acclimatization.45 Thus, alveolar oxygen pressure and subsequently arterial oxygen content increase. The resultant respiratory alkalosis persists during the stay at altitude with only partial renal compensation.

In healthy individuals, cardiac output increases,6pulmonary artery pressures (PAPs) rise,7and ventilation and perfusion matching in the lung is improved89 as oxygen then diffuses from the air to the blood. Oxygen is then carried to the tissues bound to hemoglobin by convection in the circulation. In the first few hours, hypoxemia stimulates the secretion of erythropoietin, an important growth factor that stimulates the production of RBCs in the marrow, which over the next 10 to 14 days results in an increased content of RBCs and thus oxygen-carrying capacity in the blood.10 Oxygen then diffuses from the blood to the cytosol and mitochondria of the tissues.

At the tissue level, hypoxia-inducible factor-1α stimulates vascular endothelial growth factor (VEGF), which stimulates angiogenesis, thus augmenting blood flow and supplying more oxygen to the tissues.1112 Improvement in oxidative metabolism occurs in the mitochondria, and gas exchange in the tissues is achieved.9 These latter adaptations may take weeks or months. It must be emphasized that there is a great deal of individual variability in each of these steps, such that some people adapt more quickly and more successfully than others.

The atmosphere from the surface of the earth to the stratosphere contains a constant fraction of oxygen (0.2093). As one ascends, however, the barometric pressure decreases. For instance at sea level, the barometric pressure is approximately 760 mm Hg, while on the summit of Mount Everest it is approximately 250 mm Hg. Thus, the availability of oxygen to an organism is predictably lower the higher one goes. Of interest is the finding that the barometric pressure for any given altitude is lower as one goes from the equator to the poles, a phenomenon explained by the dense band of cold air that is present at the equatorial latitudes.13Low swings of barometric pressure from changes in the weather at moderate altitude also are associated with a higher incidence of altitude illness.14

Acute mountain sickness (AMS), high-altitude pulmonary edema (HAPE), and high-altitude cerebral edema (HACE) occur at increasing altitudes, but their occurrence depends on the rate of ascent to a new altitude, the altitude where the patient sleeps, and individual susceptibility. Hackett and Rennie15found an incidence of AMS of 43% at 4,343 m in trekkers in Nepal that was lower (31%) in those walking all the way to that altitude. Maggiorini et al16found an incidence in climbers in the Alps of 9% at 2,850 m, 13% at 3,050 m, and 34% at 3,650 m. Honigman et al17reported an incidence of AMS of approximately 22% in Summit County, CO, at moderate altitudes of 2,500 to 2,900 m with no difference between men and women, while only a modestly higher altitude of slightly > 3,000 m resulted in an incidence of 42%. Preexisting cardiopulmonary disease,18heavy exertion on arrival,19low-altitude residence before ascent, and obesity20 are risk factors, whereas youth and physical fitness do not convey protection.17,21 I will begin with a discussion of AMS and HACE, two disorders that share the same pathophysiology and represent different levels of severity of the same disease process, and then follow this section with a discussion of HAPE.

Definition and Presentation

The symptoms of AMS are subjective and are often thought by the patient to be secondary to nonspecific illness or “hangover.” But barring any other identifiable illness, on rapid ascent to a new altitude (2,000 to 3,000 m), the symptoms of headache, malaise, anorexia, nausea and vomiting, and trouble sleeping occurring within the first 6 to 36 h are most likely those of AMS.22The generally accepted Lake Louise scoring system23 requires the presence of headache and at least one of the other symptoms, rated in severity on a scale of 1 to 3. These symptoms may worsen over a day or two and may be worse on arising in the morning, but if the subject does not ascend further, the symptoms usually abate on their own. The illness may recur, however, if the sojourner ascends to a higher altitude. The physical examination usually does not reveal many objective findings, but mild crackles on chest examination; peripheral edema of face, hands, or feet; and tachycardia may be present, but these findings are not necessary to make the diagnosis.

Ongoing evaluation must involve documentation and observation of any neurologic signs, such as ataxia, hallucinations, confusion, vomiting, decreased activity, upper motor neuron signs, stupor, or coma. If any of these symptoms occur after the presence of AMS, especially at higher altitudes, > 3,000 to 4,000 m, then the subject has HACE until proven otherwise and may die if not recognized and treated promptly. Other diagnoses must be considered because the nonspecific symptoms are consistent with such entities as hypoglycemia, migraine, electrolyte abnormalities, drug and alcohol ingestion, meningitis, encephalitis, diabetic ketoacidosis, hyperthermia, and hypothermia.

Mechanism of Disease
Edema and Vascular Reactivity:

Wide avenues of investigation have attempted to understand the mechanism of cerebral edema that leads to AMS and HACE. Symptoms are, in part, secondary to increased intracranial pressures,2426 but the data are not yet compelling to ascribe the symptoms of AMS to increased intracranial pressures.

The most compelling evidence of cerebral edema during the acute phase of cerebral AMS and HACE comes from the study of Hackett et al,27 in which MRI showed intense T2 signals in the white matter, particularly in the splenium and corpus callosum (Fig 1 ). These data suggest that the leak is vasogenic in origin with an increase in permeability of the endothelium. The cause of the leak may be an increase in intravascular pressures or the effect of hypoxemia per se. The alternate hypothesis of cytotoxic edema is failure of the active, energy-dependent pumps in the cellular membranes that cause an influx of fluid. This theory has been discounted because of the profound level of hypoxemia (Po2 levels from 12 to 19 mm Hg) necessary to cause this failure.

As mentioned, the symptoms of AMS and HACE are consistent with an increase in intracranial pressure secondary to the presence of extravascular water,24 documented by Hackett et al27(Fig 1), but the findings are not consistent with respect to a substantial increase in tissue volume and ensuing symptoms, especially in AMS. One of the initial hypotheses was that individuals susceptible to AMS had relative hypoventilation and higher Pco2 values with a subsequently higher cerebral blood flow (CBF) leading to a vasogenic cerebral edema.

Results of studies to test this hypothesis have been variable. Jensen et al28showed no difference in CBF between AMS and healthy subjects. Using middle cerebral artery flow measurements with intracranial Doppler techniques, Baumgartner et al29and Jansen et al30showed a rather hyperactive chemosensitivity to hypoxia and hypercarbia and thus vasodilatation in subjects with AMS. Van Osta et al31 found that symptoms of AMS correlated with the loss of precise autoregulation but without a substantial increase in CBF.

Variation of cerebral oxygenation has been studied to elucidate individual differences and thus potential susceptibility to illness. An interesting observation by Imray et al32showed that CBF and cerebral oxygenation was optimal at 5,260 m at 30% of maximum oxygen uptake during exercise but then decreased as the exercise intensity increased. Subudhi et al33 studied cerebral oxygenation during normoxic and hypoxic exercise and found cerebral oxygenation fell with increasing levels of exertion but could not speculate on the relationship of this observation and the development of either cerebral limits to exercise or the formation of edema. All of these findings suggest that vasoreactivity of CBF plays a role in the susceptibility or occurrence of AMS, but how it does so remains a mystery.

There has been a flurry of interest in the roles of oxidative stress, vascular permeability, and antioxidant vitamins in the development of AMS. Bailey and Davies34noted free-radical–induced vascular permeability in muscular beds of male volunteers exposed to high altitude that the authors believed may be a similar mechanism to the cerebral edema of AMS. Subjects ascending rapidly to 4,559 m had an increase in cytokines, markers of muscle damage, reactive oxygen species (ROS), and neuronal damage, but these variables did not correlate with the symptoms and severity of AMS.35In two studies, Magalhães et al3637 exposed mice to an equivalent altitude of 7,000 m, measured the response of ROS, and then blocked the response. The extreme exposure increased measurable ROS, and blockade decreased the ROS. These authors3637 reported similar results from a study in humans exposed to 5,500 m. Bailey et al38 exposed humans to an fraction of inspired oxygen of 0.12 for 18 h and measured ROS, brain MRI, lumbar punctures, and symptoms of AMS. One half of the subjects experienced AMS, but there were no correlations between the severity of AMS and any of the variables.

Another hypoxia-induced mediator of vascular proliferation and permeability, VEGF, increases on ascent to 4,559 m, but here again there was no difference between subjects with or without AMS.39Schoch et al40exposed mice to hypoxia and found an increase of VEGF and evidence of cerebral edema that was prevented in other mice that were given a neutralizing antibody to VEGF. Tissot van Patot et al41 did find higher levels of VEGF in subjects exposed to 4,559 m, which was associated with symptoms of AMS. Thus, the roles of oxidative stress and VEGF in the vascular permeability and symptoms of AMS still need to be clarified.

Accentuated Hypoxemia:

The HVR defends the body immediately from profound hypoxemia,4 but most studies4246 measuring HVR in subjects going to altitude do not show a consistent relationship between a low HVR and the subsequent development of AMS. However, Burtscher et al47 used the poikilocapnic HVR test. AMS susceptibility was correctly predicted 86% in selected individuals exposed to short-term hypoxia. Because of the heterogeneity of HVR between individuals, there is a range of Pao2 (40 to 70 mm Hg) that stimulates ventilation that makes accurate prediction of disease difficult.

What has been more convincing, though, has been the relationship between a low arterial oxygen saturation (Sao2) at altitude and the subsequent development of AMS,4748 which is related, in part, to alveolar ventilation as well as to impaired gas exchange.49Whether there is subclinical, interstitial pulmonary edema or not is not clear.50 Exercise on arrival at altitude that may impose a stress on both the pulmonary and cerebral microvasculature has been associated with the development of AMS.19

Fluid Balance:

If tissue edema is a critical component of altitude illnesses, then excess fluid retention may predispose individuals to altitude illnesses.51The time course of the symptoms of AMS suggests that a slower process, such as is necessary to retain fluid, compounds the acute exposure to hypoxia. Although a mild diuresis is the normal response to exposure to high altitude, studies52in individuals with AMS have demonstrated fluid retention53with an increase in aldosterone54and the activity of renin-angiotensin.5556 A relationship between the ventilatory response to hypoxia and diuresis has been documented,57 thus allowing one to speculate that a more blunted ventilatory response to hypoxia and greater hypoxemia on ascent results in less of a diuresis and fluid retention. Not all studies confirm the hormonal mechanism of the fluid retention, but the clinical observation of weight gain and an antidiuresis occurs in subjects with AMS.

Clinical Guidelines

Since HACE is likely a continuum of AMS, the most important recommendation is to recognize when AMS may evolve into HACE. AMS is generally considered self-limited, while HACE can be fatal. Thus, in addition to evaluating the presence and severity of AMS with the Lake Louise scoring system as a guideline, one must look for other neurologic signs, eg, ataxia, confusion, and hallucinations, which could mark the onset of HACE. While AMS can be treated with rest and some medication at the same altitude, victims of HACE must descend to a lower altitude if at all possible (see below for specific recommendations).

Prevention of all altitude maladies involves ascending at a gradual rate, allowing time for natural acclimatization. A general guideline is that at > 3000 m, one should not spend subsequent nights 300 m higher than the previous night. A rest day every 2 to 3 days is recommended. Anyone with symptoms of AMS should not ascend until the symptoms are improved. This technique works for even the most “susceptible” individuals, but here again one must remember that there is great individual variability, and the individual who is slow to acclimatize may be the strongest at the end of the trip.

The clinician should evaluate patients who are seeking advice on trips to high altitude. A history of high-altitude problems, the altitude profile and speed of ascent of the planned trip, the accessibility of medical care or lack thereof, and the geographic layout of the trip that may make descent difficult are all important factors. The physician should educate patients about the signs and symptoms of high-altitude illness and inform them of the risks that must then be assumed by the traveler.

If a traveler has been to high altitude (approximately 2,500 to 4,000 m) before and has had no problems, the trip should still be taken with acclimatization in mind. Medications that are useful to prevent and treat illness should be taken along in case symptoms occur (Table 1 ). Travelers who have had problems with AMS should use medications to prevent recurrence of symptoms because AMS can be debilitating and may necessitate a change of itinerary in a journey that may be in a remote part of the world. Early judicious use of medications can minimize the risk of AMS proceeding to HAPE or HACE. If symptoms of AMS do not abate or if they worsen at any point within 24 to 48 h, then patients should descend while they still can under their own power and thus not put their fellow travelers under undo risk as well. At no time should an individual with symptoms of altitude illness descend alone.

Medications that are effective in prevention and treatment are few. Acetazolamide has long been known to be effective in preventing15,5861 and treating62AMS. The side effects of paresthesias, loss of appetite and nausea, and making carbonated beverages distasteful are self-limited and can be minimized by a dose of 125 mg bid begun a day before ascent.63A higher dose of 250 mg bid or tid or use of a 500-mg, sustained-release capsule are effective, but the side effects are greater. Some have recommended a higher dose of 375 mg bid, but this dose is not necessary. Taking a test dose at sea level under physician supervision a couple of weeks before ascent is prudent to make sure that the side effects of the drug are tolerable or that a true allergy does not exist. The recommended duration of treatment has never been established, but a 3- to 5-day course during the first part of a trip seems reasonable, but it is often taken safely for the duration of a high altitude ascent or trek. Acetazolamide has also been shown to be effective in treating AMS if started early.64 Patients with known allergies to sulfa drugs should not take acetazolamide.

The mechanism of acetazolamide in altitude illness is not understood,65but the action of carbonic-anhydrase inhibition mimics some of those of normal acclimatization. Carbonic-anhydrase inhibition impairs the normal transport of carbon dioxide from the cell to the lung. The resulting tissue acidosis is probably responsible for stimulation of the chemosensors and increase in ventilation, as well as a prevention of periodic breathing and accentuated hypoxemia during sleep,66 which occurs commonly in acclimatizing individuals. This respiratory stimulation is furthered by an increased excretion of bicarbonate in the kidneys that results in a more profound metabolic acidosis. The lower recommended dose of 125 mg bid has little effect on the cellular respiratory acidosis but probably exerts its renal effect on the induction of the renal metabolic acidosis.65,67 These effects are all part of normal acclimatization but are hastened by acetazolamide.

Dexamethasone is an excellent drug to prevent and treat AMS and HACE6870; but, unlike acetazolamide, dexamethasone does not facilitate acclimatization and may give one a sense of false security by masking symptoms. Cessation of the drug may result in a recurrence of symptoms71and even death if descent has not been undertaken in severe cases. Dexamethasone is effective when administered in high doses (8 to 10 mg IM, IV, or po initially and 4 mg q6h) until descent has been achieved. In previously healthy individuals, the side effects are inconsequential; and if the drug is started at the onset of symptoms of HACE while descent is undertaken, the drug can be life saving. The drug is therefore an excellent rescue drug, especially at higher altitudes in remote areas, where it should be part of the medical kit. The drug, along with acetazolamide, should be considered as a prophylactic for altitude illness by mountain rescue teams who have to ascend to approximately 3,500 m rapidly, for which they have to be as physically healthy and effective as possible. The dose for prophylaxis of altitude illness has not been well-established, but 2 to 4 mg po qd is generally used successfully. The mechanism of its efficacy is not known, but as in the cerebral edema from intracranial tumors, this potent glucocorticoid presumably minimizes the extravascular leak in the brain. Schoene72 discussed the misuse of this potent glucocorticoid to improve performance at high altitude and the subsequent ethical considerations.

The popularity of portable, inflatable hyperbaric bags has increased because they are effective in treating patients with all altitude illnesses,7376 especially when injury or weather prevents descent. Supplemental oxygen, if available, is very effective in those patients for whom descent is not available. Over the years, there has been a flurry of interest in other drugs and remedies (diuretics, theophylline, ginkgo biloba), but evaluations of their benefit have been unconvincing and for the time-being should not be considered part of the high-altitude drug kit.

Although there are accounts of HAPE in the literature as early as the late eighteenth century and most impressively from South America in the 1950s, the first descriptions of HAPE as a recognized form of noncardiogenic pulmonary edema were in 1960 by Hultgren and Spickard77and Houston.78 A number of extensive reviews7880 as well as histories of the quest to understand the mechanism of the disease72 are available.

Definition and Presentation

HAPE typically occurs at altitudes > 3,000 m and causes the most deaths from altitude illness. As with AMS, it affects previously healthy individuals ascending to a new altitude. It may be preceded by AMS, and its symptoms typically begin 2 to 4 days after arrival at a new altitude. HAPE begins with a subtle nonproductive cough and shortness of breath, both at rest and especially with attempts to exercise modestly, and progresses to a debilitating degree of dyspnea, even at rest, and a cough productive of pink, frothy sputum. Subjects are tachypneic and tachycardic, need to rest frequently, and have crackles on chest auscultation. If the condition worsens, lethargy, coma, and death may ensue. As the subject deteriorates, the severe hypoxemia may also lead to HACE. HAPE can present as low as 1,400 m81 and has been seen as high as 7,000 m, but usually occurs at > 3,000 m.

Men seem more susceptible to HAPE than women. Individuals with a history of HAPE appear to be prone to get sick again, thus generating a population of HAPE susceptible (HAPE-S) individuals who have been the focus of intense and revealing investigation. People, especially children, who live at high altitude and descend to low altitude and reascend and get HAPE have been described in North and South America.8283 HAPE-S individuals with congenital absence of one pulmonary artery have been described.8485 Any other condition that affects the pulmonary vasculature (acute and chronic pulmonary embolism, primary pulmonary hypertension, Down syndrome) may predispose individuals to the development of HAPE. Alleman et al86 tested the hypothesis that the burden on the hemodynamics of the right side of the heart as well as the hypoxemia could be accentuated by a patent foramen ovale (PFO). They studied HAPE-S individuals as well as individuals who had gone to altitude with no episodes of HAPE with transesophageal echocardiography to evaluate PAPs and presence of PFOs at low and high altitude and found that the frequency of PFO was four-times higher in HAPE-S subject. These intriguing results need to be followed up with studies in larger populations of HAPE-S and control subjects.

The susceptible number of sojourners is often difficult to determine, but figures of 0.2% in individuals ascending to the Campana Margherita Hut on Monta Rosa (4,559 m) to 2.5% at 4,400 m on Denali or on the way to Everest Basecamp,15 to 15% in Indian troops flown rapidly to 3,500 m87 have been reported.

Imaging of the thorax reveals patchy opacities with inconsistent predominance of location, but often infiltrates are seen initially in the region of the right middle lobe8790 (Fig 2 ). A recent study91 using chest ultrasonography at 4,240 m in Nepal demonstrated that the “comet-tail sign” (echogenic patterns in the peripheral lung arising with increased lymphatic flow in the lobular septae), which has been used to track the course of cardiogenic pulmonary edema, was useful in diagnosing HAPE and following up patients with HAPE. They propose that this noninvasive technique could become a useful research tool in studying the clinical and physiologic course of HAPE patients.

Mechanism of Disease

Investigations in the past four and a half decades have largely unraveled the mechanisms of leak in the lungs of HAPE.80 Insightful clinical observations in HAPE were followed by physiologic studies, and as technology and scientific understanding evolved, cellular, molecular, and genetic research have helped to elucidate the very basic inherent conditions and steps that result in excess extravascular lung water accumulation.

Pulmonary Vasoreactivity:

Studies using pulmonary artery catheterization documented that HAPE victims, both during and after bouts of HAPE and with exercise, had abnormally accentuated pulmonary vascular responses to hypoxia (HPVR) with normal pulmonary capillary wedge pressures, compared to individuals who did not get HAPE.90,9296 More recently, noninvasive echocardiography has substantiated these earlier findings and found that a number of individuals had abnormally high PAP even during rest at sea level97102 (Fig 3, 4 ).

These studies have provided a vital clue to the initiating condition of high intravascular pressures that, more likely than not, leads to stress failure of the pulmonary microvascular endothelium. The stresses may be accentuated by the fact that HPVR occurs in a heterogeneous pattern, thus imposing higher stresses in the overperfused areas. Rabbit models in which the left atrial pressures were acutely elevated to pressures consistent with that encountered with ascent to high altitude demonstrated disruption of the capillary endothelial layer and leak of high protein fluid into the extravascular space that resolved when the pressures were returned to normal.103106 These findings are consistent with the fragile capillary wall that must be thin enough to permit efficient gas exchange while maintaining integrity of these small vessels. As hypoxic pulmonary vasoconstriction is patchy, stresses on the microvasculature are distributed to subsegments of the pulmonary vascular bed that are not protected by vasoconstriction. A disproportionate portion of the cardiac output is delivered to these vulnerable areas of the capillary bed.107109 The concept of heterogeneity of HPVR is an important one that helps to explain the pattern of edema seen in HAPE.

Ventilation:

Accentuated hypoxemia at high altitude can result from a lower HVR, as compared to others with a more brisk HVR. The lower alveolar hypoxia could result in more brisk hypoxic vasoreactivity and thus higher vascular pressures. Animal studies have shown that there is a link between HVR and HPVR that is vagally mediated, such that stimulation of the carotid body attenuates HPVR that can be blocked by both surgical and chemical blockade of the carotid body.110111 Furthermore, a blunted ventilatory response has been found in HAPE-S subjects.112115 Thus, two inherent mechanisms that lead to pulmonary hypertension, a blunted HVR and an alteration of vasoregulatory mediators with a resultant accentuated HPVR, may play an important role in the initiation of this disease.

Mechanism of Vasoreactivity:

An imbalance of vasoactive mediators may lead to an exaggerated HPVR. Individuals may have genetic predisposition to this imbalance. Early studies of BAL in victims of HAPE at high altitude documented high concentrations of thromboxane B2, a vasoconstrictor, compared to healthy control subjects.116117 More recently, the opposing influences of endothelin-1 and nitric oxide (NO) have drawn attention. NO emanates from the endothelial lining of most vascular beds, is transiently available, and is a potent vasodilator. Studies have shown that concentrations of NO are lower in patients at 4,559 m with HAPE, showing an inverse relationship with PAPs118 (Fig 5 ) and a lower concentration of exhaled NO in HAPE-S subjects (Fig 6 ). Busch et al,101 exposed HAPE-S subjects to 2 h of hypoxia and found a decrease in NO and increase in PAP, compared to control subjects who had no change in NO. Two variants for the gene polymorphisms for endothelial-derived NO synthase were found in approximately 25% of HAPE-S subjects vs 7 to 9% of control subjects,119120 but not all investigators have generated similar results.121123

Endothelin-1 is an intense vasoconstrictor that was found to be 33% higher in HAPE-S subjects with high PAPs at 4,559 m than control subjects.123It is not clear whether these higher concentrations were secondary to increased production or decreased clearance. Furthermore, an increased sympathetic activity on ascent that affects vasoconstriction is also higher in the HAPE-S group.124 Thus, as in so many other physiologic responses, the ying and yang of reactions that modulate a delicate balance in so many systems may have some genetic imbalance in the pulmonary vasculature in HAPE-S subjects.

Alveolar Fluid:

Early speculation centered around the nature of the leak, reflected in the makeup of the alveolar fluid. The question arose as to whether the leak was the classic low-protein fluid of “hydrostatic” edema, such as in congestive heart failure, or the high-protein “permeability” leak, associated with inflammation and/or the stress failure of high pressures on the endothelial lining. This arbitrary categorization of edema fluid was found to be inadequate to help delineate the mechanism of leak.

Schoene et al116117 undertook BAL with a fiberoptic bronchoscope at 4,400 m on Denali in the Alaska Range in climbers with HAPE and healthy control subjects. Secondary to the inability of the investigators to control the time of the lavage with the course of the disease, climbers were studied at variable periods of time after the onset of their illness. The results in the HAPE subjects compared to high-altitude and low-altitude healthy control subjects showed very high concentrations of high-molecular-weight proteins, a high cell count, especially of alveolar macrophages, RBC, and high concentrations of thromboxane B2 and leukotriene B4. These results were in contrast to BAL in patients with ARDS who showed elevated proteins, not as high as the HAPE subjects, and a high cell count, primarily of neutrophils. Thus, the nature of the edema fluid in these two entities was quite different, showing similarly high protein levels but a much more profound inflammatory response in ARDS. The finding of fluid both high in protein and inflammatory mediators brought into question the potential role of inflammation as an instigator of permeability edema or an innocent byproduct of the high-protein edema caused by high intravascular pressures.

A number of years later, Erik Swenson, a member of the original research team on Denali in the 1980s, and colleagues125 repeated the studies in an attempt to answer the question. After initial studies at low altitude, they took HAPE-S subjects rapidly to the Campana Margherita Hut at 4,559 m on the summit of Monta Rosa in Northern Italy and performed BAL as soon as clinical HAPE began to develop, a study design not possible on Denali. The BAL fluid showed high protein concentrations that correlated with the subjects’ PAP but no incidence of inflammation. Thus, this elegant study supported the contention that the leak from HAPE is caused by violation of the endothelial lining of the pulmonary vasculature by high intravascular pressures, not inflammation. The inflammatory mediators in the first studies are believed to be a post facto response instigated by the initial leak into the interstitial and alveolar spaces.

Alveolar Fluid Clearance:

The all-important balance of the fluid in the lung parenchyma depends on the extravasation of that fluid from the intravascular space to the interstitium and alveoli and the degree of alveolar fluid clearance by the lymphatics. Alveolar fluid is actively pumped out of the alveolar space to the interstitium, where it is cleared by lymphatic drainage (Fig 7 ). Hypoxia inhibits the active alveolar epithelial Na+-K+ adenosine triphosphatase pump.126128 Attention turned to impaired or inherently lower alveolar fluid clearance (AFC) as a predisposing factor in HAPE.

Sodium and water transport mechanisms in the nasal epithelium help provide insight into the issues of AFC.128130 HAPE-S subjects have a disruption of the gene for the α subunit of the amiloride-sensitive epithelial sodium channel. Using this information and the fact that β2-agonists facilitate AFC by this active epithelial pump, Sartori et al,129 used doses of salmeterol (125 μg bid) that are higher than those used in asthma in HAPE-S subjects rapidly ascending to 4,559 m and essentially prevented HAPE. These subjects also had a 30%-lower level of transnasal epithelial sodium transport than control subjects. β-Agonists also have other antiinflammatory effects and lower PAP, so the exact mechanism of their beneficial effect is not known. Maggiorini et al131 used dexamethasone in HAPE-S subjects at the Monte Rosa facility to test the findings of the study by Sartori et al.130 They were unable to convincingly confirm that dexamethasone facilitated AFC but did find that there was reduction of hypoxic pulmonary vasoconstriction, which was a new and unpredicted finding. None of the subjects receiving dexamethasone experienced HAPE.

Clinical Guidelines

As in other types of altitude illness, adequate time for acclimatization minimizes or prevents the development of HAPE. Even HAPE-S subjects can drastically decrease the incidence of HAPE if they ascend gradually and minimize excessive exercise.

As in AMS, in individuals who have ascended to altitudes > 3,000 m without a history of HAPE, there is no need for pharmacologic prophylaxis. However, research over the last 15 years has provided important insight into possible interventions that may prevent and/or treat HAPE. These have centered primarily on the fact that accentuated pulmonary hypertension on ascent contributes to the development of HAPE (Table 1).

Bartsch et al132took this physiologic observation and tested the hypothesis that minimizing the pulmonary hypertension on ascent to high altitude would prevent HAPE. They used a calcium-channel blocker, nifedipine, in HAPE-S subjects on rapid ascent to the 4,559 m and essentially prevented HAPE. This study was considered an important link between clinical and physiologic observation and therapeutic tools.133

Acetazolamide, an important medication to prevent AMS, may also be efficacious in preventing HAPE. Swenson134demonstrated that acetazolamide reduced HPVR by a modest degree, probably by its effect on calcium channels. In human subjects, Teppema et al135 demonstrated a 57% decrease in calculated pulmonary vascular resistance with acute hypoxia and a 34% decrease in pulmonary vascular resistance after sustained poikilocapnic hypoxia. Thus, further studies may support this preliminary work and show that this drug, used in the prevention and treatment of AMS, may also be adjunctive therapy in HAPE, but for the present acetazolamide should not be considered a substitute for nifedipine or other agents tested as a prophylaxis for HAPE.

Phosphodiesterase-5 inhibitors promote pulmonary vasodilatation. Use of sildenafil and tadalfil promotes cyclic guanosine monophosphate accumulation in the lungs and has been shown to decrease PAP. Sildenafil improves exercise performance at high altitude135137, whereas only tadalafil has been shown to reduce the incidence of HAPE131 and prevent HAPE as well. Although these drugs have been used empirically to treat HAPE, there are no good studies to demonstrate their efficacy in treatment of HAPE. This category of drugs gives hope for all types of diseases associated with pulmonary hypertension.

Glucocorticoids have also been shown to helpful in treating HAPE, but their protean effects make understanding the mechanism difficult. Stelzner et al138showed that a leak of high protein fluid developed in intact rats as well as pulmonary artery endothelial monolayer cell cultures exposed to a hypoxic milieu (Fig 8 ). The addition of dexamethasone to the milieu prevented this leak. Other effects of glucocorticoids— the augmentation of the Na+-K+ adenosine triphosphatase pump at the epithelium139 and the promotion of endothelial-derived NO synthase by inhibiting hypoxia-induced endothelial dysfunction and thus minimizing PAP140—may also play a role in its efficacy in preventing and treating HAPE. Dexamethasone was also found to be more effective in lowering PAP than other vasodilating agents,131 presumably secondary to its sympatholytic effect. HAPE-S subjects have increased sympathetic tone such that attenuation of that vasoreactivity with dexamethasone may be particularly effective in preventing HAPE in this group.

Guidelines

Physicians who are advising patients who wish to go to high altitude should use the following guidelines in HAPE. In patients with no history of altitude problems, ascent to ≥ 3,000 m should not impose any inordinate risk for the development of HAPE so long as time is taken to acclimatize. If patients present with HAPE in a recreational area where medical care is available, and if the application of low-flow oxygen results in an improvement in dyspnea and Sao2 > 90%, the subject can be treated with oxygen and observation at altitude.139 If symptoms worsen or if oxygen saturation does not improve, then the patient should be sent to a medical facility at a lower altitude. Use of a lightweight, portable end-expiratory pressure mask has also been shown to improve oxygenation142 and may also be an important temporizing measure. Most patients with HAPE incurred near medical facilities can be treated with rest and oxygen, remain at altitude, recover over 2 to 3 days, and resume his/her holiday.

If individuals are ascending to a high remote area where descent is difficult and medical care and supplemental oxygen are not available, then the travelers should be educated about the symptoms of HAPE and be supplied with a selection of drugs known to be efficacious for HAPE, with instructions on careful utilization of the medications (Table 1). Nifedipine has been used for emergent treatment for HAPE with some success when descent in a remote area was not possible.143 It is reasonable to have a couple of inexpensive (approximately $300) pulse oximeters. The Sao2 values of the symptomatic subject can be compared with healthy fellow travelers. A portable hyperbaric bag can be taken on treks or expeditions and can also be a valuable temporizing measure. Descent should be undertaken as soon as possible.

In individuals with a history of HAPE, pharmacologic prophylaxis is prudent. The choice of these drugs should be made based on the known underlying pathophysiology of these HAPE-S patients. Drugs that promote pulmonary vasodilatation and AFC are usually safe and efficacious (see “Discussion” section above). At this time, nifedipine (30 mg bid extended release) is the only well-studied medication,132 while there have been some promising results with the phosphodiesterase-5 inhibitors (tadalafil, 10 mg bid).131 Both of these drugs decrease PAP. Acetazolamide133 and glucocorticoids131,140 may also have similar effects, but no studies in the prevention or treatment of HAPE have been undertaken. Inhaled β-agonists, such as salmeterol, that facilitate AFC, may also be a safe, adjunctive therapy in the HAPE-S patient,130 although not as effectively as nifedipine. Potent loop diuretics should be avoided because most victims are already intravascularly volume depleted, which, if augmented, could worsen the patient’s overall hemodynamic status.

This article briefly reviewed the physiologic adaptations in humans ascending to high altitude and has emphasized the setting in which altitude illnesses in sojourners can be encountered. The entities of AMS and HACE are probably a continuum of the same process of edema in the brain, whereas HAPE is a reflection of the extravasation of fluid from the intravascular to extravascular space in the lung parenchyma. This review has emphasized the research that has led to the much of the understanding of the mechanism of these altitude illnesses, while there is still much to be done to further this understanding as well as increase public awareness of the diseases so that people can enjoy their sojourns to high-altitude safely.

Abbreviations: AFC = alveolar fluid clearance; AMS = acute mountain sickness; CBF = cerebral blood flow; HACE = high-altitude cerebral edema; HAPE = high-altitude pulmonary edema; HAPE-S = high-altitude pulmonary edema susceptible; HPVR = pulmonary vascular responses to hypoxia; HVR = hypoxic ventilatory response; NO = nitric oxide; PAP = pulmonary artery pressure; PFO = patent foramen ovale; ROS = reactive oxygen species; Sao2 = arterial oxygen saturation; VEGF = vascular-endothelial growth factor

The author has no conflict of interest to disclose.

Figure Jump LinkFigure 1. Left: Axial T2-weighted MRI of patient 4 showing markedly increased signal in corpus callosum (arrows), including both the genu and the splenium, as well as increased signal of periventricular and subcortical white matter. Right: Axial T2-weighted MRI of the same patient 5 weeks after original presentation demonstrating no residual abnormality in splenium (arrow).27Grahic Jump Location
Table Graphic Jump Location
Table 1. Pharmacologic Treatment Option for Altitude Illnesses, Not Including Recommendations of Ascent Rates, Descent Rescue
Figure Jump LinkFigure 2. Top, A: Radiograph of a 37-year-old male mountaineer with HAPE that shows a patchy to confluent distribution of edema, predominantly on the right side. Bottom, B: CT scan of 27-year-old mountaineer with recurrent HAPE showing patchy distribution of edema.82Grahic Jump Location
Figure Jump LinkFigure 3. Pulmonary artery systolic pressure (PASP) response to prolonged hypoxia; discrimination between control subjects (n = 11) and HAPE-S subjects (n = 9) by their pulmonary artery systolic pressure response to hypoxia estimated by Doppler echocardiography. The study was discontinued at 55 min of hypoxia in one control subject. No significant differences were seen at rest between both groups (p = 0.36). *Pulmonary artery systolic pressure in HAPE-S subjects compared with control subjects at 45 min (p = 0.0012), 90 min (p = 0.0016), and 240 min (p < 0.02) of hypoxia.101Grahic Jump Location
Figure Jump LinkFigure 4. Effects of prolonged hypoxia (12% oxygen) on PASP in HAPE-S subjects (open columns, n = 8) and control subjects (solid columns, n = 9) resistant to such disease. In both groups, hypoxia induced a significant increase in PASP when compared with normoxia. Compared with control subjects, the effect was significantly enhanced in HAPE-S subjects, indicating a more sustained pulmonary hypoxic vasoconstriction in these subjects. Values are presented as means ± SEM; *p < 0.05 compared with normoxia; §p < 0.05, HAPE-S vs control subjects.101 See Figure 3 legend for expansion of abbreviation.Grahic Jump Location
Figure Jump LinkFigure 5. Plot of relationship between exhaled pulmonary NO and PASP in 26 HAPE-S (closed squares) and 16 control subjects (open circles); r = 0.51; p < 0.001.118 See Figure 3 legend for expansion of abbreviation.Grahic Jump Location
Figure Jump LinkFigure 6. Line graphs showing effects of high-altitude exposure (4,559 m) on exhaled pulmonary NO (mean ± SE) in 13 HAPE-S subjects with pulmonary edema (open squares), 15 HAPE-S without pulmonary edema (closed squares), and 24 control subjects (open circles). Throughout the sojourn at high altitude, exhaled pulmonary NO was significantly lower (p < 0.001) in HAPE-S subjects than in control subjects. In the HAPE-S with pulmonary edema, exhaled NO was lower than in those without edema (p < 0.01) and did not show any tendency to increase before the development of edema.118Grahic Jump Location
Figure Jump LinkFigure 7. Alveolar fluid balance. Top, 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+ adenosine triphosphatases. Thus, active Na reabsorption generates the osmotic gradient for the reabsorption of water. Bottom, 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.128Grahic Jump Location
Figure Jump LinkFigure 8. ALC (percentage of liquid instilled) in rats for different times of hypoxic exposure (8% O2) [hatched bars] and after 24 h of reoxygenation (stippled bars) of rats exposed to 24-h hypoxia. Results are expressed as mean ± SE of three to five experiments. ALC was significantly decreased (*p < 0.05, **p < 0.01, ***p < 0.001) compared with that measured in normoxic rats128).Grahic Jump Location
Hornbein, TF Schoene, RB eds. High altitude: an exploration of human adaptation. Vol. 161 in Lenfant C, ed. Lung biology in health and disease series. 2001; Marcel Dekker Publishers. New York, NY:.
 
West, JB, Schoene, RB, Milledge, JS. High altitude medicine and physiology. 2007; Hodder Arnold Publishers. London, UK:.
 
Hackett, PH, Roach, RC High-altitude illness.N Engl J Med2001;345,107-114. [PubMed] [CrossRef]
 
Bisgard, GE, Forster, HV Ventilatory responses to acute and chronic hypoxia. Fregly, MJ Blatteis, CM eds.Handbook of physiology, environmental physiology1996,1207-1239 Oxford University Press. New York, NY:
 
Basu, CK, Selvamurthy, W, Bhaumick, G, et al Respiratory changes during initial days of acclimatization to increasing altitudes.Aviat Space Environ Med1996;67,40-45. [PubMed]
 
Wolfel, EE, Levine, BD The cardiovascular system at high altitude: heart and systemic circulation. Hornbein, TF Schoene, RB eds.High altitude: an exploration of human adaptation. Vol. 161 in Lenfant C, ed. Lung biology in health and disease series2001,235-292 Marcel Dekker Publishers, New York. New York, NY:
 
Reeves, JT, Stenmark, KR The pulmonary circulation at high altitude. Hornbein, TF Schoene, RB eds.High altitude: an exploration of human adaptation. Vol. 161 in Lenfant C, ed. Lung biology in health and disease series2001,293-342 Marcel Dekker Publishers, New York. New York, NY:
 
Wagner, PD Gas exchange. Hornbein, TF Schoene, RB eds.High altitude: an exploration of human adaptation. Vol. 161 in Lenfant C, ed. Lung biology in health and disease series2001,199-234 Marcel Dekker Publishers, New York. New York, NY:
 
Schoene, RB Gas exchange in lung and muscle at high altitude. Roca, J Rodrigues-Roisin, R Wagner, PD eds.Pulmonary and peripheral gas exchange in health and disease. In: Lenfant C, ed. Lung biology in health and disease2000,525-552 Marcel Dekker. New York, NY:
 
Grover, RF, Bartsch, P Blood. Hornbein, TF Schoene, RB eds.High altitude: an exploration of human adaptation. Vol. 161 in Lenfant C, ed. Lung biology in health and disease series2001,493-523 Marcel Dekker Publishers, New York. New York, NY:
 
Semenza, GL HIF-1: mediator of physiological and pathophysiological responses to hypoxia.J Appl Physiol2000;88,1474-1480. [PubMed]
 
LaManna, JC, Chavez, JC, Pichiule, P Structural and functional adaptation to hypoxia in the rat brain.J Exp Biol2004;207,3163-3169. [PubMed]
 
West, JB The atmosphere in high altitude: an exploration of human adaptation Hornbein, TF Schoene, RB eds. Vol. 161 in Lenfant C, ed. Lung biology in health and disease series. 2001; Marcel Dekker Publishers, New York. New York, NY:.
 
Reeves, JT, Zafren, J, et al Seasonal variation in barometric pressure and temperature: effect on altitude illness. Sutton, JR Houston, CS Coates, G eds.Hypoxia and molecular medicine1993,275-281 Queen City Printers. Burlington, VT:
 
Hackett, PH, Rennie, D The incidence, importance, and prophylaxis of acute mountain sickness.Lancet1976;7996,1149-1155
 
Maggiorini, M, Bühler, B, Walter, M, et al Prevalence of acute mountain sickness in the Swiss Alps.BMJ1990;301,853-855. [PubMed]
 
Honigman, B, Theis, MK, Koziol-McLain, J, et al Acute mountain sickness in a general tourist population at moderate altitudes.Ann Intern Med1993;118,587-592. [PubMed]
 
Hackett, PH Hornbein, TF Schoene, RB eds.High altitude: an exploration of human adaptation. Vol. 161 in Lenfant C, ed. Lung biology in health and disease series2001,839-885 Marcel Dekker Publishers. New York, NY:
 
Roach, RC, Maes, D, Sandoval, D, et al Exercise exacerbates acute mountain sickness at simulated altitude.J Appl Physiol2000;88,581-585. [PubMed]
 
Ri-Li, G, Chase, PJ, Witkowski, S, et al Obesity: associations with acute mountain sickness.Ann Intern Med2003;139,253-257. [PubMed]
 
Savourey, G, Garcia, N, Besnard, Y, et al Physiological changes induced by pre-adaptation to high altitude.Eur J Appl Physiol Occup Physiol1994;69,221-227. [PubMed]
 
Bartsch, P, Roach, RC Hornbein, TF Schoene, RB eds.High altitude: an exploration of human adaptation. Vol. 161 in Lenfant C, ed. Lung biology in health and disease series2001,731-776 Marcel Dekker Publishers, New York. New York, NY:
 
Roach, RC, Bartsch, P, Hackett, PH, et al The Lake Louise acute mountain sickness scoring system. Sutton, JR Houston, CS Coates, G eds.Hypoxia and molecular medicine1993,272-274 Queens City Press. Burlington, VT:
 
Singh, I, Khanna, PK, Srivastava, MC, et al Acute mountain sickness.N Engl J Med1969;280,175-184. [PubMed]
 
Dickinson, JG Severe acute mountain sickness.Postgrad Med J1979;645,454-460
 
Hackett, PH High altitude cerebral edema and acute mountain sickness: a pathophysiology update.Adv Exp Med Biol1999;474,23-45. [PubMed]
 
Hackett, PH, Yarnell, PR, Hill, R, et al High-altitude cerebral edema evaluated with magnetic resonance imaging: clinical correlation and pathophysiology.JAMA1998;280,1920-1925. [PubMed]
 
Jensen, JB, Wright, AD, Lassen, NA, et al Cerebral blood flow in acute mountain sickness.J Appl Physiol1990;69,430-433. [PubMed]
 
Baumgartner, RW, Bartsch, P, Maggiorini, M, et al Enhanced cerebral blood flow in acute mountain sickness.Aviat Space Environ Med1994;65,726-729. [PubMed]
 
Jansen, GFA, Krins, A, Basnyat, B Cerebral vasomotor reactivity at high altitude in humans.J Appl Physiol1999;86,681-686. [PubMed]
 
Van Osta, A, Moraine, JJ, Mélot, C, et al Effects of high altitude exposure on cerebral hemodynamics in normal subjects.Stroke2005;36,557. [PubMed]
 
for the Birmingham Medical Research Expeditionary Society.. Imray, CHE, Myers, SD, Pattinson, KTS, et al Effect of exercise on cerebral perfusion in humans at high altitude.J Appl Physiol2005;99,699-706. [PubMed]
 
Subudhi, AW, Dimmen, AC, Roach, RC Effects of acute hypoxia on cerebral and muscle oxygenation during incremental exercise.Appl Physiol2007;103,177-183
 
Bailey, DM, Davies, B Acute mountain sickness; prophylactic benefits of antioxidant vitamin supplementation at high altitude.High Alt Med Biol2001;2,21-29. [PubMed]
 
Bailey, DM, Davies, B, Castell, LM, et al Symptoms of infection and acute mountain sickness: associated metabolic sequelae and problems in differential diagnosis.High Alt Med Biol2003;4,319-331. [PubMed]
 
Magalhães, J, Ascensão, A, Soares, JMC, et al Acute and severe hypobaric hypoxia-induced muscle oxidative stress in mice: the role of glutathione against oxidative damage.Eur J Appl Physiol2004;91,185-191. [PubMed]
 
Magalhães, J, Ascensão, A, Soares, MC, et al Acute and chronic exposition of mice to severe hypoxia: the role of acclimatization against skeletal muscle oxidative stress.Int J Sports Med2005;26,102-109. [PubMed]
 
Bailey, DM, Roukens, R, Knauth, M, et al Free radical-mediated damage to barrier function is not associated with altered brain morphology in high-altitude headache.J Cereb Blood Flow Metab2006;26,99-111. [PubMed]
 
Walter, R, Maggiorini, M, Scherrer, U Effects of high-altitude exposure on vascular endothelial growth factor levels in man.Eur J Appl Physiol2001;85,113-117. [PubMed]
 
Schoch, HJ, Fischer, S, Marti, HH Hypoxia-induced vascular endothelial growth factor expression causes vascular leakage in the brain.Brain2002;125,2549-2557. [PubMed]
 
Tissot van Patot, MC, Leadbetter, G, Keyes, LE, et al Greater free plasma VEGF and lower soluble VEGF receptor-1 in acute mountain sickness.J Appl Physiol2005;98,1626-1629. [PubMed]
 
Milledge, JS, Thomas, PS, Beeley, JM, et al Hypoxic ventilatory response and acute mountain sickness.Eur Respir J1988;1,948-951. [PubMed]
 
Milledge, JS, Beeley, JM, Broome, J, et al Acute mountain sickness susceptibility, fitness and hypoxic ventilatory response.Eur Respir J1991;8,1000-1003
 
Hackett, PH, Roach, RC, Harrison, GL, et al Respiratory stimulants and sleep periodic breathing at high altitude: almitrine versus acetazolamide.Am Rev Respir Dis1987;135,896-898. [PubMed]
 
Hohenhaus, E, Paul, A, McCullough, RE, et al Ventilatory and pulmonary vascular response to hypoxia and susceptibility to high altitude pulmonary oedema.Eur Respir J1995;8,1825-1833. [PubMed]
 
Bartsch, P, Swenson, ER, Paul, A, et al Hypoxic ventilatory response, ventilation, gas exchange, and fluid balance in acute mountain sickness.High Alt Med Biol2002;3,361-376. [PubMed]
 
Burtscher, M, Flatz, M, Faulhaber, M Prediction of susceptibility to acute mountain sickness by Sao2values during short-term exposure to hypoxia.High Alt Med Biol2004;5,335-340. [PubMed]
 
Roach, RC, Greene, ER, Schoene, RB, et al Arterial oxygen saturation for prediction of acute mountain sickness.Aviat Space Environ Med1998;69,1182-1185. [PubMed]
 
Pollard, AJ, Barry, PW, Mason, NP, et al Hypoxia, hypocapnia and spirometry at altitude.Clin Sci (Lond)1997;92,593-598. [PubMed]
 
Cremona, G, Asnaghi, R, Baderna, P, et al Pulmonary extravascular fluid accumulation in recreational climbers: a prospective study.Lancet2002;359,303-309. [PubMed]
 
Loeppky, JA, Icenogle, MV, Maes, D, et al Early fluid retention and severe acute mountain sickness.J Appl Physiol2005;98,591-597. [PubMed]
 
Loeppky, JA, Roach, RC, Selland, MA Body fluid alterations during head-down bed rest in men at moderate altitude.Aviat Space Environ Med1993;64,265-274. [PubMed]
 
Hackett, PH, Rennie, D, Hofmeister, SE, et al Fluid retention and relative hypoventilation in acute mountain sickness.Respiration1982;43,321-329. [PubMed]
 
Loeppky, JA, Icenogle, MV, Maes, D, et al Early fluid retention and severe acute mountain sickness.J Appl Physiol2005;98,591-597. [PubMed]
 
Bartsch, P, Shaw, S, Franciolli, M, et al Atrial natriuretic peptide in acute mountain sickness.J Appl Physiol1988;65,1929-1937. [PubMed]
 
Milledge, JS, Beeley, JM, McArthur, S, et al Atrial natriuretic peptide, altitude and acute mountain sickness.Clin Sci (Lond)1989;77,509-514. [PubMed]
 
Swenson, ER, Duncan, TB, Goldberg, SV, et al Diuretic effect of acute hypoxia in humans: relationship to hypoxic ventilatory responsiveness and renal hormones.J Appl Physiol1995;78,377-383. [PubMed]
 
Forwand, SA, Landowne, M, Follansbee, JN, et al Effect of acetazolamide on acute mountain sickness.N Engl J Med1968;279,839-845. [PubMed]
 
Larson, EB, Roach, RC, Schoene, RB, et al Acute mountain sickness and acetazolamide: clinical efficacy and effect on ventilation.JAMA1982;248,1460-1461
 
Basnyat, B, Gertsch, JH, Johnson, EW, et al Efficacy of low-dose acetazolamide (125 mg bid) for the prophylaxis of acute mountain sickness: a prospective, double-blind, randomized, placebo-controlled trial.High Alt Med Biol2003;4,45-52. [PubMed]
 
Basnyat, B, Gertsch, JH, Holck, PS, et al Acetazolamide 125 mg BD is not significantly different from 375 mg BD in the prevention of acute mountain sickness: the Prophylactic Acetazolamide Dosage Comparison for Efficacy (PACE) trial.High Alt Med Biol2006;7,17-27. [PubMed]
 
Grissom, CK, Roach, RC, Sarnquist, FH, et al Acetazolamide in the treatment of acute mountain sickness: clinical efficacy and effect on gas exchange.Ann Intern Med1992;116,461-465. [PubMed]
 
Basnyat, B, Gertsch, JH, Johnson, EW Efficacy of low-dose acetazolamide (125 mg bid) for the prophylaxis of acute mountain sickness: a prospective, double-blind, randomized, placebo-controlled trial.High Alt Med Biol2003;4,45-52. [PubMed]
 
Grissom, CK, Roach, RC, Sarnquist, FH, et al Acetazolamide in the treatment of acute mountain sickness: clinical efficacy and effect on gas exchange.Ann Intern Med1992;116,461-465. [PubMed]
 
Swenson, ER, Teppema, LJ Prevention of acute mountain sickness by acetazolamide: as yet an unfinished story.J Appl Physiol2007;102,1305-1307. [PubMed]
 
Sutton, JR, Houston, CS, Mansell, AL, et al Effect of acetazolamide on hypoxemia during sleep at high altitude.N Engl J Med1979;301,1329-1331. [PubMed]
 
Leaf, DE, Goldfarb, DS Mechanisms of action of acetazolamide in the prophylaxis and treatment of acute mountain sickness.J Appl Physiol2007;102,1313-1322. [PubMed]
 
Johnson, TS, Rock, PB, Fulco, CS, et al Prevention of acute mountain sickness by dexamethasone.N Engl J Med1984;310,683-686. [PubMed]
 
Ellsworth, AJ, Meyer, EF, Larson, EB Acetazolamide or dexamethasone use versus placebo to prevent acute mountain sickness on Mount Rainier.West J Med1991;154,289-293. [PubMed]
 
Ferrazzini, G, Maggiorini, M, Kriemler, S, et al Successful treatment of acute mountain sickness with dexamethasone.BMJ1987;294,1380-1382. [PubMed]
 
Rock, PB, Johnson, TS, Larsen, RF, et al Dexamethasone as prophylaxis for acute mountain sickness: effect of dose level.Chest1989;95,568-573. [PubMed]
 
Schoene, RB Dexamethasone: by safe means, by fair means.High Alt Med Biol2005;6,273-275. [PubMed]
 
Kasic, JF, Yaron, M, Nicholas, RA, et al Treatment of acute mountain sickness: hyperbaric versus oxygen therapy.Ann Emerg Med1991;20,1109-1112. [PubMed]
 
Bartsch, P, Merki, B, Hofstetter, D, et al Treatment of acute mountain sickness by simulated descent: a randomised controlled trial.BMJ1993;306,1098-1101. [PubMed]
 
Kayser, B, Jean, D, Herry, JP, et al Pressurization and acute mountain sickness.Aviat Space Environ Med1993;64,928-931. [PubMed]
 
Keller, HR, Maggiorini, M, Bartsch, P, et al Simulated descent v dexamethasone in treatment of acute mountain sickness: a randomized trial.BMJ1995;310,1232-1235. [PubMed]
 
Hultgren, H, Spickard, W Medical experiences in Peru.Stanford Med Bull1960;18,76-95
 
Houston, CS Acute pulmonary edema of high altitude.N Engl J Med1960;263,478-480. [PubMed]
 
Schoene, RB Hornbein, TF Schoene, RB eds.High altitude: an exploration of human adaptation. Vol. 161 in Lenfant C, ed. Lung biology in health and disease series2001,777-814 Marcel Dekker Publishers. New York, NY:
 
Schoene, RB Unraveling the mechanism of high altitude pulmonary edema.High Alt Med Biol2004;5,125-135. [PubMed]
 
Gabry, AL, Ledoux, X, Mozziconacci, M, et al High-altitude pulmonary edema at moderate altitude (< 2,400 m; 7,870 feet): a series of 52 patients.Chest2003;123,49-53. [PubMed]
 
Bärtsch, P, Mairbäurl, H, Maggiorini, M, et al Physiological aspects of high-altitude pulmonary edema.J Appl Physiol2005;98,1101-1110. [PubMed]
 
Scoggin, CH, Hyers, TM, Reeves, JT, et al High-altitude pulmonary edema in the children and young adults of Leadville, Colorado.N Engl J Med1977;297,1269-1272. [PubMed]
 
Hackett, PH, Creagh, CE, Grover, RF, et al High-altitude pulmonary edema in persons without the right pulmonary artery.N Engl J Med1980;302,1070-1073. [PubMed]
 
Schoene, RB Fatal high altitude pulmonary edema associated with absence of the left pulmonary artery.High Alt Med Biol2001;2,405-406. [PubMed]
 
Allemann, Y, Hutter, D, Lipp, E, et al Patent foramen ovale and high-altitude pulmonary edema.JAMA2006;296,2954-2958. [PubMed]
 
Menon, ND High-altitude pulmonary edema: a clinical study.N Engl J Med1965;273,66-73. [PubMed]
 
Vock, P, Fretz, C, Franciolli, M, et al High-altitude pulmonary edema: findings at high-altitude chest radiography and physical examination.Radiology1989;170,661-666. [PubMed]
 
Vock, P, Brutsche, MH, Nanzer, A, et al Variable radiomorphologic data of high altitude pulmonary edema: features from 60 patients.Chest1991;100,1306-1311. [PubMed]
 
Hultgren, HN, Honigman, B, Theis, K, et al High-altitude pulmonary edema at a ski resort.West J Med1996;164,222-227. [PubMed]
 
Fagenholz, PJ, Gutman, JA, Murray, AF, et al Chest ultrasonography for the diagnosis and monitoring of high-altitude pulmonary edema.Chest2007;131,1013-1018. [PubMed]
 
Fred, HL, Schmidt, AM, Bates, T, et al Acute pulmonary edema of altitude clinical and physiologic observations.Circulation1962;25,929-937
 
Hultgren, HN, Lopez, CE, Lundberg, E, et al Physiologic studies of pulmonary edema at high altitude.Circulation1964;29,393-408. [PubMed]
 
Roy, SB, Guleria, JS, Khanna, PK, et al Haemodynamic studies in high altitude pulmonary oedema.Br Heart J1969;31,52-58. [PubMed]
 
Penaloza, D, Sime, F Circulatory dynamics during high altitude pulmonary edema.Am J Cardiol1969;23,369-378. [PubMed]
 
Dehnert, C, Grünig, E, Mereles, D, et al Identification of individuals susceptible to high-altitude pulmonary oedema at low altitude.Eur Respir J2005;25,545-551. [PubMed]
 
Kawashima, A, Kubo, K, Kobayashi, T, et al Hemodynamic responses to acute hypoxia, hypobaria, and exercise in subjects susceptible to high-altitude pulmonary edema.J Appl Physiol1989;67,1982-1989. [PubMed]
 
Yagi, H, Yamada, H, Kobayashi, T, et al Doppler assessment of pulmonary hypertension induced by hypoxic breathing in subjects susceptible to high altitude pulmonary edema.Am Rev Respir Dis1990;142,796-801. [PubMed]
 
Hackett PH, Roach RC, Hartig GS, et al. The effect of vasodilators on pulmonary hemodynamics in high altitude pulmonary edema: a comparison. Int J Sports Med, 1992.
 
Vachiery, JL, McDonagh, T, Moraine, JJ, et al Doppler assessment of hypoxic pulmonary vasoconstriction and susceptibility to high altitude pulmonary oedema.Thorax1995;50,22-27. [PubMed]
 
Busch, T, Bärtsch, P, Pappert, D, et al Hypoxia decreases exhaled nitric oxide in mountaineers susceptible to high-altitude pulmonary edema.Am J Respir Crit Care Med2001;163,368-373. [PubMed]
 
Berger, MM, Hesse, C, Dehnert, C, et al Hypoxia impairs systemic endothelial function in individuals prone to high-altitude pulmonary edema.Am J Respir Crit Care Med2005;172,763-767. [PubMed]
 
West, JB, Tsukimoto, K, Mathieu-Costello, O, et al Stress failure in pulmonary capillaries.J Appl Physiol1991;70,1731-1742. [PubMed]
 
Tsukimoto, K, Mathieu-Costello, O, Prediletto, R, et al Ultrastructural appearances of pulmonary capillaries at high transmural pressures.J Appl Physiol1991;71,573-582. [PubMed]
 
Elliott, R, Fu, Z, Tsukimoto, K, et al Short-term reversibility of ultrastructural changes in pulmonary capillaries caused by stress failure.J Appl Physiol1992;73,1150-1158. [PubMed]
 
Fu, Z, Costello, ML, Tsukimoto, K, et al High lung volume increases stress failure in pulmonary capillaries.J Appl Physiol1992;73,123-133. [PubMed]
 
Hopkins, SR Functional magnetic resonance imaging of the lung: a physiological perspective.J Thorac Imaging2004;19,228-234. [PubMed]
 
Hopkins, SR, Garg, J, Bolar, DS, et al Pulmonary blood flow heterogeneity during hypoxia and high-altitude pulmonary edema.Am J Respir Crit Care Med2005;171,83-87. [PubMed]
 
Dehnert, C, Risse, F, Ley, S, et al Magnetic resonance imaging of uneven pulmonary perfusion in hypoxia in humans.Am J Respir Crit Care Med2006;174,1132-1138. [PubMed]
 
Wilson, LB, Levitzky, MG Chemoreflex blunting of hypoxic pulmonary vasoconstriction is vagally mediated.J Appl Physiol1989;66,782-791. [PubMed]
 
Naeije, R, Lejeune, P, Leeman, M, et al Pulmonary vascular responses to surgical chemodenervation and chemical sympathectomy in dogs.J Appl Physiol1989;66,42-50. [PubMed]
 
Hyers, TM, Scoggin, CH, Will, DH, et al Accentuated hypoxemia at high altitude in subjects susceptible to high-altitude pulmonary edema.J Appl Physiol1979;46,41-46. [PubMed]
 
Hackett, PH, Roach, RC, Schoene, RB, et al Abnormal control of ventilation in high-altitude pulmonary edema.J Appl Physiol1988;64,1268-1272. [PubMed]
 
Matsuzawa, Y, Fujimoto, K, Kobayashi, T, et al Blunted hypoxic ventilatory drive in subjects susceptible to high-altitude pulmonary edema.J Appl Physiol1989;66,1152-1157. [PubMed]
 
Selland, MA, Stelzner, TJ, Stevens, T, et al Pulmonary function and hypoxic ventilatory response in subjects susceptible to high-altitude pulmonary edema.Chest1993;103,111-116. [PubMed]
 
Schoene, RB, Hackett, PH, Henderson, WR, et al High-altitude pulmonary edema: characteristics of lung lavage fluid.JAMA1986;256,63-69. [PubMed]
 
Schoene, RB, Swenson, ER, Pizzo, CJ, et al The lung at high altitude: bronchoalveolar lavage in acute mountain sickness and pulmonary edema.J Appl Physiol1988;64,2605-2613. [PubMed]
 
Duplain, H, Sartori, C, Lepori, M, 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 Med2000;162,221-224. [PubMed]
 
Droma, Y, Hanaoka, M, Ota, M, et al Positive association of the endothelial nitric oxide synthase gene polymorphisms with high-altitude pulmonary edema.Circulation2002;106,826-830. [PubMed]
 
SoRelle, R Endothelial nitric oxide synthase gene polymorphisms at heart of high-altitude pulmonary edema.Circulation2002;106,e9013-e9014. [PubMed]
 
Weiss, J, Haefeli, WE, Gasse, C, et al Lack of evidence for association of high altitude pulmonary edema and polymorphisms of the NO pathway.High Alt Med Biol2003;4,355-366. [PubMed]
 
Sartori, C, Lepori, M, Busch, T, et al Exhaled nitric oxide does not provide a marker of vascular endothelial function in healthy humans.Am J Respir Crit Care Med1999;160,879-882. [PubMed]
 
Sartori, C, Vollenweider, L, Löffler, BM, et al Exaggerated endothelin release in high-altitude pulmonary edema.Circulation1999;99,2665-2668. [PubMed]
 
Duplain, H, Vollenweider, L, Delabays, A, et al Augmented sympathetic activation during short-term hypoxia and high-altitude exposure in subjects susceptible to high-altitude pulmonary edema.Circulation1999;99,1713-1718. [PubMed]
 
Swenson, ER, Maggiorini, M, Mongovin, S, et al Pathogenesis of high-altitude pulmonary edema inflammation is not an etiologic factor.JAMA2002;287,2228-2235. [PubMed]
 
Planes, C, Escoubet, B, Blot-Chabaud, M, et al Hypoxia downregulates expression and activity of epithelial sodium channels in rat alveolar epithelial cells.Am J Respir Cell Mol Biol1997;17,508-518. [PubMed]
 
Pham, I, Uchida, T, Planes, C, et al Hypoxia upregulates VEGF expression in alveolar epithelial cellsin vitroandin vivo.Am J Physiol Lung Cell Mol Physiol2002;283,L1133-L1142. [PubMed]
 
Vivona, ML, Matthay, M, Chabaud, MB, et al Hypoxia reduces alveolar epithelial sodium and fluid transport in rats reversal by β-adrenergic agonist treatmentAm J Respir Cell Mol Biol2001;25,554-561. [PubMed]
 
Sartori, C, Duplain, H, Lepori, M, et al High altitude impairs nasal transepithelial sodium transport in HAPE-prone subjects.Eur Respir J2004;23,916-920. [PubMed]
 
Sartori, C, Alleman, Y, Duplain, H, et al Salmeterol for the prevention of high-altitude pulmonary edema.N Engl J Med2002;346,1631-1636. [PubMed]
 
Maggiorini, M, Brunner-La Rocca, H-P, Peth, S, et al Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema: a randomized trial.Ann Intern Med2006;145,497-506. [PubMed]
 
Bartsch, P, Maggiorini, M, Ritter, M, et al Prevention of high-altitude pulmonary edema by nifedipine,N Engl J Med1991;325,1284-1289. [PubMed]
 
Reeves, JT, Schoene, RB When lungs on mountains leak: studying pulmonary edema at high altitudes.N Engl J Med1991;325,1306-1307. [PubMed]
 
Swenson, ER Carbonic anhydrase inhibitors and hypoxic pulmonary vasoconstriction.Respir Physiol Neurobiol2006;151,209-216. [PubMed]
 
Teppema, LJ, Balanos, GM, Steinback, CD, et al Effects of acetazolamide on ventilatory, cerebrovascular, and pulmonary vascular response to hypoxia.Am J Respir Crit Care Med2006;175,277-281. [PubMed]
 
Ghofrani, HA, Reichenberger, F, Kohstall, MG, 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;141,169-177. [PubMed]
 
Richalet, JP, Gratadour, P, Pham, I, et al A Sildenafil inhibits altitude-induced hypoxia and pulmonary hypertension.Am J Respir Crit Care Med2005;171,275-281. [PubMed]
 
Stelzner, TJ, O'Brien, RF, Sato, K, et al Hypoxia-induced increases in pulmonary transvascular protein escape in rats: modulation by glucocorticoids.J Clin Invest1988;82,1840-1847. [PubMed]
 
Noda, M, Suzuki, S, Tsubochi, H, et al Single dexamethasone injection increases alveolar fluid clearance in adult rats.Crit Care Med2003;31,1183-1189. [PubMed]
 
Murata, T, Hori, M, Sakamoto, K, et al Dexamethasone blocks hypoxia-induced endothelial dysfunction in organ-cultured pulmonary arteries.Am J Respir Crit Care Med2004;170,647-655. [PubMed]
 
Zafren, K, Reeves, JT, Schoene, R Treatment of high-altitude pulmonary edema by bed rest and supplemental oxygen.Wilderness Environ Med1996;7,127-132. [PubMed]
 
Schoene, RB, Roach, RC, Hackett, PH, et al High altitude pulmonary edema and exercise at 4,400 meters on Mount McKinley: effect of expiratory positive airway pressure.Chest1985;87,330-333. [PubMed]
 
Oelz, O, Maggiorini, M, Ritter, M, et al Nifedipine for high altitude pulmonary oedema.Lancet1989;2,1241-1244. [PubMed]
 
Grünig, E, Mereles, D, Hildebrandt, W, et al Stress Doppler echocardiography for identification of susceptibility to high altitude pulmonary edema.J Am Coll Cardiol2000;35,980-987. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Left: Axial T2-weighted MRI of patient 4 showing markedly increased signal in corpus callosum (arrows), including both the genu and the splenium, as well as increased signal of periventricular and subcortical white matter. Right: Axial T2-weighted MRI of the same patient 5 weeks after original presentation demonstrating no residual abnormality in splenium (arrow).27Grahic Jump Location
Figure Jump LinkFigure 2. Top, A: Radiograph of a 37-year-old male mountaineer with HAPE that shows a patchy to confluent distribution of edema, predominantly on the right side. Bottom, B: CT scan of 27-year-old mountaineer with recurrent HAPE showing patchy distribution of edema.82Grahic Jump Location
Figure Jump LinkFigure 3. Pulmonary artery systolic pressure (PASP) response to prolonged hypoxia; discrimination between control subjects (n = 11) and HAPE-S subjects (n = 9) by their pulmonary artery systolic pressure response to hypoxia estimated by Doppler echocardiography. The study was discontinued at 55 min of hypoxia in one control subject. No significant differences were seen at rest between both groups (p = 0.36). *Pulmonary artery systolic pressure in HAPE-S subjects compared with control subjects at 45 min (p = 0.0012), 90 min (p = 0.0016), and 240 min (p < 0.02) of hypoxia.101Grahic Jump Location
Figure Jump LinkFigure 4. Effects of prolonged hypoxia (12% oxygen) on PASP in HAPE-S subjects (open columns, n = 8) and control subjects (solid columns, n = 9) resistant to such disease. In both groups, hypoxia induced a significant increase in PASP when compared with normoxia. Compared with control subjects, the effect was significantly enhanced in HAPE-S subjects, indicating a more sustained pulmonary hypoxic vasoconstriction in these subjects. Values are presented as means ± SEM; *p < 0.05 compared with normoxia; §p < 0.05, HAPE-S vs control subjects.101 See Figure 3 legend for expansion of abbreviation.Grahic Jump Location
Figure Jump LinkFigure 5. Plot of relationship between exhaled pulmonary NO and PASP in 26 HAPE-S (closed squares) and 16 control subjects (open circles); r = 0.51; p < 0.001.118 See Figure 3 legend for expansion of abbreviation.Grahic Jump Location
Figure Jump LinkFigure 6. Line graphs showing effects of high-altitude exposure (4,559 m) on exhaled pulmonary NO (mean ± SE) in 13 HAPE-S subjects with pulmonary edema (open squares), 15 HAPE-S without pulmonary edema (closed squares), and 24 control subjects (open circles). Throughout the sojourn at high altitude, exhaled pulmonary NO was significantly lower (p < 0.001) in HAPE-S subjects than in control subjects. In the HAPE-S with pulmonary edema, exhaled NO was lower than in those without edema (p < 0.01) and did not show any tendency to increase before the development of edema.118Grahic Jump Location
Figure Jump LinkFigure 7. Alveolar fluid balance. Top, 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+ adenosine triphosphatases. Thus, active Na reabsorption generates the osmotic gradient for the reabsorption of water. Bottom, 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.128Grahic Jump Location
Figure Jump LinkFigure 8. ALC (percentage of liquid instilled) in rats for different times of hypoxic exposure (8% O2) [hatched bars] and after 24 h of reoxygenation (stippled bars) of rats exposed to 24-h hypoxia. Results are expressed as mean ± SE of three to five experiments. ALC was significantly decreased (*p < 0.05, **p < 0.01, ***p < 0.001) compared with that measured in normoxic rats128).Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Pharmacologic Treatment Option for Altitude Illnesses, Not Including Recommendations of Ascent Rates, Descent Rescue

References

Hornbein, TF Schoene, RB eds. High altitude: an exploration of human adaptation. Vol. 161 in Lenfant C, ed. Lung biology in health and disease series. 2001; Marcel Dekker Publishers. New York, NY:.
 
West, JB, Schoene, RB, Milledge, JS. High altitude medicine and physiology. 2007; Hodder Arnold Publishers. London, UK:.
 
Hackett, PH, Roach, RC High-altitude illness.N Engl J Med2001;345,107-114. [PubMed] [CrossRef]
 
Bisgard, GE, Forster, HV Ventilatory responses to acute and chronic hypoxia. Fregly, MJ Blatteis, CM eds.Handbook of physiology, environmental physiology1996,1207-1239 Oxford University Press. New York, NY:
 
Basu, CK, Selvamurthy, W, Bhaumick, G, et al Respiratory changes during initial days of acclimatization to increasing altitudes.Aviat Space Environ Med1996;67,40-45. [PubMed]
 
Wolfel, EE, Levine, BD The cardiovascular system at high altitude: heart and systemic circulation. Hornbein, TF Schoene, RB eds.High altitude: an exploration of human adaptation. Vol. 161 in Lenfant C, ed. Lung biology in health and disease series2001,235-292 Marcel Dekker Publishers, New York. New York, NY:
 
Reeves, JT, Stenmark, KR The pulmonary circulation at high altitude. Hornbein, TF Schoene, RB eds.High altitude: an exploration of human adaptation. Vol. 161 in Lenfant C, ed. Lung biology in health and disease series2001,293-342 Marcel Dekker Publishers, New York. New York, NY:
 
Wagner, PD Gas exchange. Hornbein, TF Schoene, RB eds.High altitude: an exploration of human adaptation. Vol. 161 in Lenfant C, ed. Lung biology in health and disease series2001,199-234 Marcel Dekker Publishers, New York. New York, NY:
 
Schoene, RB Gas exchange in lung and muscle at high altitude. Roca, J Rodrigues-Roisin, R Wagner, PD eds.Pulmonary and peripheral gas exchange in health and disease. In: Lenfant C, ed. Lung biology in health and disease2000,525-552 Marcel Dekker. New York, NY:
 
Grover, RF, Bartsch, P Blood. Hornbein, TF Schoene, RB eds.High altitude: an exploration of human adaptation. Vol. 161 in Lenfant C, ed. Lung biology in health and disease series2001,493-523 Marcel Dekker Publishers, New York. New York, NY:
 
Semenza, GL HIF-1: mediator of physiological and pathophysiological responses to hypoxia.J Appl Physiol2000;88,1474-1480. [PubMed]
 
LaManna, JC, Chavez, JC, Pichiule, P Structural and functional adaptation to hypoxia in the rat brain.J Exp Biol2004;207,3163-3169. [PubMed]
 
West, JB The atmosphere in high altitude: an exploration of human adaptation Hornbein, TF Schoene, RB eds. Vol. 161 in Lenfant C, ed. Lung biology in health and disease series. 2001; Marcel Dekker Publishers, New York. New York, NY:.
 
Reeves, JT, Zafren, J, et al Seasonal variation in barometric pressure and temperature: effect on altitude illness. Sutton, JR Houston, CS Coates, G eds.Hypoxia and molecular medicine1993,275-281 Queen City Printers. Burlington, VT:
 
Hackett, PH, Rennie, D The incidence, importance, and prophylaxis of acute mountain sickness.Lancet1976;7996,1149-1155
 
Maggiorini, M, Bühler, B, Walter, M, et al Prevalence of acute mountain sickness in the Swiss Alps.BMJ1990;301,853-855. [PubMed]
 
Honigman, B, Theis, MK, Koziol-McLain, J, et al Acute mountain sickness in a general tourist population at moderate altitudes.Ann Intern Med1993;118,587-592. [PubMed]
 
Hackett, PH Hornbein, TF Schoene, RB eds.High altitude: an exploration of human adaptation. Vol. 161 in Lenfant C, ed. Lung biology in health and disease series2001,839-885 Marcel Dekker Publishers. New York, NY:
 
Roach, RC, Maes, D, Sandoval, D, et al Exercise exacerbates acute mountain sickness at simulated altitude.J Appl Physiol2000;88,581-585. [PubMed]
 
Ri-Li, G, Chase, PJ, Witkowski, S, et al Obesity: associations with acute mountain sickness.Ann Intern Med2003;139,253-257. [PubMed]
 
Savourey, G, Garcia, N, Besnard, Y, et al Physiological changes induced by pre-adaptation to high altitude.Eur J Appl Physiol Occup Physiol1994;69,221-227. [PubMed]
 
Bartsch, P, Roach, RC Hornbein, TF Schoene, RB eds.High altitude: an exploration of human adaptation. Vol. 161 in Lenfant C, ed. Lung biology in health and disease series2001,731-776 Marcel Dekker Publishers, New York. New York, NY:
 
Roach, RC, Bartsch, P, Hackett, PH, et al The Lake Louise acute mountain sickness scoring system. Sutton, JR Houston, CS Coates, G eds.Hypoxia and molecular medicine1993,272-274 Queens City Press. Burlington, VT:
 
Singh, I, Khanna, PK, Srivastava, MC, et al Acute mountain sickness.N Engl J Med1969;280,175-184. [PubMed]
 
Dickinson, JG Severe acute mountain sickness.Postgrad Med J1979;645,454-460
 
Hackett, PH High altitude cerebral edema and acute mountain sickness: a pathophysiology update.Adv Exp Med Biol1999;474,23-45. [PubMed]
 
Hackett, PH, Yarnell, PR, Hill, R, et al High-altitude cerebral edema evaluated with magnetic resonance imaging: clinical correlation and pathophysiology.JAMA1998;280,1920-1925. [PubMed]
 
Jensen, JB, Wright, AD, Lassen, NA, et al Cerebral blood flow in acute mountain sickness.J Appl Physiol1990;69,430-433. [PubMed]
 
Baumgartner, RW, Bartsch, P, Maggiorini, M, et al Enhanced cerebral blood flow in acute mountain sickness.Aviat Space Environ Med1994;65,726-729. [PubMed]
 
Jansen, GFA, Krins, A, Basnyat, B Cerebral vasomotor reactivity at high altitude in humans.J Appl Physiol1999;86,681-686. [PubMed]
 
Van Osta, A, Moraine, JJ, Mélot, C, et al Effects of high altitude exposure on cerebral hemodynamics in normal subjects.Stroke2005;36,557. [PubMed]
 
for the Birmingham Medical Research Expeditionary Society.. Imray, CHE, Myers, SD, Pattinson, KTS, et al Effect of exercise on cerebral perfusion in humans at high altitude.J Appl Physiol2005;99,699-706. [PubMed]
 
Subudhi, AW, Dimmen, AC, Roach, RC Effects of acute hypoxia on cerebral and muscle oxygenation during incremental exercise.Appl Physiol2007;103,177-183
 
Bailey, DM, Davies, B Acute mountain sickness; prophylactic benefits of antioxidant vitamin supplementation at high altitude.High Alt Med Biol2001;2,21-29. [PubMed]
 
Bailey, DM, Davies, B, Castell, LM, et al Symptoms of infection and acute mountain sickness: associated metabolic sequelae and problems in differential diagnosis.High Alt Med Biol2003;4,319-331. [PubMed]
 
Magalhães, J, Ascensão, A, Soares, JMC, et al Acute and severe hypobaric hypoxia-induced muscle oxidative stress in mice: the role of glutathione against oxidative damage.Eur J Appl Physiol2004;91,185-191. [PubMed]
 
Magalhães, J, Ascensão, A, Soares, MC, et al Acute and chronic exposition of mice to severe hypoxia: the role of acclimatization against skeletal muscle oxidative stress.Int J Sports Med2005;26,102-109. [PubMed]
 
Bailey, DM, Roukens, R, Knauth, M, et al Free radical-mediated damage to barrier function is not associated with altered brain morphology in high-altitude headache.J Cereb Blood Flow Metab2006;26,99-111. [PubMed]
 
Walter, R, Maggiorini, M, Scherrer, U Effects of high-altitude exposure on vascular endothelial growth factor levels in man.Eur J Appl Physiol2001;85,113-117. [PubMed]
 
Schoch, HJ, Fischer, S, Marti, HH Hypoxia-induced vascular endothelial growth factor expression causes vascular leakage in the brain.Brain2002;125,2549-2557. [PubMed]
 
Tissot van Patot, MC, Leadbetter, G, Keyes, LE, et al Greater free plasma VEGF and lower soluble VEGF receptor-1 in acute mountain sickness.J Appl Physiol2005;98,1626-1629. [PubMed]
 
Milledge, JS, Thomas, PS, Beeley, JM, et al Hypoxic ventilatory response and acute mountain sickness.Eur Respir J1988;1,948-951. [PubMed]
 
Milledge, JS, Beeley, JM, Broome, J, et al Acute mountain sickness susceptibility, fitness and hypoxic ventilatory response.Eur Respir J1991;8,1000-1003
 
Hackett, PH, Roach, RC, Harrison, GL, et al Respiratory stimulants and sleep periodic breathing at high altitude: almitrine versus acetazolamide.Am Rev Respir Dis1987;135,896-898. [PubMed]
 
Hohenhaus, E, Paul, A, McCullough, RE, et al Ventilatory and pulmonary vascular response to hypoxia and susceptibility to high altitude pulmonary oedema.Eur Respir J1995;8,1825-1833. [PubMed]
 
Bartsch, P, Swenson, ER, Paul, A, et al Hypoxic ventilatory response, ventilation, gas exchange, and fluid balance in acute mountain sickness.High Alt Med Biol2002;3,361-376. [PubMed]
 
Burtscher, M, Flatz, M, Faulhaber, M Prediction of susceptibility to acute mountain sickness by Sao2values during short-term exposure to hypoxia.High Alt Med Biol2004;5,335-340. [PubMed]
 
Roach, RC, Greene, ER, Schoene, RB, et al Arterial oxygen saturation for prediction of acute mountain sickness.Aviat Space Environ Med1998;69,1182-1185. [PubMed]
 
Pollard, AJ, Barry, PW, Mason, NP, et al Hypoxia, hypocapnia and spirometry at altitude.Clin Sci (Lond)1997;92,593-598. [PubMed]
 
Cremona, G, Asnaghi, R, Baderna, P, et al Pulmonary extravascular fluid accumulation in recreational climbers: a prospective study.Lancet2002;359,303-309. [PubMed]
 
Loeppky, JA, Icenogle, MV, Maes, D, et al Early fluid retention and severe acute mountain sickness.J Appl Physiol2005;98,591-597. [PubMed]
 
Loeppky, JA, Roach, RC, Selland, MA Body fluid alterations during head-down bed rest in men at moderate altitude.Aviat Space Environ Med1993;64,265-274. [PubMed]
 
Hackett, PH, Rennie, D, Hofmeister, SE, et al Fluid retention and relative hypoventilation in acute mountain sickness.Respiration1982;43,321-329. [PubMed]
 
Loeppky, JA, Icenogle, MV, Maes, D, et al Early fluid retention and severe acute mountain sickness.J Appl Physiol2005;98,591-597. [PubMed]
 
Bartsch, P, Shaw, S, Franciolli, M, et al Atrial natriuretic peptide in acute mountain sickness.J Appl Physiol1988;65,1929-1937. [PubMed]
 
Milledge, JS, Beeley, JM, McArthur, S, et al Atrial natriuretic peptide, altitude and acute mountain sickness.Clin Sci (Lond)1989;77,509-514. [PubMed]
 
Swenson, ER, Duncan, TB, Goldberg, SV, et al Diuretic effect of acute hypoxia in humans: relationship to hypoxic ventilatory responsiveness and renal hormones.J Appl Physiol1995;78,377-383. [PubMed]
 
Forwand, SA, Landowne, M, Follansbee, JN, et al Effect of acetazolamide on acute mountain sickness.N Engl J Med1968;279,839-845. [PubMed]
 
Larson, EB, Roach, RC, Schoene, RB, et al Acute mountain sickness and acetazolamide: clinical efficacy and effect on ventilation.JAMA1982;248,1460-1461
 
Basnyat, B, Gertsch, JH, Johnson, EW, et al Efficacy of low-dose acetazolamide (125 mg bid) for the prophylaxis of acute mountain sickness: a prospective, double-blind, randomized, placebo-controlled trial.High Alt Med Biol2003;4,45-52. [PubMed]
 
Basnyat, B, Gertsch, JH, Holck, PS, et al Acetazolamide 125 mg BD is not significantly different from 375 mg BD in the prevention of acute mountain sickness: the Prophylactic Acetazolamide Dosage Comparison for Efficacy (PACE) trial.High Alt Med Biol2006;7,17-27. [PubMed]
 
Grissom, CK, Roach, RC, Sarnquist, FH, et al Acetazolamide in the treatment of acute mountain sickness: clinical efficacy and effect on gas exchange.Ann Intern Med1992;116,461-465. [PubMed]
 
Basnyat, B, Gertsch, JH, Johnson, EW Efficacy of low-dose acetazolamide (125 mg bid) for the prophylaxis of acute mountain sickness: a prospective, double-blind, randomized, placebo-controlled trial.High Alt Med Biol2003;4,45-52. [PubMed]
 
Grissom, CK, Roach, RC, Sarnquist, FH, et al Acetazolamide in the treatment of acute mountain sickness: clinical efficacy and effect on gas exchange.Ann Intern Med1992;116,461-465. [PubMed]
 
Swenson, ER, Teppema, LJ Prevention of acute mountain sickness by acetazolamide: as yet an unfinished story.J Appl Physiol2007;102,1305-1307. [PubMed]
 
Sutton, JR, Houston, CS, Mansell, AL, et al Effect of acetazolamide on hypoxemia during sleep at high altitude.N Engl J Med1979;301,1329-1331. [PubMed]
 
Leaf, DE, Goldfarb, DS Mechanisms of action of acetazolamide in the prophylaxis and treatment of acute mountain sickness.J Appl Physiol2007;102,1313-1322. [PubMed]
 
Johnson, TS, Rock, PB, Fulco, CS, et al Prevention of acute mountain sickness by dexamethasone.N Engl J Med1984;310,683-686. [PubMed]
 
Ellsworth, AJ, Meyer, EF, Larson, EB Acetazolamide or dexamethasone use versus placebo to prevent acute mountain sickness on Mount Rainier.West J Med1991;154,289-293. [PubMed]
 
Ferrazzini, G, Maggiorini, M, Kriemler, S, et al Successful treatment of acute mountain sickness with dexamethasone.BMJ1987;294,1380-1382. [PubMed]
 
Rock, PB, Johnson, TS, Larsen, RF, et al Dexamethasone as prophylaxis for acute mountain sickness: effect of dose level.Chest1989;95,568-573. [PubMed]
 
Schoene, RB Dexamethasone: by safe means, by fair means.High Alt Med Biol2005;6,273-275. [PubMed]
 
Kasic, JF, Yaron, M, Nicholas, RA, et al Treatment of acute mountain sickness: hyperbaric versus oxygen therapy.Ann Emerg Med1991;20,1109-1112. [PubMed]
 
Bartsch, P, Merki, B, Hofstetter, D, et al Treatment of acute mountain sickness by simulated descent: a randomised controlled trial.BMJ1993;306,1098-1101. [PubMed]
 
Kayser, B, Jean, D, Herry, JP, et al Pressurization and acute mountain sickness.Aviat Space Environ Med1993;64,928-931. [PubMed]
 
Keller, HR, Maggiorini, M, Bartsch, P, et al Simulated descent v dexamethasone in treatment of acute mountain sickness: a randomized trial.BMJ1995;310,1232-1235. [PubMed]
 
Hultgren, H, Spickard, W Medical experiences in Peru.Stanford Med Bull1960;18,76-95
 
Houston, CS Acute pulmonary edema of high altitude.N Engl J Med1960;263,478-480. [PubMed]
 
Schoene, RB Hornbein, TF Schoene, RB eds.High altitude: an exploration of human adaptation. Vol. 161 in Lenfant C, ed. Lung biology in health and disease series2001,777-814 Marcel Dekker Publishers. New York, NY:
 
Schoene, RB Unraveling the mechanism of high altitude pulmonary edema.High Alt Med Biol2004;5,125-135. [PubMed]
 
Gabry, AL, Ledoux, X, Mozziconacci, M, et al High-altitude pulmonary edema at moderate altitude (< 2,400 m; 7,870 feet): a series of 52 patients.Chest2003;123,49-53. [PubMed]
 
Bärtsch, P, Mairbäurl, H, Maggiorini, M, et al Physiological aspects of high-altitude pulmonary edema.J Appl Physiol2005;98,1101-1110. [PubMed]
 
Scoggin, CH, Hyers, TM, Reeves, JT, et al High-altitude pulmonary edema in the children and young adults of Leadville, Colorado.N Engl J Med1977;297,1269-1272. [PubMed]
 
Hackett, PH, Creagh, CE, Grover, RF, et al High-altitude pulmonary edema in persons without the right pulmonary artery.N Engl J Med1980;302,1070-1073. [PubMed]
 
Schoene, RB Fatal high altitude pulmonary edema associated with absence of the left pulmonary artery.High Alt Med Biol2001;2,405-406. [PubMed]
 
Allemann, Y, Hutter, D, Lipp, E, et al Patent foramen ovale and high-altitude pulmonary edema.JAMA2006;296,2954-2958. [PubMed]
 
Menon, ND High-altitude pulmonary edema: a clinical study.N Engl J Med1965;273,66-73. [PubMed]
 
Vock, P, Fretz, C, Franciolli, M, et al High-altitude pulmonary edema: findings at high-altitude chest radiography and physical examination.Radiology1989;170,661-666. [PubMed]
 
Vock, P, Brutsche, MH, Nanzer, A, et al Variable radiomorphologic data of high altitude pulmonary edema: features from 60 patients.Chest1991;100,1306-1311. [PubMed]
 
Hultgren, HN, Honigman, B, Theis, K, et al High-altitude pulmonary edema at a ski resort.West J Med1996;164,222-227. [PubMed]
 
Fagenholz, PJ, Gutman, JA, Murray, AF, et al Chest ultrasonography for the diagnosis and monitoring of high-altitude pulmonary edema.Chest2007;131,1013-1018. [PubMed]
 
Fred, HL, Schmidt, AM, Bates, T, et al Acute pulmonary edema of altitude clinical and physiologic observations.Circulation1962;25,929-937
 
Hultgren, HN, Lopez, CE, Lundberg, E, et al Physiologic studies of pulmonary edema at high altitude.Circulation1964;29,393-408. [PubMed]
 
Roy, SB, Guleria, JS, Khanna, PK, et al Haemodynamic studies in high altitude pulmonary oedema.Br Heart J1969;31,52-58. [PubMed]
 
Penaloza, D, Sime, F Circulatory dynamics during high altitude pulmonary edema.Am J Cardiol1969;23,369-378. [PubMed]
 
Dehnert, C, Grünig, E, Mereles, D, et al Identification of individuals susceptible to high-altitude pulmonary oedema at low altitude.Eur Respir J2005;25,545-551. [PubMed]
 
Kawashima, A, Kubo, K, Kobayashi, T, et al Hemodynamic responses to acute hypoxia, hypobaria, and exercise in subjects susceptible to high-altitude pulmonary edema.J Appl Physiol1989;67,1982-1989. [PubMed]
 
Yagi, H, Yamada, H, Kobayashi, T, et al Doppler assessment of pulmonary hypertension induced by hypoxic breathing in subjects susceptible to high altitude pulmonary edema.Am Rev Respir Dis1990;142,796-801. [PubMed]
 
Hackett PH, Roach RC, Hartig GS, et al. The effect of vasodilators on pulmonary hemodynamics in high altitude pulmonary edema: a comparison. Int J Sports Med, 1992.
 
Vachiery, JL, McDonagh, T, Moraine, JJ, et al Doppler assessment of hypoxic pulmonary vasoconstriction and susceptibility to high altitude pulmonary oedema.Thorax1995;50,22-27. [PubMed]
 
Busch, T, Bärtsch, P, Pappert, D, et al Hypoxia decreases exhaled nitric oxide in mountaineers susceptible to high-altitude pulmonary edema.Am J Respir Crit Care Med2001;163,368-373. [PubMed]
 
Berger, MM, Hesse, C, Dehnert, C, et al Hypoxia impairs systemic endothelial function in individuals prone to high-altitude pulmonary edema.Am J Respir Crit Care Med2005;172,763-767. [PubMed]
 
West, JB, Tsukimoto, K, Mathieu-Costello, O, et al Stress failure in pulmonary capillaries.J Appl Physiol1991;70,1731-1742. [PubMed]
 
Tsukimoto, K, Mathieu-Costello, O, Prediletto, R, et al Ultrastructural appearances of pulmonary capillaries at high transmural pressures.J Appl Physiol1991;71,573-582. [PubMed]
 
Elliott, R, Fu, Z, Tsukimoto, K, et al Short-term reversibility of ultrastructural changes in pulmonary capillaries caused by stress failure.J Appl Physiol1992;73,1150-1158. [PubMed]
 
Fu, Z, Costello, ML, Tsukimoto, K, et al High lung volume increases stress failure in pulmonary capillaries.J Appl Physiol1992;73,123-133. [PubMed]
 
Hopkins, SR Functional magnetic resonance imaging of the lung: a physiological perspective.J Thorac Imaging2004;19,228-234. [PubMed]
 
Hopkins, SR, Garg, J, Bolar, DS, et al Pulmonary blood flow heterogeneity during hypoxia and high-altitude pulmonary edema.Am J Respir Crit Care Med2005;171,83-87. [PubMed]
 
Dehnert, C, Risse, F, Ley, S, et al Magnetic resonance imaging of uneven pulmonary perfusion in hypoxia in humans.Am J Respir Crit Care Med2006;174,1132-1138. [PubMed]
 
Wilson, LB, Levitzky, MG Chemoreflex blunting of hypoxic pulmonary vasoconstriction is vagally mediated.J Appl Physiol1989;66,782-791. [PubMed]
 
Naeije, R, Lejeune, P, Leeman, M, et al Pulmonary vascular responses to surgical chemodenervation and chemical sympathectomy in dogs.J Appl Physiol1989;66,42-50. [PubMed]
 
Hyers, TM, Scoggin, CH, Will, DH, et al Accentuated hypoxemia at high altitude in subjects susceptible to high-altitude pulmonary edema.J Appl Physiol1979;46,41-46. [PubMed]
 
Hackett, PH, Roach, RC, Schoene, RB, et al Abnormal control of ventilation in high-altitude pulmonary edema.J Appl Physiol1988;64,1268-1272. [PubMed]
 
Matsuzawa, Y, Fujimoto, K, Kobayashi, T, et al Blunted hypoxic ventilatory drive in subjects susceptible to high-altitude pulmonary edema.J Appl Physiol1989;66,1152-1157. [PubMed]
 
Selland, MA, Stelzner, TJ, Stevens, T, et al Pulmonary function and hypoxic ventilatory response in subjects susceptible to high-altitude pulmonary edema.Chest1993;103,111-116. [PubMed]
 
Schoene, RB, Hackett, PH, Henderson, WR, et al High-altitude pulmonary edema: characteristics of lung lavage fluid.JAMA1986;256,63-69. [PubMed]
 
Schoene, RB, Swenson, ER, Pizzo, CJ, et al The lung at high altitude: bronchoalveolar lavage in acute mountain sickness and pulmonary edema.J Appl Physiol1988;64,2605-2613. [PubMed]
 
Duplain, H, Sartori, C, Lepori, M, 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 Med2000;162,221-224. [PubMed]
 
Droma, Y, Hanaoka, M, Ota, M, et al Positive association of the endothelial nitric oxide synthase gene polymorphisms with high-altitude pulmonary edema.Circulation2002;106,826-830. [PubMed]
 
SoRelle, R Endothelial nitric oxide synthase gene polymorphisms at heart of high-altitude pulmonary edema.Circulation2002;106,e9013-e9014. [PubMed]
 
Weiss, J, Haefeli, WE, Gasse, C, et al Lack of evidence for association of high altitude pulmonary edema and polymorphisms of the NO pathway.High Alt Med Biol2003;4,355-366. [PubMed]
 
Sartori, C, Lepori, M, Busch, T, et al Exhaled nitric oxide does not provide a marker of vascular endothelial function in healthy humans.Am J Respir Crit Care Med1999;160,879-882. [PubMed]
 
Sartori, C, Vollenweider, L, Löffler, BM, et al Exaggerated endothelin release in high-altitude pulmonary edema.Circulation1999;99,2665-2668. [PubMed]
 
Duplain, H, Vollenweider, L, Delabays, A, et al Augmented sympathetic activation during short-term hypoxia and high-altitude exposure in subjects susceptible to high-altitude pulmonary edema.Circulation1999;99,1713-1718. [PubMed]
 
Swenson, ER, Maggiorini, M, Mongovin, S, et al Pathogenesis of high-altitude pulmonary edema inflammation is not an etiologic factor.JAMA2002;287,2228-2235. [PubMed]
 
Planes, C, Escoubet, B, Blot-Chabaud, M, et al Hypoxia downregulates expression and activity of epithelial sodium channels in rat alveolar epithelial cells.Am J Respir Cell Mol Biol1997;17,508-518. [PubMed]
 
Pham, I, Uchida, T, Planes, C, et al Hypoxia upregulates VEGF expression in alveolar epithelial cellsin vitroandin vivo.Am J Physiol Lung Cell Mol Physiol2002;283,L1133-L1142. [PubMed]
 
Vivona, ML, Matthay, M, Chabaud, MB, et al Hypoxia reduces alveolar epithelial sodium and fluid transport in rats reversal by β-adrenergic agonist treatmentAm J Respir Cell Mol Biol2001;25,554-561. [PubMed]
 
Sartori, C, Duplain, H, Lepori, M, et al High altitude impairs nasal transepithelial sodium transport in HAPE-prone subjects.Eur Respir J2004;23,916-920. [PubMed]
 
Sartori, C, Alleman, Y, Duplain, H, et al Salmeterol for the prevention of high-altitude pulmonary edema.N Engl J Med2002;346,1631-1636. [PubMed]
 
Maggiorini, M, Brunner-La Rocca, H-P, Peth, S, et al Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema: a randomized trial.Ann Intern Med2006;145,497-506. [PubMed]
 
Bartsch, P, Maggiorini, M, Ritter, M, et al Prevention of high-altitude pulmonary edema by nifedipine,N Engl J Med1991;325,1284-1289. [PubMed]
 
Reeves, JT, Schoene, RB When lungs on mountains leak: studying pulmonary edema at high altitudes.N Engl J Med1991;325,1306-1307. [PubMed]
 
Swenson, ER Carbonic anhydrase inhibitors and hypoxic pulmonary vasoconstriction.Respir Physiol Neurobiol2006;151,209-216. [PubMed]
 
Teppema, LJ, Balanos, GM, Steinback, CD, et al Effects of acetazolamide on ventilatory, cerebrovascular, and pulmonary vascular response to hypoxia.Am J Respir Crit Care Med2006;175,277-281. [PubMed]
 
Ghofrani, HA, Reichenberger, F, Kohstall, MG, 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;141,169-177. [PubMed]
 
Richalet, JP, Gratadour, P, Pham, I, et al A Sildenafil inhibits altitude-induced hypoxia and pulmonary hypertension.Am J Respir Crit Care Med2005;171,275-281. [PubMed]
 
Stelzner, TJ, O'Brien, RF, Sato, K, et al Hypoxia-induced increases in pulmonary transvascular protein escape in rats: modulation by glucocorticoids.J Clin Invest1988;82,1840-1847. [PubMed]
 
Noda, M, Suzuki, S, Tsubochi, H, et al Single dexamethasone injection increases alveolar fluid clearance in adult rats.Crit Care Med2003;31,1183-1189. [PubMed]
 
Murata, T, Hori, M, Sakamoto, K, et al Dexamethasone blocks hypoxia-induced endothelial dysfunction in organ-cultured pulmonary arteries.Am J Respir Crit Care Med2004;170,647-655. [PubMed]
 
Zafren, K, Reeves, JT, Schoene, R Treatment of high-altitude pulmonary edema by bed rest and supplemental oxygen.Wilderness Environ Med1996;7,127-132. [PubMed]
 
Schoene, RB, Roach, RC, Hackett, PH, et al High altitude pulmonary edema and exercise at 4,400 meters on Mount McKinley: effect of expiratory positive airway pressure.Chest1985;87,330-333. [PubMed]
 
Oelz, O, Maggiorini, M, Ritter, M, et al Nifedipine for high altitude pulmonary oedema.Lancet1989;2,1241-1244. [PubMed]
 
Grünig, E, Mereles, D, Hildebrandt, W, et al Stress Doppler echocardiography for identification of susceptibility to high altitude pulmonary edema.J Am Coll Cardiol2000;35,980-987. [PubMed]
 
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