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The Physiologic Basis of High-Altitude Diseases

John B. West, MD, PhD
[+] Article, Author, and Disclosure Information

From University of California, San Diego, La Jolla, California.

Grant Support: By National Institutes of Health grant RO1 HL 60698.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: John B. West, MD, PhD, Department of Medicine, University of California, San Diego, 0623A, 9500 Gilman Drive, La Jolla, CA 92093-0623; e-mail, jwest@ucsd.edu.

Ann Intern Med. 2004;141(10):789-800. doi:10.7326/0003-4819-141-10-200411160-00010
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The adaptive changes collectively known as acclimatization greatly improve the tolerance of human beings to high altitude. Physiologists often cite high-altitude acclimatization as one of the best examples of how the body responds to a hostile environment. However, although acclimatization is critically important, several misconceptions have developed.

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Figure 1.
Relationship among altitude, barometric pressure, and inspired Po2.

Note that at an altitude of 5000 m, the highest at which humans reside, the inspired Po2 is only approximately half of the sea level value. On the summit of Mount Everest, the inspired Po2 is less than 30% of the value at sea level. CO = Colorado.

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Figure 2.
Alveolar Po2 at high altitude for persons acutely exposed and persons fully acclimatized.

The altitudes of several observatories where astronomers work are shown. Note that fully acclimatized astronomers on the summit of Mauna Kea have an alveolar Po2 , and therefore an arterial Po2 , lower than the threshold for continuous oxygen therapy in patients with chronic obstructive pulmonary disease (COPD ). The dashed-and-dotted lines indicate the normal value at sea level (upper line) and the threshold for continuous O2 therapy in COPD (lower line).

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Figure 3.
Alveolar Po2 and Pco2 of acclimatized humans at high altitude.

Sea level is at the top right of the graph, and the summit of Mount Everest is at the bottom left. The squares show the means of the measurements at 3 altitudes on the American Medical Research Expedition to Everest; the circles are previously reported data from many sources. Note that after a certain altitude has been exceeded, alveolar Po2 does not decrease further. It is defended at a level of about 35 mm Hg by the process of extreme hyperventilation, which reduces the Pco2 to less than 10 mm Hg. Modified from reference 20.

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Figure 4.
Ultrastructural changes in the wall of a pulmonary capillary when the capillary hydrostatic pressure is raised.

The arrows at the top show a disruption in the alveolar epithelial layer; the arrows at the bottom show a break in the capillary endothelial layer, with a platelet apparently adhering to the exposed basement membrane. These changes are caused by the high mechanical stress in the capillary wall. Modified from reference 56 . ALV = alveolus; CAP = capillary lumen.

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Figure 5.
The sequence of events in the pathogenesis of high-altitude pulmonary edema.

See text for details. Modified from reference 62 . PA = pulmonary artery.

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Submit a Comment/Letter
Ginko biloba does not work in the prevention of acute mountain sickness
Posted on November 17, 2004
Buddha Basnyat
Nepal International Clinic
Conflict of Interest: None Declared

Dear Sir,

I read with interest West's review of The Physiological Basis of High Altitude Diseases which was recently published in your journal (1). A large recent trial in the Nepal Himalayas involoving 614 Western trekkers convincingly showed ginko biloba not to be effective in the prevention of acute mountain sickness(2),and perhaps this study needed to have been included in the review. Although this field study did have some limitations, it actually revealed that ginko when combined with acetazolamide caused significantly increased headache as compared to acetazolamide alone.

1 West JB The Physiologic Basis of High-Altitude Diseases Ann Intern Med 2004; 141: 789-800

2 Gertsch JH, Basnyat B, Johnson EW, Onopa J, Holck S on behalf of the Prevention of High Altitude Illness Trial Research Group. Randomised, controlled trial of ginko biloba and acetazolamide for the prevention of acute mountain sickness:the prevention of high altitude illness trial ( PHAIT) BMJ 2004;328:797-799.

Sincerely yours,

Buddha Basnyat MD Nepal International Clinic

Conflict of Interest:

None declared

The Role of Alveolar-Fluid Clearance in pathogenesis of High Altitude Pulmonary Edema
Posted on December 3, 2004
Anil Pandit
Mountain Medicine Society of Nepal, Kathmandu, Nepal
Conflict of Interest: None Declared

Dear Editor

The role of alveolar-fluid clearance in the patho-physiology of High Altitude Pulmonary Edema (HAPE) though important, is not mentioned by West in his review article on "The Physiologic Basis of High Altitude Diseases."[1]

Alveolar-fluid clearance mediated by sodium, potassium ATPase pump present in apical surface of alveolar epithelium is well-established concept[2]. Blunting of this process may impair clearance of alveolar fluid and predispose individuals to pulmonary edema3. Intervention of this patho-physiological key step for theraupetic benefit has already been successfully tried and put into practice by the experts in the field of high altitude medicine.

A double-blind, randomized, placebo-controlled study of HAPE- susceptible mountaineers has shown 50% reduction in incidence of HAPE by Beta-adrenergic agonist; salmeterol.[4] In animal models, Beta agonists have shown to up-regulate the clearance of alveolar fluid and lessen pulmonary edema.[5,6] However, salmeterol may have additional hemodynamic advantage of preventing HAPE. The same study showed that, in low altitude, the nasal tansepithelial sodium and water transport in the distal airway was more than 30% lower in HAPE susceptible people than in non-susceptible people.

These findings clearly support the concept that alveolar fluid clearance may have a pathogenic role in pulmonary edema.


1. West, J. The Physiologic Basis of High-Altitude Diseases. Ann Intern Med.2004;141:789-800

2. Sartori C, Matthay MA, Scherrer U. Transepithelial sodium and water transport in the lung: major player and novel therapeutic target in pulmonary edema. Adv Exp Med Biol 2001; 502: 315"“38.

3. Basnyat, B, Murdoch D R. High Altitude Illness.Lancet 2003; 361: 1967"“74.

4. Sartori C, Allemann Y, Duplain H, et al. Salmeterol for the prevention of high-altitude pulmonary edema. N Engl J Med 2002; 346: 1631"“36.

5. Berthiaume Y, Broaddus VC, Gropper MA, Tanita T, Matthay MA..Alveolar liquid and protein clearance from normal dog lungs. J Appl Physiol 1988; 65: 585"“93.

6. Berthiaume Y, Staub NC, Matthay MA. Beta-adrenergic agonists increase lung liquid clearance in anesthetized sheep. J Clin Invest.1987; 79: 335"“43.

Conflict of Interest:

None declared

Is High-Altitude Related to an Increase in Pulmonary Capillary Pressure?
Posted on January 25, 2005
Kenneth B. Desser
Banner Good Samaritan Medical Center, Phoenix, AZ
Conflict of Interest: None Declared

West's review of high altitude disease (Ann Intern Med 2004; 141: 789) indicates that high altitude pulmonary edema is a "high-permeability type of edema." It is also stated that studies demonstrate "normal pulmonary wedge pressures so this is not a form of left-heart failure." The reference for the latter conclusion is an article by Penaloza and Sime which is over 30 years old (Am J Card 1969; 23: 369). In 2001, Maggiorini et. al., in an elegant study (Circulation 2001; 103: 2078) demonstrated that all susceptible subjects who developed high-altitude pulmonary edema had a pulmonary capillary pressure >19mm Hg (range: 20 to 26mm Hg). Additionally, the pulmonary transcapillary escape of radiolabeled transferrin increased slightly from low to high altitude in the pulmonary edema susceptible group but remained within the limits of normal and did not differ significantly from the control subjects. These data seem to contradict West's conclusions regarding pulmonary wedge pressures and capillary permeability in patients with high-altitude pulmonary edema.

Conflict of Interest:

None declared

High-Altitude Diseases
Posted on January 24, 2005
John B. West
University of California San Diego
Conflict of Interest: None Declared

All three letters make useful points.

The statement in the article "Gingko biloba has been suggested as a useful prophylactic agent but has not been sufficiently studied" was inserted because there are several conflicting published reports as noted by Gertsch and colleagues (1). However I agree with Basnyat that their randomized, double blind, placebo controlled study is strong evidence against the value of Gingko for the prevention of acute mountain sickness.

I also agree with Pandit that there is compelling evidence that alveolar fluid clearance in pulmonary edema is assisted by the sodium, potassium ATPase pump, and this might well have been referred to in the review. However in my defense it seems likely that the initial events in the pathogenesis of high-altitude pulmonary edema (HAPE) are the increased pulmonary vascular pressures leading to stress failure of pulmonary capillaries as set out in the review. It is not necessary to invoke defective alveolar fluid clearance in the initial mechanism. The convincing study showing the prophylactic effects of inhalation of the beta-adrenergic agonist salmeterol on the incidence of HAPE (2) is consistent with the fact that stimulation of the sodium, potassium ATPase pump helps to remove alveolar fluid, but does not prove that this is a factor in the initial pathogenesis of the condition.

Matiram Pun, who must be an exceptional third year medical student, argues that the review should have said more about focal neurological deficits at high altitude. Again in defense, the review stated that "patients may have papilledema and occasionally focal neurologic signs affecting cranial nerves, or even hemiparesis." Certainly however the review could have cited one of the recent articles on this subject such as that by Basnyat et al. (3). Possible genetic factors in high-altitude illnesses is a topic of interest but so far this is mainly speculative. The possible role of vascular endothelial growth factor (VEGF) in HAPE is the subject of a very recent article (4).


1. Gertsch JH, Basnyat B, Johnson EW, Onopa J, Holck PS on behalf of the Prevention of High Altitude Illness Trial Research Group. Randomised, double blind, placebo controlled comparison of ginkgo biloba and acetazolamide for prevention of acute mountain sickness among Himalayan trekkers: the prevention of high altitude illness trial (PHAIT). BMJ 2004; 328:797-9.

2. Sartori C, Allemann Y, Duplain H, et al. Salmeterol for the prevention of high-altitude pulmonary edema. N Engl J Med 2002; 346:1631- 6.

3. Basnyat B, Wu T, Gertsch J H. Neurological conditions at altitude that fall outside the usual definition of altitude sickness. High Alt Med Biol 2004; 5:171-9.

4. Kaner R J, Crystal R G. Pathogenesis of high altitude pulmonary edema: does alveolar epithelial lining fluid vascular endothelial growth factor exacerbate capillary leak? High Alt Med Biol 2004; 5:399-409.

Conflict of Interest:

None declared

Posted on June 25, 2006
Dr. Rajesh Chauhan
MH Baroda, Vadodara. (309/9 A.V. Colony, Sikandra, Agra). INDIA.
Conflict of Interest: None Declared

Dear Editor,

West has brought out an exhaustive and excellent paper [1]. I considered sharing my thoughts and first hand experiences in managing high altitude related illnesses, having had two spells of continuous stay at high altitude areas in the Indian Himalayas, first for 21/2 years and the second of 21/4 years a decade later at heights varying between 12500 to 16500 feet.

In my experience, upper respiratory tract infections, overt bravado without proper acclimatization and (contrarily) apprehensive states are the frequent harbingers of high altitude related illnesses. Pre-existing hypertension and ischemic heart diseases, cold induced asthma and prior pneumonic illnesses tend to aggravate the issue. Almost 80% or more new entrees to high altitude area that had upper respiratory infections had an increased propensity and liability to suffer from high altitude related illnesses when left untreated. Therefore my first priority based on my observations and experience, was to ensure quick recovery from upper respiratory tract infections and continuous monitoring throughout their acclimatization period, which had to be extended in many cases. Acclimatization also plays an important role when proceeding on to further heights and during re-entry in high altitude region after an absence of over a fortnight.

Apprehension plays an important role in high altitude related illnesses, especially in acute mountain sickness. Nausea, headache, and anorexia immediately after arrival to a high altitude area can also be related to motion sickness, if the journey has been performed in a vehicle or a small swift chopper, rather than being ascribed to acute mountain sickness. However, caution needs to be applied. There might be certain circumstances, which may lead a person to a high altitude area against his/her will. In such cases, malingering should also be kept in the differential diagnosis when considering acute mountain sickness.

Another observation was that the frequency of high altitude related illnesses increased in rough and cloudy weathers, probably related to disturbances in the environmental availability and saturation of oxygen. It has been my experience that high altitude pulmonary oedema usually starts manifesting late in the evenings and in the middle of nights, although most of the patients had been feeling unwell all throughout the day. Cough with frothy expectoration (which may be blood tinged) and respiratory distress associated with air hunger are the hallmark for acute pulmonary oedema, leading rapidly to a moribund state with features of cerebral edema. Immediate oxygen supplementation, nifedipine, lasix, and well-diluted morphine in small repeat doses are useful for the management. Rapid descent to lower altitudes remains a sure shot answer but may not be feasible all the times, owing to the vagaries of nature. Therefore, rapid descent must be resorted to immediately, and at the first opportunity, before it is lost. In difficult times, when a vehicle or choppers are not able to assist, piggy rides on the back can be the only life saving alternative available.

A word of caution needs to be expressed while using portable hyperbaric bags. Since it works on the principle of absorbing CO2 in the enclosed environment of the bag, it must be realized that the cake present in the re-breathing apparatus shall continue to perform well only for 3 to 4 hours, until it becomes saturated and no more able to absorb the CO2. Usually a patient who has been placed inside the bag starts feeling well initially. But it is after 3-4 hours his condition starts deteriorating as the basic element, the cartridge fitted in the rebreathing mask becoming saturated now, is unable to absorb CO2 any further. This turns the condition of a patient precarious by having to re-breathe air that is now getting depleted of oxygen and simultaneously getting enriched by CO2 instead. Therefore, the cartridge needs to be changed regularly for the continued safety of the patient. Similarly whenever depending on acetazolamide rather letting the body getting acclimatized, one would be well advised to carry sufficient quantities of spare acetazolamides as your program to come down within stipulated time may not always work, owing to vagaries of nature.



1. West JB. The Physiologic Basis of High-Altitude Diseases. Ann Intern Med 2004; 141 (10): 789-800.

Conflict of Interest:

None declared

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