the physiologic basis of high-altitude diseases

The Physiologic Basis of High-Altitude DiseasesJohn B. West, MD, PhD

Many physicians are surprised to learn how many peo-ple live, work, and play at high altitude. Some 140million persons reside at altitudes over 2500 m, mainly inNorth, Central, and South America; Asia; and easternAfrica (1). Increasingly, people are moving to work athigh altitude. For example, there are telescopes at alti-tudes over 5000 m (2) and mines at over 4500 m (3), andthe GolmudLhasa railroad being constructed in Tibet willhave 30 000 to 50 000 workers at high altitudes, includingmany who work at more than 4000 m. Skiers, mountain-eers, and trekkers go to altitudes of 3000 m to more than8000 m for recreation, and sudden ascents to high altitudewithout the benefits of acclimatization are common. All ofthese groups are prone to high-altitude diseases that some-times have fatal consequences. In addition, the physiologyof hypoxia, which is at the basis of high-altitude medicine,plays an important role in many lung and heart diseases.

HYPOXIA OF HIGH ALTITUDERelationship of Altitude to Barometric Pressure

Evangelista Torricelli (16081647) was the first per-son to realize that the atmosphere above us creates a pres-sure that can, for example, support a column of mercury.In a memorable sentence, he stated, We live submerged atthe bottom of an ocean of the element air, which by un-questioned experiments is known to have weight (4). Fig-ure 1 shows the relationship between altitude and baro-metric pressure in the regions where human exposure tohigh altitude is common. Table 1 lists some of the baro-metric pressures and the consequent inspired PO2. At analtitude of 3000 m, which is commonly encountered in skiresorts, the barometric pressure and inspired PO2 are onlyabout 70% of the sea level value. At an altitude of 5000 m,the highest at which humans reside, the inspired PO2 isonly about half of the sea level value. On the summit of

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Clinical Principles Physiologic Principles

Three major high-altitude diseases

Acute mountain sickness (headache, lightheadedness,fatigue, insomnia, anorexia)

High-altitude pulmonary edema (dyspnea, reduced exercisetolerance, cough, tachycardia, crepitations)

High-altitude cerebral edema (confusion, ataxia, moodchanges, coma, papilledema)

Other high-altitude conditions

Chronic mountain sickness (severe polycythemia, headache,somnolence, fatigue, depression)

Subacute mountain sickness (affects infants and adults;right-heart failure with peripheral edema)

Retinal hemorrhage (common at extreme altitude butusually causes no visual impairment)

Hypoxia of high altitude impairs physical performance,mental performance, and sleep.

In acclimatization, hyperventilation is the most importantfeature. Acclimatization reduces but does not abolish theeffects of hypoxia.

Extreme altitude causes severe hypoxemia, respiratoryalkalosis, and greatly reduced maximal oxygenconsumption.

The mechanisms of acute mountain sickness andhigh-altitude cerebral edema are not fully understood, butbrain swelling may be a feature. Acetazolamide reduces theincidence of acute mountain sickness.

The mechanism of high-altitude pulmonary edema isprobably uneven hypoxic pulmonary vasoconstriction thatexposes some capillaries to a high pressure, damaging theirwalls and leading to a high-permeability form of edema.

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Mount Everest, at an altitude of 8848 m, the inspired PO2is less than 30% of its value at sea level. These numbersemphasize the hypoxic insult of going to high altitude.

Note that the barometric pressures shown here arehigher than those found in some textbooks of medicineand physiology, which use the so-called standard atmo-sphere (5). The aviation industry introduced the standardatmosphere in the 1920s to refer to average conditions inthe atmosphere. However, it is now appreciated that mostof the high-altitude areas frequented by humans, includingthe Himalayas and the South American Andes, have ahigher barometric pressure than the standard atmosphereindicates. This is because they are relatively near the equa-tor, where the solar radiation causes upwelling of the at-mosphere; consequently, the column of air is higher. Thedifference between the standard atmosphere and the actualbarometric pressures becomes very significant at extremealtitudes, such as at the summit of Mount Everest. If thebarometric pressure predicted by the standard atmospherewere correct, the mountain could probably not be climbedwithout supplementary oxygen (6).

Effects of the Hypoxia of High AltitudeHigh altitude affects the human body because of oxy-

gen deprivation. Other factors, such as severe cold, highwinds, and intense solar radiation, may be present but canbe nullified by appropriate protection. Hypoxia is inevita-ble unless it is relieved by supplementary oxygen or unlessthe person is placed in a container at increased pressure,such as a Gamow bag.

Oxygen is critical to normal cellular function becauseit is an essential part of the electron transport chain forenergy production in cells. The cellular responses to oxy-gen deprivation have been clarified by the discovery of the

hypoxia-inducible factor-1 complex, which regulates genetranscription. This complex is a heterodimer protein com-plex that activates transcription through binding to specifichypoxic-responsive sequences present in various genes en-coding for glycolytic enzymes, growth factors, and vasoac-tive peptide (7).

The physiologic effects of the hypoxia of high altitudeon the human body are legion. The most important in thepresent context can be considered under 3 headings: phys-ical performance, mental performance, and sleep.

Maximal Oxygen Consumption

Maximal oxygen consumption is reduced as the in-spired PO2 is lowered. For example, at an altitude of3000 m, maximal oxygen consumption is reduced to about85% of the sea level value (8). At 5000 m, it is only about60% of the value at sea level, and on the summit of MountEverest, it is only approximately 20%. A coincident featureof the reduced physical performance at high altitude is agreat increase in fatigue.

The reduced maximal oxygen consumption at highaltitude is usually ascribed to the reduction in mitochon-drial PO2, which interferes with the function of the elec-tron transport chain responsible for providing cellular en-ergy. However, some investigators believe that maximaloxygen consumption is reduced by central inhibition fromthe brain (9). There is little evidence that the pulmonaryhypertension of high altitude limits maximal oxygen con-sumption, and, perhaps surprisingly, myocardial contractil-ity in healthy people is maintained up to extreme altitudes(10); these findings emphasize the difference between theeffects of hypoxemia and ischemia on the normal myocar-dium. Studies of elite mountaineers have suggested thatgenetic factors have a role in determining maximal oxygenconsumption at high altitude, since participants tend tohave the insertion rather than the deletion variant of theangiotensin-converting enzyme gene (11).

Mental Performance

Mental performance is impaired at high altitude, al-though many people are curiously reluctant to admit this.Neuropsychological testing is difficult because people canperform well in the short-term by concentrating harder

Figure 1. Relationship among altitude, barometric pressure, andinspired 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 thesummit of Mount Everest, the inspired PO2 is less than 30% of the valueat sea level. CO Colorado.

Table 1. Barometric Pressure and Inspired Po2 at VariousAltitudes

Altitude, m (ft) Barometric Pressure,mm Hg

Inspired Po2, mm Hg(% of sea level)

0 (0) 760 149 (100)1000 (3281) 679 132 (89)2000 (6562) 604 117 (79)3000 (9843) 537 103 (69)4000 (13 123) 475 90 (60)5000 (16 404) 420 78 (52)8848 (29 028) 253 43 (29)

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than they usually need to during the workday. However,most people working at an altitude of 4000 m experiencean increased number of arithmetic errors, reduced atten-tion span, and increased mental fatigue. Visual sensitivity(for example, night vision) is reduced at altitudes as low as2000 m and has been shown to decrease by about 50% atan altitude of 5000 m, where there are also measurabledifferences in attention span, short-term memory, arith-metic ability, and decision making (12).

The molecular and cellular mechanisms responsiblefor impaired mental performance during hypoxia arepoorly understood. The brain normally accounts for ap-proximately 20% of the bodys total oxygen consumption,and the oxygen is almost entirely used for the oxidation ofglucose. Suggested mechanisms for the impairment ofnerve cell function during hypoxia include altered ion ho-meostasis, changes in calcium metabolism, alterations inneurotransmitter metabolism, and impairment of synapsefunction (1315).

Sleep

Sleep is also impaired at high altitude, and many peo-ple find this one of the most distressing features of stayingthere. People at high altitude often wake frequently, haveunpleasant dreams, and do not feel refreshed in the morn-ing (16). The periodic breathing that occurs in most peo-ple at altitudes above 4000 m is probably an importantcausative factor (17). Periodic breathing is thought to re-sult from instability in the control system through the hy-poxic drive (18) or the response to carbon dioxide (19).The low levels of oxygen in the blood after apneic periodsmay be responsible for some of the arousals. Experiencedtrekkers and mountain climbers often recommend climb-ing high but sleeping low to mitigate these problems.

ACCLIMATIZATION TO HIGH ALTITUDEThe adaptive changes collectively known as acclimati-

zation greatly improve the tolerance of human beings tohigh altitude. Physiologists often cite high-altitude accli-matization as one of the best examples of how the bodyresponds to a hostile environment. However, although ac-climatization is critically important, several misconceptionshave developed.

HyperventilationBy far the most important feature of acclimatization is

the increase in depth and rate of breathing, which results inan increase in alveolar ventilation. This is brought about byhypoxic stimulation of the peripheral chemoreceptors,mainly the carotid bodies, which sense the low PO2 in thearterial blood. Hyperventilation reduces the alveolar PCO2because there is an inverse relationship between this andthe alveolar ventilation for a fixed rate of carbon dioxideproduction:

PCO2 VCO2

VA K

where VA is the alveolar ventilation and VCO2 is the CO2production. At the same time, the increased alveolar ven-tilation increases the alveolar PO2. In other words, the pro-cess of hyperventilation tends to defend the alveolar PO2against the decrease in inspired PO2 (Figure 2).

The extent of hyperventilation at high altitude can beenormous. To take an extreme example, on the summit ofMount Everest, where the inspired PO2 is only 29% of itssea level value (Table 1), the alveolar ventilation is in-creased approximately 5-fold. As a result, the alveolar PCO2is reduced to 7 to 8 mm Hg, about one fifth of its normalsea level value of 40 mm Hg (20). The alveolar PO2 is thenmaintained near 35 mm Hg, which is certainly very lowbut just sufficient to keep the climber alive.

PolycythemiaMany physicians who are asked to name the most im-

portant feature of acclimatization will probably answerpolycythemia. It is true that both lowlanders (people whonormally live at or near sea level) who remain at highaltitude for a long period and highlanders (people born andbred at high altitude) have increased erythrocyte concen-trations and therefore high blood oxygen capacities. How-ever, polycythemia develops relatively slowly. It takes sev-eral days before an increased rate of erythrocyte production

Figure 2. Alveolar PO2 at high altitude for persons acutelyexposed and persons fully acclimatized.

The altitudes of several observatories where astronomers work are shown.Note that fully acclimatized astronomers on the summit of Mauna Keahave an alveolar PO2, and therefore an arterial PO2, lower than thethreshold for continuous oxygen therapy in patients with chronic ob-structive pulmonary disease (COPD). The dashed-and-dotted lines indi-cate the normal value at sea level (upper line) and the threshold forcontinuous O2 therapy in COPD (lower line).

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can be measured, and the process is not complete for sev-eral weeks (21). Therefore, in the context of acclimatiza-tion to high altitude over the course of a week or so (theusual length of many visits to high altitude), polycythemiadoes not play an important role.

Newcomers to high altitude often develop a transientincrease in erythrocyte concentration, but this is caused bya reduced plasma volume, not an increased rate of eryth-rocyte production (22). Dehydration may be a factor in thereduced plasma volume; it is very common at high altitude,partly because of the great insensible fluid loss mainlycaused by the large ventilation of cold dry air (23). Hor-monal changes regulating plasma volume also occur (24),and thirst is inappropriately reduced. A reduced fluid in-take is often a factor, and diuresis may occur.

AcidBase ChangesThe acute reduction in alveolar and therefore arterial

PCO2, which was mentioned earlier, causes respiratory al-kalosis with an increased pH in both the cerebrospinalfluid and arterial blood. However, after a day or so, the pHof the cerebrospinal fluid changes toward normal by move-ment of bicarbonate out of the cerebrospinal fluid, andafter 2 or 3 days the pH of the arterial blood moves towardnormal by renal excretion of bicarbonate. The rate andextent of the metabolic compensation depend on the alti-tude being slower and less complete at very high altitudes.The initial alkalosis in both the cerebrospinal fluid and theblood tends to inhibit hyperventilation through the actionof both the central chemoreceptors in the brainstem andthe peripheral chemoreceptors in the carotid and aorticbodies. The sensitivity of the carotid body to hypoxia alsoincreases during prolonged exposure to high altitude (25).

Misconceptions about AcclimatizationAlmost everybody who ascends to altitudes of 2500 to

3000 m or above is aware of the advantages of acclimati-zation. However, an important misconception about accli-matization has developed, particularly among people whoare not in the medical field. I have become very aware ofthis in talking to astronomers who work in observatorieson the summit of Mauna Kea, Hawaii, where the altitudeis 4200 m. Many of these people have come to believe thatthe process of acclimatization returns the body to its sealevel condition or, in other words, that the hypoxia of highaltitude is nullified by the process of acclimatization.

The true situation is indicated in Figure 2, whichshows typical alveolar PO2 values for people after acuteexposure to high altitude and after full acclimatization.These data are based on the study of Rahn and Otis (26),although there is considerable individual variation. Figure2 shows several reference altitudes, including that of thelaboratories of the University of California White Moun-tain Research Station (3800 m); the summit of MaunaKea, where several telescopes are located (4200 m); andChajnantor, Chile, the site of construction of the enor-mous radiotelescope ALMA (Atacama Large Millimeter

Array) (5050 m). Sites near Chajnantor up to an altitude of5800 m have occasionally been used for scientific measure-ments.

Among astronomers working at Mauna Kea, acute ex-posure to the altitude of the summit after ascent from nearsea level results in an alveolar PO2 of approximately 45 mmHg. With full acclimatization, the PO2 increases to about54 mm Hg on average. However, full acclimatization takesseveral days and never occurs for astronomers on MaunaKea because of the limited accommodation and workschedules.

The severity of arterial hypoxemia is emphasized bycomparing these astronomers with patients who havechronic obstructive pulmonary disease (COPD). Even ifthe alveolar PO2 of the astronomers reached a value of 54mm Hg, the arterial PO2 would be 2 or 3 mm Hg lower,assuming normal lungs. Figure 2 also shows the arterialPO2 threshold of 55 mm Hg, below which patients withCOPD are entitled to continuous oxygen therapy underMedicare (27). In other words, if the arterial hypoxemia ofan astronomer on Mauna Kea was caused by COPD, thisperson would be entitled to continuous oxygen therapy.

Of course, there are differences between healthy per-sons at high altitude and patients with COPD. For exam-ple, the pulmonary hypertension of COPD, which is partlyrelieved by continuous oxygen therapy (27), is not solelydue to alveolar hypoxia, which is the primary factor at highaltitude. However, it is important to note that 6 months ofcontinuous oxygen therapy through nasal prongs in pa-tients with COPD, which is sufficient to raise the restingarterial PO2 to between 60 and 80 mm Hg, results in astatistically significant improvement in neuropsychologicalfunction (measured during air breathing) (28). In addition,61% of patients with COPD who have an average arterialPO2 of 54 mm Hg or less show neuropsychological deficitscompared with age- and education-matched controls (29).These findings should give pause to astronomers who electto alleviate hypoxemia by acclimatization rather than byoxygen enrichment of room air, which is discussed later inthis article.

IMPROVING WORKING EFFICIENCY AT HIGH ALTITUDEPopulations at Risk

Until recently, interest in high-altitude medicine andphysiology was mainly directed to 2 groups. One is thelarge number of lowlanders who journey to high altitudefor recreational purposes, including skiing, trekking, andmountaineering. Many of these people develop high-alti-tude diseases, although fortunately the most commonproblem by far is the relatively innocuous acute mountainsickness. The other extensively studied group involves peo-ple who reside permanently at high altitude.

In the past few years, another group has been increas-ingly studied: those who are required to work at high alti-tude. Usually, such people are commuters in the sense that




they normally live near sea level but work at high altitude.Until very recently, miners were the largest group in thiscategory, particularly in the South American Andes. As anexample, several thousand miners work in the Collahuasimine in north Chile at altitudes of approximately 4500 m,although their sleeping accommodation is somewhat lower(3800 m). Their working schedule is remarkable in thatthey and their families live on the coast at sea level. At thebeginning of their working week, they are bused up to themine, where they typically spend the next 7 days workinglong shifts of 12 hours per day. They are then bused downto their homes, where they spend the next 7 days. Theresult is that these workers acclimatize to an altitude be-tween 4500 m and sea level. A prospective study of themedical and physiologic characteristics of this group hasbeen under way for the past 3 years (3).

Oxygen Enrichment of Room AirAn important advance has been made during the past

few years to improve working conditions at high altitude:increasing the oxygen concentration of the air in rooms byadding oxygen to the room ventilation (30). Since all ofthe deleterious effects of high altitude are caused by the lowinspired PO2, it should come as no surprise that the bestway to alleviate the problem is to increase the inspired PO2by using supplementary oxygen. The availability of oxygenconcentrators has greatly increased the feasibility of oxygenenrichment of room air. Oxygen concentrators work onthe same principle as the small oxygen generators that areused at home by patients with chronic lung disease anddeliver oxygen through nasal prongs. These robust, self-contained units require only modest amounts of electricalpower. When air is pumped into a tube of synthetic zeoliteat high pressure, nitrogen is preferentially adsorbed and theeffluent gas has an oxygen concentration of approximately95%. After a short period, the zeolite cannot adsorb morenitrogen; the high-pressure air is switched to a second tubewhile the first tube is purged of nitrogen by using air atnormal pressure. The only moving parts in the oxygenconcentrator are a piston pump and switching valve.

A typical facility using this technique is a radiotele-scope station run by the California Institute of Technologyin northern Chile at an altitude of 5050 m. The astrono-mers work in rooms made from shipping containers withdimensions of 2.1 m 2.1 m 12.2 m, or half thatlength, and the oxygen concentration in the room is main-tained at 27%, that is, 6% higher than in ordinary air. Theoxygen is generated by concentrators outside the room andis injected into the ventilation duct. As a result, the in-spired PO2 is the same as that for someone breathing air atan altitude of 3200 m. In other words, from a physiologicpoint of view, the altitude has been reduced by approxi-mately 1800 m. Since the astronomers live in a village at analtitude of 2440 m when they are not observing, the alti-tude of 3200 m is easily tolerated.

Over the 4 years that this system has been in opera-

tion, the experience has been very gratifying. Work pro-ductivity has increased, workers are much less fatigued, andat night the quality of sleep is greatly improved (2). Thesame technique is planned on a much larger scale forALMA, which is located nearby at the same altitude. Thisnew advance shows great promise in improving conditionsfor people who work at high altitude, particularly thosewho commute from lower altitudes.

PHYSIOLOGIC CHANGES AT EXTREME ALTITUDESAlthough this topic is relevant to only a small popula-

tion, chiefly mountaineers, it presents fascinating medicalaspects. It is a curious coincidence that extreme altitudes,such as the summit of Mount Everest, are very near thelimit of human tolerance to oxygen deprivation. Even themost creative evolutionary biologist has not been able toaccount for this. This coincidence is underlined by the factthat climbers ascended to approximately 300 m below thesummit of Mount Everest without supplementary oxygenas early as 1924 but the summit was not reached withoutoxygen until 1978. In other words, the last 300 m took 54years. Predictions based on measured maximal oxygen con-sumption at increasing altitudes in acclimatized personswere similar. When the line relating maximal oxygen con-sumption to barometric pressure was extrapolated to thepressure on the summit of Mount Everest, it looked asthough all the oxygen available would be required for basaloxygen uptake (31). In other words, no oxygen would beleft over for the physical effort of climbing.

Figure 3. Alveolar PO2 and PCO2 of acclimatized humans at highaltitude.

Sea level is at the top right of the graph, and the summit of MountEverest is at the bottom left. The squares show the means of the mea-surements at 3 altitudes on the American Medical Research Expeditionto Everest; the circles are previously reported data from many sources.Note that after a certain altitude has been exceeded, alveolar PO2 doesnot decrease further. It is defended at a level of about 35 mm Hg by theprocess of extreme hyperventilation, which reduces the PCO2 to less than10 mm Hg. Modified from reference 20.




In 1981, the American Medical Research Expeditionto Everest was planned to obtain physiologic measure-ments at extreme altitudes, including the summit. Alveolargas samples were collected on the summit, barometric pres-sure was measured there for the first time, and many othermeasurements were made above an altitude of 8000 m andat somewhat lower altitudes in 2 laboratories (32). Figure 3shows the alveolar PO2 and PCO2 as humans ascended fromsea level to the summit of Mount Everest. The PO2 de-creased because of the reduction in inspired PO2, while thePCO2 decreased because of the increasing hyperventilation.Note that at the summit, the alveolar PCO2 was reduced tothe extraordinarily low level of 7 to 8 mm Hg. This impliesan increase in alveolar ventilation of about 5 times the sealevel value. Of interest, above an altitude of about 7000 m,alveolar PO2 did not decrease further. Rather, it was de-fended at a level of about 35 mm Hg by increasing hyper-ventilation. In other words, the extreme hyperventilationinsulated the PO2 in the alveolar gas from the decreasingPO2 in the inspired air. Hyperventilation is by far the mostimportant physiologic adaptation at these extreme alti-tudes.

It was not feasible to sample arterial blood on thesummit, but the arterial PO2 could be estimated from theBohr integration along the pulmonary capillary. In addi-tion, the arterial pH was derived from the measuredalveolar PCO2 and the measured base excess in samplesof venous blood. The results are shown in Table 2. Thebarometric pressure was 253 mm Hg, almost exactly onethird of the sea level value. This means that the inspiredPO2 on the summit was 43 mm Hg. The alveolar PO2 waskept at the just-viable value of 35 mm Hg by extremehyperventilation, but the arterial PO2 was lower because ofdiffusion limitation across the bloodgas barrier underthese extraordinary conditions. The PCO2 was 7 to 8 mmHg, and the pH exceeded 7.7 (20). An interesting result ofthis extreme alkalosis is that it increases the oxygen affinityof hemoglobin, which facilitates loading of oxygen by thepulmonary capillaries. It is astonishing that humans cantolerate and survive such extraordinary insult to their nor-mal physiologic makeup. Maximal oxygen uptake wasmeasured on well-acclimatized persons breathing an in-spired PO2 of 43 mm Hg (the same as on the summit),yielding a value of just over 1 L/min. This is equivalent tothe oxygen uptake when someone walks slowly on levelground but is just sufficient to explain how a climber canreach the summit.

Some of the physiologic changes of extreme altitude

can be studied by prolonged exposure of volunteers in alow-pressure chamber. For example, in Operation EverestII, 8 healthy persons spent approximately 40 days andnights in a chamber in which the pressure was graduallyreduced (33). However, for reasons that are not clear, fullacclimatization does not occur under these conditions.Nevertheless, the summit measurements of arterial PO2and maximal oxygen consumption agreed well with thoseobtained in the field.

Very few additional data at extreme altitudes havebeen obtained in the past 20 years. However, some mea-surements of alveolar PO2 by fuel cell and arterial oxygensaturation by pulse oximetry were taken during an ascentto 8000 m on Mount Everest (34). The results agreed withthose found on American Medical Research Expedition toEverest but did not correspond as well with those obtainedin the chamber study, again suggesting incomplete accli-matization in the latter.

HIGH-ALTITUDE DISEASESThere are 3 major high-altitude diseasesacute

mountain sickness, high-altitude pulmonary edema, andhigh-altitude cerebral edemaas well as many other lessimportant conditions.

Acute Mountain SicknessAcute mountain sickness is very common in people

who ascend from near sea level to altitudes higher thanapproximately 3000 m, but it may occur at altitudes as lowas 2000 m. It is characterized by headache, lightheaded-ness, breathlessness, fatigue, insomnia, anorexia, and nau-sea (35, 36). Typically, symptoms begin 2 or 3 hours afterascent, but the condition is generally self-limiting and mostof the symptoms disappear after 2 or 3 days. However,insomnia may persist. Descent to low altitude rapidly re-verses acute mountain sickness.

The precise pathogenesis of acute mountain sickness isnot understood. Of course, hypoxia is likely to be a majorfactor, although respiratory alkalosis may also play a role.The latter would fit with the time course of resolution.Mild cerebral edema may occur secondary to increased ce-rebral blood flow and perhaps altered permeability of thebloodbrain barrier. There is some evidence of slight brainswelling and increased intracranial pressure. A low arterialPO2 results in cerebral vasodilatation (37), while a lowPCO2 causes vasoconstriction (38).

The best way to prevent acute mountain sickness is byascending gradually and allowing time for acclimatization.

Table 2. Alveolar Gas and Estimated Arterial Blood Values on the Summit of Mount Everest

Altitude, m (ft) BarometricPressure,mm Hg

InspiredPO2, mm Hg

AlveolarPO2, mm Hg

Arterial Values

PO2, mm Hg PCO2, mm Hg pH

8848 (29 028) [summit] 253 43 35 28 7.5 7.7Sea level 760 149 100 95 40 7.40




A popular rule of thumb among trekkers is that above analtitude of 3000 m, each days ascent should not averagemore than 300 m, with a rest day every 2 or 3 days. This isa conservative ascent rate, and many people are able toincrease this to 400 m to 600 m per day. Even a briefrecent exposure to high altitude affords some protectionagainst acute mountain sickness (39).

The carbonic anhydrase inhibitor acetazolamide is use-ful for prophylaxis if rapid ascent is inevitable, as in, forexample, a flight to La Paz, Bolivia. Acetazolamide pro-duces metabolic acidosis by increasing the renal excretionof bicarbonate, which in turn stimulates ventilation. Thedosage is 250 mg once or twice daily, and 125 mg taken atnight will sometimes improve sleep. A recent meta-analysisconcluded that daily prophylactic doses of less than 750mg were ineffective (40); however, this runs contrary tomuch clinical experience and probably reflects the exclu-sion of some studies. Side effects of acetazolamide are com-mon and include diuresis, paresthesia of fingers and toes,and a flat unpleasant taste to carbonated drinks. Acetazol-amide is a sulphonamide drug, and therefore some peoplehave a hypersensitivity to it. Dexamethasone is also effec-tive in preventing acute mountain sickness, although itsmode of action is unknown. The recommended prophy-lactic dosage for adults is 2 mg every 6 to 8 hours. Inaddition, Gingko biloba has been suggested as a useful pro-phylactic agent but has not been sufficiently studied.

Treatment of acute mountain sickness by oxygen ordescent is usually not required, although aspirin, acetami-nophen, or ibuprofen may relieve headache. Acetazolamide,250 mg 3 times per day, is helpful in relieving symptoms,as is dexamethasone, 4 mg 4 times per day, if the conditionis severe. Severe prolonged acute mountain sickness re-sponds well to descent.

High-Altitude Pulmonary EdemaHigh-altitude pulmonary edema is a potentially fatal

condition that typically occurs 2 to 4 days after ascent toaltitudes above 3000 m (41). With usual ascent rates, theincidence is about 1% to 2%, but as many as 10% ofpeople ascending rapidly to 4500 m may develop the con-dition (42). High-altitude pulmonary edema is also seen inresidents of high altitudes who travel to a lower altitudeand then return; this is termed reascent high-altitude pul-monary edema. There is considerable individual variability,and people who develop high-altitude pulmonary edemaonce are more likely to do so again. Some evidence indi-cates that an upper respiratory tract infection may increasesusceptibility, and people with restricted pulmonary circu-lation, such as unilateral absence of a pulmonary artery, areparticularly at risk (43).

High-altitude pulmonary edema may be preceded byacute mountain sickness, but this is not always the case.The predominant symptom is dyspnea with reduced exer-cise tolerance. There is often a dry cough at first, but thismay progress to a cough that produces frothy, blood-

stained sputum. Tachypnea and tachycardia are commonon examination. In addition, there is often mild pyrexia,and crepitations (crackles) can be detected by auscultation.

The pathogenesis of high-altitude pulmonary edema isstill a subject of study, but strong evidence indicates that itis triggered by pulmonary hypertension as a result of hy-poxic pulmonary vasoconstriction. It is likely that the hy-poxic pulmonary vasoconstriction is patchy, with the resultthat some pulmonary capillaries are exposed to the highpressure. This causes damage to the capillary walls (stressfailure), and they leak a high-protein edema fluid witherythrocytes. Studies of alveolar fluid obtained by bron-choalveolar lavage in high-altitude pulmonary edema haveconvincingly shown that this is a high-permeability type ofedema (44). However, cardiac catheterization studies havedemonstrated normal pulmonary wedge pressures (45), sothis is not a form of left-heart failure.

The evidence for the importance of pulmonary hyper-tension can be summarized as follows. Cardiac catheriza-tion studies in patients with high-altitude pulmonaryedema have shown pulmonary artery systolic pressures ashigh as 144 mm Hg, with a usual range of 60 to 80 mmHg (46, 47). Susceptible individuals tend to have an un-usually strong hypoxic pulmonary vasoconstriction re-sponse (48) and unusually high pulmonary artery pressuresbefore the onset of high-altitude pulmonary edema (49).Pulmonary vasodilator drugs are useful in the preventionand treatment of this disorder (49, 50). As indicated ear-lier, a restricted pulmonary vascular bed (for example, uni-lateral absence of a pulmonary artery) is a recognized riskfactor (43). Exercise that increases pulmonary artery pres-sure may also play a role (51). Convincing evidence that

Figure 4. Ultrastructural changes in the wall of a pulmonarycapillary 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 capillarywall. Modified from reference 56. ALV alveolus; CAP capillarylumen.




the alveolar edema is of the high-permeability type withlarge concentrations of high-molecular-weight proteins andcells comes from bronchoalveolar lavage studies (44, 52).Later in the disease, the edema fluid contains markers of aninflammatory response (53), although this is not seen inthe very early stages (54). Changes in blood coagulationand platelet activation also occur later in the disease (55).

On the basis of these findings, a likely pathogenicmechanism for high-altitude pulmonary edema is that thehigh pulmonary artery pressure is transmitted to some ofthe capillaries and the resulting high wall stresses causeultrastructural changes. Capillaries in areas of the lungwhere vasoconstriction is not effective (for example, be-cause of the paucity of vascular smooth muscle) may beexposed to a pressure close to that in the pulmonary artery.The process has been studied in animal preparations,where the pulmonary capillary pressure was increased bycannulating the pulmonary artery and left atrium and thelung parenchyma was fixed for electron microscopy by in-travascular perfusion of buffered glutaraldehyde (56, 57).The results show disruption of the capillary endotheliallayer, alveolar epithelial layer, and, in some cases, all layersof the wall (Figure 4). These changes are seen with trans-mural pressures considerably lower than the pulmonary ar-terial pressures that have been measured in high-altitude

pulmonary edema and explain the high-permeability formof edema with the leak of high-molecular-weight proteinsand cells. Of interest, sometimes blood platelets are seenadhering to the exposed basement membrane. This couldexplain activation of these cells by this highly reactive, elec-trically charged surface and could also explain the markersof an inflammatory response that develop later in the disease.

One of the interesting features of the ultrastructuralchanges in the pulmonary capillaries is that they are readilyreversible. For example, if the pressure in the pulmonarycapillaries is first increased and then lowered to normallevels for a few minutes, approximately 70% of the disrup-tions in both the capillary endothelium and the alveolarepithelium disappear (58). This rapid resolution of thepathologic changes fits well with the remarkably rapid im-provement in patients clinical status when they are movedto a lower altitude. We do not fully understand the micro-mechanics of the processes responsible for the ultrastruc-tural changes, but it has been suggested that distortion ofthe type IV collagen matrix in the basement membranesmay be a factor (59). There is evidence that the basementmembrane is responsible for the strength of the bloodgasbarrier, at least on the thin side (60).

Additional evidence that these ultrastructural changesare caused by high wall stresses resulting from the high

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.




pulmonary capillary pressures comes from an analysis ofthe wall stresses in the extremely thin bloodgas barrierthat forms the wall of the capillary. This analysis showsthat these stresses approach the breaking stress of type IVcollagen (59). The basic reason for these extremely highwall stresses is that the bloodgas barrier on the thin side isso extraordinarily thin. The bloodgas barrier needs to beextremely thin for effective gas exchange by diffusion butalso strong enough to withstand these large stresses (61).The pathogenic processes are summarized in Figure 5.

Of interest, if high-altitude pulmonary edema doesnot develop within 4 or 5 days of someone moving to highaltitude, it does not develop at all unless the altitude isincreased again. This is probably because the alveolar hyp-oxia induces vascular remodeling along with the vaso-constriction. We know that remodeling of the pulmo-nary arteries begins very rapidly when the wall tension isincreased. For example, Tozzi and colleagues (63) showedthat the synthesis of collagen and elastin increased alongwith increased gene expression for several growth factorswithin 4 hours of applying stretch to pulmonary arterysegments in vitro. Therefore, it seems possible that thecapillaries, which are at risk because the small pulmonaryarteries upstream of them are nearly devoid of smoothmuscle, are protected when sufficient remodeling occurs.Basically, the same explanation could account for the re-ascent high-altitude pulmonary edema mentioned earlier,which occurs in residents of high altitude when they go toa lower altitude, typically for a few days, and then return.Presumably, some vascular smooth muscle undergoes invo-lution during the time spent at low altitude.

The prevention and treatment of high-altitude pulmo-nary edema are consistent with the pathogenic mechanismdescribed above. The disease is much more likely to occurafter sudden ascent to high altitude. For example, as notedearlier, a rapid ascent to 4500 m results in an incidence ofup to 10% (42), whereas the usual incidence with moregradual ascent is 1% to 2%. An additional risk factor isstrenuous exercise, particularly if coupled with a rapid as-cent (64). In people who have previously developed high-altitude pulmonary edema, nifedipine (20 mg of a slow-release preparation every 8 hours) reduces the incidence(65). The cardinal principle for treating high-altitude pul-monary edema is to remove the patient to a lower altitudeas quickly as possible. Oxygen should be administered ifavailable. In addition, nifedipine has been shown to helprelieve symptoms. The suggested regimen is 20 mg of theslow-release preparation by mouth every 6 to 12 hours (36).Other vasodilators, such as nitric oxide, may also be effectivebut are usually not feasible in the field. Recent work indicatesthat salmeterol (66) and sildenafil (67) may also be useful.

High-Altitude Cerebral EdemaHigh-altitude cerebral edema is rare but potentially

very serious (68). The condition often follows acute moun-tain sickness, and many people think that the two are

closely related and that high-altitude cerebral edema is theextreme end of the spectrum. The incidence is difficult toestimate but may be as high as 1% to 2% in people as-cending above 4500 m.

Classically, the patient becomes confused and ataxicand may experience mood changes. Hallucination has beendescribed, and serious cases involve coma followed bydeath. On examination, patients may have papilledemaand occasionally focal neurologic signs affecting cranialnerves, or even hemiparesis. The pathogenesis is almostcertainly cerebral edema, possibly related to an increasedcerebral blood flow. A few autopsies have shown cerebraledema with swollen flattened gyri (6971). Magnetic res-onance imaging scans in a few patients have shown intenseT2 signals in white matter, particularly in the splenium andcorpus callosum, consistent with edema (72).

Again, the cardinal rule in treatment is descent to alower altitude as quickly as possible. Oxygen should beadministered if possible. Dexamethasone should be given;the suggested dose is 8 mg initially followed by 4 mg every6 hours. This drug is also useful to relieve the cerebralsymptoms of severe acute mountain sickness (73). Ifdescent to a lower altitude is not feasible because of theremote situation, portable hyperbaric bags such as theGamow bag can be used for both high-altitude cerebraledema and high-altitude pulmonary edema. The patient isplaced inside the bag and the pressure is increased with afoot pump, thus reducing the effective altitude. Patientswith high-altitude cerebral edema sometimes recover veryrapidly after descent to a lower altitude.

Other High-Altitude DiseasesChronic Mountain Sickness

Permanent residents of high altitudes sometimes de-velop a condition characterized by severe polycythemia anda constellation of neurologic symptoms, including head-ache, somnolence, fatigue, and depression. The hematocritcan reach extremely high levels, and values above 0.8 havebeen recorded (74). The very high hematocrit increases theviscosity of the blood, and in fact it is often difficult todraw venous blood as a result. Typically, the conditionimproves considerably if the patient is moved to a loweraltitude but reappears after return to high altitudes. Ther-apeutic phlebotomy has been shown to reduce the symp-toms. Respiratory stimulants (for example, medroxyproges-terone acetate) have been used (75) because patients oftenexperience some hypoventilation. Of interest, this disease iscommonly seen in the Andes but is much rarer in Tibet.Some anthropologists believe that true genetic adaptationto high altitude has proceeded further in Tibetans than inAndeans because the former have resided at high altitudesfor much longer (76).

Subacute Mountain Sickness

This somewhat confusing term has been applied to 2different conditions. One involves infants at high altitude




who present with respiratory distress, marked cyanosis, andcongestive heart failure (77). The other affects youngadults in the Indian army who were posted to altitudes ofapproximately 6000 m for many months and developeddyspnea, cough, angina at effort, and dependent edema(78). These conditions may be related to so-called brisketdisease in cattle (79), which is a form of right-heart failurewith peripheral edema.

Retinal Hemorrhage

Retinal hemorrhage is very common in people whoascend above 5000 m, although it usually causes no visualimpairment (80). The condition resolves on return to alower altitude and may be related to increased retinal bloodflow.

CONCLUSIONIn summary, the basic physiologic mechanism of high-

altitude diseases is the low PO2 in the inspired gas, whichresults from the reduced barometric pressure. The mostimportant consequences of ascent to high altitude inhealthy persons can be classified under the 3 headings ofreduced maximal oxygen consumption, impaired mentalperformance, and disordered sleep. The deleterious effectsof high altitude are greatly reduced by the process of accli-matization, the most important feature of which is hyper-ventilation caused by hypoxic stimulation of peripheralchemoreceptors. However, a prevailing misconceptionabout acclimatization is that it returns the body to nearnormal, a serious error. Increasingly, people who normallylive near sea level are being required to work at high alti-tudes, and an important recent advance, oxygen enrich-ment of room air, increases productivity, reduces fatigue,and improves sleep. Extraordinary physiologic adaptationsoccur at extreme altitudes, such as the summit of MountEverest, including an arterial PO2 of approximately 30 mmHg, PCO2 of less than 10 mm Hg, and pH over 7.7. Threemain high-altitude diseases are recognized: acute mountainsickness, high-altitude pulmonary edema, and high-alti-tude cerebral edema. Acute mountain sickness is usuallyself-limiting and often resolves after 2 or 3 days. High-altitude pulmonary edema is much more serious, and re-cent work indicates that the mechanism involves damageto pulmonary capillaries caused by uneven hypoxic pulmo-nary vasoconstriction. High-altitude cerebral edema is alsopotentially fatal, but the mechanism is poorly understood.All 3 conditions respond well to immediate descent.

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 ofMedicine, University of California, San Diego, 0623A, 9500 GilmanDrive, La Jolla, CA 92093-0623; e-mail, [email protected].

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