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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
Ann Intern Med. 2004;141:789-800.For author affiliations, see
end of text.
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
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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.
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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
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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.
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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.
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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
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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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