PHYSIOLOGY IN MEDICINE: A SERIES OF ARTICLES LINKING MEDICINE WITH SCIENCE
Physiology in Medicine
Dennis A. Ausiello, MD, Editor; Dale J. Benos, PhD, Deputy Editor; Francois Abboud, MD, Associate Editor;
William Koopman, MD, Associate Editor
Review
Annals of Internal Medicine
Paul Epstein, MD, Series Editor
The Physiologic Basis of High-Altitude Diseases
John B. West, MD, PhD
Clinical Principles
Physiologic Principles
Three major high-altitude diseases
Hypoxia of high altitude impairs physical performance,
mental performance, and sleep.
Acute mountain sickness (headache, lightheadedness,
fatigue, insomnia, anorexia)
High-altitude pulmonary edema (dyspnea, reduced exercise
tolerance, cough, tachycardia, crepitations)
High-altitude cerebral edema (confusion, ataxia, mood
changes, 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 but
usually causes no visual impairment)
M
any physicians are surprised to learn how many people live, work, and play at high altitude. Some 140
million persons reside at altitudes over 2500 m, mainly in
North, Central, and South America; Asia; and eastern
Africa (1). Increasingly, people are moving to work at
high altitude. For example, there are telescopes at altitudes over 5000 m (2) and mines at over 4500 m (3), and
the Golmud–Lhasa railroad being constructed in Tibet will
have 30 000 to 50 000 workers at high altitudes, including
many who work at more than 4000 m. Skiers, mountaineers, and trekkers go to altitudes of 3000 m to more than
8000 m for recreation, and sudden ascents to high altitude
without the benefits of acclimatization are common. All of
these groups are prone to high-altitude diseases that sometimes have fatal consequences. In addition, the physiology
of hypoxia, which is at the basis of high-altitude medicine,
plays an important role in many lung and heart diseases.
In acclimatization, hyperventilation is the most important
feature. Acclimatization reduces but does not abolish the
effects of hypoxia.
Extreme altitude causes severe hypoxemia, respiratory
alkalosis, and greatly reduced maximal oxygen
consumption.
The mechanisms of acute mountain sickness and
high-altitude cerebral edema are not fully understood, but
brain swelling may be a feature. Acetazolamide reduces the
incidence of acute mountain sickness.
The mechanism of high-altitude pulmonary edema is
probably uneven hypoxic pulmonary vasoconstriction that
exposes some capillaries to a high pressure, damaging their
walls and leading to a high-permeability form of edema.
HYPOXIA
OF
HIGH ALTITUDE
Relationship of Altitude to Barometric Pressure
Evangelista Torricelli (1608 –1647) was the first person to realize that the atmosphere above us creates a pressure that can, for example, support a column of mercury.
In a memorable sentence, he stated, “We live submerged at
the bottom of an ocean of the element air, which by unquestioned experiments is known to have weight” (4). Figure 1 shows the relationship between altitude and barometric pressure in the regions where human exposure to
high altitude is common. Table 1 lists some of the barometric pressures and the consequent inspired PO2. At an
altitude of 3000 m, which is commonly encountered in ski
resorts, the barometric pressure and inspired PO2 are only
about 70% of the sea level value. At an altitude of 5000 m,
the highest at which humans reside, the inspired PO2 is
only about half of the sea level value. On the summit of
Ann Intern Med. 2004;141:789-800.
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© 2004 American College of Physicians 789
Review
The Physiologic Basis of High-Altitude Diseases
Figure 1. Relationship among altitude, barometric pressure, and
inspired PO2.
hypoxia-inducible factor-1 complex, which regulates gene
transcription. This complex is a heterodimer protein complex that activates transcription through binding to specific
hypoxic-responsive sequences present in various genes encoding for glycolytic enzymes, growth factors, and vasoactive peptide (7).
The physiologic effects of the hypoxia of high altitude
on the human body are legion. The most important in the
present context can be considered under 3 headings: physical performance, mental performance, and sleep.
Maximal Oxygen Consumption
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.
Mount Everest, at an altitude of 8848 m, the inspired PO2
is less than 30% of its value at sea level. These numbers
emphasize the hypoxic insult of going to high altitude.
Note that the barometric pressures shown here are
higher than those found in some textbooks of medicine
and physiology, which use the so-called standard atmosphere (5). The aviation industry introduced the standard
atmosphere in the 1920s to refer to average conditions in
the atmosphere. However, it is now appreciated that most
of the high-altitude areas frequented by humans, including
the Himalayas and the South American Andes, have a
higher barometric pressure than the standard atmosphere
indicates. This is because they are relatively near the equator, where the solar radiation causes upwelling of the atmosphere; consequently, the column of air is higher. The
difference between the standard atmosphere and the actual
barometric pressures becomes very significant at extreme
altitudes, such as at the summit of Mount Everest. If the
barometric pressure predicted by the standard atmosphere
were correct, the mountain could probably not be climbed
without supplementary oxygen (6).
Maximal oxygen consumption is reduced as the inspired PO2 is lowered. For example, at an altitude of
3000 m, maximal oxygen consumption is reduced to about
85% of the sea level value (8). At 5000 m, it is only about
60% of the value at sea level, and on the summit of Mount
Everest, it is only approximately 20%. A coincident feature
of the reduced physical performance at high altitude is a
great increase in fatigue.
The reduced maximal oxygen consumption at high
altitude is usually ascribed to the reduction in mitochondrial PO2, which interferes with the function of the electron transport chain responsible for providing cellular energy. However, some investigators believe that maximal
oxygen consumption is reduced by central inhibition from
the brain (9). There is little evidence that the pulmonary
hypertension of high altitude limits maximal oxygen consumption, and, perhaps surprisingly, myocardial contractility in healthy people is maintained up to extreme altitudes
(10); these findings emphasize the difference between the
effects of hypoxemia and ischemia on the normal myocardium. Studies of elite mountaineers have suggested that
genetic factors have a role in determining maximal oxygen
consumption at high altitude, since participants tend to
have the insertion rather than the deletion variant of the
angiotensin-converting enzyme gene (11).
Mental Performance
Mental performance is impaired at high altitude, although many people are curiously reluctant to admit this.
Neuropsychological testing is difficult because people can
perform well in the short-term by concentrating harder
Effects of the Hypoxia of High Altitude
High altitude affects the human body because of oxygen deprivation. Other factors, such as severe cold, high
winds, and intense solar radiation, may be present but can
be nullified by appropriate protection. Hypoxia is inevitable unless it is relieved by supplementary oxygen or unless
the person is placed in a container at increased pressure,
such as a Gamow bag.
Oxygen is critical to normal cellular function because
it is an essential part of the electron transport chain for
energy production in cells. The cellular responses to oxygen deprivation have been clarified by the discovery of the
790 16 November 2004 Annals of Internal Medicine Volume 141 • Number 10
Table 1. Barometric Pressure and Inspired Po2 at Various
Altitudes
Altitude, m (ft)
Barometric Pressure,
mm Hg
Inspired Po2, mm Hg
(% of sea level)
0
1000
2000
3000
4000
5000
8848
760
679
604
537
475
420
253
149 (100)
132 (89)
117 (79)
103 (69)
90 (60)
78 (52)
43 (29)
(0)
(3281)
(6562)
(9843)
(13 123)
(16 404)
(29 028)
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The Physiologic Basis of High-Altitude Diseases
than they usually need to during the workday. However,
most people working at an altitude of 4000 m experience
an increased number of arithmetic errors, reduced attention span, and increased mental fatigue. Visual sensitivity
(for example, night vision) is reduced at altitudes as low as
2000 m and has been shown to decrease by about 50% at
an altitude of 5000 m, where there are also measurable
differences in attention span, short-term memory, arithmetic ability, and decision making (12).
The molecular and cellular mechanisms responsible
for impaired mental performance during hypoxia are
poorly understood. The brain normally accounts for approximately 20% of the body’s total oxygen consumption,
and the oxygen is almost entirely used for the oxidation of
glucose. Suggested mechanisms for the impairment of
nerve cell function during hypoxia include altered ion homeostasis, changes in calcium metabolism, alterations in
neurotransmitter metabolism, and impairment of synapse
function (13–15).
Review
Figure 2. Alveolar PO2 at high altitude for persons acutely
exposed and persons fully acclimatized.
Sleep
Sleep is also impaired at high altitude, and many people find this one of the most distressing features of staying
there. People at high altitude often wake frequently, have
unpleasant dreams, and do not feel refreshed in the morning (16). The periodic breathing that occurs in most people at altitudes above 4000 m is probably an important
causative factor (17). Periodic breathing is thought to result from instability in the control system through the hypoxic drive (18) or the response to carbon dioxide (19).
The low levels of oxygen in the blood after apneic periods
may be responsible for some of the arousals. Experienced
trekkers and mountain climbers often recommend climbing high but sleeping low to mitigate these problems.
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).
PCO2 ⫽
V̇CO2
V̇A
䡠K
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.
where V̇A is the alveolar ventilation and V̇CO2 is the CO2
production. At the same time, the increased alveolar ventilation increases the alveolar PO2. In other words, the process of hyperventilation tends to defend the alveolar PO2
against the decrease in inspired PO2 (Figure 2).
The extent of hyperventilation at high altitude can be
enormous. To take an extreme example, on the summit of
Mount Everest, where the inspired PO2 is only 29% of its
sea level value (Table 1), the alveolar ventilation is increased approximately 5-fold. As a result, the alveolar PCO2
is reduced to 7 to 8 mm Hg, about one fifth of its normal
sea level value of 40 mm Hg (20). The alveolar PO2 is then
maintained near 35 mm Hg, which is certainly very low
but just sufficient to keep the climber alive.
Hyperventilation
Polycythemia
By far the most important feature of acclimatization is
the increase in depth and rate of breathing, which results in
an increase in alveolar ventilation. This is brought about by
hypoxic stimulation of the peripheral chemoreceptors,
mainly the carotid bodies, which sense the low PO2 in the
arterial blood. Hyperventilation reduces the alveolar PCO2
because there is an inverse relationship between this and
the alveolar ventilation for a fixed rate of carbon dioxide
production:
Many physicians who are asked to name the most important feature of acclimatization will probably answer
polycythemia. It is true that both lowlanders (people who
normally live at or near sea level) who remain at high
altitude for a long period and highlanders (people born and
bred at high altitude) have increased erythrocyte concentrations and therefore high blood oxygen capacities. However, polycythemia develops relatively slowly. It takes several days before an increased rate of erythrocyte production
ACCLIMATIZATION
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TO
HIGH ALTITUDE
16 November 2004 Annals of Internal Medicine Volume 141 • Number 10 791
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The Physiologic Basis of High-Altitude Diseases
can be measured, and the process is not complete for several weeks (21). Therefore, in the context of acclimatization to high altitude over the course of a week or so (the
usual length of many visits to high altitude), polycythemia
does not play an important role.
Newcomers to high altitude often develop a transient
increase in erythrocyte concentration, but this is caused by
a reduced plasma volume, not an increased rate of erythrocyte production (22). Dehydration may be a factor in the
reduced plasma volume; it is very common at high altitude,
partly because of the great insensible fluid loss mainly
caused by the large ventilation of cold dry air (23). Hormonal changes regulating plasma volume also occur (24),
and thirst is inappropriately reduced. A reduced fluid intake is often a factor, and diuresis may occur.
Acid–Base Changes
The acute reduction in alveolar and therefore arterial
PCO2, which was mentioned earlier, causes respiratory alkalosis with an increased pH in both the cerebrospinal
fluid and arterial blood. However, after a day or so, the pH
of the cerebrospinal fluid changes toward normal by movement of bicarbonate out of the cerebrospinal fluid, and
after 2 or 3 days the pH of the arterial blood moves toward
normal by renal excretion of bicarbonate. The rate and
extent of the metabolic compensation depend on the altitude being slower and less complete at very high altitudes.
The initial alkalosis in both the cerebrospinal fluid and the
blood tends to inhibit hyperventilation through the action
of both the central chemoreceptors in the brainstem and
the peripheral chemoreceptors in the carotid and aortic
bodies. The sensitivity of the carotid body to hypoxia also
increases during prolonged exposure to high altitude (25).
Misconceptions about Acclimatization
Almost everybody who ascends to altitudes of 2500 to
3000 m or above is aware of the advantages of acclimatization. However, an important misconception about acclimatization has developed, particularly among people who
are not in the medical field. I have become very aware of
this in talking to astronomers who work in observatories
on the summit of Mauna Kea, Hawaii, where the altitude
is 4200 m. Many of these people have come to believe that
the process of acclimatization returns the body to its sea
level condition or, in other words, that the hypoxia of high
altitude is nullified by the process of acclimatization.
The true situation is indicated in Figure 2, which
shows typical alveolar PO2 values for people after acute
exposure 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. Figure
2 shows several reference altitudes, including that of the
laboratories of the University of California White Mountain Research Station (3800 m); the summit of Mauna
Kea, where several telescopes are located (4200 m); and
Chajnantor, Chile, the site of construction of the enormous radiotelescope ALMA (Atacama Large Millimeter
792 16 November 2004 Annals of Internal Medicine Volume 141 • Number 10
Array) (5050 m). Sites near Chajnantor up to an altitude of
5800 m have occasionally been used for scientific measurements.
Among astronomers working at Mauna Kea, acute exposure to the altitude of the summit after ascent from near
sea level results in an alveolar PO2 of approximately 45 mm
Hg. With full acclimatization, the PO2 increases to about
54 mm Hg on average. However, full acclimatization takes
several days and never occurs for astronomers on Mauna
Kea because of the limited accommodation and work
schedules.
The severity of arterial hypoxemia is emphasized by
comparing these astronomers with patients who have
chronic obstructive pulmonary disease (COPD). Even if
the alveolar PO2 of the astronomers reached a value of 54
mm Hg, the arterial PO2 would be 2 or 3 mm Hg lower,
assuming normal lungs. Figure 2 also shows the arterial
PO2 threshold of 55 mm Hg, below which patients with
COPD are entitled to continuous oxygen therapy under
Medicare (27). In other words, if the arterial hypoxemia of
an astronomer on Mauna Kea was caused by COPD, this
person would be entitled to continuous oxygen therapy.
Of course, there are differences between healthy persons at high altitude and patients with COPD. For example, the pulmonary hypertension of COPD, which is partly
relieved by continuous oxygen therapy (27), is not solely
due to alveolar hypoxia, which is the primary factor at high
altitude. However, it is important to note that 6 months of
continuous oxygen therapy through nasal prongs in patients with COPD, which is sufficient to raise the resting
arterial PO2 to between 60 and 80 mm Hg, results in a
statistically significant improvement in neuropsychological
function (measured during air breathing) (28). In addition,
61% of patients with COPD who have an average arterial
PO2 of 54 mm Hg or less show neuropsychological deficits
compared with age- and education-matched controls (29).
These findings should give pause to astronomers who elect
to alleviate hypoxemia by acclimatization rather than by
oxygen enrichment of room air, which is discussed later in
this article.
IMPROVING WORKING EFFICIENCY
AT
HIGH ALTITUDE
Populations at Risk
Until recently, interest in high-altitude medicine and
physiology was mainly directed to 2 groups. One is the
large number of lowlanders who journey to high altitude
for recreational purposes, including skiing, trekking, and
mountaineering. Many of these people develop high-altitude diseases, although fortunately the most common
problem by far is the relatively innocuous acute mountain
sickness. The other extensively studied group involves people who reside permanently at high altitude.
In the past few years, another group has been increasingly studied: those who are required to work at high altitude. Usually, such people are commuters in the sense that
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The Physiologic Basis of High-Altitude Diseases
they normally live near sea level but work at high altitude.
Until very recently, miners were the largest group in this
category, particularly in the South American Andes. As an
example, several thousand miners work in the Collahuasi
mine in north Chile at altitudes of approximately 4500 m,
although their sleeping accommodation is somewhat lower
(3800 m). Their working schedule is remarkable in that
they and their families live on the coast at sea level. At the
beginning of their working week, they are bused up to the
mine, where they typically spend the next 7 days working
long shifts of 12 hours per day. They are then bused down
to their homes, where they spend the next 7 days. The
result is that these workers acclimatize to an altitude between 4500 m and sea level. A prospective study of the
medical and physiologic characteristics of this group has
been under way for the past 3 years (3).
Review
Figure 3. Alveolar PO2 and PCO2 of acclimatized humans at high
altitude.
Oxygen Enrichment of Room Air
An 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 by
adding oxygen to the room ventilation (30). Since all of
the deleterious effects of high altitude are caused by the low
inspired PO2, it should come as no surprise that the best
way to alleviate the problem is to increase the inspired PO2
by using supplementary oxygen. The availability of oxygen
concentrators has greatly increased the feasibility of oxygen
enrichment of room air. Oxygen concentrators work on
the same principle as the small oxygen generators that are
used at home by patients with chronic lung disease and
deliver oxygen through nasal prongs. These robust, selfcontained units require only modest amounts of electrical
power. When air is pumped into a tube of synthetic zeolite
at high pressure, nitrogen is preferentially adsorbed and the
effluent gas has an oxygen concentration of approximately
95%. After a short period, the zeolite cannot adsorb more
nitrogen; the high-pressure air is switched to a second tube
while the first tube is purged of nitrogen by using air at
normal pressure. The only moving parts in the oxygen
concentrator are a piston pump and switching valve.
A typical facility using this technique is a radiotelescope station run by the California Institute of Technology
in northern Chile at an altitude of 5050 m. The astronomers work in rooms made from shipping containers with
dimensions of 2.1 m ⫻ 2.1 m ⫻ 12.2 m, or half that
length, and the oxygen concentration in the room is maintained at 27%, that is, 6% higher than in ordinary air. The
oxygen is generated by concentrators outside the room and
is injected into the ventilation duct. As a result, the inspired PO2 is the same as that for someone breathing air at
an altitude of 3200 m. In other words, from a physiologic
point of view, the altitude has been reduced by approximately 1800 m. Since the astronomers live in a village at an
altitude of 2440 m when they are not observing, the altitude of 3200 m is easily tolerated.
Over the 4 years that this system has been in operawww.annals.org
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.
tion, the experience has been very gratifying. Work productivity has increased, workers are much less fatigued, and
at night the quality of sleep is greatly improved (2). The
same technique is planned on a much larger scale for
ALMA, which is located nearby at the same altitude. This
new advance shows great promise in improving conditions
for people who work at high altitude, particularly those
who commute from lower altitudes.
PHYSIOLOGIC CHANGES
AT
EXTREME ALTITUDES
Although this topic is relevant to only a small population, chiefly mountaineers, it presents fascinating medical
aspects. It is a curious coincidence that extreme altitudes,
such as the summit of Mount Everest, are very near the
limit of human tolerance to oxygen deprivation. Even the
most creative evolutionary biologist has not been able to
account for this. This coincidence is underlined by the fact
that climbers ascended to approximately 300 m below the
summit of Mount Everest without supplementary oxygen
as early as 1924 but the summit was not reached without
oxygen until 1978. In other words, the last 300 m took 54
years. Predictions based on measured maximal oxygen consumption at increasing altitudes in acclimatized persons
were similar. When the line relating maximal oxygen consumption to barometric pressure was extrapolated to the
pressure on the summit of Mount Everest, it looked as
though all the oxygen available would be required for basal
oxygen uptake (31). In other words, no oxygen would be
left over for the physical effort of climbing.
16 November 2004 Annals of Internal Medicine Volume 141 • Number 10 793
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The Physiologic Basis of High-Altitude Diseases
Table 2. Alveolar Gas and Estimated Arterial Blood Values on the Summit of Mount Everest
Altitude, m (ft)
Barometric
Pressure,
mm Hg
Inspired
PO2, mm Hg
Alveolar
PO2, mm Hg
8848 (29 028) [summit]
Sea level
253
760
43
149
35
100
In 1981, the American Medical Research Expedition
to Everest was planned to obtain physiologic measurements at extreme altitudes, including the summit. Alveolar
gas samples were collected on the summit, barometric pressure was measured there for the first time, and many other
measurements were made above an altitude of 8000 m and
at somewhat lower altitudes in 2 laboratories (32). Figure 3
shows the alveolar PO2 and PCO2 as humans ascended from
sea level to the summit of Mount Everest. The PO2 decreased because of the reduction in inspired PO2, while the
PCO2 decreased because of the increasing hyperventilation.
Note that at the summit, the alveolar PCO2 was reduced to
the extraordinarily low level of 7 to 8 mm Hg. This implies
an increase in alveolar ventilation of about 5 times the sea
level value. Of interest, above an altitude of about 7000 m,
alveolar PO2 did not decrease further. Rather, it was defended at a level of about 35 mm Hg by increasing hyperventilation. In other words, the extreme hyperventilation
insulated the PO2 in the alveolar gas from the decreasing
PO2 in the inspired air. Hyperventilation is by far the most
important physiologic adaptation at these extreme altitudes.
It was not feasible to sample arterial blood on the
summit, but the arterial PO2 could be estimated from the
Bohr integration along the pulmonary capillary. In addition, the arterial pH was derived from the measured
alveolar PCO2 and the measured base excess in samples
of venous blood. The results are shown in Table 2. The
barometric pressure was 253 mm Hg, almost exactly one
third of the sea level value. This means that the inspired
PO2 on the summit was 43 mm Hg. The alveolar PO2 was
kept at the just-viable value of 35 mm Hg by extreme
hyperventilation, but the arterial PO2 was lower because of
diffusion limitation across the blood– gas barrier under
these extraordinary conditions. The PCO2 was 7 to 8 mm
Hg, and the pH exceeded 7.7 (20). An interesting result of
this extreme alkalosis is that it increases the oxygen affinity
of hemoglobin, which facilitates loading of oxygen by the
pulmonary capillaries. It is astonishing that humans can
tolerate and survive such extraordinary insult to their normal physiologic makeup. Maximal oxygen uptake was
measured on well-acclimatized persons breathing an inspired PO2 of 43 mm Hg (the same as on the summit),
yielding a value of just over 1 L/min. This is equivalent to
the oxygen uptake when someone walks slowly on level
ground but is just sufficient to explain how a climber can
reach the summit.
Some of the physiologic changes of extreme altitude
794 16 November 2004 Annals of Internal Medicine Volume 141 • Number 10
Arterial Values
PO2, mm Hg
PCO2, mm Hg
pH
28
95
7.5
40
⬎7.7
7.40
can be studied by prolonged exposure of volunteers in a
low-pressure chamber. For example, in Operation Everest
II, 8 healthy persons spent approximately 40 days and
nights in a chamber in which the pressure was gradually
reduced (33). However, for reasons that are not clear, full
acclimatization does not occur under these conditions.
Nevertheless, the “summit” measurements of arterial PO2
and maximal oxygen consumption agreed well with those
obtained in the field.
Very few additional data at extreme altitudes have
been obtained in the past 20 years. However, some measurements of alveolar PO2 by fuel cell and arterial oxygen
saturation by pulse oximetry were taken during an ascent
to 8000 m on Mount Everest (34). The results agreed with
those found on American Medical Research Expedition to
Everest but did not correspond as well with those obtained
in the chamber study, again suggesting incomplete acclimatization in the latter.
HIGH-ALTITUDE DISEASES
There are 3 major high-altitude diseases—acute
mountain sickness, high-altitude pulmonary edema, and
high-altitude cerebral edema—as well as many other less
important conditions.
Acute Mountain Sickness
Acute mountain sickness is very common in people
who ascend from near sea level to altitudes higher than
approximately 3000 m, but it may occur at altitudes as low
as 2000 m. It is characterized by headache, lightheadedness, breathlessness, fatigue, insomnia, anorexia, and nausea (35, 36). Typically, symptoms begin 2 or 3 hours after
ascent, but the condition is generally self-limiting and most
of the symptoms disappear after 2 or 3 days. However,
insomnia may persist. Descent to low altitude rapidly reverses acute mountain sickness.
The precise pathogenesis of acute mountain sickness is
not understood. Of course, hypoxia is likely to be a major
factor, 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 cerebral blood flow and perhaps altered permeability of the
blood– brain barrier. There is some evidence of slight brain
swelling and increased intracranial pressure. A low arterial
PO2 results in cerebral vasodilatation (37), while a low
PCO2 causes vasoconstriction (38).
The best way to prevent acute mountain sickness is by
ascending gradually and allowing time for acclimatization.
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The Physiologic Basis of High-Altitude Diseases
A popular rule of thumb among trekkers is that above an
altitude of 3000 m, each day’s ascent should not average
more than 300 m, with a rest day every 2 or 3 days. This is
a conservative ascent rate, and many people are able to
increase this to 400 m to 600 m per day. Even a brief
recent exposure to high altitude affords some protection
against acute mountain sickness (39).
The carbonic anhydrase inhibitor acetazolamide is useful for prophylaxis if rapid ascent is inevitable, as in, for
example, a flight to La Paz, Bolivia. Acetazolamide produces metabolic acidosis by increasing the renal excretion
of bicarbonate, which in turn stimulates ventilation. The
dosage is 250 mg once or twice daily, and 125 mg taken at
night will sometimes improve sleep. A recent meta-analysis
concluded that daily prophylactic doses of less than 750
mg were ineffective (40); however, this runs contrary to
much clinical experience and probably reflects the exclusion of some studies. Side effects of acetazolamide are common and include diuresis, paresthesia of fingers and toes,
and a flat unpleasant taste to carbonated drinks. Acetazolamide is a sulphonamide drug, and therefore some people
have a hypersensitivity to it. Dexamethasone is also effective in preventing acute mountain sickness, although its
mode of action is unknown. The recommended prophylactic dosage for adults is 2 mg every 6 to 8 hours. In
addition, Gingko biloba has been suggested as a useful prophylactic agent but has not been sufficiently studied.
Treatment of acute mountain sickness by oxygen or
descent is usually not required, although aspirin, acetaminophen, 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 condition
is severe. Severe prolonged acute mountain sickness responds well to descent.
High-Altitude Pulmonary Edema
High-altitude pulmonary edema is a potentially fatal
condition that typically occurs 2 to 4 days after ascent to
altitudes above 3000 m (41). With usual ascent rates, the
incidence is about 1% to 2%, but as many as 10% of
people ascending rapidly to 4500 m may develop the condition (42). High-altitude pulmonary edema is also seen in
residents of high altitudes who travel to a lower altitude
and then return; this is termed reascent high-altitude pulmonary edema. There is considerable individual variability,
and people who develop high-altitude pulmonary edema
once are more likely to do so again. Some evidence indicates that an upper respiratory tract infection may increase
susceptibility, and people with restricted pulmonary circulation, such as unilateral absence of a pulmonary artery, are
particularly at risk (43).
High-altitude pulmonary edema may be preceded by
acute mountain sickness, but this is not always the case.
The predominant symptom is dyspnea with reduced exercise tolerance. There is often a dry cough at first, but this
may progress to a cough that produces frothy, bloodwww.annals.org
Review
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.
stained sputum. Tachypnea and tachycardia are common
on examination. In addition, there is often mild pyrexia,
and crepitations (crackles) can be detected by auscultation.
The pathogenesis of high-altitude pulmonary edema is
still a subject of study, but strong evidence indicates that it
is triggered by pulmonary hypertension as a result of hypoxic pulmonary vasoconstriction. It is likely that the hypoxic pulmonary vasoconstriction is patchy, with the result
that some pulmonary capillaries are exposed to the high
pressure. This causes damage to the capillary walls (stress
failure), and they leak a high-protein edema fluid with
erythrocytes. Studies of alveolar fluid obtained by bronchoalveolar lavage in high-altitude pulmonary edema have
convincingly shown that this is a high-permeability type of
edema (44). However, cardiac catheterization studies have
demonstrated normal pulmonary wedge pressures (45), so
this is not a form of left-heart failure.
The evidence for the importance of pulmonary hypertension can be summarized as follows. Cardiac catherization studies in patients with high-altitude pulmonary
edema have shown pulmonary artery systolic pressures as
high as 144 mm Hg, with a usual range of 60 to 80 mm
Hg (46, 47). Susceptible individuals tend to have an unusually strong hypoxic pulmonary vasoconstriction response (48) and unusually high pulmonary artery pressures
before the onset of high-altitude pulmonary edema (49).
Pulmonary vasodilator drugs are useful in the prevention
and treatment of this disorder (49, 50). As indicated earlier, a restricted pulmonary vascular bed (for example, unilateral absence of a pulmonary artery) is a recognized risk
factor (43). Exercise that increases pulmonary artery pressure may also play a role (51). Convincing evidence that
16 November 2004 Annals of Internal Medicine Volume 141 • Number 10 795
Review
The Physiologic Basis of High-Altitude Diseases
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.
the alveolar edema is of the high-permeability type with
large concentrations of high-molecular-weight proteins and
cells comes from bronchoalveolar lavage studies (44, 52).
Later in the disease, the edema fluid contains markers of an
inflammatory response (53), although this is not seen in
the very early stages (54). Changes in blood coagulation
and platelet activation also occur later in the disease (55).
On the basis of these findings, a likely pathogenic
mechanism for high-altitude pulmonary edema is that the
high pulmonary artery pressure is transmitted to some of
the capillaries and the resulting high wall stresses cause
ultrastructural changes. Capillaries in areas of the lung
where vasoconstriction is not effective (for example, because of the paucity of vascular smooth muscle) may be
exposed 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 by
cannulating the pulmonary artery and left atrium and the
lung parenchyma was fixed for electron microscopy by intravascular perfusion of buffered glutaraldehyde (56, 57).
The results show disruption of the capillary endothelial
layer, alveolar epithelial layer, and, in some cases, all layers
of the wall (Figure 4). These changes are seen with transmural pressures considerably lower than the pulmonary arterial pressures that have been measured in high-altitude
796 16 November 2004 Annals of Internal Medicine Volume 141 • Number 10
pulmonary edema and explain the high-permeability form
of edema with the leak of high-molecular-weight proteins
and cells. Of interest, sometimes blood platelets are seen
adhering to the exposed basement membrane. This could
explain activation of these cells by this highly reactive, electrically charged surface and could also explain the markers
of an inflammatory response that develop later in the disease.
One of the interesting features of the ultrastructural
changes in the pulmonary capillaries is that they are readily
reversible. For example, if the pressure in the pulmonary
capillaries is first increased and then lowered to normal
levels for a few minutes, approximately 70% of the disruptions in both the capillary endothelium and the alveolar
epithelium disappear (58). This rapid resolution of the
pathologic changes fits well with the remarkably rapid improvement in patients’ clinical status when they are moved
to a lower altitude. We do not fully understand the micromechanics of the processes responsible for the ultrastructural changes, but it has been suggested that distortion of
the type IV collagen matrix in the basement membranes
may be a factor (59). There is evidence that the basement
membrane is responsible for the strength of the blood– gas
barrier, at least on the thin side (60).
Additional evidence that these ultrastructural changes
are caused by high wall stresses resulting from the high
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The Physiologic Basis of High-Altitude Diseases
pulmonary capillary pressures comes from an analysis of
the wall stresses in the extremely thin blood– gas barrier
that forms the wall of the capillary. This analysis shows
that these stresses approach the breaking stress of type IV
collagen (59). The basic reason for these extremely high
wall stresses is that the blood– gas barrier on the thin side is
so extraordinarily thin. The blood– gas barrier needs to be
extremely thin for effective gas exchange by diffusion but
also strong enough to withstand these large stresses (61).
The pathogenic processes are summarized in Figure 5.
Of interest, if high-altitude pulmonary edema does
not develop within 4 or 5 days of someone moving to high
altitude, it does not develop at all unless the altitude is
increased again. This is probably because the alveolar hypoxia induces vascular remodeling along with the vasoconstriction. We know that remodeling of the pulmonary arteries begins very rapidly when the wall tension is
increased. For example, Tozzi and colleagues (63) showed
that the synthesis of collagen and elastin increased along
with increased gene expression for several growth factors
within 4 hours of applying stretch to pulmonary artery
segments in vitro. Therefore, it seems possible that the
capillaries, which are at risk because the small pulmonary
arteries upstream of them are nearly devoid of smooth
muscle, are protected when sufficient remodeling occurs.
Basically, the same explanation could account for the reascent high-altitude pulmonary edema mentioned earlier,
which occurs in residents of high altitude when they go to
a lower altitude, typically for a few days, and then return.
Presumably, some vascular smooth muscle undergoes involution during the time spent at low altitude.
The prevention and treatment of high-altitude pulmonary edema are consistent with the pathogenic mechanism
described above. The disease is much more likely to occur
after sudden ascent to high altitude. For example, as noted
earlier, a rapid ascent to 4500 m results in an incidence of
up to 10% (42), whereas the usual incidence with more
gradual ascent is 1% to 2%. An additional risk factor is
strenuous exercise, particularly if coupled with a rapid ascent (64). In people who have previously developed highaltitude pulmonary edema, nifedipine (20 mg of a slowrelease preparation every 8 hours) reduces the incidence
(65). The cardinal principle for treating high-altitude pulmonary edema is to remove the patient to a lower altitude
as quickly as possible. Oxygen should be administered if
available. In addition, nifedipine has been shown to help
relieve symptoms. The suggested regimen is 20 mg of the
slow-release preparation by mouth every 6 to 12 hours (36).
Other vasodilators, such as nitric oxide, may also be effective
but are usually not feasible in the field. Recent work indicates
that salmeterol (66) and sildenafil (67) may also be useful.
Review
closely related and that high-altitude cerebral edema is the
extreme end of the spectrum. The incidence is difficult to
estimate but may be as high as 1% to 2% in people ascending above 4500 m.
Classically, the patient becomes confused and ataxic
and may experience mood changes. Hallucination has been
described, and serious cases involve coma followed by
death. On examination, patients may have papilledema
and occasionally focal neurologic signs affecting cranial
nerves, or even hemiparesis. The pathogenesis is almost
certainly cerebral edema, possibly related to an increased
cerebral blood flow. A few autopsies have shown cerebral
edema with swollen flattened gyri (69 –71). Magnetic resonance imaging scans in a few patients have shown intense
T2 signals in white matter, particularly in the splenium and
corpus callosum, consistent with edema (72).
Again, the cardinal rule in treatment is descent to a
lower altitude as quickly as possible. Oxygen should be
administered if possible. Dexamethasone should be given;
the suggested dose is 8 mg initially followed by 4 mg every
6 hours. This drug is also useful to relieve the cerebral
symptoms of severe acute mountain sickness (73). If
descent to a lower altitude is not feasible because of the
remote situation, portable hyperbaric bags such as the
Gamow bag can be used for both high-altitude cerebral
edema and high-altitude pulmonary edema. The patient is
placed inside the bag and the pressure is increased with a
foot pump, thus reducing the effective altitude. Patients
with high-altitude cerebral edema sometimes recover very
rapidly after descent to a lower altitude.
Other High-Altitude Diseases
Chronic Mountain Sickness
Permanent residents of high altitudes sometimes develop a condition characterized by severe polycythemia and
a constellation of neurologic symptoms, including headache, somnolence, fatigue, and depression. The hematocrit
can reach extremely high levels, and values above 0.8 have
been recorded (74). The very high hematocrit increases the
viscosity of the blood, and in fact it is often difficult to
draw venous blood as a result. Typically, the condition
improves considerably if the patient is moved to a lower
altitude but reappears after return to high altitudes. Therapeutic phlebotomy has been shown to reduce the symptoms. Respiratory stimulants (for example, medroxyprogesterone acetate) have been used (75) because patients often
experience some hypoventilation. Of interest, this disease is
commonly seen in the Andes but is much rarer in Tibet.
Some anthropologists believe that true genetic adaptation
to high altitude has proceeded further in Tibetans than in
Andeans because the former have resided at high altitudes
for much longer (76).
High-Altitude Cerebral Edema
High-altitude cerebral edema is rare but potentially
very serious (68). The condition often follows acute mountain sickness, and many people think that the two are
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Subacute Mountain Sickness
This somewhat confusing term has been applied to 2
different conditions. One involves infants at high altitude
16 November 2004 Annals of Internal Medicine Volume 141 • Number 10 797
Review
The Physiologic Basis of High-Altitude Diseases
who present with respiratory distress, marked cyanosis, and
congestive heart failure (77). The other affects young
adults in the Indian army who were posted to altitudes of
approximately 6000 m for many months and developed
dyspnea, cough, angina at effort, and dependent edema
(78). These conditions may be related to so-called brisket
disease in cattle (79), which is a form of right-heart failure
with peripheral edema.
Retinal Hemorrhage
Retinal hemorrhage is very common in people who
ascend above 5000 m, although it usually causes no visual
impairment (80). The condition resolves on return to a
lower altitude and may be related to increased retinal blood
flow.
CONCLUSION
In summary, the basic physiologic mechanism of highaltitude diseases is the low PO2 in the inspired gas, which
results from the reduced barometric pressure. The most
important consequences of ascent to high altitude in
healthy persons can be classified under the 3 headings of
reduced maximal oxygen consumption, impaired mental
performance, and disordered sleep. The deleterious effects
of high altitude are greatly reduced by the process of acclimatization, the most important feature of which is hyperventilation caused by hypoxic stimulation of peripheral
chemoreceptors. However, a prevailing misconception
about acclimatization is that it returns the body to near
normal, a serious error. Increasingly, people who normally
live near sea level are being required to work at high altitudes, and an important recent advance, oxygen enrichment of room air, increases productivity, reduces fatigue,
and improves sleep. Extraordinary physiologic adaptations
occur at extreme altitudes, such as the summit of Mount
Everest, including an arterial PO2 of approximately 30 mm
Hg, PCO2 of less than 10 mm Hg, and pH over 7.7. Three
main high-altitude diseases are recognized: acute mountain
sickness, high-altitude pulmonary edema, and high-altitude cerebral edema. Acute mountain sickness is usually
self-limiting and often resolves after 2 or 3 days. Highaltitude pulmonary edema is much more serious, and recent work indicates that the mechanism involves damage
to pulmonary capillaries caused by uneven hypoxic pulmonary vasoconstriction. High-altitude cerebral edema is also
potentially 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.
798 16 November 2004 Annals of Internal Medicine Volume 141 • Number 10
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, [email protected].
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