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
Annals of Internal Medicine
Paul Epstein, MD, Series Editor
The Physiologic Basis of High-Altitude Diseases
John B. West, MD, PhD
Clinical Principles
Three major high-altitude diseases
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 peo-
ple 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 alti-
tudes 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, mountain-
eers, 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 some-
times 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.
Ann Intern Med. 2004;141:789-800.
For author affiliations, see end of text.
Downloaded From: http://annals.org/ by a University of Otago User on 12/08/2016
Review
Physiologic Principles
Hypoxia of high altitude impairs physical performance,
mental performance, and sleep.
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 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 at
the 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 to
high altitude is common. Table 1 lists some of the baro-
metric 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
© 2004 American College of Physicians 789
 Review The Physiologic Basis of High-Altitude Diseases

Figure 1. Relationship among altitude, barometric pressure, and hypoxia-inducible factor-1 complex, which regulates gene
inspired PO2. transcription. This complex is a heterodimer protein com-
plex that activates transcription through binding to specific
hypoxic-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 altitude
on the human body are legion. The most important in the
present 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 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
Note that at an altitude of 5000 m, the highest at which humans reside, of the reduced physical performance at high altitude is a
the inspired PO2 is only approximately half of the sea level value. On the great increase in fatigue.
summit of Mount Everest, the inspired PO2 is less than 30% of the value
at sea level. CO ⫽ Colorado. The reduced maximal oxygen consumption at high
altitude is usually ascribed to the reduction in mitochon-
Mount Everest, at an altitude of 8848 m, the inspired PO2 drial PO2, which interferes with the function of the elec-
is less than 30% of its value at sea level. These numbers tron transport chain responsible for providing cellular en-
emphasize the hypoxic insult of going to high altitude. ergy. However, some investigators believe that maximal
Note that the barometric pressures shown here are oxygen consumption is reduced by central inhibition from
higher than those found in some textbooks of medicine the brain (9). There is little evidence that the pulmonary
and physiology, which use the so-called standard atmo- hypertension of high altitude limits maximal oxygen con-
sphere (5). The aviation industry introduced the standard sumption, and, perhaps surprisingly, myocardial contractil-
atmosphere in the 1920s to refer to average conditions in ity in healthy people is maintained up to extreme altitudes
the atmosphere. However, it is now appreciated that most (10); these findings emphasize the difference between the
of the high-altitude areas frequented by humans, including effects of hypoxemia and ischemia on the normal myocar-
the Himalayas and the South American Andes, have a dium. Studies of elite mountaineers have suggested that
higher barometric pressure than the standard atmosphere genetic factors have a role in determining maximal oxygen
indicates. This is because they are relatively near the equa- consumption at high altitude, since participants tend to
tor, where the solar radiation causes upwelling of the at- have the insertion rather than the deletion variant of the
mosphere; consequently, the column of air is higher. The angiotensin-converting enzyme gene (11).
difference between the standard atmosphere and the actual
barometric pressures becomes very significant at extreme Mental Performance
altitudes, such as at the summit of Mount Everest. If the Mental performance is impaired at high altitude, al-
barometric pressure predicted by the standard atmosphere though many people are curiously reluctant to admit this.
were correct, the mountain could probably not be climbed Neuropsychological testing is difficult because people can
without supplementary oxygen (6). perform well in the short-term by concentrating harder
Effects of the Hypoxia of High Altitude
High altitude affects the human body because of oxy- Table 1. Barometric Pressure and Inspired Po2 at Various
gen deprivation. Other factors, such as severe cold, high Altitudes
winds, and intense solar radiation, may be present but can
be nullified by appropriate protection. Hypoxia is inevita- Altitude, m (ft) Barometric Pressure, Inspired Po2, mm Hg
mm Hg (% of sea level)
ble unless it is relieved by supplementary oxygen or unless
the person is placed in a container at increased pressure, 0 (0) 760 149 (100)
1000 (3281) 679 132 (89)
such as a Gamow bag. 2000 (6562) 604 117 (79)
Oxygen is critical to normal cellular function because 3000 (9843) 537 103 (69)
4000 (13 123) 475 90 (60)
it is an essential part of the electron transport chain for
5000 (16 404) 420 78 (52)
energy production in cells. The cellular responses to oxy- 8848 (29 028) 253 43 (29)
gen deprivation have been clarified by the discovery of the
790 16 November 2004 Annals of Internal Medicine Volume 141 • Number 10 www.annals.org

Downloaded From: http://annals.org/ by a University of Otago User on 12/08/2016


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 atten-
tion 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, arith-
metic 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 ap-
proximately 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 ho-
meostasis, changes in calcium metabolism, alterations in
neurotransmitter metabolism, and impairment of synapse
function (13–15).
Sleep
Sleep is also impaired at high altitude, and many peo-
ple 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 morn-
ing (16). The periodic breathing that occurs in most peo-
ple at altitudes above 4000 m is probably an important
causative 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 periods
may be responsible for some of the arousals. Experienced
trekkers and mountain climbers often recommend climb-
ing high but sleeping low to mitigate these problems.
ACCLIMATIZATION TO HIGH ALTITUDE
The adaptive changes collectively known as acclimati-
zation greatly improve the tolerance of human beings to
high altitude. Physiologists often cite high-altitude accli-
matization as one of the best examples of how the body
responds to a hostile environment. However, although ac-
climatization is critically important, several misconceptions
have developed.
Hyperventilation
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:
www.annals.org
Downloaded From: http://annals.org/ by a University of Otago User on 12/08/2016
The Physiologic Basis of High-Altitude Diseases Review
Figure 2. Alveolar PO2 at high altitude for persons acutely
exposed and persons fully acclimatized.
The altitudes of several observatories where astronomers work are shown.
Note that fully acclimatized astronomers on the summit of Mauna Kea
have an alveolar PO2, and therefore an arterial PO2, lower than the
threshold for continuous oxygen therapy in patients with chronic ob-
structive pulmonary disease (COPD). The dashed-and-dotted lines indi-
cate the normal value at sea level (upper line) and the threshold for
continuous O2 therapy in COPD (lower line).
V̇CO2
PCO2 ⫽ 䡠K
V̇A
where V̇A is the alveolar ventilation and V̇CO2 is the CO2
production. 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 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 in-
creased 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.
Polycythemia
Many physicians who are asked to name the most im-
portant 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 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
16 November 2004 Annals of Internal Medicine Volume 141 • Number 10 791
 Review The Physiologic Basis of High-Altitude Diseases
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 (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 eryth-
rocyte 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). 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.
Acid–Base Changes
The acute reduction in alveolar and therefore arterial
PCO2, which was mentioned earlier, causes respiratory al-
kalosis 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 move-
ment 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 alti-
tude 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 acclimati-
zation. However, an important misconception about accli-
matization 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 Moun-
tain 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 enor-
mous radiotelescope ALMA (Atacama Large Millimeter
792 16 November 2004 Annals of Internal Medicine Volume 141 • Number 10
Downloaded From: http://annals.org/ by a University of Otago User on 12/08/2016
Array) (5050 m). Sites near Chajnantor up to an altitude of
5800 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 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 per-
sons at high altitude and patients with COPD. For exam-
ple, 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 pa-
tients 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-alti-
tude diseases, although fortunately the most common
problem by far is the relatively innocuous acute mountain
sickness. 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
www.annals.org

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 be-
tween 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).
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, self-
contained 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 radiotele-
scope station run by the California Institute of Technology
in northern Chile at an altitude of 5050 m. The astrono-
mers 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 main-
tained 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 in-
spired 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 approxi-
mately 1800 m. Since the astronomers live in a village at an
altitude 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-
www.annals.org
Downloaded From: http://annals.org/ by a University of Otago User on 12/08/2016
The Physiologic Basis of High-Altitude Diseases Review
Figure 3. Alveolar PO2 and PCO2 of acclimatized humans at high
altitude.
Sea level is at the top right of the graph, and the summit of Mount
Everest is at the bottom left. The squares show the means of the mea-
surements 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 pro-
ductivity 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 popula-
tion, 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 con-
sumption at increasing altitudes in acclimatized persons
were similar. When the line relating maximal oxygen con-
sumption 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
 Review 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 Inspired
Pressure, PO2, mm Hg
mm Hg
8848 (29 028) [summit] 253 43
Sea level 760 149
In 1981, the American Medical Research Expedition
to Everest was planned to obtain physiologic measure-
ments at extreme altitudes, including the summit. Alveolar
gas samples were collected on the summit, barometric pres-
sure 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 de-
creased 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 de-
fended at a level of about 35 mm Hg by increasing hyper-
ventilation. 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 alti-
tudes.
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 addi-
tion, 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 nor-
mal physiologic makeup. Maximal oxygen uptake was
measured 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 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
Downloaded From: http://annals.org/ by a University of Otago User on 12/08/2016
Alveolar Arterial Values
PO2, mm Hg
PO2, mm Hg PCO2, mm Hg pH
35 28 7.5 ⬎7.7
100 95 40 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 mea-
surements 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 accli-
matization 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, lightheaded-
ness, breathlessness, fatigue, insomnia, anorexia, and nau-
sea (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 re-
verses 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 ce-
rebral 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.
www.annals.org

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 use-
ful for prophylaxis if rapid ascent is inevitable, as in, for
example, a flight to La Paz, Bolivia. Acetazolamide pro-
duces 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 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 people
have a hypersensitivity to it. Dexamethasone is also effec-
tive in preventing acute mountain sickness, although its
mode of action is unknown. The recommended prophy-
lactic dosage for adults is 2 mg every 6 to 8 hours. In
addition, Gingko biloba has been suggested as a useful pro-
phylactic agent but has not been sufficiently studied.
Treatment of acute mountain sickness by oxygen or
descent 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 condition
is severe. Severe prolonged acute mountain sickness re-
sponds 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 con-
dition (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 pul-
monary edema. There is considerable individual variability,
and people who develop high-altitude pulmonary edema
once are more likely to do so again. Some evidence indi-
cates that an upper respiratory tract infection may increase
susceptibility, and people with restricted pulmonary circu-
lation, 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 exer-
cise tolerance. There is often a dry cough at first, but this
may progress to a cough that produces frothy, blood-
www.annals.org
Downloaded From: http://annals.org/ by a University of Otago User on 12/08/2016
The Physiologic Basis of High-Altitude Diseases 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 hy-
poxic pulmonary vasoconstriction. It is likely that the hy-
poxic 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 bron-
choalveolar 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 hyper-
tension can be summarized as follows. Cardiac catheriza-
tion 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 un-
usually strong hypoxic pulmonary vasoconstriction re-
sponse (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 ear-
lier, a restricted pulmonary vascular bed (for example, uni-
lateral absence of a pulmonary artery) is a recognized risk
factor (43). Exercise that increases pulmonary artery pres-
sure 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, be-
cause 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 in-
travascular 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 trans-
mural pressures considerably lower than the pulmonary ar-
terial pressures that have been measured in high-altitude
796 16 November 2004 Annals of Internal Medicine Volume 141 • Number 10
Downloaded From: http://annals.org/ by a University of Otago User on 12/08/2016
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, elec-
trically 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 disrup-
tions in both the capillary endothelium and the alveolar
epithelium disappear (58). This rapid resolution of the
pathologic changes fits well with the remarkably rapid im-
provement in patients’ clinical status when they are moved
to 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 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
www.annals.org

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 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 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 re-
ascent 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 invo-
lution during the time spent at low altitude.
The prevention and treatment of high-altitude pulmo-
nary 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 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 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.
High-Altitude Cerebral Edema
High-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
www.annals.org
Downloaded From: http://annals.org/ by a University of Otago User on 12/08/2016
The Physiologic Basis of High-Altitude Diseases 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 as-
cending 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 res-
onance 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 de-
velop a condition characterized by severe polycythemia and
a constellation of neurologic symptoms, including head-
ache, 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. Ther-
apeutic phlebotomy has been shown to reduce the symp-
toms. Respiratory stimulants (for example, medroxyproges-
terone 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).
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 high-
altitude 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 accli-
matization, the most important feature of which is hyper-
ventilation 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 alti-
tudes, and an important recent advance, oxygen enrich-
ment 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-alti-
tude cerebral edema. Acute mountain sickness is usually
self-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 damage
to pulmonary capillaries caused by uneven hypoxic pulmo-
nary 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
Downloaded From: http://annals.org/ by a University of Otago User on 12/08/2016
Requests for Single Reprints: John B. West, MD, PhD, Department of
Medicine, University of California, San Diego, 0623A, 9500 Gilman
Drive, La Jolla, CA 92093-0623; e-mail, jwest@ucsd.edu.
References
1. Moore LG, Niermeyer S, Zamudio S. Human adaptation to high altitude:
regional and life-cycle perspectives. Am J Phys Anthropol. 1998;Suppl 27:25-64.
[PMID: 9881522]
2. West JB, Readhead A. Working at high altitude: medical problems, miscon-
ceptions, and solutions. Observatory. 2004;124:1-14.
3. Richalet JP, Donoso MV, Jiménez D, Antezana AM, Hudson C, Cortès G,
et al. Chilean miners commuting from sea level to 4500 m: a prospective study.
High Alt Med Biol. 2002;3:159-66. [PMID: 12162860]
4. Torricelli E. Letter of Torricelli to Michelangelo Ricci. 1644. In: West JB, ed.
High Altitude Physiology. Stroudsburg, PA: Hutchinson Ross; 1981:60-3.
5. Manual of the ICAO Standard Atmosphere. Montreal, Quebec: International
Civil Aviation Organization; 1964.
6. West JB, Lahiri S, Maret KH, Peters RM Jr, Pizzo CJ. Barometric pressures
at extreme altitudes on Mt. Everest: physiological significance. J Appl Physiol.
1983;54:1188-94. [PMID: 6863078]
7. Semenza GL. Surviving ischemia: adaptive responses mediated by hypoxia-
inducible factor 1. J Clin Invest. 2000;106:809-12. [PMID: 11018065]
8. Cerretelli P. Gas exchange at high altitude. In: West JB, ed. Pulmonary Gas
Exchange. v II. New York: Academic Pr; 1980:97-147.
9. Bigland-Ritchie B, Vollestad NK. Hypoxia and fatigue: how are they related?
In: Sutton JR, Houston CS, Coates G, eds. Hypoxia: The Tolerable Limits.
Indianapolis, IN: Benchmark Pr; 1988:315-26; discussion 326-8.
10. Suarez J, Alexander JK, Houston CS. Enhanced left ventricular systolic
performance at high altitude during Operation Everest II. Am J Cardiol. 1987;
60:137-42. [PMID: 3604926]
11. Montgomery HE, Marshall R, Hemingway H, Myerson S, Clarkson P,
Dollery C, et al. Human gene for physical performance [Letter]. Nature. 1998;
393:221-2. [PMID: 9607758]
12. McFarland RA. Psychophysiological implications of life at altitude and in-
cluding the role of oxygen in the process of aging. In: Yousef MK, Horvath SM,
Bullard RW, eds. Physiological Adaptations: Desert and Mountain. New York:
Academic Pr; 1972:157-81.
13. Siesjo BK. Brain Energy Metabolism. New York: Wiley; 1978.
14. Haddad GG, Jiang C. O2 deprivation in the central nervous system: on
mechanisms of neuronal response, differential sensitivity and injury. Prog Neu-
robiol. 1993;40:277-318. [PMID: 7680137]
15. Hossmann KA. The hypoxic brain. Insights from ischemia research. Adv Exp
Med Biol. 1999;474:155-69. [PMID: 10635000]
16. Barcroft J, Cooke A, Hartridge H, Parsons TR, Parsons W. The flow of
oxygen through the pulmonary epithelium. J Physiol (Lond). 1920;53:450-72.
17. Weil JV. Sleep at high altitude. High Alt Med Biol. 2004;5:180-9. [PMID:
15265339]
18. Lahiri S, Maret K, Sherpa MG. Dependence of high altitude sleep apnea on
ventilatory sensitivity to hypoxia. Respir Physiol. 1983;52:281-301. [PMID:
6412339]
19. Nakayama H, Smith CA, Rodman JR, Skatrud JB, Dempsey JA. Effect of
ventilatory drive on carbon dioxide sensitivity below eupnea during sleep. Am J
Respir Crit Care Med. 2002;165:1251-60. [PMID: 11991874]
20. West JB, Hackett PH, Maret KH, Milledge JS, Peters RM Jr, Pizzo CJ, et
al. Pulmonary gas exchange on the summit of Mount Everest. J Appl Physiol.
1983;55:678-87. [PMID: 6415007]
21. Pugh LG. Blood volume and haemoglobin concentration at altitudes above
18,000 ft (5500 m). J Physiol (Lond). 1964;170:344-53.
22. Singh MV, Rawal SB, Tyagi AK. Body fluid status on induction, reinduc-
tion and prolonged stay at high altitude of human volunteers. Int J Biometeorol.
1990;34:93-7. [PMID: 2228301]
23. Pugh LGCE. Animals in high altitude: man above 5000 meters—mountain
exploration. In: Dill DB, ed. Handbook of Physiology. Adaptation to Environ-
ment. Washington, DC: American Physiological Society; 1984:861-8.
www.annals.org

24. Swenson ER. Renal function and fluid homeostasis. In: Hornbein TF,
Schoene RB, eds. High Altitude. An Exploration of Human Adaptation. New
York: Marcel Dekker; 2001:525-68.
25. Smith CA, Dempsey JA, Hornbein TF. Control of breathing at high alti-
tude. In: Hornbein TF, Schoene RB, eds. High Altitude. An Exploration of
Human Adaptation. New York: Marcel Dekker; 2001:139-73.
26. Rahn H, Otis AB. Man’s respiratory response during and after acclimatiza-
tion to high altitude. Am J Physiol. 1949;157:445-62.
27. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive
lung disease: a clinical trial. Nocturnal Oxygen Therapy Trial Group. Ann Intern
Med. 1980;93:391-8. [PMID: 6776858]
28. Heaton RK, Grant I, McSweeny AJ, Adams KM, Petty TL. Psychologic
effects of continuous and nocturnal oxygen therapy in hypoxemic chronic ob-
structive pulmonary disease. Arch Intern Med. 1983;143:1941-7. [PMID:
6625781]
29. Grant I, Prigatano GP, Heaton RK, McSweeny AJ, Wright EC, Adams
KM. Progressive neuropsychologic impairment and hypoxemia. Relationship in
chronic obstructive pulmonary disease. Arch Gen Psychiatry. 1987;44:999-1006.
[PMID: 3675139]
30. West JB. Oxygen enrichment of room air to relieve the hypoxia of high
altitude. Respir Physiol. 1995;99:225-32. [PMID: 7777705]
31. West JB, Wagner PD. Predicted gas exchange on the summit of Mt. Everest.
Respir Physiol. 1980;42:1-16. [PMID: 7444223]
32. West JB. Human physiology at extreme altitudes on Mount Everest. Science.
1984;223:784-8. [PMID: 6364351]
33. Houston CS, Sutton JR, Cymerman A, Reeves JT. Operation Everest II:
man at extreme altitude. J Appl Physiol. 1987;63:877-82. [PMID: 3654448]
34. Peacock AJ, Jones PL. Gas exchange at extreme altitude: results from the
British 40th Anniversary Everest Expedition. Eur Respir J. 1997;10:1439-44.
[PMID: 9230227]
35. Bartsch P, Bailey DM, Berger MM, Knauth M, Baumgartner RW. Acute
mountain sickness: controversies and advances. High Alt Med Biol. 2004;5:110-
24. [PMID: 15265333]
36. Hackett PH, Roach RC. High-altitude illness. N Engl J Med. 2001;345:
107-14. [PMID: 11450659]
37. Borgström L, Johannsson H, Siesjö BK. The relationship between arterial
po2 and cerebral blood flow in hypoxic hypoxia. Acta Physiol Scand. 1975;93:
423-32. [PMID: 1146584]
38. Harper AM, Glass HI. Effect of alterations in the arterial carbon dioxide
tension on the blood flow through the cerebral cortex at normal and low arterial
blood pressures. J Neurol Neurosurg Psychiatry. 1965;28:449-52. [PMID:
5838479]
39. Schneider M, Bernasch D, Weymann J, Holle R, Bartsch P. Acute moun-
tain sickness: influence of susceptibility, preexposure, and ascent rate. Med Sci
Sports Exerc. 2002;34:1886-91. [PMID: 12471292]
40. Dumont L, Mardirosoff C, Tramer MR. Efficacy and harm of pharmaco-
logical prevention of acute mountain sickness: quantitative systematic review.
BMJ. 2000;321:267-72. [PMID: 10915127]
41. Schoene RB. Unraveling the mechanism of high altitude pulmonary edema.
High Alt Med Biol. 2004;5:125-35. [PMID: 15265334]
42. Bärtsch P, Vock P, Maggiorini M, Franciolli M, Fretz C, Schobersberger
W, et al. Respiratory symptoms, radiographic and physiologic correlations at high
altitude. In: Sutton JR, Coates G, Remmers JE, eds. Hypoxia: The Adaptations.
Toronto: BC Decker; 1990:241-45.
43. Hackett PH, Creagh CE, Grover RF, Honigman B, Houston CS, Reeves
JT, et al. High-altitude pulmonary edema in persons without the right pulmo-
nary artery. N Engl J Med. 1980;302:1070-3. [PMID: 7366625]
44. Schoene RB, Swenson ER, Pizzo CJ, Hackett PH, Roach RC, Mills WJ Jr,
et al. The lung at high altitude: bronchoalveolar lavage in acute mountain sick-
ness and pulmonary edema. J Appl Physiol. 1988;64:2605-13. [PMID:
3403445]
45. Penaloza D, Sime F. Circulatory dynamics during high altitude pulmonary
edema. Am J Cardiol. 1969;23:369-78. [PMID: 5777686]
46. Hultgren HN, Lopez CE, Lundberg E, Miller H. Physiologic studies of
pulmonary edema at high altitude. Circulation. 1964;29:393-408. [PMID:
14131411]
47. Antezana G, Leguia G, Guzman AM, Coudert J, Speilvogel H. Hemody-
www.annals.org
Downloaded From: http://annals.org/ by a University of Otago User on 12/08/2016
The Physiologic Basis of High-Altitude Diseases Review
namic study of high altitude pulmonary edema (12,200 ft). In: Brendel W, Zink
RA, eds. High Altitude Physiology and Medicine. New York: Springer-Verlag;
1982:232-41.
48. Hultgren HN, Grover RF, Hartley LH. Abnormal circulatory responses to
high altitude in subjects with a previous history of high-altitude pulmonary
edema. Circulation. 1971;44:759-70. [PMID: 5115068]
49. Bärtsch P, Maggiorini M, Ritter M, Noti C, Vock P, Oelz O. Prevention of
high-altitude pulmonary edema by nifedipine. N Engl J Med. 1991;325:1284-9.
[PMID: 1922223]
50. Oelz O, Maggiorini M, Ritter M, Waber U, Jenni R, Vock P, et al.
Nifedipine for high altitude pulmonary oedema. Lancet. 1989;2:1241-4. [PMID:
2573760]
51. Houston CS. Acute pulmonary edema of high altitude. N Engl J Med.
1960;263:478-80. [PMID: 14403413]
52. Hackett PH, Bertman J, Rodriguez G, Tenney J. Pulmonary edema fluid
protein in high-altitude pulmonary edema [Letter]. JAMA. 1986;256:36.
[PMID: 3712705]
53. Schoene RB, Hackett PH, Henderson WR, Sage EH, Chow M, Roach RC,
et al. High-altitude pulmonary edema. Characteristics of lung lavage fluid.
JAMA. 1986;256:63-9. [PMID: 3012134]
54. Swenson ER, Maggiorini M, Mongovin S, Gibbs JS, Greve I, Mairbäurl H,
et al. Pathogenesis of high-altitude pulmonary edema: inflammation is not an
etiologic factor. JAMA. 2002;287:2228-35. [PMID: 11980523]
55. Bärtsch P, Mairbäurl H, Swenson ER, Maggiorini M. High altitude pul-
monary oedema. Swiss Med Wkly. 2003;133:377-84. [PMID: 12947525]
56. West JB, Tsukimoto K, Mathieu-Costello O, Prediletto R. Stress failure in
pulmonary capillaries. J Appl Physiol. 1991;70:1731-42. [PMID: 2055852]
57. Tsukimoto K, Mathieu-Costello O, Prediletto R, Elliott AR, West JB.
Ultrastructural appearances of pulmonary capillaries at high transmural pressures.
J Appl Physiol. 1991;71:573-82. [PMID: 1718936]
58. Elliott AR, Fu Z, Tsukimoto K, Prediletto R, Mathieu-Costello O, West
JB. Short-term reversibility of ultrastructural changes in pulmonary capillaries
caused by stress failure. J Appl Physiol. 1992;73:1150-8. [PMID: 1400030]
59. West JB, Mathieu-Costello O. Structure, strength, failure, and remodeling of
the pulmonary blood-gas barrier. Annu Rev Physiol. 1999;61:543-72. [PMID:
10099701]
60. West JB, Mathieu-Costello O. Strength of the pulmonary blood-gas barrier.
Respir Physiol. 1992;88:141-8. [PMID: 1626133]
61. West JB. Thoughts on the pulmonary blood-gas barrier. Am J Physiol Lung
Cell Mol Physiol. 2003;285:L501-13. [PMID: 12902315]
62. West JB, Mathieu-Costello O. High altitude pulmonary edema is caused by
stress failure of pulmonary capillaries. Int J Sports Med. 1992;13 Suppl 1:S54-8.
[PMID: 1483792]
63. Tozzi CA, Poiani GJ, Harangozo AM, Boyd CD, Riley DJ. Pressure-in-
duced connective tissue synthesis in pulmonary artery segments is dependent on
intact endothelium. J Clin Invest. 1989;84:1005-12. [PMID: 2668338]
64. Singh I, Kapila CC, Khanna PK, Nanda RB, Rao BD. High-altitude pul-
monary oedema. Lancet. 1965;191:229-34. [PMID: 14238062]
65. Bärtsch P, Maggiorini M, Ritter M, Noti C, Vock P, Oelz O. Prevention of
high-altitude pulmonary edema by nifedipine. N Engl J Med. 1991;325:1284-9.
[PMID: 1922223]
66. Sartori C, Allemann Y, Duplain H, Lepori M, Egli M, Lipp E, et al.
Salmeterol for the prevention of high-altitude pulmonary edema. N Engl J Med.
2002;346:1631-6. [PMID: 12023995]
67. Zhao L, Mason NA, Morrell NW, Kojonazarov B, Sadykov A, Maripov A,
et al. Sildenafil inhibits hypoxia-induced pulmonary hypertension. Circulation.
2001;104:424-8. [PMID: 11468204]
68. Hackett PH, Roach RC. High altitude cerebral edema. High Alt Med Biol.
2004;5:136-46. [PMID: 15265335]
69. Singh I, Khanna PK, Srivastava MC, Lal M, Roy SB, Subramanyam CS.
Acute mountain sickness. N Engl J Med. 1969;280:175-84. [PMID: 5782719]
70. Houston CS, Dickinson J. Cerebral form of high-altitude illness. Lancet.
1975;2:758-61. [PMID: 52782]
71. Dickinson J, Heath D, Gosney J, Williams D. Altitude-related deaths in
seven trekkers in the Himalayas. Thorax. 1983;38:646-56. [PMID: 6623417]
72. Hackett PH, Yarnell PR, Hill R, Reynard K, Heit J, McCormick J. High-
16 November 2004 Annals of Internal Medicine Volume 141 • Number 10 799
 Review The Physiologic Basis of High-Altitude Diseases
altitude cerebral edema evaluated with magnetic resonance imaging: clinical cor-
relation and pathophysiology. JAMA. 1998;280:1920-5. [PMID: 9851477]
73. Ferrazzini G, Maggiorini M, Kriemler S, Bärtsch P, Oelz O. Successful
treatment of acute mountain sickness with dexamethasone. Br Med J (Clin Res
Ed). 1987;294:1380-2. [PMID: 3109663]
74. Hurtado A. Chronic mountain sickness. JAMA. 1942;120:1278-82.
75. Kryger M, McCullough R, Doekel R, Collins D, Weil JV, Grover RF.
Excessive polycythemia of high altitude: role of ventilatory drive and lung disease.
Am Rev Respir Dis. 1978;118:659-66. [PMID: 707889]
76. Beall CM, Brittenham GM, Strohl KP, Blangero J, Williams-Blangero S,
Goldstein MC, et al. Hemoglobin concentration of high-altitude Tibetans and
800 16 November 2004 Annals of Internal Medicine Volume 141 • Number 10
Downloaded From: http://annals.org/ by a University of Otago User on 12/08/2016
Bolivian Aymara. Am J Phys Anthropol. 1998;106:385-400. [PMID: 9696153]
77. Sui GJ, Liu YH, Cheng XS, Anand IS, Harris E, Harris P, et al. Subacute
infantile mountain sickness. J Pathol. 1988;155:161-70. [PMID: 2969047]
78. Anand IS, Malhotra RM, Chandrashekhar Y, Bali HK, Chauhan SS, Jindal
SK, et al. Adult subacute mountain sickness—a syndrome of congestive heart
failure in man at very high altitude. Lancet. 1990;335:561-5. [PMID: 1968575]
79. Hecht HH, Kuida H, Lange RL, Horne JL, Brown AM. Brisket disease. III.
Clinical features and hemodynamic observations in altitude-dependent right heart
failure of cattle. Am J Med. 1962;32:171-83. [PMID: 13905831]
80. Clarke C, Duff J. Mountain sickness, retinal haemorrhages, and acclimatisa-
tion on Mount Everest in 1975. Br Med J. 1976;2:495-7. [PMID: 953646]
www.annals.org