Beruflich Dokumente
Kultur Dokumente
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
Clinical Principles
Physiologic Principles
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 GolmudLhasa 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.
HYPOXIA
OF
HIGH ALTITUDE
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
Review
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
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
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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Review
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.
PCO2
CO2
V
K
A
V
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.
Hyperventilation
Polycythemia
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
TO
HIGH ALTITUDE
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Review
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.
AcidBase Changes
AT
HIGH ALTITUDE
Populations at Risk
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
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
Review
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
253
760
43
149
35
100
Arterial Values
PO2, mm Hg
PCO2, mm Hg
pH
28
95
7.5
40
7.7
7.40
HIGH-ALTITUDE DISEASES
There are 3 major high-altitude diseasesacute
mountain sickness, high-altitude pulmonary edema, and
high-altitude cerebral edemaas well as many other less
important conditions.
Acute Mountain Sickness
Review
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.
Review
See text for details. Modified from reference 62. PA pulmonary artery.
Review
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).
Review
Retinal Hemorrhage
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
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