572 Chapter 16
Changes in Ventilation
Starting at altitudes as low as 1,500 meters (5,000 feet), the
decreased arterial P^ O 2 stimulates the carotid bodies to produce an
increase in ventilation. This is known as the hypoxic ventilatory
response. The increased breathing is hyperventilation, which
lowers the arterial P^ CO 2 ( table 16.14 ) and thus produces a respira-
tory alkalosis. The pH of brain interstitial fluid and cerebrospinal
fluid (CSF) similarly becomes alkalotic. After a couple of days,
the kidneys increase their urinary excretion of bicarbonate and
there is a reduced amount of bicarbonate in the CSF. This helps
move the pH of blood and CSF back toward normal. However,
the carotid bodies remain sensitive to the low P^ O 2 , and so the
total minute volume becomes stabilized after a few days at about
2.5 L/min higher than at sea level.
An extreme example of the hypoxic ventilatory response was
measured in hikers climbing Mt. Everest without supplemental
oxygen. At almost 28,000 feet (near the summit at 29,029 ft), their
average arterial P^ O 2 was 24.6 mmHg and the average arterial P^ CO (^2)
was measured at 13.3 mmHg. This P^ CO 2 is significantly lower than
the normal sea-level value (about 40 mmHg), indicating hyper-
ventilation. Hyperventilation at high altitude increases tidal vol-
ume, thus reducing the contribution of air from the anatomical
dead space and increasing the proportion of fresh air brought to
the alveoli. This improves the oxygenation of the blood over what
it would be in the absence of the hyperventilation. Hyperventila-
tion, however, cannot increase blood P^ O 2 above that of the inspired
air. The P^ O 2 of arterial blood decreases with increasing altitude,
regardless of the ventilation. In the Peruvian Andes, for example,
the normal arterial P^ O 2 is reduced from about 100 mmHg (at sea
level) to 45 mmHg. The loading of hemoglobin with oxygen is
therefore incomplete, producing an oxyhemoglobin saturation
that is decreased from 97% (at sea level) to 81%.
Nitric oxide (NO) is produced in the lungs, where it may
promote vasodilation and increased pulmonary blood flow in
people who live at high altitude. Also, NO bound to sulfur atoms
in the cysteine groups of hemoglobin may be transferred to the
rhythmicity center in the medulla and contribute to the hypoxic
drive (increased breathing in response to low arterial P^ O 2 ).
These actions of NO may serve as partial compensations for the
chronic hypoxia of life at high altitude.
The Affinity of Hemoglobin for Oxygen
Normal arterial blood at sea level unloads only about 22%
of its oxygen to the tissues at rest; the percent saturation is
reduced from 97% in arterial blood to 75% in venous blood. As
a partial compensation for the decrease in oxygen content at
high altitude, the affinity of hemoglobin for oxygen is reduced
so that a higher proportion of oxygen is unloaded. This occurs
because the low oxyhemoglobin content of red blood cells
stimulates the production of 2,3-DPG, which in turn decreases
the affinity of hemoglobin for oxygen (see fig. 16.35 ).
The action of 2,3-DPG to decrease the affinity of hemoglobin
for oxygen thus predominates over the action of respiratory alka-
losis (caused by the hyperventilation) to increase the affinity. At
very high altitudes, however, the story becomes more complex.
In one study, the very low arterial P^ O 2 (28 mmHg) of subjects
at the summit of Mount Everest stimulated intense hyperventila-
tion, so that the arterial P^ CO 2 was decreased to 7.5 mmHg. The
resultant respiratory alkalosis (in this case, arterial pH greater
than 7.7) caused the oxyhemoglobin dissociation curve to shift
to the left (indicating greater affinity of hemoglobin for oxygen),
despite the antagonistic effect of increased 2,3-DPG concentra-
tions. It was suggested that the increased affinity of hemoglobin
for oxygen caused by the respiratory alkalosis may have been
beneficial at such a high altitude, because it increased the loading
of hemoglobin with oxygen in the lungs.
Clinical Investigation CLUES
Peter suffered headache and nausea at the high altitude,
but had a normal blood oxygenation measured by a pulse
oximeter.- What caused his symptoms?
- How could he have had a normal pulse oximeter
measurement and yet have these symptoms?
FITNESS APPLICATION
Acute mountain sickness occurs in up to 25% of unac-
climatized people who arrive at an altitude of 2500 m (about
8,000 feet) and in up to 85% of people at 4500 m (about
15,000 feet). Headache is the most common symptom,
often accompanied by malaise, anorexia, nausea, dizziness,
and fragmented sleep. The low arterial PO 2 stimulates vaso-
dilation in the pia mater, increasing blood flow and pressure
within the skull to produce a headache. This is reduced or
prevented by the normal hyperventilation that accompanies
acclimatization to high altitude, which produces a low arte-
rial PCO 2 (hypocapnia) that stimulates vasoconstriction. Acute
mountain sickness can be treated by rest and NSAIDs, or by
descending to lower altitude. If it is more severe, treatment
with other drugs may be needed. High-altitude pulmonary
edema may occur after a couple of days at altitudes above
3000 m (about 9,000 feet) and produce shortness of breath,
cough, and cyanosis. After a couple of days or so at an alti-
tude of 4,000 m (about 13,000 feet), a potentially danger-
ous high-altitude cerebral edema may occur and produce
confusion, a mild fever, and even coma and death. There is
less likelihood of all these conditions if the ascent is done
more gradually.Increased Hemoglobin and Red Blood Cell
Production
Kidney cells sense a decreased tissue oxygen concentration
(hypoxia), and in response produce and secrete erythropoietin
(chapter 13, section 13.2). Erythropoietin stimulates the bone mar-
row to increase its production of hemoglobin and red blood cells.