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Discuss the effects of ascending to high altitude

Altitude places the respiratory system under stress

Partial pressures of oxygen decrease with altitude as atmospheric
pressure drops but fractional concentration doesnt change

Decreasing atmospheric pressure leads to fall in alveolar PO2 and

lower mixed venous PO2 due to extraction of O2 by systemic tissues
Causes low alveolar capillary PO2 diffusion gradient so reduces
absolute O2 transport rate
Lower mixed venous PO2 almost means operating on steeper
sections of Hb-O2 dissociation curve so set change in O2 content of
pulmonary capillary blood has smaller effect on PO2 increase
Uptake of O2 by systemic tissues is the product of cardiac output
and the arteriovenous difference in O2 content. At sea level, arterial
PO2 is ~100mmHg with a Hb saturation of ~97.5%, mixed venous
PO2 is ~40mmHg and Hb saturation is ~75%. The difference
between a and v O2 is ~22.5% of Hbs maximal carrying capacity
for O2.
At altitude of 3000m, arterial PO2 is only ~60mmHg which may be
roughly 88% Hb saturation hypoxemia. If all else remains the
same, mixed a-v difference in Hb saturation must still be 22.5% so
mixed venous blood at 3000m has a Hb saturation of 65.5% (8822.5) which corresponds to PO2 of ~33mmHg. So a-v difference of
PO2 is much larger at sea level than at 3000m even though a-v
difference in O2 content is the same.
Reason for discrepancy is the O2-Hb dissociation curve, steeper in
region covered by PO2 values at high altitude

Combinations of exercise and altitude means O2 transport becomes

diffusion limited
At sufficiently high altitudes, especially if combined with exercise,
O2 may not reach a diffusion equilibrium between alveolar air and
pulmonary capillary blood by the time the blood reaches the end of
the capillary
So both alveolar PO2 and actual arterial PO2 may fall because of a
failure of pulmonary capillary blood to equilibrate with alveolar air
Oxygen diffusion rate could become rate limiting if cardiac output is
high the usually augmented concentration gradient for fast
diffusion becomes less steep, such that the normal curve when time
in capillary is plotted against partial pressure of oxygen at altitude
plateaus at around half of the normal curve at sea level
Mismatch of ventilation-perfusion ratio, low if oxygen diffusion is
rate limiting so increase in overall ventilation needed to
compensate for it (normal alveolar ventilation is approximately
4l/min, total pulmonary blood flow is 5l/min so normally ratio is 0.8)
Varies between the three zones of the lungs due to the effect of
gravity on ventilation and perfusion so airflow and blood flow both
increase down the lung
Flow proportionally greater at the base (0.7 ratio at base) and
ventilation is proportionately greater at the apex (3 ratio).

If altitude high enough, may cause hypoxia

O2 saturation doesnt decrease as much up to 3000m since arterial
PO2 doesnt fall below 60-70mmHg, which corresponds to the top,
plateau part of the O2-Hb dissociation curve so nearly all O2 is
bound to Hb
Peripheral chemoreceptors in the carotid and aortic bodies have
type 1 cells that detect changes in PO2, PCO2 and pH
Neural discharge stimulated by fall in PO2
Leads to inhibition of potassium channel activity, cell depolarisation,
calcium entry and neurotransmitter release
Leads to afferent signalling to the medulla and increased ventilation
Respond to changes in PO2 in arterial blood starting at 500mmHg,
doesnt cause a marked increase in ventilation until PO2 descends
below 60mmHg the point at which Hb is 90% saturated with
oxygen, dissociation curve gets steeper below that point so
saturation drops quickly
Hyperventilation causes arterial PCO2 to increase
Acclimatisation to a high altitude causes ventilation to increase
progressively by the same amount as the acute response after a
few days.
PO2 continues to improve, PCO2 falls
Chemosensitive areas located bilaterally at level of cranial never
roots 8-11
Superficial (200um below the surface), surrounded by brain
extracellular fluid, composition of governed by extracellular fluid,
cerebrospinal fluid and local metabolism.
CO2 can diffuse across the blood brain barrier but not H+ and
HCO3Lowered PCO2 means lower [CO2] in CSF
pH of cerebrospinal fluid decreases which counteracts the
respiratory alkalosis induced by increase in central chemoreceptors,
time course doesnt correlate tightly with the time course of the
increase in ventilation
Kidneys respond over a period of several days to the respiratory
alkalosis by decreasing their rate of acid secretion so blood pH
decreases toward normal metabolic compensation for respiratory
alkalosis causes a compensatory decrease in HCO3- (regulated by
kidneys) to maintain pH since the blood will go alkaline
pH=pKA+log[HCO3-]/[CO2], need to maintain ratio of 20
HCO3-:CO2 dissolved to maintain pH (open buffer system
modulated primarily by lungs)
Another result of this compensation is spillage of HCO2 into the
urine that leads to osmotic diuresis and production of alkaline urine
Consequence of reducing both CSF and plasma pH is to remove part
of inhibition caused by alkaline pH and allow hypoxia to drive
ventilation to higher values
Only after HCO3- levels in the CSF are lowered will central afferent
input to reduce ventilation be reduced
Hypoxic stimuli on the peripheral chemoreceptors will become
dominant so the ventilation rate will increase further output
increases in response to sustained exposure to hypoxia, proposed to

drive the further increase in ventilation previously ascribed to CSF

To raise PO2 to a level compatible with survival (33mmHg), PCO2
needs to be reduced to 8mmHg as PAO2=PIO2-PACO2[FIO2+(1FIO2)/R] where PIO2 is the partial pressure of inspired oxygen,
PACO2 is the partial pressure of CO2 in the alveoli, FIO2 is the
fractional concentration of oxygen in the inspired air, R is the
respiratory exchange ratio.
Although increases in ventilation and CO help to maintain O2
delivery, costly from energy standpoint so cant be sustained for
extended periods
During prolonged residence at high altitude, reduced arterial PO2
triggers adaptations to enhance O2 delivery to tissues lowers
energy costs compared to short term compensatory strategies
Many adaptations mediated by increase in hypoxia-inducible factor
1 (HIF-1), transcription factor that activates genes involved in
erythropoiesis, angiogenesis and other processes
After some time, polycythemia can occur red blood cell
concentration thus Hb concentration could increase so that the O2
content of arterial blood may be normal despite the low PO2 and O2
saturation of the blood
Hypoxia leads to increased production of erythropoietin, increases
the Hb levels per erythrocyte but also increases RBC number
Erythropoietin is a growth factor, stimulates production of
proerythroblasts in bone marrow and promotes accelerated
development of RBS from their progenitor cells
E.g. permanent Peruvian Andes residents, arterial PO2 is 45mmHg
and Hb saturation is 81% but oxygen content is 22.4ml/100ml
(normal 20ml/100ml at sea level) blood due to the increased Hb
content (19.8g/100ml compared to the normal 15g/100ml).
Monges disease, too high haematocrit (optimal ~45%) so viscosity
compromises blood flow, reduces oxygen delivery to extremities,
tissue hypoxia
May cause pulmonary hypertension leading to pulmonary oedema
as generalised alveolar hypoxia causes contraction of arterioles,
reducing blood supply to the alveoli, increase in pulmonary vascular
resistance so increase in pulmonary arterial pressure, pulmonary
capillary pressure increases, filtration of fluid exceeds removal
hypertension and oedema.
May double the resistance result acute mountain sickness
Increased pressure also causes ventilation-perfusion mismatch so
leads to hypoxia and thus desaturation of arterial Hb leads to
Decrease of PO2 of RBCs stimulates glycolysis increased levels of
2,3-DPG so lowers O2 affinity of Hb so markedly increases O2
release in systemic tissues where the Hb-O2 dissociation curve is
Overall effect is enhanced O2 unloading to metabolising tissues

Cheyne-Stokes respiration cycles of gradual increase in tidal

volume followed by gradual decrease in tidal volume, then period of
apnea. Seen in healthy people during sleep at high altitude

Acclimatisation to high altitude also causes a 2-3fold increase in

pulmonary diffusing capacity. Appears to result from a rise in blood
volume of pulmonary capillaries and from associated increase in
capillary surface area available for diffusion
Surface area expands further as hypoxia stimulates an increase in
depth of inspiration
Right ventricular hypertrophy raises pulmonary arterial pressure
and increases perfusion to the upper, well-ventilated regions of the
Capillary density increases due to hypoxia. Tissue angiogenesis
occurs within days triggered by growth factors released by hypoxic
Angiogenic factors vascular endothelial growth factor (VEGF),
fibroblast growth factor (FGF) and angiogenin
Oxidative enzyme expression promoted by hypoxia, enhances
tissues ability to extra O2 from blood
Acclimatisation to high altitude increases not only O2 delivery to the
periphery but also O2 uptake by tissues

Increased ventilation brings alveolar PO2 closer to the ambient PO2,

and blows off CO2 respiratory alkalosis that inhibits the peripheral
and central chemoreceptors and decreases ventilatory drive
Total ventilation during an acute exposure to 45000m is only about
twice that at sea level, whereas hypoxia itself would have produced
a much larger stimulation
Accompanying increased ventilator drive is an increase in heart
rate, probably due to heightened sympathetic drive that
accompanies acute hypoxemia so increases cardiac output which
enhances O2 delivery