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Ventilatory Control at High Altitude

John V. Weil

10.1002/cphy.cp030221

Source: Supplement 11: Handbook of Physiology, The Respiratory System, Control of Breathing

Originally published: 1986

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Acute Ventilatory Response to High Altitude
2 Subacute Ventilatory Response to High Altitude (Acclimatization)
3 Altitude Acclimatization
3.1 Role of Peripheral Chemoreceptors
3.2 Role of Hypocapnia and Hyperventilation
3.3 Role of Acid‐Base Adjustments
3.4 Role of Other Factors
4 Ventilatory Control During Long‐Term High‐Altitude Exposure
4.1 Hypoxic Desensitization
4.2 Hypoxic Ventilatory Depression
5 Sleep at High Altitude
6 Ventilatory Control in Relation to Syndromes of High Altitude
6.1 Acute Mountain Sickness
6.2 High‐Altitude Pulmonary Edema
6.3 Chronic Mountain Sickness
7 Conclusion
Figure 1. Figure 1.

Overview of ventilatory adjustments to high altitude. Initial abrupt increase in ventilation over minutes to hours is followed by a slower, progressive rise over several days and is referred to as ventilatory acclimatization. After very long exposures, from many years to a lifetime, ventilation decreases in association with decreased ventilatory responsiveness to hypoxia, which has been called hypoxic desensitization.
Figure 2. Figure 2.

Oxygen‐tension () cascade at low and high altitude. At high altitude, fall in for each step from tracheal or inspired air to venous circulation is decreased. One of the greatest decreases is that from inspired to alveolar air, which largely reflects increased ventilation at high altitude.

Adapted from Hurtado 105
Figure 3. Figure 3.

Contrast of acid‐base and oxygenation effects on ventilatory response to CO2. Acid‐base alterations shift curve position (intercept) with little or no change in slope, whereas changes in O2 tension () mainly influence the slope. , arterial partial pressure of CO2.
Figure 4. Figure 4.

Ventilatory acclimatization to high altitude depends on peripheral chemoreceptors. Intact ponies (solid line) show a rise in alveolar ventilation () and a decrease in cerebral spinal fluid partial pressure of CO2 () during sustained hypoxia. Chemodenervation (broken line) abolishes these responses.

Adapted from Forster et al. 70
Figure 5. Figure 5.

Influence of alveolar partial pressure of CO2 () on position of hypercapnic ventilatory response curve. Alterations in induced by voluntary changes in ventilation produced progressive left shifts in curve position. This effect was augmented by hypoxia. In contrast, changes in base‐line pressure of CO2 had no effect on slope of CO2 response, although slope was increased by hypoxia.

Adapted from Eger et al. 64
Figure 6. Figure 6.

Alteration in time course of ventilatory acclimatization to high altitude when hypocapnia is prevented. Four subjects were exposed to simulated high altitude. In one study, hypocapnia was allowed to develop (broken line). In another it was prevented by addition of CO2 to ambient air (solid line). Under isocapnic conditions, ventilatory response to altitude was more rapid in onset and was virtually complete by 27 h in contrast to gradual rise in ventilation typical of altitude acclimatization, which was seen in hypocapnic group. , expired ventilation.

From Cruz et al. 48
Figure 7. Figure 7.

Influence of alveolar partial pressure of CO2 on ventilatory drives at simulated high altitude. Ventilatory responses to hypoxia measured as shape parameter (A) in top panel, slope of CO2 response (S) in middle panel, and position of CO2 response (B) in lower panel during 75 h of exposure to simulated altitude. Control responses in which hypocapnia was allowed to develop normally (broken line) are compared with responses in same subjects in whom hypocapnia was prevented by addition of CO2 to ambient air (solid line). When hypocapnia was allowed to develop there was a progressive increase in ventilatory response to hypoxia, suggesting that acclimatization is associated with augmentation of hypoxic response and that this somehow may be mediated by hypocapnia.

From Cruz et al. 48
Figure 8. Figure 8.

Proposed sequence of events leading to acclimatization to high altitude. , partial pressure of CO2; CNS, central nervous system.
Figure 9. Figure 9.

Depressed ventilatory responses to hypoxia in native and nonnative residents of high altitude (HA) at 3,100 m. In HA subjects, curves are not only flattened but also shifted upward, so that ventilation at normal and high O2 tensions () is increased over that of low‐altitude subjects but ventilation is decreased in hypoxia. , expired ventilation; A, altitude.

From Weil et al. 204. Reproduced from The Journal of Clinical Investigation, 1971, vol. 50, p. 186–195, by copyright permission of The American Society for Clinical Investigation
Figure 10. Figure 10.

Depression of ventilatory responsiveness to hypoxia in nonnative residents of high altitude (3,100 m). Responses are measured as shape parameter and show progressive decline from values approaching those seen in low‐altitude subjects to markedly attenuated values found in high‐altitude natives as a function of time spent at altitude.

From Weil et al. 204. Reproduced from The Journal of Clinical Investigation, 1971, vol. 50, p. 186–195, by copyright permission of The American Society for Clinical Investigation
Figure 11. Figure 11.

Eight cats were exposed to simulated altitude (HA) of 5,500 m for 3 wk (broken lines) and ventilatory responses to hypoxia were compared to those in sea level (SL) control animals (solid lines). Numbers in parentheses indicate alveolar partial pressure of CO2 () in which tests were done. As in humans, ventilatory response curve is not only flattened or displaced leftward but is also shifted upward so that there is hyperventilation at high O2 tensions. After high‐altitude exposure, ventilatory pattern is shifted toward one of rapid, shallow breathing similar to that noted in humans at high altitude, f, Frequency; Vt, tidal volume; , expired ventilation; NS, nonsignificant.

From Tenney and Ou 199
Figure 12. Figure 12.

Flattening or left shift of hypoxic ventilatory response curve induced in cats by 3‐wk exposure to simulated altitude of 5,500 m is reversed by subsequent decortication. However, effect on respiratory frequency (f) is exaggerated by this procedure. Results suggest that suprapontine inhibition of hypoxic response, removed by decortication, may explain hypoxic desensitization. Vt, tidal volume; , expired ventilation; , arterial partial pressure of O2.

From Tenney and Ou 199
Figure 13. Figure 13.

Responses to persistent isocapnic hypoxia [alveolar partial pressure of O2 () = 45 mmHg] in 4 subjects. There is an initial increase in expired minute ventilation (Ve) to peak lasting several minutes, but thereafter there is a decrease to lower plateau ∼25% below peak. Exposure to high O2 for 10 min followed by hypoxia produces return to original peak value. These data suggest that in normal human subjects, hypoxia lasting more than a few minutes produces a decrease in Ve that may be caused by either central nervous system depression or arterial chemoreceptor accommodation and that this effect can be abolished by brief periods of hyperoxia.

From Weil and Zwillich 208
Figure 14. Figure 14.

Comparison of expired minute ventilation (Ve) during subacute isocapnic hypoxia (open circle) compared with measurements made during acute hypoxia (filled circle). Simulated altitude was produced in a chamber with co2 replacement to maintain isocapnia over several days. Minute ventilation was measured, and then subject was switched for a few minutes into high O2 mixture, and ventilatory response to acute progressive hypoxia was measured over several minutes. At original alveolar partial pressure of CO2 () = 63 mmHg, Ve measured during acute progressive hypoxia was significantly higher than that observed under basal conditions after several days. This suggests that acute measurements of hypoxic response may overestimate responses observed under subacute or chronic conditions. Pb, barometric pressure.

From Weil and Zwillich 208


Figure 1.

Overview of ventilatory adjustments to high altitude. Initial abrupt increase in ventilation over minutes to hours is followed by a slower, progressive rise over several days and is referred to as ventilatory acclimatization. After very long exposures, from many years to a lifetime, ventilation decreases in association with decreased ventilatory responsiveness to hypoxia, which has been called hypoxic desensitization.



Figure 2.

Oxygen‐tension () cascade at low and high altitude. At high altitude, fall in for each step from tracheal or inspired air to venous circulation is decreased. One of the greatest decreases is that from inspired to alveolar air, which largely reflects increased ventilation at high altitude.

Adapted from Hurtado 105


Figure 3.

Contrast of acid‐base and oxygenation effects on ventilatory response to CO2. Acid‐base alterations shift curve position (intercept) with little or no change in slope, whereas changes in O2 tension () mainly influence the slope. , arterial partial pressure of CO2.



Figure 4.

Ventilatory acclimatization to high altitude depends on peripheral chemoreceptors. Intact ponies (solid line) show a rise in alveolar ventilation () and a decrease in cerebral spinal fluid partial pressure of CO2 () during sustained hypoxia. Chemodenervation (broken line) abolishes these responses.

Adapted from Forster et al. 70


Figure 5.

Influence of alveolar partial pressure of CO2 () on position of hypercapnic ventilatory response curve. Alterations in induced by voluntary changes in ventilation produced progressive left shifts in curve position. This effect was augmented by hypoxia. In contrast, changes in base‐line pressure of CO2 had no effect on slope of CO2 response, although slope was increased by hypoxia.

Adapted from Eger et al. 64


Figure 6.

Alteration in time course of ventilatory acclimatization to high altitude when hypocapnia is prevented. Four subjects were exposed to simulated high altitude. In one study, hypocapnia was allowed to develop (broken line). In another it was prevented by addition of CO2 to ambient air (solid line). Under isocapnic conditions, ventilatory response to altitude was more rapid in onset and was virtually complete by 27 h in contrast to gradual rise in ventilation typical of altitude acclimatization, which was seen in hypocapnic group. , expired ventilation.

From Cruz et al. 48


Figure 7.

Influence of alveolar partial pressure of CO2 on ventilatory drives at simulated high altitude. Ventilatory responses to hypoxia measured as shape parameter (A) in top panel, slope of CO2 response (S) in middle panel, and position of CO2 response (B) in lower panel during 75 h of exposure to simulated altitude. Control responses in which hypocapnia was allowed to develop normally (broken line) are compared with responses in same subjects in whom hypocapnia was prevented by addition of CO2 to ambient air (solid line). When hypocapnia was allowed to develop there was a progressive increase in ventilatory response to hypoxia, suggesting that acclimatization is associated with augmentation of hypoxic response and that this somehow may be mediated by hypocapnia.

From Cruz et al. 48


Figure 8.

Proposed sequence of events leading to acclimatization to high altitude. , partial pressure of CO2; CNS, central nervous system.



Figure 9.

Depressed ventilatory responses to hypoxia in native and nonnative residents of high altitude (HA) at 3,100 m. In HA subjects, curves are not only flattened but also shifted upward, so that ventilation at normal and high O2 tensions () is increased over that of low‐altitude subjects but ventilation is decreased in hypoxia. , expired ventilation; A, altitude.

From Weil et al. 204. Reproduced from The Journal of Clinical Investigation, 1971, vol. 50, p. 186–195, by copyright permission of The American Society for Clinical Investigation


Figure 10.

Depression of ventilatory responsiveness to hypoxia in nonnative residents of high altitude (3,100 m). Responses are measured as shape parameter and show progressive decline from values approaching those seen in low‐altitude subjects to markedly attenuated values found in high‐altitude natives as a function of time spent at altitude.

From Weil et al. 204. Reproduced from The Journal of Clinical Investigation, 1971, vol. 50, p. 186–195, by copyright permission of The American Society for Clinical Investigation


Figure 11.

Eight cats were exposed to simulated altitude (HA) of 5,500 m for 3 wk (broken lines) and ventilatory responses to hypoxia were compared to those in sea level (SL) control animals (solid lines). Numbers in parentheses indicate alveolar partial pressure of CO2 () in which tests were done. As in humans, ventilatory response curve is not only flattened or displaced leftward but is also shifted upward so that there is hyperventilation at high O2 tensions. After high‐altitude exposure, ventilatory pattern is shifted toward one of rapid, shallow breathing similar to that noted in humans at high altitude, f, Frequency; Vt, tidal volume; , expired ventilation; NS, nonsignificant.

From Tenney and Ou 199


Figure 12.

Flattening or left shift of hypoxic ventilatory response curve induced in cats by 3‐wk exposure to simulated altitude of 5,500 m is reversed by subsequent decortication. However, effect on respiratory frequency (f) is exaggerated by this procedure. Results suggest that suprapontine inhibition of hypoxic response, removed by decortication, may explain hypoxic desensitization. Vt, tidal volume; , expired ventilation; , arterial partial pressure of O2.

From Tenney and Ou 199


Figure 13.

Responses to persistent isocapnic hypoxia [alveolar partial pressure of O2 () = 45 mmHg] in 4 subjects. There is an initial increase in expired minute ventilation (Ve) to peak lasting several minutes, but thereafter there is a decrease to lower plateau ∼25% below peak. Exposure to high O2 for 10 min followed by hypoxia produces return to original peak value. These data suggest that in normal human subjects, hypoxia lasting more than a few minutes produces a decrease in Ve that may be caused by either central nervous system depression or arterial chemoreceptor accommodation and that this effect can be abolished by brief periods of hyperoxia.

From Weil and Zwillich 208


Figure 14.

Comparison of expired minute ventilation (Ve) during subacute isocapnic hypoxia (open circle) compared with measurements made during acute hypoxia (filled circle). Simulated altitude was produced in a chamber with co2 replacement to maintain isocapnia over several days. Minute ventilation was measured, and then subject was switched for a few minutes into high O2 mixture, and ventilatory response to acute progressive hypoxia was measured over several minutes. At original alveolar partial pressure of CO2 () = 63 mmHg, Ve measured during acute progressive hypoxia was significantly higher than that observed under basal conditions after several days. This suggests that acute measurements of hypoxic response may overestimate responses observed under subacute or chronic conditions. Pb, barometric pressure.

From Weil and Zwillich 208
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Article Title: Ventilatory Control at High Altitude
 

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John V. Weil. Ventilatory Control at High Altitude. Compr Physiol 2011, Supplement 11: Handbook of Physiology, The Respiratory System, Control of Breathing: 703-727. First published in print 1986. doi: 10.1002/cphy.cp030221