Time (minutes)

FIGURE 10 The time course of changes in ventilation and Paco2 in a normal male subject during 8 hr of breathing 12% O2, to simulate an exposure to a 13,500-ft (4115-m) altitude. Values measured during normoxia (before and after hypoxia) are circled. Note the immediate increase in ventilation and decrease in Paco2 at onset of hypoxia, and slower changes during sustained hypoxia, indicating ventilatory acclimatization. When normoxia is restored, ventilation remains elevated and Paco2 remains low, but these values return toward the original control levels over a similar time course to the onset of ventilatory acclimatization (not shown).

between ventilatory stimulation by hypoxia and venti-latory inhibition by decreased Paco2. Hypoxic ventilatory decline (see Ventilatory Response to Pao2 section) will also limit the increase in ventilation during early exposure to altitude.

If hypoxia is sustained for several hours, ventilation increases further so Paco2 decreases more. An additional 5 mm Hg decrease in Paco2 (e.g., Fig. 10) will increase Pao2 about 6 mm Hg according to the alveolar gas equation (Chapter 21). This is an obvious benefit in hypoxia and it is remarkable that ventilation increases when hypoxic stimulation of arterial chemoreceptors actually decreases and hypocapnic (low Paco2) inhibition of arterial and central chemoreceptors increases. If the hypoxic exposure is extended beyond 8 hr, then ventilation continues to increase toward a plateau value over 2 days, but 2 weeks are required for full ventilatory acclimatization. Hence, the stimulus-response relationships of the arterial chemoreflexes are enhanced by chronic hypoxia so ventilation is significantly greater than during acute hypoxia.

The physiologic mechanisms of ventilatory acclimatization to hypoxia are not completely understood, but it is clear that they involve both arterial chemoreceptors and the CNS. Animal experiments show that carotid body chemoreceptors become more sensitive to Pao2 during prolonged exposure to hypoxia. This will increase afferent input (action potential frequency) for any given level of Pao2 and contribute to an increased hypoxic ventilatory response, and resting ventilation, after a few days at altitude. A second factor increasing arterial chemoreceptor stimulation during prolonged hypoxia is renal compensation for primary respiratory alkalosis that occurs with hyperventilation (see Chapter 20). Arterial pH will decrease back toward the normal value over hours to days, increasing arterial chemo-receptor stimulation for any given level of Pao2 and Paco2 (see Fig. 7). Finally, changes appear to happen in the CNS responsiveness to sensory input from arterial chemoreceptors during sustained hypoxia, which results in a greater ventilatory response for any given afferent input. The mechanism for this increased responsiveness of respiratory centers in the brain curing chronic hypoxia is not known.

Changes in Paco2 during acclimatization to hypoxia also support increased CNS responsiveness. When normoxia is restored after prolonged hypoxia, Paco2 remains lower than normal (see Fig. 10) despite removal of the hypoxic stimulus. Arterial chemoreceptors should not be stimulating ventilation at such high Pao2 and low Paco2 levels so a change in central chemoreceptor function is likely. As discussed earlier in the Central Chemoreceptors section, changes in CSF pH cannot explain this increase in CO2 sensitivity. However, the ventilatory response to Paco2 during acclimatization to altitude changes "as if" the H+ stimulus at central chemoreceptors changed in parallel with metabolic compensations of the respiratory alkalosis.

In contrast to the increased hypoxic ventilatory response described for acclimatization to hypoxia, individuals who live at high altitude for years show a decreased ventilatory response to hypoxia, at least until Pao2 reaches extremely low levels (Fig. 11). This change in the ventilatory response in high-altitude residents and natives is called hypoxic desensitization, or blunting of the hypoxic ventilatory response. In high-altitude natives there is a genetic component to the low hypoxic ventilatory response, and it is hypothesized that evolution reduced ventilation and the work of breathing because other steps in the oxygen transport chain adapted to hypoxia. However, hypoxic desensitization in lowlanders who live at high altitude for years indicates that these changes can occur by physiologic, as well as genetic, mechanisms.

Chronic Lung Disease

Chronic hypoxemia can result from several forms of heart and lung disease. one example is chronic obstructive pulmonary disease (COPD), which is a general term for chronic bronchitis and emphysema. Both of these pathologies can lead to airway obstruction, V/Q mismatching, and hypoxemia (Chapter 21). This severely limits the ability to exercise and patients with Pao2 < 60 mm Hg may qualify for supplemental

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