The effect of Po2 on the response to carbon dioxide and the effect of carbon dioxide on the response to Po2 have already been noted. By virtue of this interdependence, a response to hypoxia is blunted by the subsequent increased ventilation, unless Paco2 is somehow maintained, because Paco2 ordinarily falls as ventilation is stimulated (see Fig 22.7). The stimulating effect of hypoxia is blunted mainly by the central chemoreceptors, which respond more potently than the peripheral receptors to low Paco2.
The sequence of events in the response to hypoxia (e.g., ascent to high altitude) exemplifies interactions among chemoresponses. For example, if 100% oxygen is given to an individual newly arrived at high altitude, ventilation is quickly restored to its sea level value. During the next few days, ventilation in the absence of supplemental oxygen progressively rises further, but it is no longer restored to sea level value by breathing oxygen. Rising ventilation while acclimatizing to altitude could be explained by a reduction of blood and CSF bicarbonate concentrations. This would reduce the initial increase in pH created by the increased ventilation, and allow the hypoxic stimulation to be less strongly opposed. However, this mechanism is not the full explanation of altitude acclimatization. Cerebrospinal fluid pH is not fully restored to normal, and the increasing ventilation raises Pao2 while further lowering Paco2, changes that should inhibit the stimulus to breathe. In spite of much inquiry, the reason for persistent hyperventilation in altitude-acclimatized subjects, the full explanation for altitude acclimatization, and the explanation for the failure of increased ventilation in acclimatized subjects to be relieved promptly by restoring a normal Pao2 are still unknown.
Metabolic acidosis is caused by an accumulation of nonvolatile acids. The increase in blood [H+] initiates and sustains hyperventilation by stimulating the peripheral chemoreceptors. Because of the restricted movement of H+ into CSF, the fall in blood pH cannot directly stimulate the central chemoreceptors. The central effect of the hyperventilation, brought about by decreased pH via the peripheral chemoreceptors, results in a paradoxical rise of CSF pH (i.e., an alkalosis as a result of reduced Paco2) that actually restrains the hyperventilation. With time, CSF bicarbonate concentration is adjusted downward, although it changes less than does that of blood, and the pH of CSF remains somewhat higher than blood pH. Ultimately, ventilation increases more than it did initially as the paradoxical CSF alkalosis is removed.
Respiratory acidosis (accumulation of carbon dioxide) is rarely a result of elevated environmental CO2, although this occurs in submarine mishaps, while exploring wet limestone caves, and in physiology laboratories where responses to carbon dioxide are measured. Under these conditions, the response is a vigorous increase in minute ventilation proportional to the Paco2; Pao2 actually rises slightly and arterial pH falls slightly, but these have relatively little effect. If mild hypercapnia can be sustained for a few days, the intense hyperventilation subsides, probably as CSF bicarbonate is raised. More commonly, respiratory acidosis results from failure of the controller to respond to carbon dioxide (e.g., during anesthesia, following brain injury, and in some patients with chronic obstructive lung disease). Another cause of respiratory acidosis is a failure of the breathing apparatus to provide adequate ventilation at an acceptable effort, as may be the case in some patients with obstructive lung disease. When these subjects breathe room air, hypercapnia caused by reduced alveolar ventilation is accompanied by significant hypoxia and acidosis. If the hypoxic component alone is corrected—for example, by breathing oxygen-enriched air—a significant reduction in the ventilatory stimulus may result in greater underven-tilation, causing further hypercapnia and more severe acidosis. A more appropriate treatment is providing mechanical assistance for restoring adequate ventilation.
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