“Normal” PaO₂ can be shown to decrease with age and with the supine position [4]. There is significant standard deviation, and in clinical practice the normal range for most laboratories, 80 to 100 mg Hg, suffices.

In normal human homeostasis, the PaCO₂ is tightly regulated by respiration at or close to 40 mm Hg. Unlike the PaO₂, the normal PaCO₂ remains at 40 mm Hg throughout life. It is unaffected by age [4] or position [5].

The normal pH of human arterial blood is at or close to 7.40. Like the PaCO₂, there is no predicted change with age.

Low PIO₂ is a potential cause of hypoxemia. A low PIO₂ occurs only at high altitudes and in conditions when other gases are present; it is not in the differential diagnosis of normal clinical management.

It was once thought that thickening of alveolar walls could lead to an increase in the diffusion distance great enough to prevent equilibrium of the partial pressure of oxygen between the alveoli and the associated pulmonary capillary blood. This
physiologic concept is known as “alveolar–capillary block syndrome,” [8]. Subsequent data, however, indicated that even radiographically “homogeneous” pulmonary disease rarely alters alveolar–capillary membranes uniformly throughout the lung. In addition, the efficiency of gas exchange within any single alveolus is such that even with a barrier to diffusion, diffusion impairment is not a factor; by the time blood leaves the alveolar capillaries, alveolar and capillary gas partial pressures are equal. Thus, hypoxemia at rest in patients with pathologies such as interstitial disease is due not to “alveolar–capillary block” but rather to areas of low [V with dot above]/[Q with dot above] mismatch. In contrast, there may be a component of “alveolar–capillary block” in exercise; as the transit time of blood through alveolar capillaries decreases, there may be some true physiologic impairment of capillary/alveolar gas equilibrium that could result in hypoxemia [9].

In right-to-left shunt, blood from the right heart does not come into contact with oxygenated air before reaching the left heart; ventilation and perfusion are uncoupled [5]. Three kinds of shunt are recognized: cardiac, pulmonary vascular, and pulmonary parenchymal [10]. In a cardiac shunt, a defect allows blood to pass directly from the right atrium or ventricle into the left-sided chamber. For cardiac shunt to occur, there must be some relative increase in right-sided pressures. In a pulmonary vascular shunt, the shunting of blood occurs through arteriovenous malformations within the pulmonary vascular bed. These arteriovenous malformations can be small and not visible on chest imaging (as in some cases of cirrhosis), or large and visible as parenchymal densities (as with hereditary hemorrhagic telangiectasia) [11]. In pulmonary parenchymal shunt, alveolar consolidation or atelectasis prevents gases from reaching alveoli while blood flow continues through their capillary beds. Examples of conditions that cause parenchymal shunt are pneumonia, lobar collapse, and acute respiratory distress syndrome.

Note that right-to-left shunt is listed as a cause of hypoxemia but not of hypercapnia because of the capacity of alveoli with normal or high [V with dot above]/[Q with dot above] ratios to compensate for the lack of clearance of CO₂ from shunted blood [6]. If the only gas exchange defect present is shunt, increased ventilation to the perfused alveoli leads to a normal PaCO₂ [6]. This increased ventilation has no effect on the PaO₂; as already noted, the dependency on hemoglobin for blood to carry oxygen results in an inability of areas with normal or elevated [V with dot above]/[Q with dot above] ratios to compensate for areas with low [V with dot above]/[Q with dot above] ratios. Thus, shunt is a cause of nonhypercapnic hypoxemic respiratory failure.

Low [V with dot above]/[Q with dot above] mismatch is the dominant physiology in abnormalities of gas exchange. Mild to moderate degrees of low [V with dot above]/[Q with dot above] mismatch can cause hypoxemia alone, whereas more severe [V with dot above]/[Q with dot above] mismatching leads to hypoxemia with hypercapnia. (For a patient breathing room air, [V with dot above]/[Q with dot above] mismatch never causes hypercapnia in the absence of hypoxemia.) There are two reasons why a substantially greater amount of low [V with dot above]/[Q with dot above] mismatch must be present to cause hypercapnia than to cause hypoxemia. The first reason is the higher solubility of CO₂ in blood as discussed earlier [6]; there is no saturation limit for CO₂. Thus while normal alveoli cannot increase oxygen uptake significantly after hemoglobin saturation, they can increase CO₂ removal as venous CO₂ content rises. The second reason is that, just as with shunt, patients with low [V with dot above]/[Q with dot above] mismatch increase their minute ventilation to compensate for the potential elevation in CO₂ that the low [V with dot above]/[Q with dot above] areas would otherwise generate [6]. With severe [V with dot above]/[Q with dot above] mismatch, there are not enough normal and high [V with dot above]/[Q with dot above] alveoli to compensate for the hypercarbia of those with low [V with dot above]/[Q with dot above] mismatch; hypercapnia occurs in addition to hypoxemia.

Hypoventilation refers to conditions in which minute ventilation is reduced relative to the metabolic demand present for oxygen uptake and CO₂ production. By necessity, when minute ventilation is reduced alveolar ventilation must also be abnormally low, resulting in decreased gas exchange between the external environment and the alveoli [6]. Hypoventilation by definition causes both arterial hypoxemia and a raised arterial PCO₂. Some physicians use the terms “hypoventilation” and “carbon dioxide retention” interchangeably, a usage that confuses physiologies. Pure hypoventilation represents decreased minute ventilation with normal lungs. In contrast, other conditions that cause carbon dioxide retention (low [V with dot above]/[Q with dot above] mismatch) are caused by airway or parenchymal lung disease and usually are associated with increased minute ventilation.

In hypoventilation as defined earlier, the alveolar PCO₂ can rise to the point that the partial pressure of O₂ is significantly reduced. The disorders that cause hypoventilation are called the extrapulmonary causes of respiratory failure because they do not involve abnormality of the pulmonary gas exchange mechanisms [7,12,13]. A defect leading to hypoventilation can occur anywhere in the normal physiologic linkages that affect minute ventilation; the differential diagnosis of extrapulmonary respiratory failure is listed in Table 46.1. Note that in this categorization, obstruction at or above the trachea and other large airways is classified as an extrapulmonary disorder because of the fact that the gas exchange mechanisms of the lung remain intact.

The inhalation of a gas containing CO₂ can cause hypercapnia although it is not usually part of the differential diagnosis in clinical medicine. It does occur occasionally in iatrogenic situations; patients on a t-piece with extended tubing attached to the expiratory port may be forced to re-breathe exhaled CO₂ to the point of hypercapnia.