Total Pulmonary Blood Flow and Oxygen Exchange

Pulmonary O₂ exchange under steady-state conditions obeys mass balance principles. Corresponding equations can be written to describe O₂ uptake from respired air and into the pulmonary circulation.³ These equations are:

[1]

[2]

where , an unimportant difference.

In healthy lungs, alveolar PO₂, which is proportional to FAO₂ in Equation 1, is tightly related to CaO₂ in Equation 2 by the O₂-hemoglobin (Hb) dissociation curve. CaO₂ can be directly computed using alveolar PO₂ and the O₂-Hb dissociation curve.⁴ This is not true in lung disease, where for Equation 1, FAO₂ is mean alveolar [O₂] averaged over the 300 million alveoli, weighted by the ventilation of each, and CaO₂ is arterial [O₂], similarly averaged but weighted by blood flow to each of the alveoli. When ventilation or blood flow is distributed in a nonhomogeneous manner in lung disease, the PO₂ corresponding to mean alveolar gas is often much higher than that of arterial blood corresponding to CaO₂. CaO₂ cannot be accurately calculated from FAO₂ and the O₂-Hb dissociation curve.

In the normal lung, it is clear from Equation 1 that alveolar [O₂], FAO₂, is a direct function of , FIO₂, and ventilation remained unchanged. A decrease in cardiac output from dehydration, blood loss, or myocardial infarction also would not affect arterial PO₂ under the same assumptions in a normal lung.

Equation 2 shows that the sole influence of cardiac output on gas exchange in a normal lung is to affect mixed venous [O₂] and PO₂. As cardiac output decreases, so too does regions decrease because such pathways essentially fail to oxygenate flowing blood above mixed venous levels.

The contribution of such regions to arterial blood, being tightly coupled to mixed venous [O₂], is closely dependent on cardiac output. The end result is more severe arterial hypoxemia as cardiac output decreases, and less severe hypoxemia as cardiac output increases. This situation is illustrated in Figure 5-1, in which a normal lung and a lung containing as an example of disease a 25% right-to-left shunt are compared as cardiac output changes. Arterial O₂ saturation, a better reflection of the O₂ concentration of the blood, follows changes in PO₂ (Fig. 5-2). Mixed venous PO₂ (Fig. 5-3) changes similarly in both cases according to Equation 2, but arterial PO₂ and O₂ saturation vary with cardiac output only in the abnormal lung. The clinical message is clear—the degree of arterial hypoxemia in a given patient depends not only on how much shunt or mismatch is present, but also on cardiac output. If arterial PO₂ were to decrease in such a patient, changes in cardiac output should be excluded if the arterial PO₂ change is to be interpreted as a change in health of the lung. Application of the classic shunt or venous admixture equation^5,6 illustrates this principle dramatically:

Figure 5-1 Effect of changes in cardiac output on arterial PO₂ in normal and diseased lungs. In this example, the diseased lung contains a 25% right-to-left shunt. Arterial PO₂ is essentially independent of cardiac output in health, but depends significantly on cardiac output in disease.

Figure 5-2 Effect of cardiac output on arterial oxygen saturation, from the same calculations as used in Figure 5-1. Saturation varies considerably with cardiac output in diseased, but not in normal, lungs.

Figure 5-3 Change in mixed venous PO₂ with cardiac output for the conditions of Figures 5-1 and 5-2. Mixed venous PO₂ changes similarly with cardiac output in health and disease. Absolute PO₂ is slightly higher in health at a given cardiac output.

[3]

where regions of the lung.

When ) would be about twice the actual value when cardiac output is reduced by 50%, and half the real value when cardiac output is doubled if venous [O₂] is assumed to be at normal levels.

Figure 5-4 Calculated or apparent shunt as a percentage of cardiac output, when the assumption is made that oxygen concentration in mixed venous blood is constant, equaling that seen when cardiac output is 6 L • min⁻¹. This assumption leads to large errors in calculated shunt when cardiac output is reduced or increased. The dashed lines indicate conditions under which the assumption is correct, so that calculated shunt is also accurate, but only at that point.

Pulmonary Transit Time

The preceding section assumes sufficient time for O₂ to equilibrate fully across the blood gas barrier; that is, PO₂ in the capillary blood has increased from mixed venous levels all the way to alveolar PO₂ within the available red blood cell contact time. Average red blood cell contact time normally appears to be about 0.75 second. This estimate is the ratio of resting capillary blood volume (75 mL, measured by the carbon monoxide technique⁷) to the corresponding cardiac output (6 L • min⁻¹). Figure 5-5 indicates the normal PO₂ profile calculated along the pulmonary capillary and shows full equilibration in about 0.25 second, leaving 0.5 second in reserve.⁸ Although transit times in different alveoli are not uniform,⁹ the variance in such times is still small enough that full equilibration occurs at rest, even in channels with the shortest transit and even during moderate exercise. Only during heavy exercise does failure of equilibration occur in healthy individuals.¹⁰ At high altitudes, diffusion limitation is seen with even light to moderate exercise and becomes a major factor reducing arterial [O₂] under such conditions.¹¹

Figure 5-5 Time course of PO₂ change along the pulmonary capillary as oxygen moves from alveolar gas into the flowing capillary blood. Starting at a mixed venous PO₂ of 40 mm Hg, full equilibration with alveolar gas is reached in about 0.25 second, leaving a large reserve in transit time under normal conditions.

In cardiopulmonary diseases, diffusion limitation in the lung rarely occurs, even when patients are well enough to exercise. The exception is interstitial pulmonary fibrosis. Here, diffusion limitation is usually seen during exercise, which aggravates hypoxemia.¹² Diffusion limitation can also occur at rest in such patients.¹³ Pulmonary diffusing capacity must be less than about 60% of normal, however, before diffusion limitation is seen because of previously described reserves in red blood cell transit time.¹³ Hypoxemia in cirrhosis of the liver seems to have a small component of diffusion limitation as well.

In severe cardiopulmonary diseases, such as acute pulmonary edema from left ventricular failure or acute respiratory distress syndrome, conditions develop that reduce O₂ diffusing capacity. In particular, the normally thin (0.5-μm) blood-gas barrier separating alveolar gas from capillary blood can become edematous; however, it is thought that this does not produce measurable O₂ diffusion limitation. In more advanced disease, there is alveolar filling with edema fluid, cellular debris, or both, which abolishes all ventilation of affected alveoli and produces what is more commonly termed shunt (i.e., perfusion of unventilated alveoli). It could be argued that such alveoli are completely diffusion-limited because no O₂ exchange occurs at all. This becomes a semantic issue and should not detract from the more important problem of understanding the pathologic and physiologic changes that occur with these diseases.

Distribution of Blood Flow within the Lungs

In normal lungs, output from the right ventricle is not equally distributed among the 300 million alveoli. Gravity affects blood flow distribution; more blood flows through dependent than nondependent alveoli because of the weight of the blood.¹⁴ There are nongravitational influences on blood flow distribution as well. The fractal branching nature of the vascular tree produces nonuniform distribution,¹⁵ and the lack of perfect anatomic symmetry perturbs flow patterns further.¹⁶ There may also be greater perfusion of central (proximal) than peripheral (distal) lung regions,¹⁷ although this has not been resolved. As a result of all of these independent sources of nonuniformity, a substantial degree of nonhomogeneous blood flow distribution exists. It seems, however, that the distribution of ventilation is largely matched to that of blood flow, so that ventilation and blood flow are each greatest and least in the same areas.¹⁸ This matching is imperfect, but interferes only trivially with O₂ transport in the normal lung. If the ideal lung produces an arterial PO₂ of 100 mm Hg, the real lung in young healthy subjects produces an arterial PO₂ of 90 to 95 mm Hg. Because of the flat O₂-Hb dissociation curve at this PO₂, the effect on arterial [O₂] of this 5- to 10-mm Hg decrease is negligible.

Equations 1 and 2, although used previously for considering the whole lung, can be applied at the local alveolar level, where the terms now reflect local alveolar and end-capillary O₂ levels and local at this level and setting Equations 1 and 2 equal to one another yields a new relation:

[4]

Equation 4 shows that within such a local lung region, alveolar (and end-capillary) [O₂] is a unique function of the ratio and the so-called boundary conditions (i.e., the inspired and mixed venous O₂ levels). A third factor implicit to Equation 4 is the PO₂-[O₂] relation defined by the O₂-Hb dissociation curve.

Equation 4 points out how changes in the local ratios are major factors in gas exchange and in arterial oxygenation.

Figure 5-6 Alveolar PO₂ in small lung regions as a function of local ratio is reduced below normal, alveolar PO₂ is tied closely to PO₂ in the mixed venous blood.

In cardiopulmonary disease, areas of low or zero ratio of nonembolized alveoli and is a primary reason for hypoxemia when it occurs in such patients.²⁴

Of particular relevance to cardiovascular state in the context of pulmonary gas exchange is a curious, poorly understood, but reproducible phenomenon whereby, as total blood flow through the lung (usually cardiac output) increases or decreases, so too does fractional shunt or venous admixture.²⁵ Figure 5-7 is a dramatic example of this phenomenon in a patient with lung disease on variable right heart bypass.²⁶ As pulmonary blood was mechanically varied from 1 to 5 L/(min • m²), percentage of shunt increased from 15% to 40% of the cardiac output. To underline the magnitude of this effect, absolute shunt perfusion increased from 0.15 L/(min • m²) to greater than 2 L/(min • m²), a more than 10-fold increase. Because these changes are rapidly reversible within minutes, it seems unlikely that the greater blood flow is actually causing more damage and shunt on this basis.

Figure 5-7 Dependence of percentage shunt through the lungs on pulmonary blood flow in a single patient with acute respiratory distress syndrome. In this patient on partial right heart bypass, pulmonary blood flow varied between 1 L • (min • m²)⁻¹ and 5 L • (min • m²)⁻¹. Shunt varied between 15% and 40% in a linear manner.

There is probably some systematic change in blood flow distribution between ventilated, normal regions and the unventilated alveoli causing the shunt to change with total blood flow.²⁷ This change generally occurs regardless of the anatomic distribution of disease and seems to be unrelated to lung structure in any systematic way. Numerous animal studies done under many circumstances mirror the human experience, regardless of whether the cardiac output is manipulated mechanically or pharmacologically.²⁸

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