Limitations Of Pulmonary Gas Exchange

Gas exchange limitations in the lungs can reduce PO2 throughout the O2 cascade. Recall that limitations do not decrease resting Vo2, although they may limit maximal O2 consumption during exercise. Hypoxemia is defined as a decrease in blood PO2, and arterial hypoxemia, or decreased PaO2, indicates a limitation of pulmonary gas exchange. Gas exchange limitation does not imply a decrease in resting O2 consumption, because Po2 will adjust throughout the O2 cascade to maintain O2 consumption in a steady state. For example, PVO2 (and Q) will change as necessary to satisfy the cardiovascular Fick equation when O2 consumption increases.

Gas exchange limitations not only decrease PaO2, but they also can increase the alveolar-arterial PO2 difference. The concept of an "ideal" lung without limitations was introduced earlier, and under such ideal conditions, Pao2 — Pao2 = 0 mm Hg. However, in reality, Pao2 calculated from the alveolar gas equation is greater than PaO2, measured from an arterial blood sample, and this alveolar-arterial Po2 difference increases with some, but not all, mechanisms that limit gas exchange.

There are four kinds of pulmonary gas exchange limitations: (1) hypoventilation, (2) diffusion limitations, (3) pulmonary blood flow shunts, and (4) mismatching of ventilation and blood flow in different parts of the lung. The following subsections explain how each of these limitations decreases PaO2 and how the alveolar-arterial PO2 difference is useful for diagnosing the causes of hypoxemia in a patient.

Hypoventilation

Hypoventilation is the only pulmonary gas exchange limitation that does not increase the alveolar-arterial PO2 difference. Therefore, hypoxemia with an alveolar-arterial PO2 difference in the normal range is diagnostic of hypoventilation.

The magnitude of hypoxemia caused by hypoventilation is predicted by the alveolar gas equation:

Hypoventilation increases PACO2, according to the inverse relationship between Va and Paco2 described by the alveolar ventilation equation. This is easiest to understand when R = 1, and Pao2 decreases 1 mm Hg for every 1 mm Hg increase in PaCO2. Conceptually, PIO2 represents the total amount of gas inspired, and gas exchange replaces each molecule of O2 consumed with one molecule of CO2. Hence, PAO2 is simply the difference between Pio2 and Paco2 when R = 1. However, a normal value for R is 0.8, and this magnifies the effects of hypoventilation and increased PaCO2 on hypoxemia.

The two primary classes of problems that cause hypoventilation are (1) mechanical limitations and (2) ventilatory control abnormalities. Abnormal respiratory mechanics, such as increased airway resistance or decreased compliance with lung disease, may limit the effectiveness of the respiratory muscles in generating volume changes and Va. Also, the respiratory muscles themselves may be damaged and ineffective at generating the pressures necessary for normal ventilation. In all of these cases, the ventilatory control system may be normal, in terms of sensing PaO2 and PaCO2 changes and sending neural signals to the respiratory muscles, to increase ventilation. However, abnormal control of ventilation can also occur, as described in Chapter 22.

Diffusion Limitations

Pulmonary diffusion limitation is defined as disequilibrium between the partial pressure of a gas in the alveoli and in the blood leaving the pulmonary capillaries. Therefore, diffusion limitations decrease PaO2 by increasing the alveolar-arterial PO2 difference. This occurs when (1) the pressure head driving O2 diffusion across the blood-gas barrier (PAO2) is too low, or (2) the lung's diffusing capacity for O2 (Dl) is not sufficient for the O2 demands of the body.

As described earlier, diffusion limitations can occur in normal individuals when PAO2 is decreased at high altitude and O2 demand is increased during hard exercise. Increased O2 demand alone can increase the alveolar-arterial PO2 difference and cause arterial hypox-emia in some elite athletes during maximal exercise at sea level. In lung disease, the measured Dlco can decrease with destruction of surface area and capillary volume (e.g., emphysema) or thickening of the blood-gas barrier (e.g., interstitial lung disease) but Dlco has to decrease to less than 50% of normal before arterial hypoxemia is observed in resting patients. Hypoventilation and ventilation-perfusion mismatch can also lower PAO2 and decrease the pressure gradient driving diffusion.

Arterial hypoxemia caused by a diffusion limitation can be relieved rapidly by increasing inspired O2 (within several breaths). This increases the driving pressure for O2 from the alveoli into the blood.

Shunts

The ideal models used to analyze alveolar ventilation and diffusion have considered gas exchange occurring in a single compartment, so arterial PO2 equals PO2 in the blood leaving the pulmonary capillaries (Pao2 = Pc'o2). In reality, arterial blood is not pure pulmonary capillary blood; it also includes shunt flow. Shunt is defined as deoxygenated venous blood flow that enters the arterial circulation without going through ventilated alveoli in the pulmonary circulation. This kind of shunt is also called right-to-left shunt, to distinguish it from left-to-right shunt, which shunts systemic arterial blood into pulmonary artery flow with some congenital heart defects, and in the three-chambered hearts of some lower vertebrates. Right-to-left shunt decreases Pao2 by diluting end-capillary blood with deoxygenated venous blood.

Shunt is calculated by applying the principle of mass balance to a two-compartment model, which splits total cardiac output (Qt) between a shunt flow to an unventilated compartment (Qs) and flow to a normally ventilated alveolar compartment (Fig. 6). O2 delivery in arterial blood must equal the sum of O2 delivery from the two compartments:

Q tCao2 = Q sCV o2 + (Q t — Q s)Cc'o2, where Cc'o2 = O2 concentration in blood at the end of the pulmonary capillaries. This can be rearranged to the Berggren shunt equation defining shunt flow as a fraction of total cardiac output:

The value of Qs/Qt can be calculated in practice by measuring arterial and mixed-venous blood samples in an individual during 100% O2 breathing. This removes

0 200 400 600

PO2 mmHg a Qs v

0 200 400 600

PO2 mmHg

FIGURE 6 Two compartment model for shunt flow ((Qs) and effective pulmonary blood flow (Qt — Qs). Blood-O2 equilibrium curve illustrates how small shunt flows of mixed-venous blood (V) significantly decrease Po2 in arterial blood (a) relative to Po2 in end-capillary blood leaving the alveoli (c0).

any diffusion limitation in ventilated alveoli, so Pc0o2 = Pao2. Cao2 and CVo2 are measured directly. Cc0o2 is estimated from Pao2 using an O2-blood equilibrium curve, where Pao2, is calculated from the alveolar gas equation. (Note that Fio2 appears in the constant F in the alveolar gas equation, and this constant should not be neglected when Fio2 = 1.0.)

Figure 6 shows the effect of shunt on Pao2. Alveolar and end-capillary Pao2 are predicted to be more than 600 mm Hg during pure O2 breathing. However, shunt significantly decreases Pao2 because of the shape of the O2-blood equilibrium curve. The large increase in Po2 with O2 breathing does not increase Cc0o2 enough to offset the low level of CVo2. Therefore, persistent hypoxemia during 100% O2 breathing indicates a shunt if all the alveoli are effectively ventilated with 100% O2. (Exceptions to this condition may occur with ventilation-perfusion mismatching in lung disease, as described later.) If Pao2 can be increased above 150 mm Hg during O2 breathing, and cardiac output is normal, then 1% shunt increases the alveolar-arterial Po2 difference about 20 mm Hg.

In healthy individuals, shunt during O2 breathing averages less than 5% of cardiac output, including (1) venous blood from the bronchial circulation that drains directly into the pulmonary veins and (2) venous blood from the coronary circulation that enters the left ventricle through the Thebesian veins. If shunt is calculated during room air breathing, it is called venous admixture. Venous admixture is larger than the shunt during O2 breathing because it is an "as if'' shunt, which includes the effects of low Po2 from poorly ventilated alveoli. This occurs even in healthy lungs with ventilation-perfusion mismatching as described in the next section.

Ventilation-Perfusion Mismatching

Mismatching of ventilation and blood flow in different parts of the lung is the most common cause of alveolar-arterial Po2 differences in health and disease. It is also the most complicated mechanism of hypox-emia, and will be approached in two steps. First, the effect of the alveolar ventilation-perfusion ratio (Va/Q) ratio on PAO2 is described for an ideal lung. Second, the mechanisms resulting in different Va/Q ratios in different parts of real lungs and the effect of this on arterial PO2 are considered. It will be important to understand that only this second factor increases the alveolar-arterial PO2 difference.

Ventilation-Perfusion Ratio

The effect of changing Va/Q on Pao2, has already been introduced in the section on Alveolar Ventilation. Pao2 increases with Va according to the alveolar ventilation equation and alveolar gas equations. Va/Q adds the concept of blood flow. The effect of Va/Q on Pao2 can be understood by thinking of Va as bringing 02 into the alveoli, and Q as taking it away. If Q suddenly increases and removes more 02 from the alveoli (recall that 02 is normally a perfusion-limited gas), then Pao2, will decrease. However, if Va increases 02 delivery to match increased 02 removal (returning the Va/Q ratio to normal), then Pao2 will return to normal. Decreasing Va/Q has the opposite effect and decreases Pao2.

The 02-C02 diagram of Fig. 7 shows the effects of changing Va/Q in an ideal lung, modeled as a single alveolus in a steady state, with no shunts or diffusion limitations. The ventilation-perfusion ratio (Va/Q) is defined with alveolar ventilation to eliminate the effects of dead space. The Va/Q line on the C02-02 diagram shows all possible Pco2-Po2 combinations that could occur in this lung with Va/Q ratios ranging from 0 to infinity. When Va/Q = 0, this indicates a shunt. The shunt alveolus is not ventilated, so it will equilibrate with mixed-venous blood and the Va/Q = 0 point corresponds to PVo2 and PVco2. When Va/Q is infinite, this indicates dead space. There is no blood flow to dead space, so this alveolus equilibrates with inspired gas, and the infinite Va/Q point corresponds to Pio2 and Pico2. Normal Paco2 and Pao2 values are shown for a normal

The important point to notice about the Va/Q line is that changes in Va/Q around the normal value affect Paqz more than PACo2 (notice the different Co2 and o2 scales

FIGURE 7 O2-CO2 diagram. The ventilation-perfusion curve describes all possible Po2-Pco2 combinations in the alveoli (in an ideal lung, Pao2 = Pao2). Mixed-venous values occur in alveoli with no ventilation (shunt) and inspired values occur in alveoli with no perfusion (dead space). (After Rahn and Fenn, Chap. 31 in Renn and Rahn, eds., Handbook of physiology, Respiration. Bethesda, MD: American Physiological Society, 1964.)

FIGURE 7 O2-CO2 diagram. The ventilation-perfusion curve describes all possible Po2-Pco2 combinations in the alveoli (in an ideal lung, Pao2 = Pao2). Mixed-venous values occur in alveoli with no ventilation (shunt) and inspired values occur in alveoli with no perfusion (dead space). (After Rahn and Fenn, Chap. 31 in Renn and Rahn, eds., Handbook of physiology, Respiration. Bethesda, MD: American Physiological Society, 1964.)

in Fig. 7). This generalization holds even if the Va/Q line is altered by changing mixed-venous or inspired gas (which changes the end points), or by physiologic changes in the blood-o2 or Co2 equilibrium curves (which determine the exact shape of the Va/Q. line). The Va/Q line is calculated from the ventilation-perfusion equation: Va/Q = 8.63R(Cao2 - CVo2)/Paco2 with Va in LBTPS/min, Q in L/min, 02 concentrations in mL/dL, and PCo2 in mm Hg. This equation is not generally used in clinical medicine, but is included here for reference.

Va/Q Mismatching between Different Alveoli

In real lungs, total alveolar ventilation and cardiac output must be distributed between some 300 million alveoli, and this distribution is not perfectly uniform. This results in Va/Q heterogeneity, or different Va/Q ratios in different parts of the lung; Va/Q mismatching refers to spatial Va/Q heterogeneity between functional units of gas exchange in real lungs—not a mismatch between total Va and Q or a deviation of the overall Va/Q from 1. Changes in the Va/Q ratio in an ideal lung, or in a single alveolus, change PAo2 as described earlier (see Fig. 7), but this does not change the alveolar-arterial Po2 difference from the ideal value of zero. In contrast, Va/Q heterogeneity between lung units does decrease Pao2 and it increases the alveolar-arterial Po2 difference.

Regional differences in alveolar ventilation occur because of the mechanical properties of the lung, as described in Chapter 19. Briefly, gravity tends to distort the upright lung so alveoli in the apex are more expanded than those in the base of the lung. This results in basal alveoli operating on a steeper part of the lung's compliance curve, so Va is greater at the bottom than at the top of the lung (see Chapter 19, Fig. 11). VAper unit lung volume differs by a factor of 2.5 between the top and bottom of the upright human lung (Fig. 8).

Regional differences in blood flow occur because of the effects of gravity on the pulmonary circulation, as described in Chapter 18. Briefly, capillary pressure is greater at the bottom than at the top of the upright lung, which reduces local vascular resistance at the bottom of

Apex of Lung Base of Lung

FIGURE 8 Gravity results in regional differences in alveolar ventilation (Va) and blood flow between the apex and base of the lung, as described in the text. This causes the Va/Q ratio to decrease about 2.5-fold from the top to the bottom of the lung. (After West, Ventilation/bloodflow and gas exchange. New York: Blackwell Scientific, 1990.)

Apex of Lung Base of Lung

FIGURE 8 Gravity results in regional differences in alveolar ventilation (Va) and blood flow between the apex and base of the lung, as described in the text. This causes the Va/Q ratio to decrease about 2.5-fold from the top to the bottom of the lung. (After West, Ventilation/bloodflow and gas exchange. New York: Blackwell Scientific, 1990.)

the lungs and increases regional blood flow (see Chapter 18, Fig. 13). Figure 8 shows that Q per unit lung volume changes by a factor of 6 between the top and bottom of the upright human lung, or relatively more than Va. The net result is a large decrease in Va/Q between the top and bottom of the upright lung (Fig. 8).

This Va/Q heterogeneity between different regions of the lung leads to regional differences in Pao2 and Paco2 corresponding to differences predicted by the Va/Q line on the C02-02 diagram (see Fig. 7). For example, Va/Q in the upright lung at rest ranges from 3.3 at the top of the lung to 0.6 at the bottom. This decreases Pao2 from 132 mm Hg at the top of the lung to 89 mm Hg at the bottom. Paco2 increases from 28 mm Hg at the top of the lung to 42 mm Hg at the bottom. These regional differences in alveolar gas cause 02 uptake and C02 elimination to decrease from the top to the bottom of the lung. However, 02 uptake decreases more than C02 elimination, corresponding to the larger decrease in Pao2 and this decreases R (the respiratory exchange ratio) between the top and the bottom of the lung. Exercise reduces regional heterogeneity of Va/Q, alveolar gases, and gas exchange by increasing blood flow at the top of the lung.

Va/Q heterogeneity also causes heterogeneity in Po2 of the end-capillary blood (Pc0o2), because alveolar-arterial Po2 equilibrium occurs in any region with a normal diffusing capacity. Figure 9 illustrates how this leads to hypoxemia. Diffusing capacity is assumed normal, so Pc0oO2 equals Pao2 in each functional unit of gas exchange with a different Va/Q. Arterial blood is a mixture of blood draining each unit, so 02 concentration in the "mixed" arterial blood is a flow-weighted average of blood from individual units. The "high" Va/Q unit contributes relatively little to total blood flow, and Cc0o2 is not increased significantly by the high PAo2, because the blood-o2 equilibrium curve is flat at high Po2. The "low" Va/Q unit contributes relatively more to total blood flow, and Cc0o2 is decreased significantly because the blood-o2 equilibrium curve is steep at low Po2. Consequently, Cao2 is weighted toward the level in the low Va/Q units, and Pao2 is lower than the numerical average of PAo2 from all three alveoli.

Figure 9 also shows how Va/Q heterogeneity increases the measured alveolar-arterial Po2 difference, without increasing alveolar-arterial Po2 difference in any single gas exchange unit. Po2 in the mixed alveolar gas can be calculated as a flow-weighted mixture of the gas expired from all the units. Increases in Po2 can effectively balance decreases in Po2 in the gas phase, because partial pressure and concentration (or fraction, Po2) are linearly related for o2 in the gas phase, unlike o2 in blood. However, mixed PAo2, exceeds the numerical average of Po2 from the three units because pAO2 = 116

pAO2 = 116

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