Clinical Note continued

have revealed some important insights about the exact causes of hypoxemia in certain lung diseases, as well as how they respond to treatment.

Diffuse interstitial pulmonary fibrosis is a thickening of the alveolar walls with collagen and scarring in the interstitium. As expected, fibrosis decreases the diffusing capacity (Dlco) experiments hypox-emia in patients with fibrosis at rest can be explained by Va/Q heterogeneity. Uneven scarring of the lungs results in local changes in compliance and resistance (airway obstructions), leading to regional differences in time constants and ventilation (see Chapter 19). Local scarring may also affect resistance to pulmonary blood flow but not always in the same way it affects ventilation, leading to Va/Q heterogeneity. Diffusion limitation for oxygen only becomes significant in patients with fibrosis during exercise.

Another pulmonary disease that might be expected to cause a diffusion limitation is adult respiratory distress syndrome (ARDS), which can result from blunt trauma to the chest and lungs (e.g., in a car crash). ARDS begins with pulmonary edema and leads to interstitial fibrosis (which eventually reverses if the patient recovers). Oxygen therapy should relieve hypoxemia caused by a diffusion limitation from a thickening of the interstitium, but oxygen can actually decrease Pao2 in ARDS. This is because shunt can increase during oxygen breathing by a mechanism called absorption atelectasis. Alveoli with low Va/Q ratios are especially susceptible to atelectasis, or collapse, during oxygen breathing because a large diffusion gradient is driving all of the oxygen into pulmonary capillary blood, and there is no nitrogen left in the alveoli to hold them open. Experiments confirm that blood flow to low Va/Q regions in the lungs of ARDS patients is converted to shunt during O2 breathing. Hence, other treatments such as O2 administered with positive end-expiratory pressure (PEEP) artificial ventilation may be necessary.

Pulmonary thromboembolism occurs when a blood clot obstructs part of the pulmonary circulation, leading to increased pulmonary artery pressure and high Va/Q ratios in parts of the lungs that are distal to the clot and poorly perfused. This Va/Q heterogeneity leads to hypoxemia but shunt may occur also. Surfactant production requires substrates delivered by the pulmonary circulation; this is impaired in poorly perfused parts of the lungs, leading to increased surface tension and alveolar collapse. Also, pulmonary capillary pressures increase in perfused regions of the lungs, with the high pulmonary artery pressure, and this can lead to edema and alveolar flooding that causes shunt.

Chronic obstructive pulmonary disease (COPD) is a general term for patients with emphysema (see Chapter 19) and chronic bronchitis. Va/Q heterogeneity is the main cause of hypoxemia in this disease too, but at least two different patterns of Va/Q distributions are seen that correlate roughly with the arterial PCO2. Some COPD patients maintain PaCO2 in the normal range by increasing total ventilation in the face of Va/Q mismatching as described in the text. Other COPD patients hypoventilate, so their Pao2 is low and Paco2 is elevated (suggesting a problem with ventilatory control; see Chapter 22). The COPD patients with normal Paco2 tend to have less chronic bronchitis and high Va/Q regions in their lungs, consistent with emphysema destroying part of the alveolar capillary bed. In contrast, COPD patients with elevated PaCO2 typically have advanced chronic bronchitis and low Va/Q regions in the lungs, consistent with increased airway resistance in the inflamed airways.

Asthma is the other main obstructive pulmonary disease. Asthma causes severe bronchoconstriction leading to low Va/Q regions in the lung but no shunt. A big advance in the treatment of asthma was the development of selective p2-adrenergic agents (e.g., albuterol) to stimulate bronchodilation. Older, non-selective ^-adrenergic agents (e.g., isoproterenol) stimulated receptors on the heart also, which increased blood flow to low Va/Q regions of the lung and could actually decrease PaO2. The benefits of relieving bronchoconstriction and increasing ventilation generally outweighed the negative side effects of ^-adrenergic agents on gas exchange, but the selective ^2-adrener-gic agents completely obviate these side effects.

For normal values of Vco2 = 240 mL of C02/min and Q = 6 L/min, the arterial-venous C02 concentration difference is 4 mL/dL. This differs from the normal value for 02 only by the difference in Vco2 and Vo2 (or by their ratio, which equals R).

Differences between C02 and 02 exchange result mainly from (1) differences in the 02 and C02 dissociation curves and (2) differences in the effects of C02 and 02 on ventilatory control reflexes. As explained in Chapter 20, Pco2 differences are much smaller than Po2 differences between arterial and venous blood, although the concentrations are similar, because C02 is more soluble in blood. As explained in Chapter 22, Paco2 is the most important value in determining the resting level of ventilation, and ventilatory reflexes tend to increase Va as much as necessary to restore normal Paco2 when gas exchange is altered.

Hypoventilation has almost the same effect on both 02 and C02. Differences between decreases in Pao2 and increases in Paco2 with hypoventilation are explained by the effect of the normal respiratory exchange ratio (R) in the alveolar gas equation. A normal R = 0.8 magnifies Pao2 changes for a given Paco2 change.

Diffusion limitation affects C02 and 02 similarly, but normal ventilatory control reflexes will increase Va and return Paco2 to normal. Calculating a diffusing capacity for C02 is less certain than for 02 because resistances from the chemical reactions of C02 in the blood are more uncertain. Membrane-diffusing capacity for C02 is greater than Dmo2 because C02 solubility is much greater than 02 solubility, but other factors are similar or identical. [Recall that D = (solubility/MW)gas • (area/ thickness)membrane]. However, under normal circumstances, the rate of equilibration between alveolar gas and capillary blood is estimated to be similar for C02 and 02, requiring approximately 0.25 sec for equilibrium. C02 equilibrium is slower than expected with its large membrane-diffusing capacity, in part because chemical reactions for C02 in blood are slow. Also, both membrane and blood solubility are high for CO2, and the membrane-to-blood solubility ratio determines rate of diffusion equilibrium (see the Diffusion- and Perfusion-Limited Gases section).

The effects of shunts and ventilation-perfusion mismatching on Paco2 are similar, and relatively small for two reasons: (1) Paco2 changes little when shunt or low Va/Q units increase CO2 concentration, because the CO2-blood equilibrium curve is so steep (see Chapter 20, Fig. 4); and (2) the linearity of the physiologic CO2 dissociation curve (see Chapter 20, Fig. 4) means that increases in CO2 concentration can be offset by increasing Va, which decreases PaCO2. As explained earlier, Va/Q mismatching will increase the alveolar-arterial partial pressure difference for any gas, including CO2. However, the normal ventilatory control system will increase the overall V as necessary to restore PaCO2 to normal. In fact, some patients with shunts and low Va/Q units may actually have decreased PaCO2 if hypoxemia is severe enough to override the normal control of PaCO2 arid induce hyperventilation (see Chapter 22).

The extra ventilation necessary to compensate for shunt and low Va/Q units contributes to physiologic dead space calculated by the Bohr method. The difference between physiologic and anatomic dead space is sometimes called alveolar dead space. This represents an "as if" amount of wasted ventilation that could explain measured CO2 exchange if there was no shunt or Va/Q mismatching in the lung.

Suggested Readings

Farhi LE, SM Tenney, eds. Gas exchange, Vol IV. In Handbook of physiology: Section 3, The respiratory system. Bethesda, MD: American Physiological Society, 1987. Taylor CR, Karas RH, Weibel ER, Hoppler H. Adaptive variation in the mammalian respiratory system in relation to energetic demand. Respir Physiol 1987;69:1-127. Wagner PD. Diffusion and chemical reaction in pulmonary gas exchange. Physiol Rev 1977;57:257. West JB, Wagner PD. Ventilation-perfusion relationships. In Crystal RG, West JB, Weibel WR, Barnes PJ, eds. The lung: Scientific foundations, Vol 1, 2nd ed. Philadelphia: Lippincott-Raven, 1997;1693-1710.

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