Point:Counterpoint: Exercise-induced intrapulmonary shunting is imaginary vs. real

Pulmonary gas exchange efficiency deteriorates with exercise in both humans and other species, increasing the alveolararterial PO2 difference (AaDO2) (2). The potential contributors to this are ventilation-perfusion inequality, alveolar-capillary diffusion limitation, and shunt (20). These have been well documented under varying exercise conditions including normoxia, hypoxia, and hyperoxia, in particular by the multiple inert gas elimination technique (MIGET) (19). Alveolar, arterial, and mixed venous concentrations of inert gases of differing solubility can be measured and used to quantify ventilationperfusion inequality, alveolar-capillary diffusion limitation (plus any post-pulmonary venous admixture), and intrapulmonary shunt. From this, their individual contributions to AaDO2 can be determined (4, 19), and intrapulmonary shunt has consistently been the least important of the three. Recently, intrapulmonary shunting, the passage of mixed venous blood through the pulmonary circulation without contact with ventilated regions of the lung (20), has attracted renewed attention as a potential cause of exercising gas exchange impairment (3, 7, 15). This is because of transpulmonary passage of intravenously injected microbubbles demonstrated by agitated saline contrast echocardiography during exercise, but not at rest (3, 7, 15). The appearance of the microbubbles in the left atrium after three to five cardiac cycles is held as evidence of intrapulmonary shunts. Furthermore, it is suggested that these are important determinants of pulmonary gas exchange during exercise (3, 7, 15). Although we do not think transpulmonary bubble transmission is imaginary, we are reminded of the book Horton Hears A Who by Theodore Geisel (“Dr. Seuss”; 14). In this children’s classic, Horton the Elephant hears a sound from a speck of dust, which is home to tiny inhabitants known as Whos. The book reinforces the moral that “a person’s a person, no matter how small. ” While it can be argued that a “shunt is a shunt, no matter how small,” several important points should be considered, especially when evaluating what microbubble transmission implies for exercising pulmonary gas exchange. First, the size of transmitted bubbles remains unknown and there are several assumptions that potentially affect the interpretation of the data, reviewed recently in the context of detecting intracardiac shunting via a patent foramen ovale (21). The technique assumes that most bubbles induced by agitating air in saline are larger than pulmonary capillaries and therefore are trapped by the pulmonary circulation. Although the size of the microbubbles is not uniform, the bubbles that are less than the diameter of a pulmonary capillary during exercise ( 10 m) are argued to degrade to such a small size after transit through the pulmonary circulation that they are no longer detectable (21). This was shown experimentally some 28 years ago using M-mode echocardiography (10); however, these experiments have never been repeated using more sensitive modern echo techniques (21). Consequently the size of the bubbles detected in the left heart may be smaller than is assumed, and some bubbles may traverse a normal pulmonary capillary during exercise. In addition, microbubbles are assumed to be rigid, to not deform in the pulmonary circulation, or degrade and then reform with changing gas partial pressures, and that the extent of pulmonary capillary dilation as pulmonary vascular pressures rise during exercise is insufficient to allow passage of bubbles larger than 8–10 m. Second, agitated saline contrast echocardiography gives only a qualitative assessment of the presence or absence of microbubbles appearing in the left atrium after a specific delay. It cannot quantify blood flow through the responsible vessels. Where flow in these vessels has been quantified using microspheres of 25 and 50 m diameter, it has either been zero (9) or very small. In Dr. Stickland, Lovering, and Eldridge’s own data from isolated perfused lungs, such flow averaged 0.01% of cardiac output in baboons, 0.06–0.07% in humans (8), and 0.001–0.05% in dogs. The sole published exception to these observations is in exercising dogs, where microsphere transmission indicated flows 1% of cardiac output (16) in two animals and 3.1% in one. Notably in these animals, there was no evidence of gas exchange impairment and PaO2 was maintained. To explain the average AaDO2 seen during heavy normoxic exercise in man of 19 Torr (5, 6, 11–13) the shunt would have to be 2.6%, some 37 times greater than the 0.07% value indicated above. Third, the magnitude of the intrapulmonary shunt measured using MIGET in a large number of human subjects during exercise is consistent with the quantitative intrapulmonary shunt data. Although the statement is made that intrapulmonary shunting measured by the MIGET is not observed during exercise in healthy subjects, this is not strictly true. Intrapulmonary shunts are sometimes observed, but they are so small as to be physiologically insignificant. Table 1 shows summarized data from MIGET studies during heavy cycle exercise (90% of V̇O2 max) in both normoxia and hypoxia published by our laboratory since 1996 (5, 6, 11–13). In these studies, where V̇O2 max ranged from 2,000 to 6,000 ml/min, intrapulmonary shunt was always less than 1% of the cardiac output, averaging just 0.2% in normoxia and 0.1% in hypoxia. Importantly, the effect of this level of shunt on gas exchange is minimal, increasing the AaDO2 by less than 2 Torr (Table 1). As a percentage of the total AaDO2, intrapulmonary shunt explains only 7% in normoxia and much less ( 1%) in hypoxia.