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

POINT-COUNTERPOINTPoint:Counterpoint: Exercise-induced intrapulmonary shunting is imaginary vs. realSusan R. Hopkins, I. Mark Olfert, and Peter D. WagnerSusan R. Hopkins, I. Mark Olfert, and Peter D. WagnerPublished Online:01 Sep 2009https://doi.org/10.1152/japplphysiol.91489.2008This is the final version - click for previous versionMoreSectionsPDF (46 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations POINT: EXERCISE-INDUCED INTRAPULMONARY SHUNTING IS IMAGINARYPulmonary gas exchange efficiency deteriorates with exercise in both humans and other species, increasing the alveolar-arterial 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 ventilation-perfusion 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 μm) 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 μm.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 μm 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.Table 1.Normoxia (21%)Hypoxia (12.5%)VO2, ml/min, STPD3,685 (728)2,893 (630)Cardiac output, l/min24.9 (5.1)24.6 (5.4)Intrapulmonary shunt, %0.2 (0.7)0.1 (0.3)AaDO2, Torr19 (10)21 (7)AaDO2 from Shunt, Torr1.40.1% of AaDO2 from shunt7.40.005Values in parentheses are SD. Metabolic and gas exchange data during very heavy exercise in normoxia (n = 64) and hypoxia (n = 57) from previously published studies (5, 6, 11–13). In all cases the measured intrapulmonary shunt measured by the multiple inert gas technique was less than 1% of cardiac output and had a minimal effect on pulmonary gas exchange.That intrapulmonary shunt is miniscule is further confirmed by a recent study reporting venous admixture in very fit athletes during exercise breathing pure O2 (18). During 100% oxygen breathing, alveolar PO2 is elevated to such an extent that ventilation-perfusion inequality and diffusion limitation no longer contribute to the AaDO2—it can be explained only by right to left shunting (18). In this study (16), venous admixture during 100% oxygen averaged 0.5%, a value also consistent with the previously reported microsphere and inert gas data.Fourth, it has never been shown that oxygen exchange across the vessels responsible for microbubble transmission is impaired. It is entirely possible that oxygen exchange is normal, and indeed, as stated above in exercising dogs (14), arterial oxygenation was not impaired, suggesting this to be the case.Finally, it has been argued by Drs. Stickland, Lovering, and Eldridge that proximal vessel (precapillary) gas inert gas exchange occurring by diffusion may result in an underestimation of intrapulmonary shunt (3, 17) by MIGET. This is because diffusion equilibration of inert gases is much faster than for O2. However, were that the case, the problem for O2 exchange becomes one of diffusion limitation and not shunt. But even here, there is spectrophotometric evidence (1) that O2 can also take part in precapillary exchange, casting doubt on this explanation.In summary, flow through vessels responsible for microbubble transmission in exercising humans has never been shown to impair gas exchange and should not be equated to a shunt, which implies an absence of gas exchange. Furthermore, when intrapulmonary shunts have been quantified, irrespective of technique, they are tiny, like the Whos that Horton the Elephant heard, and can account for no more than 1.4 mmHg, or 7%, of the total AaDO2 of 19 mmHg. We leave it to the reader to decide if microbubble transmission really implies a shunt, whether a "shunt is a shunt no matter how small," and if the effect of intrapulmonary shunt on pulmonary gas exchange is significant.GRANTSThis work was supported by National Heart, Lung, and Blood Institute Grant HL-081171, American Heart Association Grant 054002N, and the Parker B. Francis Foundation.REFERENCES1 Conhaim RL, Staub NC. Reflection spectrophotometric measurement of O2 uptake in pulmonary arterioles of cats. J Appl Physiol 48: 848–856, 1980.Link | ISI | Google Scholar2 Dempsey JA, Wagner PD. Exercise-induced arterial hypoxemia. J Appl Physiol 87: 1997–2006, 1999.Link | ISI | Google Scholar3 Eldridge MW, Dempsey JA, Haverkamp HC, Lovering AT, Hokanson JS. Exercise-induced intrapulmonary arteriovenous shunting in healthy humans. J Appl Physiol 97: 797–805, 2004.Link | ISI | Google Scholar4 Hlastala MP, Robertson HT. Inert gas elimination characteristics of the normal and abnormal lung. J Appl Physiol 44: 258–266, 1978.Link | ISI | Google Scholar5 Hopkins SR, Gavin TP, Siafakas NM, Haseler LJ, Olfert IM, Wagner H, Wagner PD. Effect of prolonged, heavy exercise on pulmonary gas exchange in athletes. J Appl Physiol 85: 1523–1532, 1998.Link | ISI | Google Scholar6 Jonk AM, van den Berg IP, Olfert IM, Wray DW, Arai T, Hopkins SR, Wagner PD. Effect of acetazolamide on pulmonary and muscle gas exchange during normoxic and hypoxic exercise. J Physiol 579: 909–921, 2007.Crossref | ISI | Google Scholar7 Lovering AT, Romer LM, Haverkamp HC, Pegelow DF, Hokanson JS, Eldridge MW. Intrapulmonary shunting and pulmonary gas exchange during normoxic and hypoxic exercise in healthy humans. J Appl Physiol 104: 1418–1425, 2008.Link | ISI | Google Scholar8 Lovering AT, Stickland MK, Kelso AJ, Eldridge MW. Direct demonstration of 25- and 50-μm arteriovenous pathways in healthy human and baboon lungs. Am J Physiol Heart Circ Physiol 292: H1777–H1781, 2007.Link | ISI | Google Scholar9 Manohar M, Goetz TE. Intrapulmonary arteriovenous shunts of >15 μm in diameter probably do not contribute to arterial hypoxemia in maximally exercising Thoroughbred horses. J Appl Physiol 99: 224–229, 2005.Link | ISI | Google Scholar10 Meltzer RS, Tickner EG, Popp RL. Why do the lungs clear ultrasonic contrast? Ultrasound Med Biol 6: 263–269, 1980.Crossref | PubMed | ISI | Google Scholar11 Olfert IM, Balouch J, Kleinsasser A, Knapp A, Wagner H, Wagner PD, Hopkins SR. Does gender affect human pulmonary gas exchange during exercise? J Physiol 557: 529–541, 2004.Crossref | ISI | Google Scholar12 Podolsky A, Eldridge MW, Richardson RS, Knight DR, Johnson EC, Hopkins SR, Johnson DH, Michimata H, Grassi B, Feiner J, Kurdak SS, Bickler PE, Severinghaus JW, Wagner PD. Exercise-induced VA/Q inequality in subjects with prior high-altitude pulmonary edema. 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J Physiol 561: 321–329, 2004.Crossref | PubMed | ISI | Google Scholar18 Vogiatzis I, Zakynthinos S, Boushel R, Athanasopoulos D, Guenette JA, Wagner H, Roussos C, Wagner PD. The contribution of intrapulmonary shunts to the alveolar-to-arterial oxygen difference during exercise is very small. J Physiol 586: 2381–2391, 2008.Crossref | PubMed | ISI | Google Scholar19 Wagner PD, Saltzman HA, West JB. Measurement of continuous distributions of ventilation-perfusion ratios:theory. J Appl Physiol 36: 588–599, 1974.Link | ISI | Google Scholar20 West JB. Respiratory Physiology: The Essentials. Baltimore, MD: Lippincott, Williams & Wilkins, 2005.Google Scholar21 Woods TD, Patel A. A critical review of patent foramen ovale detection using saline contrast echocardiography: when bubbles lie. J Am Soc Echocardiogr 19: 215–222, 2006.Crossref | PubMed | ISI | Google Scholar Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Cited ByA century of exercise physiology: lung fluid balance during and following exercise20 October 2022 | European Journal of Applied Physiology, Vol. 123, No. 1Blunted hypoxic pulmonary vasoconstriction in apnoea divers16 September 2022 | Experimental Physiology, Vol. 107, No. 11Implication of Blood Rheology and Pulmonary Hemodynamics on Exercise-Induced Hypoxemia at Sea Level and Altitude in AthletesInternational Journal of Sport Nutrition and Exercise Metabolism, Vol. 31, No. 5Influence of blood Po2 on the stability of agitated saline contrastLindsey M. Boulet, Tyler D. Vermeulen, Paul D. Cotton, and Glen E. 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Eldridge1 May 2011 | Journal of Applied Physiology, Vol. 110, No. 5Pulmonary Vascular Diseases1 April 2011Effect of initial gas bubble composition on detection of inducible intrapulmonary arteriovenous shunt during exercise in normoxia, hypoxia, or hyperoxiaJonathan E. Elliott, Yujung Choi, Steven S. Laurie, Ximeng Yang, Igor M. Gladstone, and Andrew T. Lovering1 January 2011 | Journal of Applied Physiology, Vol. 110, No. 1Sonic echocardiography: what does it mean when there are no bubbles in the left ventricle?Hugh D. Van Liew, and Richard D. Vann1 January 2011 | Journal of Applied Physiology, Vol. 110, No. 1Pulmonary pathways and mechanisms regulating transpulmonary shunting into the general circulation: An updateInjury, Vol. 41Last Word on Point:Counterpoint: Exercise-induced intrapulmonary shunting is imaginary vs. realSusan R. Hopkins, I. Mark Olfert, and Peter D. Wagner1 September 2009 | Journal of Applied Physiology, Vol. 107, No. 3Comments on Point:Counterpoint: Exercise-induced intrapulmonary shunting is imaginary vs. realRichard L. Jones1 September 2009 | Journal of Applied Physiology, Vol. 107, No. 3Last Word on Point:Counterpoint: Exercise-induced intrapulmonary shunting is imaginary vs. realAndrew T. Lovering, Marlowe W. Eldridge, and Michael K. Stickland1 September 2009 | Journal of Applied Physiology, Vol. 107, No. 3Rebuttal from Hopkins, Olfert, and Wagner1 September 2009 | Journal of Applied Physiology, Vol. 107, No. 3Rebuttal from Lovering, Eldridge, and Stickland1 September 2009 | Journal of Applied Physiology, Vol. 107, No. 3Transpulmonary passage of 99mTc macroaggregated albumin in healthy humans at rest and during maximal exerciseAndrew T. Lovering, Hans C. Haverkamp, Lee M. Romer, John S. Hokanson, and Marlowe W. Eldridge1 June 2009 | Journal of Applied Physiology, Vol. 106, No. 6 More from this issue > Volume 107Issue 3September 2009Pages 993-994 Copyright & PermissionsCopyright © 2009 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.91489.2008PubMed19023012History Published online 1 September 2009 Published in print 1 September 2009 Metrics

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