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Gas Exchange in Disease: Asthma, Chronic Obstructive Pulmonary Disease, Cystic Fibrosis, and Interstitial Lung Disease

Iven H. Young, Peter T.P. Bye

10.1002/cphy.c090012

Source: Volume 1, Issue 2, April 2011

Published online: April 2011

Full Article on Wiley Online Library



Abstract

Ventilation‐perfusion ( a/ ) inequality is the underlying abnormality determining hypoxemia and hypercapnia in lung diseases. Hypoxemia in asthma is characterized by the presence of low a/ units, which persist despite improvement in airway function after an attack. This hypoxemia is generally attenuated by compensatory redistribution of blood flow mediated by hypoxic vasoconstriction and changes in cardiac output, however, mediator release and bronchodilator therapy may cause deterioration. Patients with chronic obstructive pulmonary disease have more complex patterns of a/ inequality, which appear more fixed, and changes in blood flow and ventilation have less benefit in improving gas exchange efficiency. The inability of ventilation to match increasing cardiac output limits exercise capacity as the disease progresses. Deteriorating hypoxemia during exacerbations reflects the falling mixed venous oxygen tension from increased respiratory muscle activity, which is not compensated by any redistribution of a/ ratios. Shunt is not a feature of any of these diseases. Patients with cystic fibrosis (CF) have no substantial shunt when managed according to modern treatment regimens. Interstitial lung diseases demonstrate impaired oxygen diffusion across the alveolar‐capillary barrier, particularly during exercise, although a/ inequality still accounts for most of the gas exchange abnormality. Hypoxemia may limit exercise capacity in these diseases and in CF. Persistent hypercapnic respiratory failure is a feature of advancing chronic obstructive pulmonary disease and CF, closely associated with sleep disordered breathing, which is not a prominent feature of the other diseases. Better understanding of the mechanisms of hypercapnic respiratory failure, and of the detailed mechanisms controlling the distribution of ventilation and blood flow in the lung, are high priorities for future research. © 2011 American Physiological Society. Compr Physiol 1:663‐697, 2011.

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Figure 1. Figure 1.

Minute ventilation (e) and alveolar ventilation (a) in relation to % predicted FEV1 in 30 patients presenting with acute asthma. Both measures of ventilation increase, with a widening gap representing a/ inequality, causing hypocapnia until the FEV1 decreases below 15% to 20% predicted. Then both ventilation measures decrease below normal and hypercapnia ensues. Note the small initial increase in Bohr dead space [(e − a)/e], which increases rapidly around 15% to 20% predicted FEV1. (Modified from reference 136.)
Figure 2. Figure 2.

Typical patterns of ventilation‐perfusion (a/) distributions found in subjects with asthma at different stages and in normal subjects. Ventilation (open circles) and blood flow (closed circles) are plotted against a/ on a log scale. The normal distribution is narrow, unimodal, and centered around a a/ of 1. Subjects with episodic or well‐controlled asthma show broadly unimodal distributions, whereas more severe asthma may be characterized by a bimodal pattern. Shunt is absent and acetone dead space (approximating anatomic dead space) is normal in each condition (upper right open circle). (From reference 193.)
Figure 3. Figure 3.

The evolution of a/ ratio inequality as acute severe asthma resolves. The axes and symbols are the same as in Figure 2. Considerable a/ inequality may remain despite improvement in FEV1 to approximately 60% predicted by day 5, and recovery to a normal distribution does not occur until weeks after discharge from hospital. (From reference 188.)
Figure 4. Figure 4.

Two measures of a/ inequality are shown, plotted against % predicted FEV1 indicating the clinical spectrum of asthma. The dispersion of the blood flow distribution (log SD ) (A) is abnormal in mild asthma and does not increase dramatically until the FEV1 deteriorates to less than 40% predicted. The dispersion of ventilation (log SD ) (B) is only mildly abnormal, even in severe asthma. (From reference 236.)
Figure 5. Figure 5.

Four distinct patterns of a/ distribution measured in patients with chronic obstructive pulmonary disease. Shunt and acetone (anatomic) dead space are not shown. (A) Broad unimodal distributions of ventilation and blood flow; (B) bimodal distribution of blood flow; (C) bimodal distribution of ventilation; and (D) bimodal distribution of both blood flow and ventilation. The significance of these patterns is discussed in the text. (From reference 19.)
Figure 6. Figure 6.

Each point represents a comparison of the measured Pao2 and that predicted from the a/ distribution for every measurement during rest (closed circles) and exercise (open circles) from the chronic obstructive pulmonary disease (COPD) patients studied by Wagner et al. 232. There is a scale change at 100 mmHg to incorporate the measurements breathing 100% oxygen. Note that there is no systematic difference between the two measurements, except where the Pao2 is greater than 300 mmHg where errors in the measurements of Pao2 will weigh the points above the line of identity. Thus, there is no evidence to support a diffusion limitation to oxygen transfer across the alveolar‐capillary barrier at rest or during exercise in COPD. (From reference 232.)
Figure 7. Figure 7.

Theoretical analysis of the relative contributions of the factors that determined the change in the ratio of arterial oxygen tension to inspired oxygen fraction (Pao2/Fio2) during an acute exacerbation of chronic obstructive pulmonary disease, in the patients studied by Barberà et al. 22. Dashed bars indicate the Pao2/Fio2 measured under stable clinical conditions minus that predicted to result from the measured changes during the exacerbation in minute ventilation, cardiac output, oxygen consumption, all these extrapulmonary factors together, and a/ inequality. The solid bar indicates the actual change in Pao2/Fio2 that was measured during the exacerbation. Note that the major contributing factor to the fall in Pao2/Fio2 was an increase in oxygen consumption, while the major ameliorating factor was an increase in cardiac output. (From reference 19, and data from reference 22.)
Figure 8. Figure 8.

Relation between resting mean pulmonary artery pressure and the EMI number of the lowest fifth percentile in computerized tomography scans, the latter as a measurement of lung tissue density and the degree of emphysema in the study of 32 patients with chronic obstructive pulmonary disease by Biernacki et al. 26. A more negative EMI number indicates less tissue density and more advanced emphysema. Closed circles represent patients with resting Pao2 ≤ 60 mmHg and Paco2 ≥ 45 mmHg, open triangles Pao2 ≤ 60 mmHg and Paco2 < 45 mmHg, and open circles Pao2 > 60 mmHg and Paco2 < 45 mmHg. There is no significant relation between mean pulmonary artery pressure and either the degree of emphysema or the degree of resting gas exchange disturbance in this study. (From reference 26.)
Figure 9. Figure 9.

Measurements of minute ventilation (A) and the multiple inert gas elimination technique measurements of dispersion of ventilation (log SD ) (B) are shown for the subjects studied by Robinson et al. 186 during an acute exacerbation of chronic obstructive pulmonary disease while breathing air and 100% oxygen. Minute ventilation fell and log SD increased significantly (*) only in the group that retained carbon dioxide (Group R) and not in the group that did not retain (Group NR) (see text). (From reference 186.)
Figure 10. Figure 10.

Measurements of the dispersion of blood flow (log SD ) in the same patients and under the same conditions as those described in Figure 9 186. Note that log SD significantly (*) increased in both the carbon dioxide retaining and non‐retaining groups, representing the release of hypoxic vasoconstriction, and that there was no significant difference between the responses of the R and NR groups. (From reference 186.)
Figure 11. Figure 11.

Diagram of the exercise responses, to increasing levels of oxygen consumption, of dead space ventilation, alveolar ventilation, total minute ventilation, and the ratio of minute ventilation‐to‐maximum ventilatory capacity in patients with chronic obstructive pulmonary disease (COPD) (dashed lines) compared with normal subjects (solid lines). Note that dead space ventilation is higher and that minute ventilation progresses as a substantially higher proportion of the maximum voluntary capacity in the COPD patients. From Gallagher CG. Exercise limitation and clinical exercise testing in chronic obstructive pulmonary disease. Clin Chest Med 15: 305‐326, 1994. © Elsevier.
Figure 12. Figure 12.

Changes in Pao2 and Paco2 from rest to exercise in patients with severe chronic obstructive pulmonary disease (COPD) (mean FEV1 0.6 liters, Subgroup 1) and patients with more moderate COPD (mean FEV1 1.2 liters, Subgroup 2). Exercise hypoxemia and hypercapnia are features of more advanced COPD. (From reference 179.)
Figure 13. Figure 13.

Summary of percent changes from rest to exercise in Pao2, minute ventilation (e), cardiac output (T), Paco2, log SD , and the ratio e/T. The open bars represent normal subjects, dashed bars those with mild chronic obstructive pulmonary disease (COPD), and the closed bars those with severe COPD. Exercise hypoxemia and hypercapnia are only seen in patients with severe COPD and this is largely related to the inability to increase e/T during exercise. (From reference 19.)
Figure 14. Figure 14.

Ventilation‐perfusion (a/) distributions measured in six young adults with cystic fibrosis 52 at rest. The striking finding is the presence of substantial shunt as the main mechanism accounting for hypoxemia in this patient group studied in the early 1980s (see text). (From reference 52.)
Figure 15. Figure 15.

Ventilation‐perfusion (a/) distributions measured in four young adults with cystic fibrosis 119, studied in the late 1990s. There is no substantial shunt found in these subjects who were managed with a more intensive regular treatment regimen than the patients illustrated in Figure 14 (see text). (From reference 119.)
Figure 16. Figure 16.

Ventilation‐perfusion (a/) distributions measured in two representative patients (JSS top panels and MRG bottom panels) with idiopathic pulmonary fibrosis (IPF). The left column shows distributions recovered breathing air at rest, the middle column breathing 100% oxygen at rest, and the right column during exercise breathing air. See text for further discussion. (From reference 7.)
Figure 17. Figure 17.

The Pao2 predicted from the a/ distributions compared with measured Pao2 during rest (closed circles) and exercise (open circles) from the patients with idiopathic pulmonary fibrosis (IPF) studied by Agustí et al. 7. There is evidence for limitation of oxygen diffusion across the alveolar‐capillary barrier at rest and that this increases during exercise (see text). (From reference 3, and data from reference 7.)
Figure 18. Figure 18.

Individual measurements of exercise duration are compared during normal breathing (abscissa) and while breathing supplemental oxygen through an added dead space load (ordinate) in the patient group with interstitial lung disease studied by Harris‐Eze et al. 91. The dotted line of identity is shown. Despite the extra load to ventilation imposed by the additional dead space, relief of hypoxemia resulted in substantially longer exercise endurance times (see text). (From reference 91.)
Figure 19. Figure 19.

Pulmonary capillary wedge pressure is plotted against cardiac output from rest to exercise in normal subjects (open squares) and in patients with sarcoidosis (downward triangles), idiopathic pulmonary fibrosis (diamonds) and other interstitial lung diseases (upward triangles). The increased wedge pressures recorded in the interstitial diseases is evidence for impaired cardiac function during exercise in these conditions (see text). (From reference 3.)
Figure 20. Figure 20.

On the abscissa, the % change in dispersion of the blood flow distribution (log SD ) from breathing air to breathing 100% oxygen is shown, plotted against mean exercise pulmonary artery pressure (left panel) and minimum Pao2 during exercise (right panel) for the patients with idiopathic pulmonary fibrosis studied by Agustí et al. 7. A larger change in % baseline log SD indicates greater release of hypoxic vasoconstriction and a more responsive pulmonary vasculature. Patients with a more responsive vasculature tend to have lower exercise pulmonary artery pressure and a higher Pao2 during exercise (see text). (From reference 3, and data from reference 7.)


Figure 1.

Minute ventilation (e) and alveolar ventilation (a) in relation to % predicted FEV1 in 30 patients presenting with acute asthma. Both measures of ventilation increase, with a widening gap representing a/ inequality, causing hypocapnia until the FEV1 decreases below 15% to 20% predicted. Then both ventilation measures decrease below normal and hypercapnia ensues. Note the small initial increase in Bohr dead space [(e − a)/e], which increases rapidly around 15% to 20% predicted FEV1. (Modified from reference 136.)



Figure 2.

Typical patterns of ventilation‐perfusion (a/) distributions found in subjects with asthma at different stages and in normal subjects. Ventilation (open circles) and blood flow (closed circles) are plotted against a/ on a log scale. The normal distribution is narrow, unimodal, and centered around a a/ of 1. Subjects with episodic or well‐controlled asthma show broadly unimodal distributions, whereas more severe asthma may be characterized by a bimodal pattern. Shunt is absent and acetone dead space (approximating anatomic dead space) is normal in each condition (upper right open circle). (From reference 193.)



Figure 3.

The evolution of a/ ratio inequality as acute severe asthma resolves. The axes and symbols are the same as in Figure 2. Considerable a/ inequality may remain despite improvement in FEV1 to approximately 60% predicted by day 5, and recovery to a normal distribution does not occur until weeks after discharge from hospital. (From reference 188.)



Figure 4.

Two measures of a/ inequality are shown, plotted against % predicted FEV1 indicating the clinical spectrum of asthma. The dispersion of the blood flow distribution (log SD ) (A) is abnormal in mild asthma and does not increase dramatically until the FEV1 deteriorates to less than 40% predicted. The dispersion of ventilation (log SD ) (B) is only mildly abnormal, even in severe asthma. (From reference 236.)



Figure 5.

Four distinct patterns of a/ distribution measured in patients with chronic obstructive pulmonary disease. Shunt and acetone (anatomic) dead space are not shown. (A) Broad unimodal distributions of ventilation and blood flow; (B) bimodal distribution of blood flow; (C) bimodal distribution of ventilation; and (D) bimodal distribution of both blood flow and ventilation. The significance of these patterns is discussed in the text. (From reference 19.)



Figure 6.

Each point represents a comparison of the measured Pao2 and that predicted from the a/ distribution for every measurement during rest (closed circles) and exercise (open circles) from the chronic obstructive pulmonary disease (COPD) patients studied by Wagner et al. 232. There is a scale change at 100 mmHg to incorporate the measurements breathing 100% oxygen. Note that there is no systematic difference between the two measurements, except where the Pao2 is greater than 300 mmHg where errors in the measurements of Pao2 will weigh the points above the line of identity. Thus, there is no evidence to support a diffusion limitation to oxygen transfer across the alveolar‐capillary barrier at rest or during exercise in COPD. (From reference 232.)



Figure 7.

Theoretical analysis of the relative contributions of the factors that determined the change in the ratio of arterial oxygen tension to inspired oxygen fraction (Pao2/Fio2) during an acute exacerbation of chronic obstructive pulmonary disease, in the patients studied by Barberà et al. 22. Dashed bars indicate the Pao2/Fio2 measured under stable clinical conditions minus that predicted to result from the measured changes during the exacerbation in minute ventilation, cardiac output, oxygen consumption, all these extrapulmonary factors together, and a/ inequality. The solid bar indicates the actual change in Pao2/Fio2 that was measured during the exacerbation. Note that the major contributing factor to the fall in Pao2/Fio2 was an increase in oxygen consumption, while the major ameliorating factor was an increase in cardiac output. (From reference 19, and data from reference 22.)



Figure 8.

Relation between resting mean pulmonary artery pressure and the EMI number of the lowest fifth percentile in computerized tomography scans, the latter as a measurement of lung tissue density and the degree of emphysema in the study of 32 patients with chronic obstructive pulmonary disease by Biernacki et al. 26. A more negative EMI number indicates less tissue density and more advanced emphysema. Closed circles represent patients with resting Pao2 ≤ 60 mmHg and Paco2 ≥ 45 mmHg, open triangles Pao2 ≤ 60 mmHg and Paco2 < 45 mmHg, and open circles Pao2 > 60 mmHg and Paco2 < 45 mmHg. There is no significant relation between mean pulmonary artery pressure and either the degree of emphysema or the degree of resting gas exchange disturbance in this study. (From reference 26.)



Figure 9.

Measurements of minute ventilation (A) and the multiple inert gas elimination technique measurements of dispersion of ventilation (log SD ) (B) are shown for the subjects studied by Robinson et al. 186 during an acute exacerbation of chronic obstructive pulmonary disease while breathing air and 100% oxygen. Minute ventilation fell and log SD increased significantly (*) only in the group that retained carbon dioxide (Group R) and not in the group that did not retain (Group NR) (see text). (From reference 186.)



Figure 10.

Measurements of the dispersion of blood flow (log SD ) in the same patients and under the same conditions as those described in Figure 9 186. Note that log SD significantly (*) increased in both the carbon dioxide retaining and non‐retaining groups, representing the release of hypoxic vasoconstriction, and that there was no significant difference between the responses of the R and NR groups. (From reference 186.)



Figure 11.

Diagram of the exercise responses, to increasing levels of oxygen consumption, of dead space ventilation, alveolar ventilation, total minute ventilation, and the ratio of minute ventilation‐to‐maximum ventilatory capacity in patients with chronic obstructive pulmonary disease (COPD) (dashed lines) compared with normal subjects (solid lines). Note that dead space ventilation is higher and that minute ventilation progresses as a substantially higher proportion of the maximum voluntary capacity in the COPD patients. From Gallagher CG. Exercise limitation and clinical exercise testing in chronic obstructive pulmonary disease. Clin Chest Med 15: 305‐326, 1994. © Elsevier.



Figure 12.

Changes in Pao2 and Paco2 from rest to exercise in patients with severe chronic obstructive pulmonary disease (COPD) (mean FEV1 0.6 liters, Subgroup 1) and patients with more moderate COPD (mean FEV1 1.2 liters, Subgroup 2). Exercise hypoxemia and hypercapnia are features of more advanced COPD. (From reference 179.)



Figure 13.

Summary of percent changes from rest to exercise in Pao2, minute ventilation (e), cardiac output (T), Paco2, log SD , and the ratio e/T. The open bars represent normal subjects, dashed bars those with mild chronic obstructive pulmonary disease (COPD), and the closed bars those with severe COPD. Exercise hypoxemia and hypercapnia are only seen in patients with severe COPD and this is largely related to the inability to increase e/T during exercise. (From reference 19.)



Figure 14.

Ventilation‐perfusion (a/) distributions measured in six young adults with cystic fibrosis 52 at rest. The striking finding is the presence of substantial shunt as the main mechanism accounting for hypoxemia in this patient group studied in the early 1980s (see text). (From reference 52.)



Figure 15.

Ventilation‐perfusion (a/) distributions measured in four young adults with cystic fibrosis 119, studied in the late 1990s. There is no substantial shunt found in these subjects who were managed with a more intensive regular treatment regimen than the patients illustrated in Figure 14 (see text). (From reference 119.)



Figure 16.

Ventilation‐perfusion (a/) distributions measured in two representative patients (JSS top panels and MRG bottom panels) with idiopathic pulmonary fibrosis (IPF). The left column shows distributions recovered breathing air at rest, the middle column breathing 100% oxygen at rest, and the right column during exercise breathing air. See text for further discussion. (From reference 7.)



Figure 17.

The Pao2 predicted from the a/ distributions compared with measured Pao2 during rest (closed circles) and exercise (open circles) from the patients with idiopathic pulmonary fibrosis (IPF) studied by Agustí et al. 7. There is evidence for limitation of oxygen diffusion across the alveolar‐capillary barrier at rest and that this increases during exercise (see text). (From reference 3, and data from reference 7.)



Figure 18.

Individual measurements of exercise duration are compared during normal breathing (abscissa) and while breathing supplemental oxygen through an added dead space load (ordinate) in the patient group with interstitial lung disease studied by Harris‐Eze et al. 91. The dotted line of identity is shown. Despite the extra load to ventilation imposed by the additional dead space, relief of hypoxemia resulted in substantially longer exercise endurance times (see text). (From reference 91.)



Figure 19.

Pulmonary capillary wedge pressure is plotted against cardiac output from rest to exercise in normal subjects (open squares) and in patients with sarcoidosis (downward triangles), idiopathic pulmonary fibrosis (diamonds) and other interstitial lung diseases (upward triangles). The increased wedge pressures recorded in the interstitial diseases is evidence for impaired cardiac function during exercise in these conditions (see text). (From reference 3.)



Figure 20.

On the abscissa, the % change in dispersion of the blood flow distribution (log SD ) from breathing air to breathing 100% oxygen is shown, plotted against mean exercise pulmonary artery pressure (left panel) and minimum Pao2 during exercise (right panel) for the patients with idiopathic pulmonary fibrosis studied by Agustí et al. 7. A larger change in % baseline log SD indicates greater release of hypoxic vasoconstriction and a more responsive pulmonary vasculature. Patients with a more responsive vasculature tend to have lower exercise pulmonary artery pressure and a higher Pao2 during exercise (see text). (From reference 3, and data from reference 7.)

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CORRIGENDUM

Iven H. Young, Peter T.P. Bye. Gas Exchange in Disease: Asthma, Chronic Obstructive Pulmonary Disease, Cystic Fibrosis, and Interstitial Lung Disease. Compr Physiol 2011 1:663–697. doi: 10.1002/cphy.c090012

The text on p. 668 has been changed from “substituted for the mixed alveolar tension” to “substituted for the ideal alveolar tension.”


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Article Title: Gas Exchange in Disease: Asthma, Chronic Obstructive Pulmonary Disease, Cystic Fibrosis, and Interstitial Lung Disease
 

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Iven H. Young, Peter T.P. Bye. Gas Exchange in Disease: Asthma, Chronic Obstructive Pulmonary Disease, Cystic Fibrosis, and Interstitial Lung Disease. Compr Physiol 2011, 1: 663-697. doi: 10.1002/cphy.c090012