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Determinants of Gas Exchange and Acid–Base Balance During Exercise

Robert L. Johnson, George J. F. Heigenhauser, Connie C. W. Hsia, Norman L. Jones, Peter D. Wagner

10.1002/cphy.cp120112

Source: Supplement 29: Handbook of Physiology, Exercise: Regulation and Integration of Multiple Systems

Originally published: 1996

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Structural and Functional Determinants of Gas Exchange
1.1 The Nature of O2 and CO2 Binding and Chemical Equilibria in Blood
1.2 Alveolar Gas Composition at Equilibrium with End‐Capillary Blood
1.3 Diffusive Gas Transport
1.4 Rate of Equilibration between Alveolar Air and Capillary Blood
1.5 Nonuniformity of Regional Gas Exchange
1.6 Optimizing Transport between Lung and Muscle
2 Methods of Assessment
2.1 Rates of Inert Gas Mixing in the Lung
2.2 Infusion Techniques
2.3 Ventilation/Perfusion (V.A/Q.) Relationships
2.4 Diffusing Capacity of the Lung
3 Pulmonary Gas Exchange During Exercise
3.1 Changes in Arterial PCO2 and PO2 at Incremental Workloads
3.2 Physiological Basis of Arterial Blood Gas Changes
3.3 Physiological Basis of V.A/Q. Mismatch and Diffusion Limitation
4 Acid–Base Regulation During Exercise: A Physicochemical Approach
4.1 Basic Concepts of Acid–Base Physiology
4.2 Physicochemical Approach to Factors Influencing [H+]
4.3 Systems Contributing to [H+] Regulation
4.4 Interaction between Systems
4.5 Determinants of [H+] in Different Body Compartments
4.6 Contributors to [H+] in Muscle at Rest and Exercise
4.7 Changes in Extracellular Fluid in Exercise
4.8 Venous Plasma and Erythrocytes
4.9 Lactate Oxidation and the Role of Inactive Muscle
4.10 Integration of Mechanisms in Acid–Base Balance and CO2 Excretion
4.11 The Physicochemical Approach: Advantages and Drawbacks
5 Comparative Aspects of Gas Exchange
5.1 Comparison of Structural and Physiologic Estimates of Diffusing Capacity
5.2 Recruitment of Diffusing Capacity during Exercise
5.3 Importance of Blood Volume and Hematocrit
5.4 Optimization of O2 Transport — The Role of Hemoglobin P50
6 Conclusion
Figure 1. Figure 1.

Oxyhemoglobin and oxymyoglobin dissociation curves at different levels of pH. The oxyhemoglobin dissociation curve at pH 7.4 is compared to that calculated from the Hill equation at the same P50.
Figure 2. Figure 2.

Hill plot for human whole blood to determine the value of n as defined in equation 3. At low oxygen saturations, the slope of the relationship approaches 1 as predicted for a second‐order reaction as the first heme binding site becomes filled. The steepest slope yields an n of 2.7. At very high oxygen saturations, the slope again approaches 1 as the last binding site is being filled.
Figure 3. Figure 3.

The CO2 dissociation curve for reduced and oxygenated blood. CO2 is primarily carried in the plasma as bicarbonate, but must be rapidly hydrated in the red cell by the enzyme, carbonic anhydrase, to form bicarbonate and then transported into the plasma in exchange for chloride. Part of the CO2 is bound to hemoglobin and carried as carbamate without requiring hydration or dehydration during transport. The change in shape of the hemogobin molecule as it releases oxygen in tissues enhances both the formation of bicarbonate and carbamate inside the red cell, so that more CO2 is carried at any given CO2 tension (Haldane shift). The horizontal arrows indicate the shift in PCO2 that occurs at a given CO2 content when oxyhemogobin saturation falls in tissues (upper arrow) or rises in the lung (lower arrow). The dashed line would be the effective CO2 dissociation curve. At maximal oxygen uptake, the Haldane shift minimizes the arteriovenous PCO2 and [H+] differences required for a given CO2 output.
Figure 4. Figure 4.

Estimating O2 and CO2 equilibrium in the lung or in a region of lung if mixed venous blood gases, the A/C ratio and the dissociation curves for oxygen and oxyhemoglobin are known. Results are derived from data collected at maximal oxygen uptake in a young high school athlete. The straight diagonal lines were calculated from equations 5 and 6, which were solved simultaneously for a respiratory exchange ratio of 1.05 and A/C ratio of 4.06. Equilibrium is indicated by the intersection between the straight diagonal lines with the corresponding dissociation curve.
Figure 5. Figure 5.

Relationships for the rate of uptake of CO by human red cells in suspension (1/θXO) to oxygen tension measured in vitro in two different laboratories. Closed circles represent measurements reported by Roughton, Forster, and Cander in 1957 using a steady‐state turbulent flow‐mixing technique 214 at CO tensions of about 90 mm Hg. Open circles represent measurements by a thin film technique at CO tensions of about 2 mm Hg (i.e., a value similar to the alveolar CO tension during physiological measurements of DLCO). The kinetic data of Roughton et al. for CO uptake were corrected to a low CO tension: (PCO/PO2) < 0.03. The measurements of Roughton and Forster also were constrained to a theoretical equation developed by Nicholson and Roughton to define the interaction between CO diffusion and reaction kinetics describing the CO displacement of O2 from oxyhemoglobin 180. The equation employs a ratio of diffusive permeability of the red cell membrane to that of the red cell interior (λ). Dashed lines are the constrained relationships reported by Roughton and Forster for different assumed value of λ between 1.5 and ∞. Average λ fit to the kinetic data was 1.5. Data of Park and Reeves, which are measured by a technique that minimizes error from unstirred layers, fall within the original constrained relationships of Roughton and Forster and yield similar estimates of DM and Vc from DLCO measured at different O2 tensions 187,207.
Figure 6. Figure 6.

Predicted effects of increasing the depth of inspiration on DLCO based on an electrical analog of resistances to gas phase and tissue diffusion in the lung acinus. Resistors oriented from right to left across the page represent gas phase resistance to CO diffusion in respired air. There is a resistor for each airway generation from the terminal bronchiole (TB) at the mouth of the acinus to the alveolar sac (AS) at the end. Resistors perpendicular to these represent tissue resistance to diffusive CO uptake in capillaries of alveoli arising from each airway generation. Approximate changes in depth of penetration of the convective interface at different inspired volumes are shown. DLCO increases with depth of convective penetration owing to the progressive decrease in gas phase resistance. Calculations are based on airway length and total cross‐sectional area in each generation and the fraction of total alveoli arising from each generation as reported by Weibel 191.
Figure 7. Figure 7.

Vector diagrams demonstrate the fluxes of CO from alveolar air into red cells, which act as infinite sinks. Results are shown at two levels of capillary hematocrit. Magnitude and direction of the flux are represented by the size and orientation of the arrows, respectively. A, one cell per 50 μm capillary (hematocrit = 12%). B, 6 cells per 50 μm capillary (hematocrit = 66%).

Reproduced with permission from Hsia et al. 121
Figure 8. Figure 8.

Rates at which oxygen equilibrates with oxyhemoglobin during blood transit through lung capillaries were calculated from the data in Table 2 at maximal exercise. A, Constructed based on equations 28 and 29, showing the rate of increase in oxygen saturation at an alveolar oxygen tension of 112 mm Hg and at an estimated in vivo P50 of 31.8 mm Hg. Mean transit time was 0.565 s, insufficient for complete equilibrium; oxygen tension in blood leaving the lung was estimated at approximately 104 mm Hg. B, The same data plotted in a different way based on equations 29 and 30, yielding the same information but illustrating the fact that at a given alveolar oxygen tension and P50 arterial oxygen saturation will begin to fall sharply as the ratio of /c falls below a critical level. Calculations in both graphs were repeated at a normal resting P50 of 26.5 mm Hg to illustrate the more rapid approach to equilibrium at a lower P50 owing to the higher average oxygen tension difference between‐alveolar air and capillary blood during red cell transit when P50 is lower.
Figure 9. Figure 9.

Rates of alveolar capillary CO2 equilibrium were calculated for data in Table 2 at maximal O2 uptake assuming that the rate‐limiting process is the HCO3 – Cl− shift between red cells and plasma during CO2 elimination in the lung. This shift has a half‐time for completion of about 0.15 s. Others have made similar calculations based on more sophisticated approaches involving a more comprehensive analysis of the different chemical reactions involved in CO2 transport, but similar conclusions are reached 18,110. Theoretically, these slow exchanges would be incomplete during short capillary transit times, and after red cells leave lung capillaries HCO3 would continue to enter the cells and liberate CO2 gas; hence, postcapillary CO2 tension will rise. The final difference between alveolar and arterial CO2 tension was estimated to be 3.7 mm Hg. Endothelial carbonic anhydrase in the lung will reduce this alveolar‐arterial CO2 tension gradient but not completely eliminate it 133.
Figure 10. Figure 10.

Effect of unequal distribution of ventilation–perfusion (A/c) ratios on efficiency of gas exchange. The same principals employed to estimate O2 and CO2 equilibrium in a homogeneous lung (Fig. 4) can be applied to individual regions of lung if regional A/c ratios, mixed venous gas contents, inspired gas concentrations, and the dissociation curves for oxyhemoglobin and CO2 are known. The two‐compartment model illustrated above for CO2 and O2 can explain the measured AaPO2 at maximal oxygen uptake, but it is not the only explanation. For example, Figure 11 will illustrate another possible explanation based on either uneven red cell transit times through lung capillaries or uneven distribution of /c ratios in the lung.
Figure 11. Figure 11.

Effect of uneven red cell transit times through lung capillaries or uneven ratios of /c on the alvelar–arterial oxygen tension difference (AaPO2) based on the data from Table 2. Panels a and b illustrate graphically how unequal red cell transit times or unequal ratios of /c can explain the measured 28 mm Hg AaPO2. There are an infinite number of these two‐compartment solutions that are equally plausible.
Figure 12. Figure 12.

An illustration of how the position of the oxyhemoglobin dissociation curve (P50) affects oxygen loading of blood in the lung and unloading in the tissues. A, Position of the oxyhemoglobin dissociation curve has the potential to match optimally the diffusive resistance in the lung and tissues with the pressure gradient available for oxygen loading and unloading respectively, as illustrated by this exaggeration of the sigmoidal shape of the dissociation curve. B, Optimal P50 will vary with altitude because of differences in alveolar O2 tension. Oxygen transport at sea level will be enhanced at a low pH (high P50) because of the relatively high muscle resistance to diffusive O2 uptake. Oxygen transport at high altitude will be enhanced at a more alkaline pH (lower P50) which enhances oxygen loading in the lung at the low alveolar oxygen tension.
Figure 13. Figure 13.

Recruitment of diffusing capacity of the lung for CO (DLCO), membrane diffusing capacity (DMCO), and pulmonary capillary blood volume (VC) as pulmonary blood flow increases during exercise in humans. DLCO continues to increase from rest to exercise along an approximately linear relationship with respect to pulmonary blood flow up to maximal oxygen uptake without reaching an apparent plateau.
Figure 14. Figure 14.

Comparison of and DLNO at rest and exercise calculated from the data in Figure 13 with measurements of by the Lilienthal‐Riley technique 40,158,228,229,248 and by application of MIGET 91,120 and with measurements of DLNO by a breath‐holding method 23,164. Comparisons are made with respect to blood flow where measurements of cardiac output are available (Panel 1) and with respect to oxygen uptake (Panel b). Neither oxygen uptake nor cardiac output were available for measurements of DLNO, which were all obtained at rest; hence, a cardiac index of 3.0 was assumed for each measurement of DLNO.
Figure 15. Figure 15.

Arterial PO2, arterial PCO2, and alveolar‐arterial PO2 difference as a function of exercise intensity (oxygen uptake). At heavy levels of exercise, both arterial PO2 and PCO2 fall, and as a result the alveolar‐arterial PO2 difference increases markedly 253.
Figure 16. Figure 16.

Measured and predicted alveolar–arterial PO2 differences from the same data as in Figure 15. The predicted value represents the effects of ventilation–perfusion inequality, while the measured value also includes the effects of diffusion limitation. Up to 2 liter/min ventilation–perfusion inequality accounts for virtually all of the alveolar–arterial PO2 difference. At higher exercise intensities, the contribution of ventilation–perfusion mismatching does not change, while diffusion limitation becomes increasingly important.
Figure 17. Figure 17.

At simulated altitude of 10,000 feet (barometric pressure = 523 mm Hg), considerable diffusion limitation of oxygen uptake occurs during exercise, which permits calculation of the oxygen diffusing capacity. increases essentially linearly with increasing exercise. As explained in the text, the importance of diffusion limitation depends upon the ratio DL/β falling from 1.6 (light exercise) to 1 (heavy exercise) under these conditions, resulting in incomplete diffusive equilibration as shown in the bottom right panel. Thus during moderate and heavy exercise at this altitude, diffusion equilibration proceeds but only to two‐thirds completion 253.
Figure 18. Figure 18.

Effects of altitude (simulated in a hypobaric chamber) on diffusional limitation of oxygen at a constant level of exercise (180 W). increases at altitude, at this submaximal level, presumably as a consequence of increasing blood flow causing a combination of distention and recruitment. The effective slope of the oxyhemoglobin dissociation curve (β) increases with increasing altitude as arterial and venous PO2 fall, and the result of these changes is that the ratio /β progressively falls with altitude.
Figure 19. Figure 19.

Alveolar–arterial PO2 difference during exercise as a function of altitude. During submaximal exercise the alveolar‐arterial PO2 difference is significantly higher at altitude than at sea level. This is the result of greater diffusion limitation 252.
Figure 20. Figure 20.

Abnormal ventilation–perfusion ratio distributions caused by HAPE in one subject at a simulated altitude of 20,000 ft. At rest, there was a 15% shunt and an additional 10% of the cardiac output perfusing abnormally low A/ areas. On exercise, the shunt increased to 29%, with 17% of the cardiac output perfusing areas of low A/ ratio.
Figure 21. Figure 21.

Gamblegrams to show the systems contributing to H+ ion concentration in different compartments. Independent variables are [SID], Atot, and PCO2. The two bars of the histogram represent net negative and positive changes, and are of equal height to indicate the constraint of electrical neutrality, and in which [SID] equals the sum of the dependent variables [A−] and [].
Figure 22. Figure 22.

The proportion of dissociated (A−) to undissociated (HA) forms of three weak electrolytes having pK values of 5, 7, and 9. In the physiological range of pH (6.4–7.6), the first is fully dissociated and the third is undissociated.
Figure 23. Figure 23.

Gamblegrams showing the major changes in arterial plasma and muscle ionic status from rest (upper panels) to maximum exercise (lower panels).
Figure 24. Figure 24.

Arteriovenous differences for strong ions and bicarbonate following 30 s maximal exercise, contrasting changes in blood across the exercising leg (left) and the inactive forearm (right).

From Kowalchuk et al. 148,149, with permission
Figure 25. Figure 25.

Effects of increases in muscle CO2 content, due to metabolism in exercise, on intracellular PCO2; resting values indicated by circle. Note that if [SID] is unchanged or increases, CO2 may accumulate without a large change in PCO2, but a fall in [SID] will lead to large accompanying increases in PCO2.
Figure 26. Figure 26.

The CO2 “dissociation curve” for whole blood, with isopleths of plasma [SID], constructed for blood having a hemoglobin content of 14 g/dl and O2 saturation of 97%. The points plot the classical whole blood curve of content vs. PCO2 87 for fully oxygenated blood (lower curve), and only 25% saturated (upper curve). Note that the increase in content shown by the classical relationships due to increases in PCO2 and desaturation are in part due to increases in plasma [SID]. Also, note that a sufficient venoarterial difference in CO2 content during exercise cannot be achieved through an increase in PCO2 alone; an increase in [SID] is also required by virtue of the ‐Cl− shift to avoid a very large increase in or decrease in .
Figure 27. Figure 27.

Comparison of DLCO estimates by physiologic (re‐breathing) method in dogs during heavy exercise with that in the same animals by morphometric methods at postmortem. The physiological estimate of DLCO at peak exercise is actually sightly greater than estimated by morphometry at postmortem. This result is misleading, however, because the membrane diffusing capacity by morphometry is twice the physiological estimate and the pulmonary capillary blood volume by morphometry is half that estimated physiologically at peak exercise. These differences remain unresolved.
Figure 28. Figure 28.

A, Comparison of DLCO with respect to pulmonary blood flow before and after left pneumonectomy in foxhounds. Data are normalized with respect to the normal lung and show that DLCO continues to rise after pneumonectomy as blood flow is increased to a level equivalent to 35 liters/min through two normal lungs without reaching a plateau. B, Comparison for the relationship between DLCO/C with respect to pulmonary blood flow from rest to peak exercise for the same data as that in A. The data show that in spite of continued recruitment after pneumonectomy, DL/c falls to a lower level after pneumonectomy than before so that diffusion became a significant source of exercise limitation.
Figure 29. Figure 29.

A, Change in hematocrit in normal foxhounds from rest to peak exercise. There is an approximately 40% increase in hematocrit in foxhounds owing to injection of red cells into the circulation by splenic contraction. In humans the increase of hematocrit is only about 3% under similar conditions, primarily due to a fall in plasma valume. B, Comparison of the recruitment of DLCO in foxhounds with that in humans as pulmonary blood flow increases during exercise. Recruitment of diffusing capacity is significantly steeper in foxhounds than in humans, very likely a result of the large expansion of circulating blood volume in the foxhound from exercise‐induced splenic contraction.
Figure 30. Figure 30.

Effect of P50 in optimizng maximal oxygen uptake. The principles illustrated with equation 38 were applied to available data on horses and foxhounds at maximal oxygen uptake.


Figure 1.

Oxyhemoglobin and oxymyoglobin dissociation curves at different levels of pH. The oxyhemoglobin dissociation curve at pH 7.4 is compared to that calculated from the Hill equation at the same P50.



Figure 2.

Hill plot for human whole blood to determine the value of n as defined in equation 3. At low oxygen saturations, the slope of the relationship approaches 1 as predicted for a second‐order reaction as the first heme binding site becomes filled. The steepest slope yields an n of 2.7. At very high oxygen saturations, the slope again approaches 1 as the last binding site is being filled.



Figure 3.

The CO2 dissociation curve for reduced and oxygenated blood. CO2 is primarily carried in the plasma as bicarbonate, but must be rapidly hydrated in the red cell by the enzyme, carbonic anhydrase, to form bicarbonate and then transported into the plasma in exchange for chloride. Part of the CO2 is bound to hemoglobin and carried as carbamate without requiring hydration or dehydration during transport. The change in shape of the hemogobin molecule as it releases oxygen in tissues enhances both the formation of bicarbonate and carbamate inside the red cell, so that more CO2 is carried at any given CO2 tension (Haldane shift). The horizontal arrows indicate the shift in PCO2 that occurs at a given CO2 content when oxyhemogobin saturation falls in tissues (upper arrow) or rises in the lung (lower arrow). The dashed line would be the effective CO2 dissociation curve. At maximal oxygen uptake, the Haldane shift minimizes the arteriovenous PCO2 and [H+] differences required for a given CO2 output.



Figure 4.

Estimating O2 and CO2 equilibrium in the lung or in a region of lung if mixed venous blood gases, the A/C ratio and the dissociation curves for oxygen and oxyhemoglobin are known. Results are derived from data collected at maximal oxygen uptake in a young high school athlete. The straight diagonal lines were calculated from equations 5 and 6, which were solved simultaneously for a respiratory exchange ratio of 1.05 and A/C ratio of 4.06. Equilibrium is indicated by the intersection between the straight diagonal lines with the corresponding dissociation curve.



Figure 5.

Relationships for the rate of uptake of CO by human red cells in suspension (1/θXO) to oxygen tension measured in vitro in two different laboratories. Closed circles represent measurements reported by Roughton, Forster, and Cander in 1957 using a steady‐state turbulent flow‐mixing technique 214 at CO tensions of about 90 mm Hg. Open circles represent measurements by a thin film technique at CO tensions of about 2 mm Hg (i.e., a value similar to the alveolar CO tension during physiological measurements of DLCO). The kinetic data of Roughton et al. for CO uptake were corrected to a low CO tension: (PCO/PO2) < 0.03. The measurements of Roughton and Forster also were constrained to a theoretical equation developed by Nicholson and Roughton to define the interaction between CO diffusion and reaction kinetics describing the CO displacement of O2 from oxyhemoglobin 180. The equation employs a ratio of diffusive permeability of the red cell membrane to that of the red cell interior (λ). Dashed lines are the constrained relationships reported by Roughton and Forster for different assumed value of λ between 1.5 and ∞. Average λ fit to the kinetic data was 1.5. Data of Park and Reeves, which are measured by a technique that minimizes error from unstirred layers, fall within the original constrained relationships of Roughton and Forster and yield similar estimates of DM and Vc from DLCO measured at different O2 tensions 187,207.



Figure 6.

Predicted effects of increasing the depth of inspiration on DLCO based on an electrical analog of resistances to gas phase and tissue diffusion in the lung acinus. Resistors oriented from right to left across the page represent gas phase resistance to CO diffusion in respired air. There is a resistor for each airway generation from the terminal bronchiole (TB) at the mouth of the acinus to the alveolar sac (AS) at the end. Resistors perpendicular to these represent tissue resistance to diffusive CO uptake in capillaries of alveoli arising from each airway generation. Approximate changes in depth of penetration of the convective interface at different inspired volumes are shown. DLCO increases with depth of convective penetration owing to the progressive decrease in gas phase resistance. Calculations are based on airway length and total cross‐sectional area in each generation and the fraction of total alveoli arising from each generation as reported by Weibel 191.



Figure 7.

Vector diagrams demonstrate the fluxes of CO from alveolar air into red cells, which act as infinite sinks. Results are shown at two levels of capillary hematocrit. Magnitude and direction of the flux are represented by the size and orientation of the arrows, respectively. A, one cell per 50 μm capillary (hematocrit = 12%). B, 6 cells per 50 μm capillary (hematocrit = 66%).

Reproduced with permission from Hsia et al. 121


Figure 8.

Rates at which oxygen equilibrates with oxyhemoglobin during blood transit through lung capillaries were calculated from the data in Table 2 at maximal exercise. A, Constructed based on equations 28 and 29, showing the rate of increase in oxygen saturation at an alveolar oxygen tension of 112 mm Hg and at an estimated in vivo P50 of 31.8 mm Hg. Mean transit time was 0.565 s, insufficient for complete equilibrium; oxygen tension in blood leaving the lung was estimated at approximately 104 mm Hg. B, The same data plotted in a different way based on equations 29 and 30, yielding the same information but illustrating the fact that at a given alveolar oxygen tension and P50 arterial oxygen saturation will begin to fall sharply as the ratio of /c falls below a critical level. Calculations in both graphs were repeated at a normal resting P50 of 26.5 mm Hg to illustrate the more rapid approach to equilibrium at a lower P50 owing to the higher average oxygen tension difference between‐alveolar air and capillary blood during red cell transit when P50 is lower.



Figure 9.

Rates of alveolar capillary CO2 equilibrium were calculated for data in Table 2 at maximal O2 uptake assuming that the rate‐limiting process is the HCO3 – Cl− shift between red cells and plasma during CO2 elimination in the lung. This shift has a half‐time for completion of about 0.15 s. Others have made similar calculations based on more sophisticated approaches involving a more comprehensive analysis of the different chemical reactions involved in CO2 transport, but similar conclusions are reached 18,110. Theoretically, these slow exchanges would be incomplete during short capillary transit times, and after red cells leave lung capillaries HCO3 would continue to enter the cells and liberate CO2 gas; hence, postcapillary CO2 tension will rise. The final difference between alveolar and arterial CO2 tension was estimated to be 3.7 mm Hg. Endothelial carbonic anhydrase in the lung will reduce this alveolar‐arterial CO2 tension gradient but not completely eliminate it 133.



Figure 10.

Effect of unequal distribution of ventilation–perfusion (A/c) ratios on efficiency of gas exchange. The same principals employed to estimate O2 and CO2 equilibrium in a homogeneous lung (Fig. 4) can be applied to individual regions of lung if regional A/c ratios, mixed venous gas contents, inspired gas concentrations, and the dissociation curves for oxyhemoglobin and CO2 are known. The two‐compartment model illustrated above for CO2 and O2 can explain the measured AaPO2 at maximal oxygen uptake, but it is not the only explanation. For example, Figure 11 will illustrate another possible explanation based on either uneven red cell transit times through lung capillaries or uneven distribution of /c ratios in the lung.



Figure 11.

Effect of uneven red cell transit times through lung capillaries or uneven ratios of /c on the alvelar–arterial oxygen tension difference (AaPO2) based on the data from Table 2. Panels a and b illustrate graphically how unequal red cell transit times or unequal ratios of /c can explain the measured 28 mm Hg AaPO2. There are an infinite number of these two‐compartment solutions that are equally plausible.



Figure 12.

An illustration of how the position of the oxyhemoglobin dissociation curve (P50) affects oxygen loading of blood in the lung and unloading in the tissues. A, Position of the oxyhemoglobin dissociation curve has the potential to match optimally the diffusive resistance in the lung and tissues with the pressure gradient available for oxygen loading and unloading respectively, as illustrated by this exaggeration of the sigmoidal shape of the dissociation curve. B, Optimal P50 will vary with altitude because of differences in alveolar O2 tension. Oxygen transport at sea level will be enhanced at a low pH (high P50) because of the relatively high muscle resistance to diffusive O2 uptake. Oxygen transport at high altitude will be enhanced at a more alkaline pH (lower P50) which enhances oxygen loading in the lung at the low alveolar oxygen tension.



Figure 13.

Recruitment of diffusing capacity of the lung for CO (DLCO), membrane diffusing capacity (DMCO), and pulmonary capillary blood volume (VC) as pulmonary blood flow increases during exercise in humans. DLCO continues to increase from rest to exercise along an approximately linear relationship with respect to pulmonary blood flow up to maximal oxygen uptake without reaching an apparent plateau.



Figure 14.

Comparison of and DLNO at rest and exercise calculated from the data in Figure 13 with measurements of by the Lilienthal‐Riley technique 40,158,228,229,248 and by application of MIGET 91,120 and with measurements of DLNO by a breath‐holding method 23,164. Comparisons are made with respect to blood flow where measurements of cardiac output are available (Panel 1) and with respect to oxygen uptake (Panel b). Neither oxygen uptake nor cardiac output were available for measurements of DLNO, which were all obtained at rest; hence, a cardiac index of 3.0 was assumed for each measurement of DLNO.



Figure 15.

Arterial PO2, arterial PCO2, and alveolar‐arterial PO2 difference as a function of exercise intensity (oxygen uptake). At heavy levels of exercise, both arterial PO2 and PCO2 fall, and as a result the alveolar‐arterial PO2 difference increases markedly 253.



Figure 16.

Measured and predicted alveolar–arterial PO2 differences from the same data as in Figure 15. The predicted value represents the effects of ventilation–perfusion inequality, while the measured value also includes the effects of diffusion limitation. Up to 2 liter/min ventilation–perfusion inequality accounts for virtually all of the alveolar–arterial PO2 difference. At higher exercise intensities, the contribution of ventilation–perfusion mismatching does not change, while diffusion limitation becomes increasingly important.



Figure 17.

At simulated altitude of 10,000 feet (barometric pressure = 523 mm Hg), considerable diffusion limitation of oxygen uptake occurs during exercise, which permits calculation of the oxygen diffusing capacity. increases essentially linearly with increasing exercise. As explained in the text, the importance of diffusion limitation depends upon the ratio DL/β falling from 1.6 (light exercise) to 1 (heavy exercise) under these conditions, resulting in incomplete diffusive equilibration as shown in the bottom right panel. Thus during moderate and heavy exercise at this altitude, diffusion equilibration proceeds but only to two‐thirds completion 253.



Figure 18.

Effects of altitude (simulated in a hypobaric chamber) on diffusional limitation of oxygen at a constant level of exercise (180 W). increases at altitude, at this submaximal level, presumably as a consequence of increasing blood flow causing a combination of distention and recruitment. The effective slope of the oxyhemoglobin dissociation curve (β) increases with increasing altitude as arterial and venous PO2 fall, and the result of these changes is that the ratio /β progressively falls with altitude.



Figure 19.

Alveolar–arterial PO2 difference during exercise as a function of altitude. During submaximal exercise the alveolar‐arterial PO2 difference is significantly higher at altitude than at sea level. This is the result of greater diffusion limitation 252.



Figure 20.

Abnormal ventilation–perfusion ratio distributions caused by HAPE in one subject at a simulated altitude of 20,000 ft. At rest, there was a 15% shunt and an additional 10% of the cardiac output perfusing abnormally low A/ areas. On exercise, the shunt increased to 29%, with 17% of the cardiac output perfusing areas of low A/ ratio.



Figure 21.

Gamblegrams to show the systems contributing to H+ ion concentration in different compartments. Independent variables are [SID], Atot, and PCO2. The two bars of the histogram represent net negative and positive changes, and are of equal height to indicate the constraint of electrical neutrality, and in which [SID] equals the sum of the dependent variables [A−] and [].



Figure 22.

The proportion of dissociated (A−) to undissociated (HA) forms of three weak electrolytes having pK values of 5, 7, and 9. In the physiological range of pH (6.4–7.6), the first is fully dissociated and the third is undissociated.



Figure 23.

Gamblegrams showing the major changes in arterial plasma and muscle ionic status from rest (upper panels) to maximum exercise (lower panels).



Figure 24.

Arteriovenous differences for strong ions and bicarbonate following 30 s maximal exercise, contrasting changes in blood across the exercising leg (left) and the inactive forearm (right).

From Kowalchuk et al. 148,149, with permission


Figure 25.

Effects of increases in muscle CO2 content, due to metabolism in exercise, on intracellular PCO2; resting values indicated by circle. Note that if [SID] is unchanged or increases, CO2 may accumulate without a large change in PCO2, but a fall in [SID] will lead to large accompanying increases in PCO2.



Figure 26.

The CO2 “dissociation curve” for whole blood, with isopleths of plasma [SID], constructed for blood having a hemoglobin content of 14 g/dl and O2 saturation of 97%. The points plot the classical whole blood curve of content vs. PCO2 87 for fully oxygenated blood (lower curve), and only 25% saturated (upper curve). Note that the increase in content shown by the classical relationships due to increases in PCO2 and desaturation are in part due to increases in plasma [SID]. Also, note that a sufficient venoarterial difference in CO2 content during exercise cannot be achieved through an increase in PCO2 alone; an increase in [SID] is also required by virtue of the ‐Cl− shift to avoid a very large increase in or decrease in .



Figure 27.

Comparison of DLCO estimates by physiologic (re‐breathing) method in dogs during heavy exercise with that in the same animals by morphometric methods at postmortem. The physiological estimate of DLCO at peak exercise is actually sightly greater than estimated by morphometry at postmortem. This result is misleading, however, because the membrane diffusing capacity by morphometry is twice the physiological estimate and the pulmonary capillary blood volume by morphometry is half that estimated physiologically at peak exercise. These differences remain unresolved.



Figure 28.

A, Comparison of DLCO with respect to pulmonary blood flow before and after left pneumonectomy in foxhounds. Data are normalized with respect to the normal lung and show that DLCO continues to rise after pneumonectomy as blood flow is increased to a level equivalent to 35 liters/min through two normal lungs without reaching a plateau. B, Comparison for the relationship between DLCO/C with respect to pulmonary blood flow from rest to peak exercise for the same data as that in A. The data show that in spite of continued recruitment after pneumonectomy, DL/c falls to a lower level after pneumonectomy than before so that diffusion became a significant source of exercise limitation.



Figure 29.

A, Change in hematocrit in normal foxhounds from rest to peak exercise. There is an approximately 40% increase in hematocrit in foxhounds owing to injection of red cells into the circulation by splenic contraction. In humans the increase of hematocrit is only about 3% under similar conditions, primarily due to a fall in plasma valume. B, Comparison of the recruitment of DLCO in foxhounds with that in humans as pulmonary blood flow increases during exercise. Recruitment of diffusing capacity is significantly steeper in foxhounds than in humans, very likely a result of the large expansion of circulating blood volume in the foxhound from exercise‐induced splenic contraction.



Figure 30.

Effect of P50 in optimizng maximal oxygen uptake. The principles illustrated with equation 38 were applied to available data on horses and foxhounds at maximal oxygen uptake.

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Article Title: Determinants of Gas Exchange and Acid–Base Balance During Exercise
 

How to Cite

Robert L. Johnson, George J. F. Heigenhauser, Connie C. W. Hsia, Norman L. Jones, Peter D. Wagner. Determinants of Gas Exchange and Acid–Base Balance During Exercise. Compr Physiol 2011, Supplement 29: Handbook of Physiology, Exercise: Regulation and Integration of Multiple Systems: 515-584. First published in print 1996. doi: 10.1002/cphy.cp120112