Gas Diffusion and Transport

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10/16/12 11am


Partial Pressure of O2 is 104 mmHg in alveoli at sea level (CO2 is 40 mmHg)
Effect of alveolar ventilation on the alveolar PO2 at two rates of oxygen absorption from the alveoli-250 ml/min and 1000 ml/min. Point A is the normal operating point.--Rate of O2 consumption and rate of ventilation influences how much O2 is taken from air??
Effect of alveolar ventilation on the alveolar PCO2 at two rates of carbon dioxide excretion from the blood-800 ml/min and 200 ml/min. Point A is the normal operating point.
Alveolar air has less O2 and more CO2 than dead space air
Inflammation, fibrosis, etc will influence gas exchange. Lung edema (water accumulation)
In exercise: one factor--diffusion capacity for O2 and CO2 are quite different. Membrane--more permeable provides easier for CO2 to exit. Excess CO2 can be toxic.
Changes in PO2 in pulmonary capillary and systemic blood: 4-5 mmHg drop in final outcome because some pulmonary blood isn't used for gas exchange--there are some bypasses.


Diffusion of oxygen from a peripheral tissue capillary to the cells. (PO2 in interstitial fluid = 40 mm Hg, and in tissue cells = 23 mm Hg.)
Uptake of carbon dioxide by the blood in the tissue capillaries. (PCO2 in tissue cells = 46 mm Hg, and in interstitial fluid = 45 mm Hg.)

Oxygen Transport
Dissolved Oxygen - physically dissolved in blood (2-5%); proportional to the PO2 .
Oxyhemoglobin - chemically combined with hemoglobin in the red cells (95-98%); depending on hematocrit, O2 binding capacity, and O2 saturation.
Hematocrit - the percentage of the blood volume composed of red cells (37%-42%).
Hemoglobin concentration - proportional to the blood hematocrit (15 g Hb/100 ml).

Forms and Content of O2 in Blood
Arterial Venous a-v
PO2 (mm Hg ) 100 40 60
Dissolved O2 (ml/dl ) 0.3 0.1 0.2
Oxy-Hb (ml/dl ) 19.5 14.4 5.1
Total (ml/dl ) 19.8 14.5 5.3
O2 capacity - the maximum amount of O2 (ml/dl or vol%) that the blood is capable of carrying. At [Hb] of 15 g/dl & 1.39 ml O2 / gram Hb, normal blood can contain ~ 20-21 ml O2 /dl blood bound to Hb.
O2 content - the actual amount of O2 the blood is carrying (ml/dl or vol%).
Hb O2 saturation - the % of Hb that is saturated with O2 (%) or the O2 content divided by the O2 capacity.

Dissociation Curves

O2 curve: Pretty flat at the top so still at 90% around 70-80 mmHg. Exercise--easier to consume the O2?
Oxygen curve shifts right with increase P450 (decreased affinity), increase temp, increase PCO2, increase 2,3 DPG, drop in pH
Anemia and CO drop maximum levels

CO2 Transport. Forms of CO2 in Blood.
Arterial Venous a-v
PCO2 (mm Hg ) 40 46 6
Dissolved (ml/dl ) 2.5 2.9 0.4
Carbamino (ml/dl ) 2.4 3.8 1.4
HCO3- (ml/dl ) 43.3 45.5 2.2
Total (ml/dl ) 48.2 52.2 4.0
Portions of the carbon dioxide dissociation curve when the PO2 is 100 mm Hg or 40 mm Hg. The arrow represents the Haldane effect on the transport of carbon dioxide.--More O2 then CO2 leaves faster

Notes Intro

Physical Principles of Gas Exchange; Diffusion of Oxygen and Carbon Dioxide Through the Respiratory Membrane.
After the alveoli are ventilated with fresh air, the next step in the respiratory process is diffusion of oxygen from the alveoli into the pulmonary blood and diffusion of carbon dioxide in the opposite direction, out of the blood. The process of diffusion is simply the random motion of molecules in all directions through the respiratory membrane and adjacent fluids. However, in respiratory physiology, one is concerned not only with the basic mechanism by which diffusion occurs but also with the rate at which it occurs; this is a much more complex problem, requiring a deeper understanding of the physics of diffusion and gas exchange.

Partial Pressures

Gas Pressures in a Mixture of Gases-"Partial Pressures" of Individual Gases.
Pressure is caused by multiple impacts of moving molecules against a surface. Therefore, the pressure of a gas acting on the surfaces of the respiratory passages and alveoli is proportional to the summated force of impact of all the molecules of that gas striking the surface at any given instant. This means that the pressure is directly proportional to the concentration of the gas molecules.
In respiratory physiology, one deals with mixtures of gases, mainly of oxygen, nitrogen, and carbon dioxide. The rate of diffusion of each of these gases is directly proportional to the pressure caused by that gas alone, which is called the partial pressure of that gas. The concept of partial pressure can be explained as follows.
Consider air, which has an approximate composition of 79 percent nitrogen and 21 percent oxygen. The total pressure of this mixture at sea level averages 760 mm Hg. It is clear from the preceding description of the molecular basis of pressure that each gas contributes to the total pressure in direct proportion to its concentration. Therefore, 79 percent of the 760 mm Hg is caused by nitrogen (600 mm Hg) and 21 percent by oxygen (160 mm Hg). Thus, the "partial pressure" of nitrogen in the mixture is 600 mm Hg, and the "partial pressure" of oxygen is 160 mm Hg; the total pressure is 760 mm Hg, the sum of the individual partial pressures. The partial pressures of individual gases in a mixture are designated by the symbols PO2, PCO2, PN2, PHe, and so forth.

Partial Pressures, cont'd

Pressures of Gases Dissolved in Water and Tissues
Gases dissolved in water or in body tissues also exert pressure because the dissolved gas molecules are moving randomly and have kinetic energy. Further, when the gas dissolved in fluid encounters a surface, such as the membrane of a cell, it exerts its own partial pressure in the same way that a gas in the gas phase does. The partial pressures of the separate dissolved gases are designated the same as the partial pressures in the gas state, that is, PO2, PCO2, PN2, PHe, and so forth.
Factors That Determine the Partial Pressure of a Gas Dissolved in a Fluid
The partial pressure of a gas in a solution is determined not only by its concentration but also by the solubility coefficient of the gas. That is, some types of molecules, especially carbon dioxide, are physically or chemically attracted to water molecules, whereas others are repelled. When molecules are attracted, far more of them can be dissolved without building up excess partial pressure within the solution. Conversely, in the case of those that are repelled, high partial pressure will develop with fewer dissolved molecules. These relations are expressed by the following formula, which is Henry's law: Partial Pressure=conc of dissolved gas/solubility coefficient
When partial pressure is expressed in atmospheres (1 atmosphere pressure equals 760 mm Hg) and concentration is expressed in volume of gas dissolved in each volume of water, the solubility coefficients for important respiratory gases at body temperature are the following:
Oxygen 0.024
Carbon dioxide 0.57
Carbon monoxide 0.018
Nitrogen 0.012
Helium 0.008


Oxygen 0.024
Carbon dioxide 0.57
Carbon monoxide 0.018
Nitrogen 0.012
Helium 0.008
From this table, one can see that carbon dioxide is more than 20 times as soluble as oxygen. Therefore, the partial pressure of carbon dioxide (for a given concentration) is less than onetwentieth that exerted by oxygen.
Diffusion of Gases Between the Gas Phase in the Alveoli and the Dissolved Phase in the
Pulmonary Blood
The partial pressure of each gas in the alveolar respiratory gas mixture tends to force molecules of that gas into solution in the blood of the alveolar capillaries. Conversely, the molecules of the same gas that are already dissolved in the blood are bouncing randomly in the fluid of the blood, and some of these bouncing molecules escape back into the alveoli. The rate at which they escape is directly proportional to their partial pressure in the blood.
But in which direction will net diffusion of the gas occur? The answer is that net diffusion is determined by the difference between the two partial pressures. If the partial pressure is greater in the gas phase in the alveoli, as is normally true for oxygen, then more molecules will diffuse into the blood than in the other direction. Alternatively, if the partial pressure of the gas is greater in the dissolved state in the blood, which is normally true for carbon dioxide, then net diffusion will occur toward the gas phase in the alveoli.

Vapor Pressure of Water

When nonhumidified air is breathed into the respiratory passageways, water immediately evaporates from the surfaces of these passages and humidifies the air. This results from the fact that water molecules, like the different dissolved gas molecules, are continually escaping from the water surface into the gas phase. The partial pressure that the water molecules exert to escape through the surface is called the vapor pressure of the water. At normal body temperature, 37°C, this vapor pressure is 47 mm Hg. Therefore, once the gas mixture has become fully humidified-that is, once it is in "equilibrium" with the water-the partial pressure of the water vapor in the gas mixture is 47 mm Hg. This partial pressure, like the other partial pressures, is designated PH2O.
The vapor pressure of water depends entirely on the temperature of the water. The greater the temperature, the greater the kinetic activity of the molecules and, therefore, the greater the likelihood that the water molecules will escape from the surface of the water into the gas phase. For instance, the water vapor pressure at 0°C is 5 mm Hg, and at 100°C it is 760 mm Hg. But the most important value to remember is the vapor pressure at body temperature, 47 mm Hg; this value appears in many of our subsequent discussions.

Diffusion of Gases thru fluid-pressure difference causes net diffusion

From the preceding discussion, it is clear that when the partial pressure of a gas is greater in one area than in another area, there will be net diffusion from the high-pressure area toward the low-pressure area. For instance, returning to Fig. 1, one can readily see that the molecules in the area of high pressure, because of their greater number, have a greater chance of moving randomly into the area of low pressure than do molecules attempting to go in the other direction. However, some molecules do bounce randomly from the area of low pressure toward the area of high pressure. Therefore, the net diffusion of gas from the area of high pressure to the area of low pressure is equal to the number of molecules bouncing in this forward direction minus the number bouncing in the opposite direction; this is proportional to the gas partial pressure difference between the two areas, called simply the pressure difference for causing diffusion.

Quantifying the Net Rate of Diffusion in Fluids

In addition to the pressure difference, several other factors affect the rate of gas diffusion in a fluid. They are (1) the solubility of the gas in the fluid, (2) the cross-sectional area of the fluid, (3) the distance through which the gas must diffuse, (4) the molecular weight of the gas, and (5) the temperature of the fluid. In the body, the last of these factors, the temperature, remains reasonably constant and usually need not be considered.
The greater the solubility of the gas, the greater the number of molecules available to diffuse for any given partial pressure difference. The greater the cross-sectional area of the diffusion pathway, the greater the total number of molecules that diffuse. Conversely, the greater the distance the molecules must diffuse, the longer it will take the molecules to diffuse the entire distance. Finally, the greater the velocity of kinetic movement of the molecules, which is inversely proportional to the square root of the molecular weight, the greater the rate of diffusion of the gas. All these factors can be expressed in a single formula, as follows: D is proportional to deltaPxAxS over dXsquare root of MW
in which D is the diffusion rate, ΔP is the partial pressure difference between the two ends of the diffusion pathway, A is the cross-sectional area of the pathway, S is the solubility of the gas, d is the distance of diffusion, and MW is the molecular weight of the gas.


It is obvious from this formula that the characteristics of the gas itself determine two factors of the formula: solubility and molecular weight. Together, these two factors determine the diffusion coefficient of the gas, which is proportional to that is, the relative rates at which different gases at the same partial pressure levels will diffuse are proportional to their diffusion coefficients. Assuming that the diffusion coefficient for oxygen is 1, the relative diffusion coefficients for different gases of respiratory importance in the body fluids are as follows: Oxygen 1.0 Carbon dioxide 20.3 Carbon monoxide 0.81 Nitrogen 0.53 Helium 0.95
Diffusion of Gases Through Tissues
The gases that are of respiratory importance are all highly soluble in lipids and, consequently, are highly soluble in cell membranes. Because of this, the major limitation to the movement of gases in tissues is the rate at which the gases can diffuse through the tissue water instead of through the cell membranes. Therefore, diffusion of gases through the tissues, including through the respiratory membrane, is almost equal to the diffusion of gases in water, as given in the preceding list.

Compositions of Alveolar Air and Atmospheric Air are different

Alveolar air does not have the same concentrations of gases as atmospheric air by any means, which can readily be seen by comparing the alveolar air composition in Table 1 with that of atmospheric air. There are several reasons for the differences. First, the alveolar air is only partially replaced by atmospheric air with each breath. Second, oxygen is constantly being absorbed into the pulmonary blood from the alveolar air. Third, carbon dioxide is constantly diffusing from the pulmonary blood into the alveoli. And fourth, dry atmospheric air that enters the respiratory passages is humidified even before it reaches the alveoli.
Atmospheric Air* (mm Hg)--Humidified Air (mm Hg)--Alveolar Air (mm Hg)--Expired Air (mm Hg)
N2 597.0 (78.62%) 563.4 (74.09%) 569.0 (74.9%) 566.0 (74.5%)
O2 159.0 (20.84%) 149.3 (19.67%) 104.0 (13.6%) 120.0 (15.7%)
CO2 0.3 (0.04%) 0.3 (0.04%) 40.0 (5.3%) 27.0 (3.6%)
H2O 3.7 (0.50%) 47.0 (6.20%) 47.0 (6.2%) 47.0 (6.2%)
TOTAL 760.0 (100.0%) 760.0 (100.0%) 760.0 (100.0%) 760.0 (100.0%)


Humidification of the Air in the Respiratory Passages
Table 1 shows that atmospheric air is composed almost entirely of nitrogen and oxygen; it normally contains almost no carbon dioxide and little water vapor. However, as soon as the atmospheric air enters the respiratory passages, it is exposed to the fluids that cover the respiratory surfaces. Even before the air enters the alveoli, it becomes (for all practical purposes) totally humidified.
The partial pressure of water vapor at a normal body temperature of 37°C is 47 mm Hg, which is therefore the partial pressure of water vapor in the alveolar air. Because the total pressure in the alveoli cannot rise to more than the atmospheric pressure (760 mm Hg at sea level), this water vapor simply dilutes all the other gases in the inspired air. Table 1 also shows that humidification of the air dilutes the oxygen partial pressure at sea level from an average of 159 mm Hg in atmospheric air to 149 mm Hg in the humidified air, and it dilutes the nitrogen partial pressure from 597 to 563 mm Hg.
Rate at Which Alveolar Air Is Renewed by Atmospheric Air
The average male functional residual capacity of the lungs (the volume of air remaining in the lungs at the end of normal expiration) measures about 2300 milliliters. Yet only 350 milliliters of new air is brought into the alveoli with each normal inspiration, and this same amount of old alveolar air is expired. Therefore, the volume of alveolar air replaced by new atmospheric air with each breath is only one seventh of the total, so multiple breaths are required to exchange most of the alveolar air. Fig. 2 shows this slow rate of renewal of the alveolar air. In the first alveolus of the figure, excess gas is present in the alveoli, but note that even at the end of 16 breaths, the excess gas still has not been completely removed from the alveoli.

Slow Replacement of AIr

Fig. 3 demonstrates graphically the rate at which excess gas in the alveoli is normally removed, showing that with normal alveolar ventilation, about one-half the gas is removed in 17 seconds. When a person's rate of alveolar ventilation is only one-half normal, one-half the gas is removed in 34 seconds, and when the rate of ventilation is twice normal, one half is removed in about 8 seconds.
Importance of the Slow Replacement of Alveolar Air
The slow replacement of alveolar air is of particular importance in preventing sudden changes in gas concentrations in the blood. This makes the respiratory control mechanism much more stable than it would be otherwise, and it helps prevent excessive increases and decreases in tissue oxygenation, tissue carbon dioxide concentration, and tissue pH when respiration is temporarily interrupted.
Oxygen Concentration and Partial Pressure in the Alveoli
Oxygen is continually being absorbed from the alveoli into the blood of the lungs, and new oxygen is continually being breathed into the alveoli from the atmosphere. The more rapidly oxygen is absorbed, the lower its concentration in the alveoli becomes; conversely, the more rapidly new oxygen is breathed into the alveoli from the atmosphere, the higher its concentration becomes. Therefore, oxygen concentration in the alveoli, as well as its partial pressure, is controlled by (1) the rate of absorption of oxygen into the blood and (2) the rate of entry of new oxygen into the lungs by the ventilatory process.


Fig. 4 shows the effect of both alveolar ventilation and rate of oxygen absorption into the blood on the alveolar partial pressure of oxygen (PO2). One curve represents oxygen absorption at a rate of 250 ml/min, and the other curve represents a rate of 1000 ml/min. At a normal ventilatory rate of 4.2 L/min and an oxygen consumption of 250 ml/min, the normal operating point in Fig. 4 is point A. The figure also shows that when 1000 milliliters of oxygen is being absorbed each minute, as occurs during moderate exercise, the rate of alveolar ventilation must increase fourfold to maintain the alveolar Po2 at the normal value of 104 mm Hg.
Another effect shown in Fig. 4 is that an extremely marked increase in alveolar ventilation can never increase the alveolar PO2 above 149 mm Hg as long as the person is breathing normal atmospheric air at sea level pressure, because this is the maximum PO2 in humidified air at this pressure. If the person breathes gases that contain partial pressures of oxygen higher than 149 mm Hg, the alveolar PO2 can approach these higher pressures at high rates of ventilation.

CO2 Concentration and Partial Pressure in the alveoli

Carbon dioxide is continually being formed in the body and then carried in the blood to the alveoli; it is continually being removed from the alveoli by ventilation. Fig. 5 shows the effects on the alveolar partial pressure of carbon dioxide (PCO2) of both alveolar ventilation and two rates of carbon dioxide excretion, 200 and 800 ml/min. One curve represents a normal rate of carbon dioxide excretion of 200 ml/min. At the normal rate of alveolar ventilation of 4.2 L/min, the operating point for alveolar PCO2 is at point A in Fig. 5 (i.e., 40 mm Hg).
Two other facts are also evident from Fig. 5: First, the alveolar PCO2 increases directly in proportion to the rate of carbon dioxide excretion, as represented by the fourfold elevation of the curve (when 800 milliliters of CO2 are excreted per minute). Second, the alveolar PCO2 decreases in inverse proportion to alveolar ventilation. Therefore, the concentrations and partial pressures of both oxygen and carbon dioxide in the alveoli are determined by the rates of absorption or excretion of the two gases and by the amount of alveolar ventilation.

Expired Air

Expired Air Is a Combination of Dead Space Air and Alveolar Air
The overall composition of expired air is determined by (1) the amount of the expired air that is dead space air and (2) the amount that is alveolar air. Fig. 6 shows the progressive changes in oxygen and carbon dioxide partial pressures in the expired air during the course of expiration. The first portion of this air, the dead space air from the respiratory passageways, is typical humidified air, as shown in Table 1. Then, progressively more and more alveolar air becomes mixed with the dead space air until all the dead space air has finally been washed out and nothing but alveolar air is expired at the end of expiration. Therefore, the method of collecting alveolar air for study is simply to collect a sample of the last portion of the expired air after forceful expiration has removed all the dead space air.
Normal expired air, containing both dead space air and alveolar air, has gas concentrations and partial pressures approximately as shown in Table 1 (i.e., concentrations between those of alveolar air and humidified atmospheric air).

Diffusion of Gases

Diffusion of Gases Through the Respiratory Membrane
Respiratory Unit
Fig. 7 shows the respiratory unit (also called "respiratory lobule"), which is composed of a respiratory bronchiole, alveolar ducts, atria, and alveoli. There are about 300 million alveoli in the two lungs, and each alveolus has an average diameter of about 0.2 millimeter. The alveolar walls are extremely thin, and between the alveoli is an almost solid network of interconnecting capillaries, shown in Fig. 8. Indeed, because of the extensiveness of the capillary plexus, the flow of blood in the alveolar wall has been described as a "sheet" of flowing blood. Thus, it is obvious that the alveolar gases are in very close proximity to the blood of the pulmonary capillaries. Further, gas exchange between the alveolar air and the pulmonary blood occurs through the membranes of all the terminal portions of the lungs, not merely in the alveoli themselves. All these membranes are collectively known as the respiratory membrane, also called the pulmonary membrane.
Respiratory Membrane
Fig. 9 shows the ultrastructure of the respiratory membrane drawn in cross section on the left and a red blood cell on the right. It also shows the diffusion of oxygen from the alveolus into the red blood cell and diffusion of carbon dioxide in the opposite direction. Note the following different layers of the respiratory membrane: 1. A layer of fluid lining the alveolus and containing surfactant that reduces the surface tension of the alveolar fluid
2. The alveolar epithelium composed of thin epithelial cells
3. An epithelial basement membrane
4. A thin interstitial space between the alveolar epithelium and the capillary membrane
5. A capillary basement membrane that in many places fuses with the alveolar epithelial basement membrane
6. The capillary endothelial membrane


Despite the large number of layers, the overall thickness of the respiratory membrane in some areas is as little as 0.2 micrometer, and it averages about 0.6 micrometer, except where there are cell nuclei. From histological studies, it has been estimated that the total surface area of the respiratory membrane is about 70 square meters in the normal adult human male. This is equivalent to the floor area of a 25-by-30-foot room. The total quantity of blood in the capillaries of the lungs at any given instant is 60 to 140 milliliters. Now imagine this small amount of blood spread over the entire surface of a 25-by-30-foot floor, and it is easy to understand the rapidity of the respiratory exchange of oxygen and carbon dioxide.
The average diameter of the pulmonary capillaries is only about 5 micrometers, which means that red blood cells must squeeze through them. The red blood cell membrane usually touches the capillary wall, so oxygen and carbon dioxide need not pass through significant amounts of plasma as they diffuse between the alveolus and the red cell. This, too, increases the rapidity of diffusion.

Factors that affect the rate of gas diffusion thru the respiratory membrane

Referring to the earlier discussion of diffusion of gases in water, one can apply the same principles and mathematical formulas to diffusion of gases through the respiratory membrane. Thus, the factors that determine how rapidly a gas will pass through the membrane are (1) the thickness of the membrane, (2) the surface area of the membrane, (3) the diffusion coefficient of the gas in the substance of the membrane, and (4) the partial pressure difference of the gas between the two sides of the membrane.
The thickness of the respiratory membrane occasionally increases-for instance, as a result of edema fluid in the interstitial space of the membrane and in the alveoli-so the respiratory gases must then diffuse not only through the membrane but also through this fluid. Also, some pulmonary diseases cause fibrosis of the lungs, which can increase the thickness of some portions of the respiratory membrane. Because the rate of diffusion through the membrane is inversely proportional to the thickness of the membrane, any factor that increases the thickness to more than two to three times normal can interfere significantly with normal respiratory exchange of gases.
The surface area of the respiratory membrane can be greatly decreased by many conditions. For instance, removal of an entire lung decreases the total surface area to one half normal. Also, in emphysema, many of the alveoli coalesce, with dissolution of many alveolar walls. Therefore, the new alveolar chambers are much larger than the original alveoli, but the total surface area of the respiratory membrane is often decreased as much as fivefold because of loss of the alveolar walls. When the total surface area is decreased to about one-third to one-fourth normal, exchange of gases through the membrane is impeded to a significant degree, even under resting conditions, and during competitive sports and other strenuous exercise even the slightest decrease in surface area of the lungs can be a serious detriment to respiratory exchange of gases.


The diffusion coefficient for transfer of each gas through the respiratory membrane depends on the gas's solubility in the membrane and, inversely, on the square root of the gas's molecular weight. The rate of diffusion in the respiratory membrane is almost exactly the same as that in water, for reasons explained earlier. Therefore, for a given pressure difference, carbon dioxide diffuses about 20 times as rapidly as oxygen. Oxygen diffuses about twice as rapidly as nitrogen.
The pressure difference across the respiratory membrane is the difference between the partial pressure of the gas in the alveoli and the partial pressure of the gas in the pulmonary capillary blood. The partial pressure represents a measure of the total number of molecules of a particular gas striking a unit area of the alveolar surface of the membrane in unit time, and the pressure of the gas in the blood represents the number of molecules that attempt to escape from the blood in the opposite direction. Therefore, the difference between these two pressures is a measure of the net tendency for the gas molecules to move through the membrane.
When the partial pressure of a gas in the alveoli is greater than the pressure of the gas in the blood, as is true for oxygen, net diffusion from the alveoli into the blood occurs; when the pressure of the gas in the blood is greater than the partial pressure in the alveoli, as is true for carbon dioxide, net diffusion from the blood into the alveoli occurs.

Diffusing Capacity of the respiratory membrane

Diffusing Capacity of the Respiratory Membrane
The ability of the respiratory membrane to exchange a gas between the alveoli and the pulmonary blood is expressed in quantitative terms by the respiratory membrane's diffusing capacity, which is defined as the volume of a gas that will diffuse through the membrane each minute for a partial pressure difference of 1 mm Hg. All the factors discussed earlier that affect diffusion through the respiratory membrane can affect this diffusing capacity.
Diffusing Capacity for Oxygen
In the average young man, the diffusing capacity for oxygen under resting conditions averages 21 ml/min/mm Hg. In functional terms, what does this mean? The mean oxygen pressure difference across the respiratory membrane during normal, quiet breathing is about 11 mm Hg. Multiplication of this pressure by the diffusing capacity (11 × 21) gives a total of about 230 milliliters of oxygen diffusing through the respiratory membrane each minute; this is equal to the rate at which the resting body uses oxygen.
Increased Oxygen Diffusing Capacity During Exercise
During strenuous exercise or other conditions that greatly increase pulmonary blood flow and alveolar ventilation, the diffusing capacity for oxygen increases in young men to a maximum of about 65 ml/min/mm Hg, which is three times the diffusing capacity under resting conditions. This increase is caused by several factors, among which are (1) opening up of many previously dormant pulmonary capillaries or extra dilation of already open capillaries, thereby increasing the surface area of the blood into which the oxygen can diffuse; and (2) a better match between the ventilation of the alveoli and the perfusion of the alveolar capillaries with blood, called the ventilation-perfusion ratio, which is explained in detail later in this chapter. Therefore, during exercise, oxygenation of the blood is increased not only by increased alveolar ventilation but also by greater diffusing capacity of the respiratory membrane for transporting oxygen into the blood.

Diffusing Capacity for CO2

The diffusing capacity for carbon dioxide has never been measured because of the following technical difficulty: Carbon dioxide diffuses through the respiratory membrane so rapidly that the average PCO2 in the pulmonary blood is not far different from the PCO2 in the alveoli-the average difference is less than 1 mm Hg-and with the available techniques, this difference is too small to be measured.
Nevertheless, measurements of diffusion of other gases have shown that the diffusing capacity varies directly with the diffusion coefficient of the particular gas. Because the diffusion coefficient of carbon dioxide is slightly more than 20 times that of oxygen, one would expect a diffusing capacity for carbon dioxide under resting conditions of about 400 to 450 ml/min/mm Hg and during exercise of about 1200 to 1300 ml/min/mm Hg. Fig. 10 compares the measured or calculated diffusing capacities of carbon monoxide, oxygen, and carbon dioxide at rest and during exercise, showing the extreme diffusing capacity of carbon dioxide and the effect of exercise on the diffusing capacity of each of these gases.

Transport of O2 and CO2 in blood and tissue fluids

Once oxygen has diffused from the alveoli into the pulmonary blood, it is transported to the peripheral tissue capillaries almost entirely in combination with hemoglobin. The presence of hemoglobin in the red blood cells allows the blood to transport 30 to 100 times as much oxygen as could be transported in the form of dissolved oxygen in the water of the blood.
In the body's tissue cells, oxygen reacts with various foodstuffs to form large quantities of carbon dioxide. This carbon dioxide enters the tissue capillaries and is transported back to the lungs. Carbon dioxide, like oxygen, also combines with chemical substances in the blood that increase carbon dioxide transport 15- to 20-fold.
The purpose of this chapter is to present both qualitatively and quantitatively the physical and chemical principles of oxygen and carbon dioxide transport in the blood and tissue fluids.
Transport of Oxygen from the Lungs to the Body Tissues
The gases can move from one point to another by diffusion and that the cause of this movement is always a partial pressure difference from the first point to the next. Thus, oxygen diffuses from the alveoli into the pulmonary capillary blood because the oxygen partial pressure (PO2) in the alveoli is greater than the PO2 in the pulmonary capillary blood. In the other tissues of the body, a higher PO2 in the capillary blood than in the tissues causes oxygen to diffuse into the surrounding cells.
Conversely, when oxygen is metabolized in the cells to form carbon dioxide, the intracellular carbon dioxide pressure (PCO2) rises to a high value, which causes carbon dioxide to diffuse into the tissue capillaries. After blood flows to the lungs, the carbon dioxide diffuses out of the blood into the alveoli, because the PCO2 in the pulmonary capillary blood is greater than that in the alveoli. Thus, the transport of oxygen and carbon dioxide by the blood depends on both diffusion and the flow of blood. We now consider quantitatively the factors responsible for these effects.

Diffusion of O2 from the alveoli to the pulmonary capillary blood

The top part of Fig. 11 shows a pulmonary alveolus adjacent to a pulmonary capillary, demonstrating diffusion of oxygen molecules between the alveolar air and the pulmonary blood. The PO2 of the gaseous oxygen in the alveolus averages 104 mm Hg, whereas the PO2 of the venous blood entering the pulmonary capillary at its arterial end averages only 40 mm Hg because a large amount of oxygen was removed from this blood as it passed through the peripheral tissues. Therefore, the initial pressure difference that causes oxygen to diffuse into the pulmonary capillary is 104 - 40, or 64 mm Hg. In the graph at the bottom of the figure, the curve shows the rapid rise in blood PO2 as the blood passes through the capillary; the blood PO2 rises almost to that of the alveolar air by the time the blood has moved a third of the distance through the capillary, becoming almost 104 mm Hg.

O2 uptake by pulmonary blood during exercise

During strenuous exercise, a person's body may require as much as 20 times the normal amount of oxygen. Also, because of increased cardiac output during exercise, the time that the blood remains in the pulmonary capillary may be reduced to less than one-half normal. Yet because of the great safety factor for diffusion of oxygen through the pulmonary membrane, the blood still becomes almost saturated with oxygen by the time it leaves the pulmonary capillaries. This can be explained as follows.
First, the diffusing capacity for oxygen increases almost threefold during exercise; this results mainly from increased surface area of capillaries participating in the diffusion and also from a more nearly ideal ventilation-perfusion ratio in the upper part of the lungs.
Second, note in the curve of Fig. 12 that under nonexercising conditions, the blood becomes almost saturated with oxygen by the time it has passed through one third of the pulmonary capillary, and little additional oxygen normally enters the blood during the latter two thirds of its transit. That is, the blood normally stays in the lung capillaries about three times as long as needed to cause full oxygenation. Therefore, during exercise, even with a shortened time of exposure in the capillaries, the blood can still become fully oxygenated, or nearly so.

Transport of O2 in the arterial blood

About 98 percent of the blood that enters the left atrium from the lungs has just passed through the alveolar capillaries and has become oxygenated up to a PO2 of about 104 mm Hg. Another 2 percent of the blood has passed from the aorta through the bronchial circulation, which supplies mainly the deep tissues of the lungs and is not exposed to lung air. This blood flow is called "shunt flow," meaning that blood is shunted past the gas exchange areas. On leaving the lungs, the PO2 of the shunt blood is about that of normal systemic venous blood, about 40 mm Hg. When this blood combines in the pulmonary veins with the oxygenated blood from the alveolar capillaries, this so-called venous admixture of blood causes the PO2 of the blood entering the left heart and pumped into the aorta to fall to about 95 mm Hg. These changes in blood PO2 at different points in the circulatory system are shown in Fig. 12.
When the arterial blood reaches the peripheral tissues, its PO2 in the capillaries is still 95 mm Hg. Yet, as shown in Fig. 13, the PO2 in the interstitial fluid that surrounds the tissue cells averages only 40 mm Hg. Thus, there is a tremendous initial pressure difference that causes oxygen to diffuse rapidly from the capillary blood into the tissues-so rapidly that the capillary PO2 falls almost to equal the 40 mm Hg pressure in the interstitium. Therefore, the PO2 of the blood leaving the tissue capillaries and entering the systemic veins is also about 40 mm Hg.

Effect of Rate of Blood Flow on Interstitial Fluid PO2

If the blood flow through a particular tissue is increased, greater quantities of oxygen are transported into the tissue and the tissue PO2 becomes correspondingly higher. This is shown in Fig. 14. Note that an increase in flow to 400 percent of normal increases the PO2 from 40 mm Hg (at point A in the figure) to 66 mm Hg (at point B). However, the upper limit to which the PO2 can rise, even with maximal blood flow, is 95 mm Hg because this is the oxygen pressure in the arterial blood. Conversely, if blood flow through the tissue decreases, the tissue PO2 also decreases, as shown at point C.
Effect of Rate of Tissue Metabolism on Interstitial Fluid PO2
If the cells use more oxygen for metabolism than normally, this reduces the interstitial fluid PO2. Fig. 15 also demonstrates this effect, showing reduced interstitial fluid PO2 when the cellular oxygen consumption is increased and increased PO2 when consumption is decreased.
In summary, tissue PO2 is determined by a balance between (1) the rate of oxygen transport to the tissues in the blood and (2) the rate at which the oxygen is used by the tissues.

Diffusion of Oxygen from the Peripheral Capillaries to the Tissue Cells

Oxygen is always being used by the cells. Therefore, the intracellular PO2 in the peripheral tissue cells remains lower than the PO2 in the peripheral capillaries. Also, in many instances, there is considerable physical distance between the capillaries and the cells. Therefore, the normal intracellular PO2 ranges from as low as 5 mm Hg to as high as 40 mm Hg, averaging (by direct measurement in lower animals) 23 mm Hg. Because only 1 to 3 mm Hg of oxygen pressure is normally required for full support of the chemical processes that use oxygen in the cell, one can see that even this low intracellular PO2 of 23 mm Hg is more than adequate and provides a large safety factor.
Diffusion of Carbon Dioxide from the Peripheral Tissue Cells into the Capillaries and from the Pulmonary Capillaries into the Alveoli
When oxygen is used by the cells, virtually all of it becomes carbon dioxide, and this increases the intracellular PCO2; because of this high tissue cell PCO2, carbon dioxide diffuses from the cells into the tissue capillaries and is then carried by the blood to the lungs. In the lungs, it diffuses from the pulmonary capillaries into the alveoli and is expired.


Thus, at each point in the gas transport chain, carbon dioxide diffuses in the direction exactly opposite to the diffusion of oxygen. Yet there is one major difference between diffusion of carbon dioxide and of oxygen: carbon dioxide can diffuse about 20 times as rapidly as oxygen. Therefore, the pressure differences required to cause carbon dioxide diffusion are, in each instance, far less than the pressure differences required to cause oxygen diffusion. The CO2 pressures are approximately the following:
1. Intracellular PCO2, 46 mm Hg; interstitial PCO2, 45 mm Hg. Thus, there is only a 1 mm Hg pressure differential, as shown in Fig. 16.
2. PCO2 of the arterial blood entering the tissues, 40 mm Hg; PCO2 of the venous blood leaving the tissues, 45 mm Hg. Thus, as shown in Fig. 15, the tissue capillary blood comes almost exactly to equilibrium with the interstitial PCO2 of 45 mm Hg.
3. PCO2 of the blood entering the pulmonary capillaries at the arterial end, 45 mm Hg; PCO2 of the alveolar air, 40 mm Hg. Thus, only a 5 mm Hg pressure difference causes all the required carbon dioxide diffusion out of the pulmonary capillaries into the alveoli. Furthermore, as shown in Fig. 16, the PCO2 of the pulmonary capillary blood falls to almost exactly equal the alveolar PCO2 of 40 mm Hg before it has passed more than about one third the distance through the capillaries. This is the same effect that was observed earlier for oxygen diffusion, except that it is in the opposite direction.

Effect of Rate of Tissue Metabolism and Tissue Blood Flow on Interstitial PCO2

Tissue capillary blood flow and tissue metabolism affect the PCO2 in ways exactly opposite to their effect on tissue PO2. Fig. 17 shows these effects, as follows:
1. A decrease in blood flow from normal (point A) to one quarter-normal (point B) increases peripheral tissue PCO2 from the normal value of 45 mm Hg to an elevated level of 60 mm Hg. Conversely, increasing the blood flow to six times normal (point C) decreases the interstitial PCO2 from the normal value of 45 mm Hg to 41 mm Hg, down to a level almost equal to the PCO2 in the arterial blood (40 mm Hg) entering the tissue capillaries.
2. Note also that a 10-fold increase in tissue metabolic rate greatly elevates the interstitial fluid PCO2 at all rates of blood flow, whereas decreasing the metabolism to one-quarter normal causes the interstitial fluid PCO2 to fall to about 41 mm Hg, closely approaching that of the arterial blood, 40 mm Hg.


Role of Hemoglobin in Oxygen Transport
Normally, about 97 percent of the oxygen transported from the lungs to the tissues is carried in chemical combination with hemoglobin in the red blood cells. The remaining 3 percent is transported in the dissolved state in the water of the plasma and blood cells. Thus, under normal conditions, oxygen is carried to the tissues almost entirely by hemoglobin.
Reversible Combination of Oxygen with Hemoglobin
The oxygen molecule combines loosely and reversibly with the heme portion of hemoglobin. When PO2 is high, as in the pulmonary capillaries, oxygen binds with the hemoglobin, but when PO2 is low, as in the tissue capillaries, oxygen is released from the hemoglobin. This is the basis for almost all oxygen transport from the lungs to the tissues.
Oxygen-Hemoglobin Dissociation Curve
Fig. 18 shows the oxygen-hemoglobin dissociation curve, which demonstrates a progressive increase in the percentage of hemoglobin bound with oxygen as blood PO2 increases, which is called the percent saturation of hemoglobin. Because the blood leaving the lungs and entering the systemic arteries usually has a PO2 of about 95 mm Hg, one can see from the dissociation curve that the usual oxygen saturation of systemic arterial blood averages 97 percent. Conversely, in normal venous blood returning from the peripheral tissues, the PO2 is about 40 mm Hg, and the saturation of hemoglobin averages 75 percent.

Maximum amount of O2 that can combine with the Hb of the blood

blood, and each gram of hemoglobin can bind with a maximum of 1.34 milliliters of oxygen (1.39 milliliters when the hemoglobin is chemically pure, but impurities such as methemoglobin reduce this). Therefore, 15 times 1.34 equals 20.1, which means that, on average, the 15 grams of hemoglobin in 100 milliliter of blood can combine with a total of about 20 milliliters of oxygen if the hemoglobin is 100 percent saturated. This is usually expressed as 20 volumes percent. The oxygen-hemoglobin dissociation curve for the normal person can also be expressed in terms of volume percent of oxygen, as shown by the far right scale in Fig. 19, instead of percent saturation of hemoglobin.
Amount of Oxygen Released from the Hemoglobin When Systemic Arterial Blood Flows Through the Tissues The total quantity of oxygen bound with hemoglobin in normal systemic arterial blood, which is 97 percent saturated, is about 19.4 milliliters per 100 milliliters of blood. This is shown in Fig. 19. On passing through the tissue capillaries, this amount is reduced, on average, to 14.4 milliliters (PO2 of 40 mm Hg, 75 percent saturated hemoglobin). Thus, under normal conditions, about 5 milliliters of oxygen are transported from the lungs to the tissues by each 100 milliliters of blood flow.

Transport of Oxygen During Strenuous Exercise

During heavy exercise, the muscle cells use oxygen at a rapid rate, which, in extreme cases, can cause the muscle interstitial fluid PO2 to fall from the normal 40 mm Hg to as low as 15 mm Hg. At this low pressure, only 4.4 milliliters of oxygen remain bound with the hemoglobin in each 100 milliliters of blood, as shown in Fig. 20. Thus, 19.4 - 4.4, or 15 milliliters, is the quantity of oxygen actually delivered to the tissues by each 100 milliliters of blood flow. Thus, three times as much oxygen as normal is delivered in each volume of blood that passes through the tissues. And keep in mind that the cardiac output can increase to six to seven times normal in well-trained marathon runners. Thus, multiplying the increase in cardiac output (6- to 7-fold) by the increase in oxygen transport in each volume of blood (3-fold) gives a 20-fold increase in oxygen transport to the tissues. We see later in the chapter that several other factors facilitate delivery of oxygen into muscles during exercise, so muscle tissue PO2 often falls on slightly below normal even during very strenuous exercise.

Utilization Coefficient

The percentage of the blood that gives up its oxygen as it passes through the tissue capillaries is called the utilization coefficient. The normal value for this is about 25 percent, as is evident from the preceding discussion-that is, 25 percent of the oxygenated hemoglobin gives its oxygen to the tissues. During strenuous exercise, the utilization coefficient in the entire body can increase to 75 to 85 percent. And in local tissue areas where blood flow is extremely slow or the metabolic rate is very high, utilization coefficients approaching 100 percent have been recorded-that is, essentially all the oxygen is given to the tissues.
Effect of Hemoglobin to "Buffer" the Tissue PO2
Although hemoglobin is necessary for the transport of oxygen to the tissues, it performs another function essential to life. This is its function as a "tissue oxygen buffer" system. That is, the hemoglobin in the blood is mainly responsible for stabilizing the oxygen pressure in the tissues. This can be explained as follows.

Role of Hemoglobin in Maintaining Nearly Constant PO2 in the Tissues

Under basal conditions, the tissues require about 5 milliliters of oxygen from each 100 milliliters of blood passing through the tissue capillaries. Referring to the oxygen-hemoglobin dissociation curve in Fig. 20, one can see that for the normal 5 milliliters of oxygen to be released per 100 milliliters of blood flow, the PO2 must fall to about 40 mm Hg. Therefore, the tissue PO2 normally cannot rise above this 40 mm Hg level because, if it did, the amount of oxygen needed by the tissues would not be released from the hemoglobin. In this way, the hemoglobin normally sets an upper limit on the oxygen pressure in the tissues at about 40 mm Hg.
Conversely, during heavy exercise, extra amounts of oxygen (as much as 20 times normal) must be delivered from the hemoglobin to the tissues. But this can be achieved with little further decrease in tissue PO2 because of (1) the steep slope of the dissociation curve and (2) the increase in tissue blood flow caused by the decreased PO2; that is, a very small fall in PO2 causes large amounts of extra oxygen to be released from the hemoglobin. It can be seen, then, that the hemoglobin in the blood automatically delivers oxygen to the tissues at a pressure that is held rather tightly between about 15 and 40 mm Hg.

When Atmospheric Oxygen Concentration Changes Markedly, the Buffer Effect of Hemoglobin Still Maintains Almost Constant Tissue PO2

The normal PO2 in the alveoli is about 104 mm Hg, but as one ascends a mountain or ascends in an airplane, the PO2 can easily fall to less than half this amount. Alternatively, when one enters areas of compressed air, such as deep in the sea or in pressurized chambers, the PO2 may rise to 10 times this level. Even so, the tissue PO2 changes little.
It can be seen from the oxygen-hemoglobin dissociation curve in Fig. 19 that when the alveolar PO2 is decreased to as low as 60 mm Hg, the arterial hemoglobin is still 89 percent saturated with oxygen-only 8 percent below the normal saturation of 97 percent. Further, the tissues still remove about 5 milliliters of oxygen from each 100 milliliter of blood passing through the tissues; to remove this oxygen, the PO2 of the venous blood falls to 35 mm Hg-only 5 mm Hg below the normal value of 40 mm Hg. Thus, the tissue PO2 hardly changes, despite the marked fall in alveolar PO2 from 104 to 60 mm Hg.
Conversely, when the alveolar PO2 rises as high as 500 mm Hg, the maximum oxygen saturation of hemoglobin can never rise above 100 percent, which is only 3 percent above the normal level of 97 percent. Only a small amount of additional oxygen dissolves in the fluid of the blood, as will be discussed subsequently. Then, when the blood passes through the tissue capillaries and loses several milliliters of oxygen to the tissues, this reduces the PO2 of the capillary blood to a value only a few milliliters greater than the normal 40 mm Hg. Consequently, the level of alveolar oxygen may vary greatly-from 60 to more than 500 mm Hg PO2-and still the PO2 in the peripheral tissues does not vary more than a few milliliters from normal, demonstrating beautifully the tissue "oxygen buffer" function of the blood hemoglobin system.

Factors That Shift the Oxygen-Hemoglobin Dissociation Curve-Their Importance for Oxygen Transport

The oxygen-hemoglobin dissociation curves of Figs. 18 and 19 are for normal, average blood. However, a number of factors can displace the dissociation curve in one direction or the other in the manner shown in Fig. 20. This figure shows that when the blood becomes slightly acidic, with the pH decreasing from the normal value of 7.4 to 7.2, the oxygen-hemoglobin dissociation curve shifts, on average, about 15 percent to the right. Conversely, an increase in pH from the normal 7.4 to 7.6 shifts the curve a similar amount to the left.
In addition to pH changes, several other factors are known to shift the curve. Three of these, all of which shift the curve to the right, are (1) increased carbon dioxide concentration, (2) increased blood temperature, and (3) increased 2,3-biphosphoglycerate (BPG) (or diphosphoglycerate (DPG)), a metabolically important phosphate compound present in the blood in different concentrations under different metabolic conditions.

Increased Delivery of Oxygen to the Tissues When Carbon Dioxide and Hydrogen Ions Shift the Oxygen-Hemoglobin Dissociation Curve-The Bohr Effect

A shift of the oxygen-hemoglobin dissociation curve to the right in response to increases in blood carbon dioxide and hydrogen ions has a significant effect by enhancing the release of oxygen from the blood in the tissues and enhancing oxygenation of the blood in the lungs. This is called the Bohr effect, which can be explained as follows: As the blood passes through the tissues, carbon dioxide diffuses from the tissue cells into the blood. This increases the blood PCO2, which in turn raises the blood H2CO3 (carbonic acid) and the hydrogen ion concentration. These effects shift the oxygen-hemoglobin dissociation curve to the right and downward, as shown in Fig. 20, forcing oxygen away from the hemoglobin and therefore delivering increased amounts of oxygen to the tissues.
Exactly the opposite effects occur in the lungs, where carbon dioxide diffuses from the blood into the alveoli. This reduces the blood PCO2 and decreases the hydrogen ion concentration, shifting the oxygen-hemoglobin dissociation curve to the left and upward. Therefore, the quantity of oxygen that binds with the hemoglobin at any given alveolar PO2 becomes considerably increased, thus allowing greater oxygen transport to the tissues.

Effect of BPG to Cause Rightward Shift of the Oxygen-Hemoglobin Dissociation Curve

The normal BPG in the blood keeps the oxygen-hemoglobin dissociation curve shifted slightly to the right all the time. In hypoxic conditions that last longer than a few hours, the quantity of BPG in the blood increases considerably, thus shifting the oxygen-hemoglobin dissociation curve even farther to the right. This causes oxygen to be released to the tissues at as much as 10 mm Hg higher tissue oxygen pressure than would be the case without this increased BPG. Therefore, under some conditions, the BPG mechanism can be important for adaptation to hypoxia, especially to hypoxia caused by poor tissue blood flow.
Rightward Shift of the Oxygen-Hemoglobin Dissociation Curve During Exercise During exercise, several factors shift the dissociation curve considerably to the right, thus delivering extra amounts of oxygen to the active, exercising muscle fibers. The exercising muscles, in turn, release large quantities of carbon dioxide; this and several other acids released by the muscles increase the hydrogen ion concentration in the muscle capillary blood. In addition, the temperature of the muscle often rises 2° to 3°C, which can increase oxygen delivery to the muscle fibers even more. All these factors act together to shift the oxygen-hemoglobin dissociation curve of the muscle capillary blood considerably to the right. This rightward shift of the curve forces oxygen to be released from the blood hemoglobin to the muscle at PO2 levels as great as 40 mm Hg, even when 70 percent of the oxygen has already been removed from the hemoglobin. Then, in the lungs, the shift occurs in the opposite direction, allowing the pickup of extra amounts of oxygen from the alveoli.

Metabolic Use of Oxygen by the Cells
Effect of Intracellular PO2 on Rate of Oxygen Usage

Only a minute level of oxygen pressure is required in the cells for normal intracellular chemical reactions to take place. The reason for this is that the respiratory enzyme systems of the cell are geared so that when the cellular PO2 is more than 1 mm Hg, oxygen availability is no longer a limiting factor in the rates of the chemical reactions. Instead, the main limiting factor is the concentration of adenosine diphosphate (ADP) in the cells. This effect is demonstrated in Fig. 21 which shows the relation between intracellular PO2 and the rate of oxygen usage at different concentrations of ADP. Note that whenever the intracellular PO2 is above 1 mm Hg, the rate of oxygen usage becomes constant for any given concentration of ADP in the cell. Conversely, when the ADP concentration is altered, the rate of oxygen usage changes in proportion to the change in ADP concentration.
When adenosine triphosphate (ATP) is used in the cells to provide energy, it is converted into ADP. The increasing concentration of ADP increases the metabolic usage of oxygen as it combines with the various cell nutrients, releasing energy that reconverts the ADP back to ATP. Under normal operating conditions, the rate of oxygen usage by the cells is controlled ultimately by the rate of energy expenditure within the cells-that is, by the rate at which ADP is formed from ATP.

Effect of Diffusion Distance from the Capillary to the Cell on Oxygen Usage

Tissue cells are seldom more than 50 micrometers away from a capillary, and oxygen normally can diffuse readily enough from the capillary to the cell to supply all the required amounts of oxygen for metabolism. However, occasionally, cells are located farther from the capillaries, and the rate of oxygen diffusion to these cells can become so low that intracellular PO2 falls below the critical level required to maintain maximal intracellular metabolism. Thus, under these conditions, oxygen usage by the cells is said to be diffusion limited and is no longer determined by the amount of ADP formed in the cells. But this almost never occurs, except in pathological states.
Effect of Blood Flow on Metabolic Use of Oxygen
The total amount of oxygen available each minute for use in any given tissue is determined by (1) the quantity of oxygen that can be transported to the tissue in each 100 ml of blood and (2) the rate of blood flow. If the rate of blood flow falls to zero, the amount of available oxygen also falls to zero. Thus, there are times when the rate of blood flow through a tissue can be so low that tissue Po2 falls below the critical 1 mm Hg required for intracellular metabolism. Under these conditions, the rate of tissue usage of oxygen is blood flow limited. Neither diffusion-limited nor blood flow-limited oxygen states can continue for long, because the cells receive less oxygen than is required to continue the life of the cells.

Transport of Oxygen in the Dissolved State

At the normal arterial PO2 of 95 mm Hg, about 0.29 milliliter of oxygen is dissolved in every 100 milliliters of water in the blood, and when the PO2 of the blood falls to the normal 40 mm Hg in the tissue capillaries, only 0.12 milliliters of oxygen remains dissolved. In other words, 0.17 milliliters of oxygen is normally transported in the dissolved state to the tissues by each 100 milliliters of arterial blood flow. This compares with almost 5 milliliters of oxygen transported by the red cell hemoglobin. Therefore, the amount of oxygen transported to the tissues in the dissolved state is normally slight, only about 3 percent of the total, as compared with 97 percent transported by the hemoglobin.
During strenuous exercise, when hemoglobin release of oxygen to the tissues increases another threefold, the relative quantity of oxygen transported in the dissolved state falls to as little as 1.5 percent. But if a person breathes oxygen at very high alveolar PO2 levels, the amount transported in the dissolved state can become much greater, sometimes so much so that a serious excess of oxygen occurs in the tissues, and "oxygen poisoning" ensues.

Combination of Hemoglobin with Carbon Monoxide-Displacement of Oxygen

Carbon monoxide combines with hemoglobin at the same point on the hemoglobin molecule as does oxygen; it can therefore displace oxygen from the hemoglobin, thereby decreasing the oxygen-carrying capacity of blood. Further, it binds with about 250 times as much tenacity as oxygen, which is demonstrated by the carbon monoxide-hemoglobin dissociation curve in Fig. 22. This curve is almost identical to the oxygen-hemoglobin dissociation curve, except that the carbon monoxide partial pressures, shown on the abscissa, are at a level 1/250 of those for the oxygen-hemoglobin dissociation curve of Fig. 19. Therefore, a carbon monoxide partial pressure of only 0.4 mm Hg in the alveoli, 1/250 that of normal alveolar oxygen (100 mm Hg PO2), allows the carbon monoxide to compete equally with the oxygen for combination with the hemoglobin and causes half the hemoglobin in the blood to become bound with carbon monoxide instead of with oxygen. Therefore, a carbon monoxide pressure of only 0.6 mm Hg (a volume concentration of less than one part per thousand in air) can be lethal.
Even though the oxygen content of blood is greatly reduced in carbon monoxide poisoning, the PO2 of the blood may be normal. This makes exposure to carbon monoxide especially dangerous because the blood is bright red and there are no obvious signs of hypoxemia, such as a bluish color of the fingertips or lips (cyanosis). Also, PO2 is not reduced, and the feedback mechanism that usually stimulates increased respiration rate in response to lack of oxygen (usually reflected by a low PO2) is absent. Because the brain is one of the first organs affected by lack of oxygen, the person may become disoriented and unconscious before becoming aware of the danger.
A patient severely poisoned with carbon monoxide can be treated by administering pure oxygen because oxygen at high alveolar pressure can displace carbon monoxide rapidly from its combination with hemoglobin. The patient can also benefit from simultaneous administration of 5 percent carbon dioxide because this strongly stimulates the respiratory center, which increases alveolar ventilation and reduces the alveolar carbon monoxide. With intensive oxygen and carbon dioxide therapy, carbon monoxide can be removed from the blood as much as 10 times as rapidly as without therapy.

Transport of Carbon Dioxide in the Blood

Transport of carbon dioxide by the blood is not nearly as problematical as transport of oxygen is because even in the most abnormal conditions, carbon dioxide can usually be transported in far greater quantities than oxygen can be. However, the amount of carbon dioxide in the blood has a lot to do with the acid-base balance of the body fluids. Under normal resting conditions, an average of 4 milliliters of carbon dioxide is transported from the tissues to the lungs in each 100 milliliters of blood.
Chemical Forms in Which Carbon Dioxide Is Transported
To begin the process of carbon dioxide transport, carbon dioxide diffuses out of the tissue cells in the dissolved molecular carbon dioxide form. On entering the tissue capillaries, the carbon dioxide initiates a host of almost instantaneous physical and chemical reactions, shown in Fig. 23, which are essential for carbon dioxide transport.

Transport of CO2 in the dissolved state

A small portion of the carbon dioxide is transported in the dissolved state to the lungs. Recall that the PCO2 of venous blood is 45 mm Hg and that of arterial blood is 40 mm Hg. The amount of carbon dioxide dissolved in the fluid of the blood at 45 mm Hg is about 2.7 ml/dl (2.7 volumes percent). The amount dissolved at 40 mm Hg is about 2.4 milliliters, or a difference of 0.3 milliliter. Therefore, only about 0.3 milliliter of carbon dioxide is transported in the dissolved form by each 100 milliliters of blood flow. This is about 7 percent of all the carbon dioxide normally transported.
Transport of Carbon Dioxide in the Form of Bicarbonate Ion
Reaction of Carbon Dioxide with Water in the Red Blood Cells-Effect of Carbonic Anhydrase
The dissolved carbon dioxide in the blood reacts with water to form carbonic acid. This reaction would occur much too slowly to be of importance were it not for the fact that inside the red blood cells is a protein enzyme called carbonic anhydrase, which catalyzes the reaction between carbon dioxide and water and accelerates its reaction rate about 5000-fold. Therefore, instead of requiring many seconds or minutes to occur, as is true in the plasma, the reaction occurs so rapidly in the red blood cells that it reaches almost complete equilibrium within a very small fraction of a second. This allows tremendous amounts of carbon dioxide to react with the red blood cell water even before the blood leaves the tissue capillaries.

Dissociation of Carbonic Acid into Bicarbonate and Hydrogen Ions

In another fraction of a second, the carbonic acid formed in the red cells (H2CO3) dissociates into hydrogen and bicarbonate ions (H+ and HCO3_). Most of the H+ ions then combine with the hemoglobin in the red blood cells because the hemoglobin protein is a powerful acid-base buffer. In turn, many of the HCO3_ ions diffuse from the red cells into the plasma, while chloride ions diffuse into the red cells to take their place. This is made possible by the presence of a special bicarbonate-chloride carrier protein in the red cell membrane that shuttles these two ions in opposite directions at rapid velocities. Thus, the chloride content of venous red blood cells is greater than that of arterial red cells, a phenomenon called the chloride shift.
The reversible combination of carbon dioxide with water in the red blood cells under the influence of carbonic anhydrase accounts for about 70 percent of the carbon dioxide transported from the tissues to the lungs. Thus, this means of transporting carbon dioxide is by far the most important. Indeed, when a carbonic anhydrase inhibitor (acetazolamide) is administered to an animal to block the action of carbonic anhydrase in the red blood cells, carbon dioxide transport from the tissues becomes so poor that the tissue PCO2 can be made to rise to 80 mm Hg instead of the normal 45 mm Hg.

Transport of Carbon Dioxide in Combination with Hemoglobin and Plasma Proteins-Carbaminohemoglobin

In addition to reacting with water, carbon dioxide reacts directly with amine radicals of the hemoglobin molecule to form the compound carbaminohemoglobin (CO2Hgb). This combination of carbon dioxide and hemoglobin is a reversible reaction that occurs with a loose bond, so the carbon dioxide is easily released into the alveoli, where the PCO2 is lower than in the pulmonary capillaries.
A small amount of carbon dioxide also reacts in the same way with the plasma proteins in the tissue capillaries. This is much less significant for the transport of carbon dioxide because the quantity of these proteins in the blood is only one fourth as great as the quantity of hemoglobin.
The quantity of carbon dioxide that can be carried from the peripheral tissues to the lungs by carbamino combination with hemoglobin and plasma proteins is about 30 percent of the total quantity transported-that is, normally about 1.5 milliliters of carbon dioxide in each 100 milliliters of blood. However, because this reaction is much slower than the reaction of carbon dioxide with water inside the red blood cells, it is doubtful that under normal conditions this carbamino mechanism transports more than 20 percent of the total carbon dioxide.

Carbon Dioxide Dissociation Curve

The curve shown in Fig. 24 called the carbon dioxide dissociation curve-depicts the dependence of total blood carbon dioxide in all its forms on PCO2. Note that the normal blood PCO2 ranges between the limits of 40 mm Hg in arterial blood and 45 mm Hg in venous blood, which is a very narrow range. Note also that the normal concentration of carbon dioxide in the blood in all its different forms is about 50 volumes percent, but only 4 volumes percent of this is exchanged during normal transport of carbon dioxide from the tissues to the lungs. That is, the concentration rises to about 52 volumes percent as the blood passes through the tissues and falls to about 48 volumes percent as it passes through the lungs.

When Oxygen Binds with Hemoglobin, Carbon Dioxide Is Released (the Haldane Effect) to Increase CO2 Transport

Earlier in the chapter, it was pointed out that an increase in carbon dioxide in the blood causes oxygen to be displaced from the hemoglobin (the Bohr effect), which is an important factor in increasing oxygen transport. The reverse is also true: binding of oxygen with hemoglobin tends to displace carbon dioxide from the blood. Indeed, this effect, called the Haldane effect, is quantitatively far more important in promoting carbon dioxide transport than is the Bohr effect in promoting oxygen transport.
The Haldane effect results from the simple fact that the combination of oxygen with hemoglobin in the lungs causes the hemoglobin to become a stronger acid. This displaces carbon dioxide from the blood and into the alveoli in two ways: (1) The more highly acidic hemoglobin has less tendency to combine with carbon dioxide to form carbaminohemoglobin, thus displacing much of the carbon dioxide that is present in the carbamino form from the blood. (2) The increased acidity of the hemoglobin also causes it to release an excess of hydrogen ions, and these bind with bicarbonate ions to form carbonic acid; this then dissociates into water and carbon dioxide, and the carbon dioxide is released from the blood into the alveoli and, finally, into the air.


Fig. 25 demonstrates quantitatively the significance of the Haldane effect on the transport of carbon dioxide from the tissues to the lungs. This figure shows small portions of two carbon dioxide dissociation curves: (1) when the PO2 is 100 mm Hg, which is the case in the blood capillaries of the lungs, and (2) when the PO2 is 40 mm Hg, which is the case in the tissue capillaries. Point A shows that the normal PCO2 of 45 mm Hg in the tissues causes 52 volumes percent of carbon dioxide to combine with the blood. On entering the lungs, the PCO2 falls to 40 mm Hg and the PO2 rises to 100 mm Hg. If the carbon dioxide dissociation curve did not shift because of the Haldane effect, the carbon dioxide content of the blood would fall only to 50 volumes percent, which would be a loss of only 2 volumes percent of carbon dioxide. However, the increase in PO2 in the lungs lowers the carbon dioxide dissociation curve from the top curve to the lower curve of the figure, so the carbon dioxide content falls to 48 volumes percent (point B). This represents an additional two volumes percent loss of carbon dioxide. Thus, the Haldane effect approximately doubles the amount of carbon dioxide released from the blood in the lungs and approximately doubles the pickup of carbon dioxide in the tissues.

Change in Blood Acidity During Carbon Dioxide Transport

The carbonic acid formed when carbon dioxide enters the blood in the peripheral tissues decreases the blood pH. However, reaction of this acid with the acid-base buffers of the blood prevents the H+ concentration from rising greatly (and the pH from falling greatly). Ordinarily, arterial blood has a pH of about 7.41, and as the blood acquires carbon dioxide in the tissue capillaries, the pH falls to a venous value of about 7.37. In other words, a pH change of 0.04 unit takes place. The reverse occurs when carbon dioxide is released from the blood in the lungs, with the pH rising to the arterial value of 7.41 once again. In heavy exercise or other conditions of high metabolic activity, or when blood flow through the tissues is sluggish, the decrease in pH in the tissue blood (and in the tissues themselves) can be as much as 0.50, about 12 times normal, thus causing significant tissue acidosis.

Respiratory Exchange Ratio

The discerning student will have noted that normal transport of oxygen from the lungs to the tissues by each 100 milliliters of blood is about 5 milliliters, whereas normal transport of carbon dioxide from the tissues to the lungs is about 4 milliliters. Thus, under normal resting conditions, only about 82 percent as much carbon dioxide is expired from the lungs as oxygen is taken up by the lungs. The ratio of carbon dioxide output to oxygen uptake is called the respiratory exchange ratio (R). That is, R=rate of CO2 output over rate of O2 uptake
The value for R changes under different metabolic conditions. When a person is using exclusively carbohydrates for body metabolism, R rises to 1.00. Conversely, when a person is using exclusively fats for metabolic energy, the R level falls to as low as 0.7. The reason for this difference is that when oxygen is metabolized with carbohydrates, one molecule of carbon dioxide is formed for each molecule of oxygen consumed; when oxygen reacts with fats, a large share of the oxygen combines with hydrogen atoms from the fats to form water instead of carbon dioxide. In other words, when fats are metabolized, the respiratory quotient of the chemical reactions in the tissues is about 0.70 instead of 1.00. For a person on a normal diet consuming average amounts of carbohydrates, fats, and proteins, the average value for R is considered to be 0.825.

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