GAS EXCHANGE BETWEEN AIR AND BLOOD

DIFFUSION

Chapter objectives

After studying this chapter you should be able to:

1. Explain the ‘series’ nature of diffusion in the lungs.

2. State Fick’s Law of Diffusion.

3. Define diffusing capacity and explain why the term transfer factor is preferred.

4. Relate the properties of O₂ and CO₂ to the influence of pathology on their transfer.

5. Explain why the equilibrium for O₂ is established at about the same rate as that for CO₂.

6. Outline the important components limiting rate of transfer in the lungs and how they are affected by disease.

7. Explain the selection of CO as a gas to measure transfer factor.

8. Explain why ventilation rather than diffusion is the most important factor in the transfer of CO₂.

The path from air to tissue

The lungs are so good at maintaining O₂ levels in the blood that it was until quite recently thought to be an active process, with the body actively extracting O₂ from the air. It is now known that the process is purely passive diffusion down concentration gradients. Diffusion is so important to our obtaining O₂ that the ability of the lungs to allow diffusion to happen is frequently measured, and is sometimes called the lung’s diffusing capacity. This capacity is reduced in many diseases, including fibrosis, asbestosis, sarcoidosis and pneumonia.

In Chapter 5 we described the way in which ventilation of different regions of the lung results in different compositions of gas in the alveoli. In understanding the next step in the journey from air to blood or blood to air it is important to differentiate clearly between the amount of a gas present in a mixture and the fraction or concentration of that gas, frequently expressed as partial pressure (P). This concept is important because it is only the difference in partial pressure that drives diffusion from one place to another. To use an analogy: the pressure across the enormous lock gates holding the Atlantic Ocean out of a dock in which the water is 10 cm lower than the ocean is the same as that across the walls of a child’s paddling pool containing water 10 cm deep. The amounts of water either side (or gas in the case of the lung) having nothing to do with the motive force (driving pressure): the difference in depth of water (or difference in partial pressure of gas) provides the motive force.

The partial pressure of a gas depends on its concentration, and so the partial pressure gradient across a membrane depends on the difference in concentration on either side. It is diffusion alone that transports gas between air and blood at the lungs, and between blood and cells at the tissues, and the circulation of blood effectively links the two sites. In the case of O₂ (Fig. 6.1) we can see that diffusion at the lungs is sufficient to reduce to virtually zero any difference in partial pressure (concentration) between alveolar air and pulmonary blood, whereas at the tissues a large difference in partial pressure between arterial blood and the mitochondria ensures a vigorous flow into these organelles of oxidative metabolism.

Fig. 6.1 The path of oxygen. The physical path is shown as a diagram above. The partial pressure of O₂ in air, blood and tissue fluid at the different points on its journey is shown below.

The single step of O₂ from air to blood in Figure 6.1 is in fact a series of steps through components which are in series and which will be considered in detail below. The important thing to remember is that they are in series (i.e. one after another), like the segments of a hosepipe made up of a number of bits joined together. Constricting one segment reduces flow in all.

Lung disease and diffusion

The lungs have such an enormous capacity for diffusion that there is some doubt in many diseases (e.g. emphysema) as to what part the impairment of diffusion plays in producing the characteristic hypoxia of the disease. In many cases a diffusional component can only be demonstrated when the patient is exercising. The destruction of the architecture of the respiratory regions in emphysema (Fig. 4.16) must impair diffusion, but the effect on distribution of ventilation and blood flow must be at least as important. Other diseases (e.g. interstitial pulmonary fibrosis) which produce profound thickening of the respiratory membranes reduce the lungs’ capacity for diffusion to one-sixth of normal, and it is difficult to assume that this does not affect their function.

Case 6.1 Gas exchange between air and blood: diffusion: 1

Fibrosing alveolitis

Mr Paterson is 65 years old. Although he has never smoked, he has become increasingly breathless over the past few months, particularly when he exerts himself. He went to see his doctor, who examined him. He found that Mr Paterson was rather breathless and had finger-clubbing (see Fig. 1.4). He found that Mr Paterson’s chest expansion was reduced on both sides and on auscultation he heard fine inspiratory crepitations (crackles) all over Mr Paterson’s chest, but particularly over the bases of his lungs. He decided to refer Mr Paterson to a respiratory physician at the local hospital.

In this chapter we will consider:

1. The clinical features of cryptogenic fibrosing alveolitis.

2. The diagnosis and treatment of cryptogenic fibrosing alveolitis.

Fick’s Law of Diffusion

The movement of gas into and out the blood is described by Fick’s Law (Appendix, p. 155), which describes the rate of diffusion of a gas across a membrane as follows:

where A is the area of the membrane available for diffusion. S is the solubility of the gas in the membrane, ΔC is the concentration gradient – brought about by the differences in concentration (or partial pressure) either side of the membrane – t is the thickness of the membrane and MW is the molecular weight of the gas (Fig. 6.2).

Fig. 6.2 Diffusion through a membrane. It is obvious that gas will diffuse more quickly if the area is great, the thickness is small and the concentration difference of the gas, which is highly soluble in the membrane, is high.

The area available for diffusion is the area of the pulmonary capillaries that is in contact with alveolar air. This area can be changed by diseases which destroy alveolar septa, and by changes during exercise, when capillaries that were closed at rest open up and those already open become distended.

The solubility of a gas determines the rate of diffusion of a gas in solution. The gases we are particularly interested in are CO₂ and O₂. Carbon dioxide is 23 times more soluble in tissue fluid than is O₂ but has a higher molecular weight; it will therefore diffuse from blood to air 20 times more readily for the same partial pressure gradient than will O₂ moving in the opposite direction. However, equilibrium for CO₂ is established at about the same rate as for O₂ because:

1. the reaction releasing CO₂ from blood is relatively slow

2. the concentration gradient driving CO₂ from blood to alveolar air is only 0.8 kPa, whereas that driving O₂ in the opposite direction is 8 kPa.

Although the process of diffusion is a physical one, chemical reactions exert their influence on this process in the lungs. In particular, the rate at which O₂ can be taken up or released by haemoglobin in the red blood corpuscles (RBC) acts as a rate-limiting step, reducing its overall rate of transfer.

Although there are situations when the lung can be so damaged as to restrict the diffusion of CO₂ it is usually O₂ that is first affected by diffusional difficulties. The rate of removal of CO₂ is governed primarily by alveolar ventilation (chapter 5; p. 62 and p.83 of this chapter).

In Figure 6.1 there are three places where diffusion is the major transport mechanism and where this transport can effectively be impeded by failure of diffusion:

1. Within the alveoli

2. From the alveolar air to the RBC

3. From the RBC to the tissue mitochondria.

As this is a textbook on the respiratory system we will concentrate on the first two. The anatomical sites of these two sources of impedance to diffusion are shown in Figure 6.3.

Fig. 6.3 The site of diffusion in the lungs. The distance involved in diffusion within the alveolar space is much greater than the distance within the lung tissue. However, diffusion within the alveolar space is in air and therefore much more rapid than in the tissue. The diffusional barrier between blood and alveolar air consists of attenuated cytoplasm of a Type 1 pneumocyte P₁, a common basement membrane BM, cytoplasm of a capillary endothelial cell E. Er is an erythrocyte in a capillary. Source: Stevens et al., 2002.

Within the alveoli

In healthy lungs the average diameter of the alveoli is about 200 μm. Any differences in the concentrations of the respiratory gases at different points within the alveolus will be obliterated by diffusion over these distances in less than 10 ms. It might be imagined, however, that in emphysema (where the air spaces are enlarged) increased distances for diffusion slow O₂ transport to unacceptable levels. Although it is true that these changes in geometry must have an effect, destruction of the alveolar septa, reducing surface area, together with ventilation/perfusion mismatching, exerts a malign influence in this disease well before diffusion problems need be considered.

Air to RBC

This step from air to blood or blood to air has a number of components of its own:

• Length of time blood is in the capillaries

• Crossing the alveolar/capillary membrane

• Diffusion in the blood plasma

• Reaction with haemoglobin.

Time in the capillaries

Although blood flow through the lungs is highly pulsatile (p. 87) it is legitimate when considering diffusion to consider blood flowing smoothly and taking on average 0.8 s to transit the pulmonary capillary. The way concentration and hence the partial pressure of O₂ in the blood changes during transit along the capillary is shown in Figure 6.4.

Fig. 6.4 Partial pressure of O₂ in blood during its transit through a pulmonary capillary. This example shows the mean transit time for a population which has a high degree of variation. The broken line represents reduced partial pressure of oxygen (as at altitude).

Consideration of this figure reveals a number of potential complications which can arise because:

• There are great differences in transit time through different regions of the lung. Transit times less than 0.2 s do not allow sufficient time for equilibration, and capillaries with these low transit times pass deoxygenated blood to the pulmonary veins. This is functionally equivalent to a spread of (ventilation/perfusion) ratios, and this is ‘a bad thing’ (see Chapter 7).

• During heavy exercise cardiac output increases and all transit times are reduced.

• At altitude the partial pressure of ambient O₂ driving O₂ into the blood is reduced. This effect is shown as a dotted line in Figure 6.4. Clearly, exercise at altitude is the worst of all possible combinations, except for disease, and these effects account for much of the limitation of mountaineering achievement.

Crossing the alveolar membrane

The lining epithelium and basement membrane of the alveoli and the endothelium and basement membrane of the pulmonary capillaries are each about 0.2 μm thick on one side of the capillary and somewhat thicker on the other supporting side (Fig. 6.3). The capillaries occupy most of the alveolar wall, generally being less than one capillary diameter apart, and with each capillary passing through up to three alveoli. It might be expected that diseases such as pulmonary fibrosis, sarcoidosis, asbestosis and pulmonary oedema, which affect the alveolar/capillary membrane, would interfere with diffusion. Remarkably, however, these problems seem to affect diffusion less than might be expected, because they are usually found on the inactive, supporting, side of the pulmonary capillary, leaving the functional side relatively undamaged. Their major effects are to reduce the surface area for diffusion by gross destruction of tissue and increased ventilation/perfusion mismatching.

Diffusion in blood plasma

Red blood corpuscles are about the same diameter as pulmonary capillaries: in fact, they have to be distorted to squeeze through many capillaries. This means there is very little plasma between the corpuscle and the capillary wall for gas to diffuse through. Also, the ‘doughnut’ shape of the corpuscles means that most of the haemoglobin within is close to the wall, again shortening the distance for diffusion. The ‘kneading’ of the corpuscles as they squeeze through the capillaries probably causes mass movements of haemoglobin within the corpuscle, which also aids diffusion.

Reaction with haemoglobin

As the vast majority of O₂ in the blood is carried by haemoglobin, the rate at which they combine is an important limiting step in O₂ diffusion into the blood.

Because the transfer of O₂ into the blood is profoundly affected by such factors as reaction rates with haemoglobin and transit time through pulmonary capillaries, which have nothing to do with the physical process of diffusion, it has been suggested that ‘diffusing capacity’ is an inappropriate term to describe the process. In England, where both the language and the technique for measuring this transfer were developed, the term transfer factor is generally preferred.

Case 6.1 Gas exchange between air and blood: diffusion: 2

Diagnosis and treatment of fibrosing alveolitis

At the local hospital, Mr Paterson was seen by the respiratory physician. The physician took a careful history from Mr Paterson, including details of all the occupations which Mr Paterson had had since he left school. His examination confirmed all the findings of Mr Paterson’s GP. He performed pulmonary function tests on Mr Paterson, which showed a restrictive defect and a reduced carbon monoxide transfer factor. Mr Paterson also had a chest X-ray which looked like the one in Figure 6.5. In view of Mr Paterson’s age and rather poor respiratory condition, the physician decided that further investigation of Mr Paterson’s condition, which might have included lung biopsy, were not warranted, and he made a diagnosis of cryptogenic fibrosing alveolitis.

Fig. 6.5 Chest X-ray of a patient with cryptogenic fibrosing alveolitis. This shows fine reticular shadowing, which appears more pronounced towards the outer parts of the lung fields. The shadowing is also more pronounced near the bases of the lungs because there is a reduction in lung volume, and it is the bases of the lungs which tend to collapse first.

Patients with fibrosing alveolitis usually give a history of increasing breathlessness over a considerable period of time. A dry cough may be present, but wheeze is unusual. The history may also provide clues as to possible causes of fibrosing alveolitis such as exposure to metal dusts or asbestos. Clues in the history might also point to diseases or drugs that may be complicated by fibrosing alveolitis.

On examination, finger clubbing is present in the majority of patients. Fine crepitations at the end of inspiration are present throughout the lungs. In advanced cases, central cyanosis may be present.

Investigations include pulmonary function testing, which reveals a restrictive defect, and a chest X-ray which may demonstrate fine shadowing at the periphery of the lung fields (Fig. 6.5). A fine CT scan may provide more information than a chest X-ray in diagnosing the disease. Bronchoalveolar lavage, in which fluid is introduced into the airways through a bronchoscope and then sucked back up for histological analysis is sometimes used for diagnosis and a lung biopsy provides a definitive diagnosis of the condition.

Measuring transfer factor

It is important, clinically and scientifically, to be able to measure transfer factor (diffusing capacity). The physiology on which the technique of measuring transfer factor is based will repay study here.

Transfer factor is primarily to do with the rate at which the lungs allow O₂ to diffuse into the blood. We wish to measure this – or at least to compare this ability in people we know are normal with those suspected of having lung disease.

Frequently when we say we are measuring something we are in fact comparing it with a known standard. (When we carry out the simple act of measuring someone’s height we are in fact comparing their length with ‘the distance travelled by light in a vacuum in 1/29 792 458 seconds’, which is the physicists’ definition of the metre, but any other standard length would do. We could use the ‘hand’ (102 mm), normally used to measure the height of horses, so long as we define what we are using. Applying this principle to transfer factor means we do not have to actually measure the flow of O₂ into the body to compare transfer factor between people: we can measure the flux of another, more convenient, gas so long as it is influenced by the same things as those that influence O₂ transfer. This is fortunate because, as we will see, O₂ presents difficulties.)

How do we choose a gas to measure transfer factor?

We therefore need to know the rate at which our chosen gas is taken up and the pressure which is driving it into the body.

If the blood in the pulmonary capillaries is very quickly saturated with the gas we are using it cannot take up any more, and this ‘puts a stop’ to the movement of the gas into the body. In this case, the rate at which blood flows through the lungs, and not diffusion, determines the rate of transfer and we are measuring pulmonary blood flow not transfer factor. Nitrous oxide behaves in this way and is used to measure pulmonary blood flow, but it is useless for measuring transfer factor (Fig. 6.6A).

Fig. 6.6 Measuring transfer factor. Nitrous oxide immediately saturates pulmonary capillary blood and so prevents any further transfer. Its uptake is therefore limited by pulmonary blood flow, not transfer factor. Oxygen partial pressure in the pulmonary capillary is impossible to measure accurately along the capillary, and so driving pressure into the blood cannot be calculated. Carbon monoxide is so tightly bound to haemoglobin in the blood that it exerts no partial pressure there. Driving partial pressure is the partial pressure in the inhaled air.

As we are interested in the transfer of O₂ why not use O₂? We can certainly measure the rate at which O₂ is taken up by a subject, but the problem comes with having to measure the ‘driving partial pressure (air-to-blood)’. Blood enters the lung capillaries already carrying some O₂. Venous blood, which contains variable amounts of O₂ is beginning to be oxygenated in the pulmonary arterioles even before it reaches the capillaries, and so it is very difficult to know the exact driving pressure between alveolar air and this variable capillary blood. Also, except at low inhaled Po₂ blood is almost totally saturated with O₂ when it leaves the lungs, producing the same difficulties as with nitrous oxide, where uptake is governed by blood flow rather than transfer factor (Fig. 6.6B).

The gas that turns out to be most suitable for measuring transfer factor is the poisonous gas carbon monoxide (CO). This is poisonous because it competes with O₂ for binding sites on haemoglobin, and binds 250 times more strongly than O₂, thereby denying O₂ access to the haemoglobin – the victim of CO poisoning therefore dies of O₂ lack. (For this reason only very low concentrations of CO are used in measuring transfer factor.) Because it binds so strongly CO is ‘locked up’ in the haemoglobin and to all intents and purposes disappears from the blood. In other words, its partial pressure in the blood is zero. Knowing the rate at which CO disappears from a gas mixture the subject holds in his lungs for 10 seconds, and the partial pressures of CO in that mixture before and after inhalation, transfer factor can be calculated (Fig. 6.6C).

Treating diffusion difficulties

Bearing in mind that a large part of the problems of patients who might be suspected of having diffusional difficulties may be due to ventilation or abnormalities, the rational treatment of patients whose lung diffusion problems lead to hypoxaemia depends on understanding the properties of the lung membrane illustrated in Figure 6.2. In these patients diffusion may have been reduced by thickening of the membrane (fibrosis) or loss of surface area (emphysema). These conditions are usually irreversible, and so we are left with only the option of increasing the partial pressure driving O₂ into the blood. Fortunately this is very effective, and increasing the inspired fraction of O₂ from the normal 21% in room air to 30% doubles the O₂ flux into the blood. In appropriate cases of progressive lung disease O₂ supplied via a nasal cannula or mask can much improve the quality of life of the unfortunate patient who requires O₂ to relieve his breathlessness at rest. These patients, perhaps realizing how precarious their existence is, were once thought to become dependent on O₂ administration. This dependency is usually psychological and is best avoided by giving the gas only to patients who obtain relief, and then only when needed and at the minimum effective dose.

Case 6.1 Gas exchange between air and blood: diffusion: 3

Clinical features of fibrosing alveolitis

Cryptogenic fibrosing alveolitis is a rare condition that affects middle-aged and elderly patients. Its cause is unknown, but it has been suggested that it may be linked to the Epstein Barr virus and it is more common in smokers.

In its early stages, the disease is characterized by thickening of the alveolar walls. There is an increase in type II pneumocytes in the alveolar wall at the expense of type I pneumocytes. The type II cells have much more cytoplasm than the very thin type I cells and therefore represent more of a barrier to gaseous diffusion. Furthermore, the alveolar walls become infiltrated with cells of the immune system including neutrophils and lymphocytes and with time fibrin is laid down there. Because it is the tissue between the alveoli that is initially affected, pulmonary fibrosis is sometimes known as interstitial pneumonia, to distinguish it from inflammation involving the airways and the alveoli themselves.

The effect of fibrosis on gaseous diffusion is only part of the reason for the hypoxia that accompanies fibrosing alveolitis. Probably as important is the effect that fibrosis has on the ventilation–perfusion matching of the lungs, in other words it causes a mismatch of gas flow and blood flow between different areas of the lungs.

Cryptogenic fibrosing alveolitis has no known specific trigger, although it may be associated with rheumatoid arthritis. Fibrosing alveolitis is also associated with hypersensitivity to dusts, when it is known as extrinsic allergic alveolitis. The hypersensitivity is to very fine dusts containing particles of diameter of 0.5–5 μm. Dusts containing particles of a larger diameter would be deposited higher in the respiratory system and would not reach the alveoli. The dust may be associated with a particular occupation, which has led to specific names for particular types of the disease. Hence there is a farmer’s lung, bird fancier’s lung, mushroom worker’s lung, wood worker’s lung and even a sewerage worker’s lung and a maple bark stripper’s lung! In these cases, the dust may be from microorganism spores, from animal proteins or from chemicals.

Carbon dioxide and other gases

Gases such as nitrous oxide, helium or carbon monoxide may be administered experimentally to those unfortunate enough to fall into the hands of respiratory physiologists. Vapours of volatile anaesthetics such as halothane or ether are administered therapeutically.

The major determinant of how readily these substances diffuse across the lung membrane is their solubility in water. Ether is almost 600 times more soluble in water than O₂, and diffuses into the blood almost 400 times more readily. Nitrogen, on the other hand, is about half as soluble and diffuses at half the rate.

Carbon dioxide is a special case. We have seen that it is 24 times more soluble than O₂ and diffuses 20 times as readily. Returning to the series nature of transfer of gases, we know that rate of diffusion depends on the rate of supply of CO₂, which in turn depends on the chemical reactions that release CO₂ from carbamino compounds and bicarbonate in the blood. The only time hypercapnia occurs other than as a result of hypoventilation is when the enzyme that accelerates the equilibrium of bicarbonate and CO₂ in the blood (carbonic anhydrase; see p. 109) is inhibited. So, the rate of CO₂ removal from the body is determined primarily by alveolar ventilation.

Carbon dioxide diffuses so readily that its arterial partial pressure is almost entirely the result of a balance between CO₂ production by metabolism and CO₂ removal by ventilation (Fig. 6.7).

Fig. 6.7 The factors determining arterial Pco₂. In this analogy PaCO₂ is the height of water in the cylinder which is added to by metabolism and removed by ventilation.

Summary 1

• Diffusion is the result of the random movement of molecules which occurs at temperatures above absolute zero.

• Diffusion takes place from a region of high to a region of low concentration.

• Fick’s Law describes how the rate of diffusion of a gas across a membrane is proportional to the concentration gradient, the solubility of the gas in the membrane, the area of the membrane, and inversely proportional to the thickness of the membrane and the square root of the molecular weight of the gas.

• Transfer Factor (diffusing capacity) is a measure of how easily a gas diffuses from air to blood. It is usually measured using CO.

• CO₂ is such a good diffuser that there are rarely any diffusional problems with removing it from the body.