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Diffusion and impaired gas exchange
Brit. 3. Dis. Chest (z965) 59, z85.
DIFFUSION
AND
IMPAIRED
GAS EXCHANGE
BY J. B. WrST Clinical Respiratory Physiology Research Group, Department of Medicine, Postgraduate Medical School of London
THE last 15 years have seen a great increase in interest in clinical lung function in general and the diffusion properties of the lung in particular. This interest has been accelerated by the introduction of methods of measuring the "diffusing capacity" of the lung with carbon monoxide. This article looks at the diffusion process in the lung and examines its role as a cause of impaired gas exchange in clinical practice. The lung unit The prime function of the lung is to exchange gas, or in other words, its j o b is to arterialize venous blood. The functional unit of the lung is well-suited to this purpose and is shown diagrammatically in Fig. z. O f key importance is the alveolar membrane with an area of some zoo m. 2 and a mean thickness of less than z F. If its thickness were increased to i cm. and its relative dimensions remained the same, the gas-blood interface would need to cover the whole of Wales ! Air is brought to one side of the interface and blood to the other. Fig. i shows the alveolar gas volume, that is the gas which is actively engaged in exchanging oxygen and carbon dioxide. This space is connected to the outside air by a system of airways which comprise the anatomical dead space because the gas within them does not take part in gas exchange. O n the other side of the alveolar membrane is the pulmonary capillary; as blood passes along this,
olveolar / membrone,,~
copUlor.v...,~ orteriole~ifi.~' ~
,~
,,, __
FIo. I .--The functional lung unit. The alveolar membrane across which gas exchange occurs has alveolar gas on one side and pulmonary capillary blood on the other. (W~sw,J. B., Ventilation/BloodFlow and Gas Exchange. To be published by Blackwell Scientific Publications.) (Receivedfor publication, August x965) VOL. LIX 4
I
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it takes u p oxygen a n d gives up c a r b o n dioxide which passes across the m e m b r a n e b y passive diffusion.
Diffusion across the blood-gas interface Let us look more closely at the diffusion process. Fig. 2 shows the w a y in which the P o , (partial pressure o f oxygen) rises in the blood along the pulm o n a r y capillary w h e n a n o r m a l lung is b r e a t h i n g air. T h e Po2 of alveolar
i00~ jolveolor gos
P°2 mm.Hq
/
40 \vtnous blood
[I l
A
It~ exercise) ,
•
,
Time in capillary FIo. 2.--Diagram of the way in which the Po2 rises as the blood flows along the pulmonary capillary. Blood enters the capillary with a Po2 of 4° mm. Hg and this rises rapidly until it is very close to the Po2 of alveolar gas, Ioo ram. Hg (typical values only). Note that when the lung breathes air, equilibration between gas and blood is nearly complete after one-third of the time available, and that the Po2 difference between alveolar gas and blood at the end of the capillary is exceedingly small. During exercise, the available time may be reduced to a third (dashed line) but equilibration is still almost complete. The alveolar Po2 may rise o n exercise. gas is a b o u t i oo m m . H g a n d the Po2 o f mixed venous blood (blood in the pulm o n a r y artery) is a b o u t 4 ° m m . Hg. W h e n a corpuscle enters the capillary, it " s e e s " a Po2 o f Ioo m m . H g on the o t h e r side of the alveolar m e m b r a n e less t h a n I /z away. T h u s there is a driving pressure o f ( i o o - 4 o ) = 6 0 ram. H g b e t w e e n gas a n d blood with the result that o x y g e n moves rapidly across the thin interface, a n d the Po~ in the blood rises quickly. This rise in blood Po2 n o w reduces the driving pressure so the rate at which oxygen moves across the m e m b r a n e becomes less. T h e result is t h a t the blood Po~ rises in a curve. T h e precise shape o f this curve is difficult to d e t e r m i n e b u t u n i m p o r t a n t in the present context. T h u s the shape o f the oxygen dissociation curve has a large effect. I t is also k n o w n that the rate at which oxygen moves across the alveolar m e m b r a n e depends not only on the diffusion properties o f the interface itself b u t also o n the rate o f chemical c o m b i n a t i o n o f oxygen with hmmoglobin which itself varies with the Po~ o f the blood. I n addition, the larger the v o l u m e of blood in the p u l m o n a r y capillaries the faster the oxygen can m o v e across. Such complicating factors do not affect the present a r g u m e n t a n d two
I87
DIFFUSION AND IMPAIRED GAS EXCHANGE
features of Fig. 2 should be emphasized. One is that the Po~ of the blood becomes very nearly equal to that of the gas by the time the end of the capillary is reached. Theoretically a small difference must remain, but in practice this is immeasurably small in the normal lung. Secondly the Po~ of the blood has nearly reached that of the gas after only one-third of the available time in the capillary. Thus in the normal resting lung there are great reserves of diffusion. These reserves are highlighted during exercise which stresses the diffusion ability of the lung. The effect of exercise is to reduce the time spent by the blood in the pulmonary capillary, and it is clear that even if the time available for diffusion is reduced to one-third of normal, the normal lung is able to oxygenate the blood effectively. The rise of alveolar Po~ which tends to occur on exercise also helps the diffusion process. A more exacting test of the diffusion ability of the lung is alveolar hypoxia. Fig. 3 shows how the Po= of the capillary blood rises under these conditions.
olveolor9os!I 50 "
PO ~ 2 20 mm..q 0
B
¢
°lve°l°r/end copillory blood
,!{exercis'~ ,x~
difference
Time in copillory
FIG. 3 . - - C h a n g e s in capillary Po= w h e n the l u n g breathes a low oxygen m i x t u r e w h i c h
reduces the alveolar gas Po2 to 5° ram. Hg. Now the rate of rise of blood Po2 is much slower and there is an appreciable Po2 difference between gas and blood at the end of the capillary. This difference is exaggerated on exercise because the time available for equilibration is reduced. (W~sT,J. B., Ventilation[BloodFlow and Gas Exchange. To be published by Blackwell Scientific Publications.) Suppose the alveolar Po2 is only 5 ° mm. H g because the lung is breathing a low oxygen mixture, and the Po2 of the mixed venous blood is 20 mm. Hg. Now a corpuscle entering the capillary is exposed to a driving pressure of only 3° mm. H g (as opposed to 60 ram. Hg in Fig. 2) and the rate of movement of oxygen across the alveolar membrane is correspondingly slower. Thus, as Fig. 3 shows, an appreciable difference between the Po~ of gas and blood may remain at the end of the capillary. Furthermore, if alveolar hypoxia is combined with heavy exercise, the reduction of the time available for diffusion under these difficult conditions exaggerates the diffusion defect.
Hypox~emia and diffusion We have seen that the diffusion ability of the lung is under greatest stress when the alveolar Po2 is low and the oxygen consumption is high. However the reserves of diffusion i n the normal lung are so great that measurable hypox~emia rarely occurs as a result of diffusion insufficiency. One apparent
~88
WEST
exception is during severe exercise in subjects acclimatized to very high altitudes. Fig. 4 shows the results of measurements made during the 196o-61 Himalayan Scientific and Mountaineering Expedition when a small party lived for several months in a prefabricated hut at 19,ooo ft. (5,800 m.) (West et al., 1962 ). During this period their exercise tolerance steadily increased because of acclimatization in spite of an inspired Po, of about 7° mm. Hg (equivalent to breathing a io per cent. oxygen mixture at sea level). It can be seen that an alveolar Po= of about 44 mm. Hg at rest resulted in an oxygen saturation of 67 per cent. As the exercise level increased (with a bicycle ergometer), the
70 60 50
40 30 I
Rest
I
300.
I
900
Work level (Kqrn./min) FIo. 4.--Effect of increasing work levels on the alveolar Po= and the arterial oxygen saturation in acclimatized normal subjects living at 19,ooo ft. (5,800 m.). The progressive fall in oxygen saturation in the face of the rising alveolar Po= was attributable to the diffusion limitations of the lung (modified from o7. appl. Physiol., x9, 43 I, I964).
alveolar Po2 rose because of over-breathing but the arterial oxygen saturation fell markedly, sometimes to less than 5 ° per cent. This fall in arterial oxygen saturation in the face of a rising alveolar Po2 is strong evidence of diffusion insufficiency. Measurements of the diffusion capacity of these normal subjects made with carbon monoxide showed that this did not increase during acclimatization (West, 1962 ) . There is some evidence that, even at sea level, exhausting exercise can reveal diffusion limitations of the normal lung. Thus, Holmgren and Linderholm (i958) showed that the arterial Po, fell by about 20 ram. Hg when young trained subjects pedalled a bicycle ergometer to exhaustion. Rowell and his colleagues (I964) measured falls of as much as IO per cent. in the arterial oxygen saturation of college students who ran to the limit of their capacity on a treadmill.
DIFFUSION A N D I M P A I R E D GAS E X C H A N G E
I89
Impairment of diffusion by disease There are conditions where microscopically the alveolar blood-gas barrier appears to be thickened, and it is commonly believed that some of the arterial hypox~emia is caused by defective diffusion. Such diseases include diffuse interstitial fibrosis, sarcoidosis, asbestosis and alveolar carcinomatosis. The term "alveolar-capillary block" was coined for these situations and certainly the phrase is descriptive and trips lightly off the tongue. Recently, however, the contribution of defective diffusion to the hypox~emia observed in these conditions has been questioned. Finley and his colleagues (I962) have argued that the amount of thickening that could occur in an alveolus and still permit normal ventilation and blood flow would be unlikely to interfere seriously with oxygen diffusion. These authors calculated that before diffusion limitations caused a measurable (for example, i mm. Hg) fall in end-capillary Po~, the thickness of the alveolar membrane would have to increase from about I ~ to about 6-8 ~. They pointed out that it is unlikely that the thickening would be uniform and considerable inequality of ventilation appears inevitable. In addition, it is easy to imagine that such a gross change in the alveolar wall would severely interfere with capillary blood flow. An equally important reason for questioning the role of diffusion in the hypox~emia of these conditions is the accumulating evidence of the uneven ventilation and blood flow which exists, and which must seriously interfere with gas exchange. Various studies including those of Donald and his coworkers (i952), Read and Williams (I959) , Holland (I96O), and Finley et al. (i962), have emphasized the abnormal ventilation-blood flow relationships which are inevitable in these generalized lung diseases, and the principle of Occam's Razor warns us against accepting a doubtful cause of hypox~emia when an undisputed mechanism clearly exists. How does the inequality of blood flow and ventilation in these abnormal lungs interfere with gas exchange ?
The non-homogeneous lung Diagrams such as Figs. 2 and 3 are based on the assumption that the lung is homogeneous, that is that every functional unit (Fig. I) is operating under the same conditions. It is now known that this is not so even in the normal lung. Because of the weight of the column of blood in the upright lung and the consequent increase in pulmonary arterial pressure down the lung, there is a much higher blood flow at the base than at the apex which indeed is barely perfused at rest. In addition, ventilation also increases down the lung, this inequality being apparently caused by the gradient ofintrapleural pressure down the lung which in turn results from the weight of the lung on the thoracic cage. Because blood flow increases more rapidly than ventilation down the lung, the ratio of ventilation to blood flow (ventilatlon-perfusion ratio) changes from region to region. This ventilation-perfusion ratio controls the regional Po~, Pco2, blood gas contents, etc., so that even in the normal lung considerable inhomogeneity must exist (West, I962b ). Fig. 5 shows for example that differences of Po~ of over 4o ram. Hg are calculated to exist between the upper and lower regions
z9o
WEST
of the lung. Differences of Pco~ of some 14 mm. Hg and consequent differences in blood-gas contents and pH are also inevitable. This inhomogeneity is enormously increased by generalized disease of the lung such as diffuse interstitial fibrosis. Calculations show that the alveolar Po~ in different functional units must range between about 4o and i5o ram. Hg, that is between the Po~ of mixed venous blood and inspired gas. In addition, there will be correspondingly large variations in the oxygen content of blood draining from these various lung units.
°/. tt./~ !.'1
P;rf.
7 Jilt,' .07 3:3
i
I
:,'
]
r I "l~a,tI c°"t 32I 28 1,00'~42 75i
{{\
x
{ 'I, I
I
l\ I
I/
13 .e2l 1.29 0.63
FIO. 5.--Differences in ventilation, blood-flow and gas exchange thought to exist in the normal upright lung. The lung is divided into nine imaginary horizontal slices of equal thickness. For clarity, only values for uppermost and lowermost slices are shown. The columns show (left to right) the volume of the lung at each level (as a percentage of the total), ventilation and blood flow (litres per minute), ventilation-perfusion ratio, oxygen and carbon dioxide tensions (mm. Hg), and oxygen saturation (per cent.) carbon dioxide content (vols. per zoo vols.) and p H in blood draining from the slices (from Lancet, ii, io55 , z963).
Impairment of overall gas exchange by uneven ventilation and bloodflow An inevitable result of this regional inhomogeneity is impairment of overall gas exchange with lowering of the arterial Po2. Essentially this is because the major contributions to the arterial blood come from areas of the lung with a low Po2 and therefore a low content of oxygen in the blood. The reason is that well-perfused areas tend to have a low ventilafion-perfusion ratio and therefore a low Po~. Fig. 6 shows that in the normal upright lung, the major contribution to the systemic arterial blood comes from the base of the lung which has a low alveolar Po~ (89 mm. Hg). By contrast, a greater proportion of mixed alveolar gas comes from the apex of the lung where the Po~ is high (I3~ mm. Hg). The
DIFFUSION AND IMPArteD GAS EXCHANGE
IgI
inevitable result is therefore depression of the arterial Po2 and elevation of the alveolar Po2 thus giving an "alveolar-arterial difference" for oxygen. This " A - a difference" is a measure of the ventilation-blood flow imbalance. The consequent hypox~emia in the normal lung is very small but in the diseased lung it may be severe.
Pn
=1~1mm.H 9
Fzo. 6 . - - D i a g r a m to s h o w how the unevenness of ventilation and blood flow in the lung interfere with overall gas exchange and depress the Po2 of arterial blood. Relative sizes of the bronchi and pulmonary veins to the upper and lower zones indicate their relative ventilations and blood flows. Only two groups of alveoli are shown, corresponding to those in the uppermost and lowermost slices of Fig. 5- Mixed pulmonary venous blood has a slightly low Po2 (97 mm. Hg) because most of the blood comes from the base of the lung which has a low Po2 (89 mm. Hg), while a greater proportion of mixed alveolar gas comes from the apex of the lung where the Po2 is high (z32 ram. Hg). T h e inevitable result is therefore depression of the arterial Po2 and an alveolar-arterial difference for oxygen (from Lancet, ii, zo55 , x963).
In summary, the non-homogeneous lung not only has large regional differences in regional gas exchange which are seen as local variations in Po2, Pco2, etc. (Fig. 5), but more important, the lung becomes less efficient as a gas exchanger and arterial hypox~emia is inevitable. This is the mechanism responsible for the bulk of the hypox~emia of generalized lung diseases such as diffuse interstitial fibrosis, asbestosis and sarcoidosis as well as chronic bronchitis and emphysema.
Carbon monoxide "diffusing capacity" of the normal lung It remains for us to look at the tests of diffusing capacity which have been used extensively in lung function laboratories over the last few years. The methods can be divided into single breath techniques (for example, Ogilvie et al., I957) and multibreath steady state techniques (for example, Bates et al.,
92
W~:ST
I955), but the principles of both are the same. T h e subject inhales a low concentration of carbon monoxide and the rate of loss of the gas from the alveoli is measured. Whereas in the case of oxygen uptake from alveolar gas, the capillary Po2 has a dominating effect on the driving pressure responsible for the transfer of the gas (Figs. 2 and 3), for carbon monoxide, the avidity of haemoglobin is so enormous that the back pressure in the blood can be neglected. Thus the rate of loss of carbon monoxide from the alveolar gas of a lung unit (Fig. I) depends only on the alveolar concentration and the transfer characteristics of the alveolar membrane and the blood. Roughton and Forster (I957) have shown that about half of the barrier to carbon monoxide transfer is in the alveolar membrane and about half in the capillary blood itself. The latter depends on the volume of blood exchanging gas, and the rate of combination of carbon monoxide with h~emoglobin which is determined by the Po2. Indeed, it is possible to estimate the volume of the capillary blood which is actively exchanging gas by measuring the carbon monoxide uptake at different alveolar Po~. These techniques have now been used extensively to follow changes in the diffusion characteristics of the normal lung under a variety of conditions such as change of posture, exercise, on positive pressure ventilation, during a Valsalva manoeuvre and after acclimatization to high altitudes. Although the non-homogeneity of the normal lung (Fig. 5) introduces uncertainty into the interpretation of some of the results, the carbon monoxide technique undoubtedly gives useful information about the normal lung.
Carbon monoxide "diffusing capacity" of the diseased lung Unfortunately, the disorganization of function of the lung with generalized disease such as diffuse interstitial fibrosis, pulmonary emphysema, sarcoidosis o r asbestosis makes the interpretation of carbon monoxide tests extremely difficult. One reason for this is the sequential emptying of the diseased lung, that is the tendency for poorly ventilated alveoli to empty last, which makes any reasonable measurement of the alveolar concentration of carbon monoxide impossible. In addition, the regional variations in diffusion properties of the alveolar membrane, capillary blood volume and prevailing alveolar Po2 make the n u m b e r which comes out of the calculations almost impossible to interpret. In view of these difficulties, can any useful information be obtained from these tests in patients with generalized lung disease ? Empirically the answer is yes, but not because they enable us to measure the diffusing characteristics of the lung. If the transfer of carbon monoxide is affected by the uneven ventilation and blood flow of generalized lung disease, it is not surprising that the transfer of oxygen and carbon dioxide are also impaired. For example, it is found in practice that the carbon monoxide uptake is of value for the prognosis of patients with pulmonary emphysema (Bates and Christie, i964) , and the assessment of the progression of disease in patients with asbestosis (Williams and Itugh-Jones, 196o ). In other words, the tests are of value not in the analysis of pulmonary function but rather to define groups of patients in which patterns of disease behaviour can be recognized to occur.
DIFFUSION AND IMPAIRED GAS EXCHANGE
I93
Cotes (I963) has emphasized that the term "diffusing capacity" is misleading for these tests of carbon monoxide uptake. As we have seen, the volume of capillary blood and its reaction rates play just as much part as the diffusion properties of the alveolar membrane in determining the uptake of carbon monoxide from alveolar gas. In addition, the uptake is dominated by the inhomogeneity of function of the lung with generalized disease. For these reasons, the term "transfer factor" has been adopted by many workers (Cotes, 1963), and it is hoped that its use will prevent much of the confusion which has been generated in the past by the term "diffusing capacity".
Diffusion in the smaU airways of the lung Throughout this short review, "diffusion" has been used in the traditional way to refer to the movement of gas across the alveolar membrane into the pulmonary capillary. Recently another type of diffusion has received more attention, namely diffusion in the gas phase in the small airways. It is now accepted that inspired gas does not reach the alveoli by ordinary bulk flow but that the last few millimetres are covered by gaseous diffusion. In the normal lung, the distances to be covered are so small compared with the rapid diffusion rates of the gas molecules that complete mixing occurs rapidly. However, in the diseased lung any dilatation of smaller airways will interfere with this normal process. An obvious example is the centrilobular type of chronic obstructive lung disease where histologically the lesion is ideally situated to impair diffusion to the alveoli. It is not yet known how significant is the uneven ventilation which results from this mechanism in clinical practice. However, any pathological process which disrupts the normal architecture of the airways must be regarded with suspicion, and this applies to most generalized lung diseases. It is a curious twist that while diffusion across the blood-gas interface is now being largely exonerated as a cause of hypox~emia in the medical wards, another type of diffusion abnormality is being incriminated. REFERt~NCES BATES, D. V., BOUCOT,N. O., & DORMER, A. 1~. (I955). 07. Physiol., 129, 237. BATES, D. V., & CHRISTIE,R. V. (I964). Respiratory Function in Disease. London: Saunders.
COTES,J. E. (1963). Lancet, ii, 843.
DONALD,K. W., t(ENZETTI, A., RILEY, R. L., & COURNAND,A. (I952) . 07. appl. Physiol., 4, 497. FINLEY, T. N., SWENSON,1~. W., & COMROE,J. H. (i962). 07. din. Invest., 4x, 618.
HOLLAND,R. A. B. (196o). Amer. 07. Med., 28, 6i.
HOLMGREN, A., & LINDERHOLM,H. (1958). Acta physiol, scan&, 44, 203. OGILVIE, C. M., FORSTER,R. E., BLAKEMORE,W. S., • 1VIORTON,J. W. (1957). 07. din. Invest.,
36, I. READ,J., & WILLIAMS,t~. S. (1959). Amer. 07. Med., 27, 545ROUGHTON,F.J.W., & FORSTER,R. E. (1957). 07. appl. Physiol., xI, e9o. ROWELL,L. B., TAYLOR,H. L., WANG,Y., & CARLSON,W. S. (1964). J. appl. Physiol., I9, 284. WEST,J. B. (I962). 07. appl. Physiol., 17, 421. WEST,J. B. (I962). 07. appl. Physiol., 17, 893. ~rEST, J. B., LAHIRI,S., GILL, ~V~.B., MILLEDGE,J. s., PUGH,L. G. C. E., & WARD, M.P. (196~). 07. appl. Physiol., xT, 617. WILLIAMS,R., & HUGH-JoNES, P. (I96o). Thorax, I5, Io9.
DIFFUSION
AND
IMPAIRED
GAS EXCHANGE
BY J. B. WrST Clinical Respiratory Physiology Research Group, Department of Medicine, Postgraduate Medical School of London
THE last 15 years have seen a great increase in interest in clinical lung function in general and the diffusion properties of the lung in particular. This interest has been accelerated by the introduction of methods of measuring the "diffusing capacity" of the lung with carbon monoxide. This article looks at the diffusion process in the lung and examines its role as a cause of impaired gas exchange in clinical practice. The lung unit The prime function of the lung is to exchange gas, or in other words, its j o b is to arterialize venous blood. The functional unit of the lung is well-suited to this purpose and is shown diagrammatically in Fig. z. O f key importance is the alveolar membrane with an area of some zoo m. 2 and a mean thickness of less than z F. If its thickness were increased to i cm. and its relative dimensions remained the same, the gas-blood interface would need to cover the whole of Wales ! Air is brought to one side of the interface and blood to the other. Fig. i shows the alveolar gas volume, that is the gas which is actively engaged in exchanging oxygen and carbon dioxide. This space is connected to the outside air by a system of airways which comprise the anatomical dead space because the gas within them does not take part in gas exchange. O n the other side of the alveolar membrane is the pulmonary capillary; as blood passes along this,
olveolar / membrone,,~
copUlor.v...,~ orteriole~ifi.~' ~
,~
,,, __
FIo. I .--The functional lung unit. The alveolar membrane across which gas exchange occurs has alveolar gas on one side and pulmonary capillary blood on the other. (W~sw,J. B., Ventilation/BloodFlow and Gas Exchange. To be published by Blackwell Scientific Publications.) (Receivedfor publication, August x965) VOL. LIX 4
I
z86
'WEST
it takes u p oxygen a n d gives up c a r b o n dioxide which passes across the m e m b r a n e b y passive diffusion.
Diffusion across the blood-gas interface Let us look more closely at the diffusion process. Fig. 2 shows the w a y in which the P o , (partial pressure o f oxygen) rises in the blood along the pulm o n a r y capillary w h e n a n o r m a l lung is b r e a t h i n g air. T h e Po2 of alveolar
i00~ jolveolor gos
P°2 mm.Hq
/
40 \vtnous blood
[I l
A
It~ exercise) ,
•
,
Time in capillary FIo. 2.--Diagram of the way in which the Po2 rises as the blood flows along the pulmonary capillary. Blood enters the capillary with a Po2 of 4° mm. Hg and this rises rapidly until it is very close to the Po2 of alveolar gas, Ioo ram. Hg (typical values only). Note that when the lung breathes air, equilibration between gas and blood is nearly complete after one-third of the time available, and that the Po2 difference between alveolar gas and blood at the end of the capillary is exceedingly small. During exercise, the available time may be reduced to a third (dashed line) but equilibration is still almost complete. The alveolar Po2 may rise o n exercise. gas is a b o u t i oo m m . H g a n d the Po2 o f mixed venous blood (blood in the pulm o n a r y artery) is a b o u t 4 ° m m . Hg. W h e n a corpuscle enters the capillary, it " s e e s " a Po2 o f Ioo m m . H g on the o t h e r side of the alveolar m e m b r a n e less t h a n I /z away. T h u s there is a driving pressure o f ( i o o - 4 o ) = 6 0 ram. H g b e t w e e n gas a n d blood with the result that o x y g e n moves rapidly across the thin interface, a n d the Po~ in the blood rises quickly. This rise in blood Po2 n o w reduces the driving pressure so the rate at which oxygen moves across the m e m b r a n e becomes less. T h e result is t h a t the blood Po~ rises in a curve. T h e precise shape o f this curve is difficult to d e t e r m i n e b u t u n i m p o r t a n t in the present context. T h u s the shape o f the oxygen dissociation curve has a large effect. I t is also k n o w n that the rate at which oxygen moves across the alveolar m e m b r a n e depends not only on the diffusion properties o f the interface itself b u t also o n the rate o f chemical c o m b i n a t i o n o f oxygen with hmmoglobin which itself varies with the Po~ o f the blood. I n addition, the larger the v o l u m e of blood in the p u l m o n a r y capillaries the faster the oxygen can m o v e across. Such complicating factors do not affect the present a r g u m e n t a n d two
I87
DIFFUSION AND IMPAIRED GAS EXCHANGE
features of Fig. 2 should be emphasized. One is that the Po~ of the blood becomes very nearly equal to that of the gas by the time the end of the capillary is reached. Theoretically a small difference must remain, but in practice this is immeasurably small in the normal lung. Secondly the Po~ of the blood has nearly reached that of the gas after only one-third of the available time in the capillary. Thus in the normal resting lung there are great reserves of diffusion. These reserves are highlighted during exercise which stresses the diffusion ability of the lung. The effect of exercise is to reduce the time spent by the blood in the pulmonary capillary, and it is clear that even if the time available for diffusion is reduced to one-third of normal, the normal lung is able to oxygenate the blood effectively. The rise of alveolar Po~ which tends to occur on exercise also helps the diffusion process. A more exacting test of the diffusion ability of the lung is alveolar hypoxia. Fig. 3 shows how the Po= of the capillary blood rises under these conditions.
olveolor9os!I 50 "
PO ~ 2 20 mm..q 0
B
¢
°lve°l°r/end copillory blood
,!{exercis'~ ,x~
difference
Time in copillory
FIG. 3 . - - C h a n g e s in capillary Po= w h e n the l u n g breathes a low oxygen m i x t u r e w h i c h
reduces the alveolar gas Po2 to 5° ram. Hg. Now the rate of rise of blood Po2 is much slower and there is an appreciable Po2 difference between gas and blood at the end of the capillary. This difference is exaggerated on exercise because the time available for equilibration is reduced. (W~sT,J. B., Ventilation[BloodFlow and Gas Exchange. To be published by Blackwell Scientific Publications.) Suppose the alveolar Po2 is only 5 ° mm. H g because the lung is breathing a low oxygen mixture, and the Po2 of the mixed venous blood is 20 mm. Hg. Now a corpuscle entering the capillary is exposed to a driving pressure of only 3° mm. H g (as opposed to 60 ram. Hg in Fig. 2) and the rate of movement of oxygen across the alveolar membrane is correspondingly slower. Thus, as Fig. 3 shows, an appreciable difference between the Po~ of gas and blood may remain at the end of the capillary. Furthermore, if alveolar hypoxia is combined with heavy exercise, the reduction of the time available for diffusion under these difficult conditions exaggerates the diffusion defect.
Hypox~emia and diffusion We have seen that the diffusion ability of the lung is under greatest stress when the alveolar Po2 is low and the oxygen consumption is high. However the reserves of diffusion i n the normal lung are so great that measurable hypox~emia rarely occurs as a result of diffusion insufficiency. One apparent
~88
WEST
exception is during severe exercise in subjects acclimatized to very high altitudes. Fig. 4 shows the results of measurements made during the 196o-61 Himalayan Scientific and Mountaineering Expedition when a small party lived for several months in a prefabricated hut at 19,ooo ft. (5,800 m.) (West et al., 1962 ). During this period their exercise tolerance steadily increased because of acclimatization in spite of an inspired Po, of about 7° mm. Hg (equivalent to breathing a io per cent. oxygen mixture at sea level). It can be seen that an alveolar Po= of about 44 mm. Hg at rest resulted in an oxygen saturation of 67 per cent. As the exercise level increased (with a bicycle ergometer), the
70 60 50
40 30 I
Rest
I
300.
I
900
Work level (Kqrn./min) FIo. 4.--Effect of increasing work levels on the alveolar Po= and the arterial oxygen saturation in acclimatized normal subjects living at 19,ooo ft. (5,800 m.). The progressive fall in oxygen saturation in the face of the rising alveolar Po= was attributable to the diffusion limitations of the lung (modified from o7. appl. Physiol., x9, 43 I, I964).
alveolar Po2 rose because of over-breathing but the arterial oxygen saturation fell markedly, sometimes to less than 5 ° per cent. This fall in arterial oxygen saturation in the face of a rising alveolar Po2 is strong evidence of diffusion insufficiency. Measurements of the diffusion capacity of these normal subjects made with carbon monoxide showed that this did not increase during acclimatization (West, 1962 ) . There is some evidence that, even at sea level, exhausting exercise can reveal diffusion limitations of the normal lung. Thus, Holmgren and Linderholm (i958) showed that the arterial Po, fell by about 20 ram. Hg when young trained subjects pedalled a bicycle ergometer to exhaustion. Rowell and his colleagues (I964) measured falls of as much as IO per cent. in the arterial oxygen saturation of college students who ran to the limit of their capacity on a treadmill.
DIFFUSION A N D I M P A I R E D GAS E X C H A N G E
I89
Impairment of diffusion by disease There are conditions where microscopically the alveolar blood-gas barrier appears to be thickened, and it is commonly believed that some of the arterial hypox~emia is caused by defective diffusion. Such diseases include diffuse interstitial fibrosis, sarcoidosis, asbestosis and alveolar carcinomatosis. The term "alveolar-capillary block" was coined for these situations and certainly the phrase is descriptive and trips lightly off the tongue. Recently, however, the contribution of defective diffusion to the hypox~emia observed in these conditions has been questioned. Finley and his colleagues (I962) have argued that the amount of thickening that could occur in an alveolus and still permit normal ventilation and blood flow would be unlikely to interfere seriously with oxygen diffusion. These authors calculated that before diffusion limitations caused a measurable (for example, i mm. Hg) fall in end-capillary Po~, the thickness of the alveolar membrane would have to increase from about I ~ to about 6-8 ~. They pointed out that it is unlikely that the thickening would be uniform and considerable inequality of ventilation appears inevitable. In addition, it is easy to imagine that such a gross change in the alveolar wall would severely interfere with capillary blood flow. An equally important reason for questioning the role of diffusion in the hypox~emia of these conditions is the accumulating evidence of the uneven ventilation and blood flow which exists, and which must seriously interfere with gas exchange. Various studies including those of Donald and his coworkers (i952), Read and Williams (I959) , Holland (I96O), and Finley et al. (i962), have emphasized the abnormal ventilation-blood flow relationships which are inevitable in these generalized lung diseases, and the principle of Occam's Razor warns us against accepting a doubtful cause of hypox~emia when an undisputed mechanism clearly exists. How does the inequality of blood flow and ventilation in these abnormal lungs interfere with gas exchange ?
The non-homogeneous lung Diagrams such as Figs. 2 and 3 are based on the assumption that the lung is homogeneous, that is that every functional unit (Fig. I) is operating under the same conditions. It is now known that this is not so even in the normal lung. Because of the weight of the column of blood in the upright lung and the consequent increase in pulmonary arterial pressure down the lung, there is a much higher blood flow at the base than at the apex which indeed is barely perfused at rest. In addition, ventilation also increases down the lung, this inequality being apparently caused by the gradient ofintrapleural pressure down the lung which in turn results from the weight of the lung on the thoracic cage. Because blood flow increases more rapidly than ventilation down the lung, the ratio of ventilation to blood flow (ventilatlon-perfusion ratio) changes from region to region. This ventilation-perfusion ratio controls the regional Po~, Pco2, blood gas contents, etc., so that even in the normal lung considerable inhomogeneity must exist (West, I962b ). Fig. 5 shows for example that differences of Po~ of over 4o ram. Hg are calculated to exist between the upper and lower regions
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of the lung. Differences of Pco~ of some 14 mm. Hg and consequent differences in blood-gas contents and pH are also inevitable. This inhomogeneity is enormously increased by generalized disease of the lung such as diffuse interstitial fibrosis. Calculations show that the alveolar Po~ in different functional units must range between about 4o and i5o ram. Hg, that is between the Po~ of mixed venous blood and inspired gas. In addition, there will be correspondingly large variations in the oxygen content of blood draining from these various lung units.
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FIO. 5.--Differences in ventilation, blood-flow and gas exchange thought to exist in the normal upright lung. The lung is divided into nine imaginary horizontal slices of equal thickness. For clarity, only values for uppermost and lowermost slices are shown. The columns show (left to right) the volume of the lung at each level (as a percentage of the total), ventilation and blood flow (litres per minute), ventilation-perfusion ratio, oxygen and carbon dioxide tensions (mm. Hg), and oxygen saturation (per cent.) carbon dioxide content (vols. per zoo vols.) and p H in blood draining from the slices (from Lancet, ii, io55 , z963).
Impairment of overall gas exchange by uneven ventilation and bloodflow An inevitable result of this regional inhomogeneity is impairment of overall gas exchange with lowering of the arterial Po2. Essentially this is because the major contributions to the arterial blood come from areas of the lung with a low Po2 and therefore a low content of oxygen in the blood. The reason is that well-perfused areas tend to have a low ventilafion-perfusion ratio and therefore a low Po~. Fig. 6 shows that in the normal upright lung, the major contribution to the systemic arterial blood comes from the base of the lung which has a low alveolar Po~ (89 mm. Hg). By contrast, a greater proportion of mixed alveolar gas comes from the apex of the lung where the Po~ is high (I3~ mm. Hg). The
DIFFUSION AND IMPArteD GAS EXCHANGE
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inevitable result is therefore depression of the arterial Po2 and elevation of the alveolar Po2 thus giving an "alveolar-arterial difference" for oxygen. This " A - a difference" is a measure of the ventilation-blood flow imbalance. The consequent hypox~emia in the normal lung is very small but in the diseased lung it may be severe.
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Fzo. 6 . - - D i a g r a m to s h o w how the unevenness of ventilation and blood flow in the lung interfere with overall gas exchange and depress the Po2 of arterial blood. Relative sizes of the bronchi and pulmonary veins to the upper and lower zones indicate their relative ventilations and blood flows. Only two groups of alveoli are shown, corresponding to those in the uppermost and lowermost slices of Fig. 5- Mixed pulmonary venous blood has a slightly low Po2 (97 mm. Hg) because most of the blood comes from the base of the lung which has a low Po2 (89 mm. Hg), while a greater proportion of mixed alveolar gas comes from the apex of the lung where the Po2 is high (z32 ram. Hg). T h e inevitable result is therefore depression of the arterial Po2 and an alveolar-arterial difference for oxygen (from Lancet, ii, zo55 , x963).
In summary, the non-homogeneous lung not only has large regional differences in regional gas exchange which are seen as local variations in Po2, Pco2, etc. (Fig. 5), but more important, the lung becomes less efficient as a gas exchanger and arterial hypox~emia is inevitable. This is the mechanism responsible for the bulk of the hypox~emia of generalized lung diseases such as diffuse interstitial fibrosis, asbestosis and sarcoidosis as well as chronic bronchitis and emphysema.
Carbon monoxide "diffusing capacity" of the normal lung It remains for us to look at the tests of diffusing capacity which have been used extensively in lung function laboratories over the last few years. The methods can be divided into single breath techniques (for example, Ogilvie et al., I957) and multibreath steady state techniques (for example, Bates et al.,
92
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I955), but the principles of both are the same. T h e subject inhales a low concentration of carbon monoxide and the rate of loss of the gas from the alveoli is measured. Whereas in the case of oxygen uptake from alveolar gas, the capillary Po2 has a dominating effect on the driving pressure responsible for the transfer of the gas (Figs. 2 and 3), for carbon monoxide, the avidity of haemoglobin is so enormous that the back pressure in the blood can be neglected. Thus the rate of loss of carbon monoxide from the alveolar gas of a lung unit (Fig. I) depends only on the alveolar concentration and the transfer characteristics of the alveolar membrane and the blood. Roughton and Forster (I957) have shown that about half of the barrier to carbon monoxide transfer is in the alveolar membrane and about half in the capillary blood itself. The latter depends on the volume of blood exchanging gas, and the rate of combination of carbon monoxide with h~emoglobin which is determined by the Po2. Indeed, it is possible to estimate the volume of the capillary blood which is actively exchanging gas by measuring the carbon monoxide uptake at different alveolar Po~. These techniques have now been used extensively to follow changes in the diffusion characteristics of the normal lung under a variety of conditions such as change of posture, exercise, on positive pressure ventilation, during a Valsalva manoeuvre and after acclimatization to high altitudes. Although the non-homogeneity of the normal lung (Fig. 5) introduces uncertainty into the interpretation of some of the results, the carbon monoxide technique undoubtedly gives useful information about the normal lung.
Carbon monoxide "diffusing capacity" of the diseased lung Unfortunately, the disorganization of function of the lung with generalized disease such as diffuse interstitial fibrosis, pulmonary emphysema, sarcoidosis o r asbestosis makes the interpretation of carbon monoxide tests extremely difficult. One reason for this is the sequential emptying of the diseased lung, that is the tendency for poorly ventilated alveoli to empty last, which makes any reasonable measurement of the alveolar concentration of carbon monoxide impossible. In addition, the regional variations in diffusion properties of the alveolar membrane, capillary blood volume and prevailing alveolar Po2 make the n u m b e r which comes out of the calculations almost impossible to interpret. In view of these difficulties, can any useful information be obtained from these tests in patients with generalized lung disease ? Empirically the answer is yes, but not because they enable us to measure the diffusing characteristics of the lung. If the transfer of carbon monoxide is affected by the uneven ventilation and blood flow of generalized lung disease, it is not surprising that the transfer of oxygen and carbon dioxide are also impaired. For example, it is found in practice that the carbon monoxide uptake is of value for the prognosis of patients with pulmonary emphysema (Bates and Christie, i964) , and the assessment of the progression of disease in patients with asbestosis (Williams and Itugh-Jones, 196o ). In other words, the tests are of value not in the analysis of pulmonary function but rather to define groups of patients in which patterns of disease behaviour can be recognized to occur.
DIFFUSION AND IMPAIRED GAS EXCHANGE
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Cotes (I963) has emphasized that the term "diffusing capacity" is misleading for these tests of carbon monoxide uptake. As we have seen, the volume of capillary blood and its reaction rates play just as much part as the diffusion properties of the alveolar membrane in determining the uptake of carbon monoxide from alveolar gas. In addition, the uptake is dominated by the inhomogeneity of function of the lung with generalized disease. For these reasons, the term "transfer factor" has been adopted by many workers (Cotes, 1963), and it is hoped that its use will prevent much of the confusion which has been generated in the past by the term "diffusing capacity".
Diffusion in the smaU airways of the lung Throughout this short review, "diffusion" has been used in the traditional way to refer to the movement of gas across the alveolar membrane into the pulmonary capillary. Recently another type of diffusion has received more attention, namely diffusion in the gas phase in the small airways. It is now accepted that inspired gas does not reach the alveoli by ordinary bulk flow but that the last few millimetres are covered by gaseous diffusion. In the normal lung, the distances to be covered are so small compared with the rapid diffusion rates of the gas molecules that complete mixing occurs rapidly. However, in the diseased lung any dilatation of smaller airways will interfere with this normal process. An obvious example is the centrilobular type of chronic obstructive lung disease where histologically the lesion is ideally situated to impair diffusion to the alveoli. It is not yet known how significant is the uneven ventilation which results from this mechanism in clinical practice. However, any pathological process which disrupts the normal architecture of the airways must be regarded with suspicion, and this applies to most generalized lung diseases. It is a curious twist that while diffusion across the blood-gas interface is now being largely exonerated as a cause of hypox~emia in the medical wards, another type of diffusion abnormality is being incriminated. REFERt~NCES BATES, D. V., BOUCOT,N. O., & DORMER, A. 1~. (I955). 07. Physiol., 129, 237. BATES, D. V., & CHRISTIE,R. V. (I964). Respiratory Function in Disease. London: Saunders.
COTES,J. E. (1963). Lancet, ii, 843.
DONALD,K. W., t(ENZETTI, A., RILEY, R. L., & COURNAND,A. (I952) . 07. appl. Physiol., 4, 497. FINLEY, T. N., SWENSON,1~. W., & COMROE,J. H. (i962). 07. din. Invest., 4x, 618.
HOLLAND,R. A. B. (196o). Amer. 07. Med., 28, 6i.
HOLMGREN, A., & LINDERHOLM,H. (1958). Acta physiol, scan&, 44, 203. OGILVIE, C. M., FORSTER,R. E., BLAKEMORE,W. S., • 1VIORTON,J. W. (1957). 07. din. Invest.,
36, I. READ,J., & WILLIAMS,t~. S. (1959). Amer. 07. Med., 27, 545ROUGHTON,F.J.W., & FORSTER,R. E. (1957). 07. appl. Physiol., xI, e9o. ROWELL,L. B., TAYLOR,H. L., WANG,Y., & CARLSON,W. S. (1964). J. appl. Physiol., I9, 284. WEST,J. B. (I962). 07. appl. Physiol., 17, 421. WEST,J. B. (I962). 07. appl. Physiol., 17, 893. ~rEST, J. B., LAHIRI,S., GILL, ~V~.B., MILLEDGE,J. s., PUGH,L. G. C. E., & WARD, M.P. (196~). 07. appl. Physiol., xT, 617. WILLIAMS,R., & HUGH-JoNES, P. (I96o). Thorax, I5, Io9.