oxygen in pulmonary - thoraxsince the description of 'alveolar-capillary block' by...

Thorax (1964), 19, 507

Cause of low arterial oxygen saturation inpulmonary fibrosis

JOHN HAMER'

From the Medical Unit, King's College Hospital, London

Since the description of 'alveolar-capillary block'by Austrian, McClement, Renzetti, Donald, Riley,and Cournand (1951), impairment of diffusionacross the alveolar-capillary membrane has beenregarded as an important factor in the productionof low arterial oxygen saturations in patients withdiffuse pulmonary disease. However, Luchsinger,Moser, Buhlmann, and Rossier (1957) suggestedthat restriction of the capillary bed might beresponsible, and the demonstration by Roughtonand Forster (1957) that the relatively slowchemical reaction with haemoglobin was a majorresistance to the absorption of respiratory gaseslent support to this view. More recently, Motley(1958) and Finley, Swenson, and Comroe (1962)have shown the importance of uneven distributionof ventilation and perfusion in producinghypoxaemia.

In view of the doubt as to the importance ofdiffusion in gas absorption, Cotes (1963) hassuggested the non-committal term 'transfer factor'instead of 'diffusing capacity' (DL) to describe theprocess. Roughton and Forster (1957) showed thatit was possible to separate the red cell and themembrane components of gas transfer by makinguse of the competition between carbon monoxideand oxygen for the available haemoglobin (Fig. 1).This technique gives an estimate of the volume ofthe pulmonary capillaries (Vc) if the rate ofcombination of the gas with blood (9) is known.However, both the capillary volume (Vc) and themembrane component (DM) estimated in this wayare probably influenced by uneven distributioneffects (Hamer, 1963b) which limit the contactbetween alveolar gas and capillary blood. The rela-tion between the factors is given by the formula

I I IDL =DM #V-C

In the present study, the technique of Roughtonand Forster (1957) was used to analyse the processof gas transfer in seven patients with diffuse1 Present address: Institute of Cardiology, 35 Wimpo'e Street,London W.1.

ALVEOLUS alveolar-capllary

OXYGEN

CARBONMONOXIDE

CAPILLARY

RESISTANCETO GAS . MEMBRANE + RED CELLTRANSFER COMPONENT COMPONENT

chemicaldiffusion reaction

FIG. 1. Diagrammatic representation of the absorption of0. and CO in the lungs. The gases diffuse across thealveolar-capillary membrane andcombine with haemoglobinin the red cells of the pulmonary capillaries. The competi-tion between the two gases can be used to separate themembrane and the red cell components of the process.

interstitial pulmonary fibrosis and two with diffusemetastatic carcinoma of the lung. The findings arecompared with the changes reported in 30 patientswith pulmonary sarcoidosis (Hamer, 1963a).Cardiac catheterization was performed in four ofthe patients with interstitial pulmonary fibrosisand four of the sarcoidosis group, three of thesepatients having radiological evidence of fibrosisin addition to infiltration in the lungs.

METHODS

The measurement of the components of gas transferin these patients was performed in the same way asin the study of pulmonary sarcoidosis (Hamer, 1963b).The single-breath technique described by Ogilvie.Forster, Blakemore, and Morton (1957) was used.with some modifications, to measure the carbonmonoxide uptake at two levels of oxygen tension ineach subject. After a full but unforced expiration, a

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maximal breath of gas containing approximately 0-2%CO and 15% helium was inspired and held for about10 seconds. Two gas mixtures were used, one madeup in pure 02 and the other with 20/ 02 and theremainder N2 (referred to as the 'air' mixture). Strain-ing during breath-holding was avoided as much aspossible. A single three-way tap was used to reducethe dead space of the apparatus. Rubber bags wereapplied to the outlet of the tap, using tapered air-tight connectors. and were then evacuated by a suc-tion line. A sample was collected after the expirationof about 1 litre to flush out the dead space. Undulyforceful expiration was avoided, and the samplingtime was kept as small as possible. In general,approximately I litre of expirate was collected inabout half a second.

Part of each sample was transferred to a mercurytonometer for the subsequent measurement of 02 andC02 content by the Scholander method. Theremainder of the sample was then drawn through aC02 absorber to the gas analysers at approximately0 5 1./min. The gas to be inspired was drawn througha humidifier to the analysers before each estimation.Approximately 0 5 litre of gas was needed for accu-rate measurement of CO and He. The gas passedfirst to a Cambridge catharometer set to read Heconcentrations in moist air. The catharometer read-ings were corrected for variations in oxygen contenton the basis of a reading of 1-9% He with 100% 02,assuming a linear increase in the reading between21%/ and 100% 02 in the gas carrying the helium.After passing through a water absorber (magnesiumperchlorate), the gas passed through a CO analyser(type SCLA).' This instrument was calibrated beforeeach study with a standard gas mixture supplied bythe makers. One scale, extending from 0-03 to 0-25%CO. was used for measurement of both the inspiredand expired gas, and the linearity of the response wasconfirmed by comparison with the catharometerreadings, using serial dilutions of mixtures of COand He. All measurements were made as soon as theinstruments had reached a steady reading after flowhad stopped. The CO and He contents of the expiredsample were corrected for the C02 absorbed.The duration of breath-holding and the volume of

gas inspired were obtained from the spirometer chart.Breath-holding was measured from the beginning ofinspiration to the beginning of sample collection, andthe value was corrected as suggested by Jones andMeade (1961), i.e., half the sampling time was addedand three-tenths of the inspiratory time subtracted,to allow for variations in the timing of inspirationand expiration. The effective lung capacity duringbreath-holding was calculated from the dilution ofthe inspired He. as suggested by McGrath and Thom-son (1959), after subtraction of an estimated value forthe dead space. The effective capacity calculated inthis way is preferred to the total capacity as measuredby the closed-circuit method or by body plethysmo-graphy as it gives a better estimate of the volume of

1 Infra Red Development Co.

lung taking part in the absorption of CO from thesingle breath.Measurements with the oxygen mixture were per-

formed first in each subject to minimize the correc-tion necessary for the progressive increase in circu-lating carboxyhaemoglobin. The pulmonary capillarycarbon monoxide concentration was estimated byequilibration at high oxygen tensions before and aftereach study. An equilibrated sample was obtainedafter a preliminary period breathing oxygen by re-breathing for four minutes in a 6-litre closed circuitfilled with oxygen and containing a CO) absorber(Siosteen and Sjostrand. 1951). Values for each experi-ment were obtained by interpolation and corrected tothe appropriate Po, by direct proportion. The esti-mated pulmonary capillary CO concentration wassubtracted from both the initial and final alveolarCO concentrations before calculation of the diffusingcapacity. A small further correction was made to theinitial concentration for the CO in the residualvolume before each experiment.The rate of uptake of CO by the blood (0) was

calculated for each experiment from the relation

0-33 + 0-0057 P02 obtained from Fig. 1 of Roughton andForster (1957) for A cc. i.e., on the assumptionthat there is no increase in the resistance to gastransfer at the red cell surface. Recent work showsno evidence of such a resistance in vivo (Thews andNiesel, 1959; Kreuzer and Yahr, 1960: Sirs. 1963).The appropriate P02 was obtained, as suggested byMcNeill, Rankin, and Forster (1958), by adding 5mm. Hg to the Po2 of the expired sample to give anestimate of the mean alveolar Po2, and subtractingthe alveolar-capillary oxygen difference estimated as

V02 - DLO, Oxygen uptake (V02) was taken fromtables, assuming a metabolic rate 20% above basal,and DLO was assumed to be 1-23 times DLCo,- Thevalue obtained for 0 was corrected proportionatelyfor changes in the venous haematocrit.Two or three measurements of DL and 0 were

obtained at both levels of oxygen tension in most ofthese subjects, and the mean values were used in thesubsequent calculations. The membrane componentof carbon monoxide transfer (DM) and the pulmonarycapillary volume (Vc) were obtained from the simul-

taneous equations + Iat each oxygenLL L)M +.VC

tension. A standard value for the transfer factor (DL)at an oxygen tension of about 120 mm. Hg wasobtained by putting 0 = 1. The graphical solution of

the equation is shown in Fig. 2 in whichI

is plottedagainst which is linearly related to Po,. The transfer

0factors (DLand DM) are expressed throughout in ml./mm. Hg/min., C in ml. CO/ml. blood/mm. Hg/min.,and capillary volume (Vc) in millilitres. Values morethan three standard errors from the regression forage in normal subjects (Hamer. 1962) were regarded

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Cause of low arterial oxygen saturation in pulmonary fibrosis

1o0LO

20 oos5

80-0-

I ~~I I

i C=80

I --DLair 30Intercept DM-50

2 3

O 200 400 600

P02

FIG. 2. Graphical calculation of DM and VC. is1 DL

plotted against -, which varies linearly with oxygen0'1

tension. As the oxygen tension is increased, becomes0

larger and DL is reduced. The slope of the line joiningobservations at two different oxygen tensions gives thecapillary volume (Vc). The intercept gives the membranecomponent (DM). A standard value for DL is obtained at0=1.

as abnormal. Lung volumes were expressed as per-centages of the values predicted for residual volumeand vital capacity in Table X of Needham, Rogan,and McDonald (1954), corrected to B.T.P.S.

Cardiac catheterization was carried out under basalconditions without sedation. Pressure measurementswere referred to a base line at the middle of the chestat the level of the fourth costal cartilage. Cardiacoutput was determined from the Fick principle, usingoxygen saturations obtained with a Kipp reflectionoximeter and estimating oxygen consumption fromtables at 10% above the basal level. The pulmonaryvascular resistance was calculated using the pul-monary artery wedge pressure as an estimate of pul-monary venous pressure. In three patients the cathetercould not be wedged; the pulmonary venous pressurein these patients was assumed to be similar to thatin the other cases studied. The contact time betweenblood and alveolar gas in the pulmonary capillarieswas calculated from the relation between capillaryvolume and flow (t (sec.) = Vc (ml.) Qc (ml./ sec.)).

RESULTS

LUNG VOLUMES The age and physical character-istics of each patient are described in Table I.All but W. L. and E. F. were non-smokers. Theeffective lung capacity obtained from the dilutionof helium in each single-breath test is shown inTable II. The results obtained using the twodifferent gas mixtures are similar, providing

TABLE IPHYSICAL DATA

Haemo-Age Sex Height Weight B.S.A. globin

Patient (yr) (in.) (lb.) (m.2) (g./100 ml.)

Pulmonary fibrosisC.M. 25 M 67 119 1-62 13-9R.G. 30 M 68 177 1-96 14-4J.D. 72 M 71 186 2-04 14-8W.L. 59 M 70 145 1-82 14-9A.L. 71 F 62 105 1-45 12-8M.G.* 47 F 59 120 1-48 12-7E.F. 63 M 67 125 1-64 15-1

Diffuse carcinomaL.C. 62 M 67 175 191 155W.C. 56 M 59 120 1-48 12-7

* Diffuse systemic sclerosis.

confirmation of the accuracy of the correction ofthe helium reading for changes in the oxygencontent of the gas. The effective lung capacitiesfor a series of tests in any given subject showlittle variation, the range being less than 15% ofthe total capacity. The effective residual volumemeasurements follow a similar pattern.The patients with pulmonary fibrosis show a

considerable reduction of effective lung capacityand residual volume, the average lung capacitybeing 58% and the residual volume 68% of thepredicted value (Table III). The two patients withdiffuse carcinomatous infiltration had grosslyreduced effective lung volumes, the total capacityaveraging 37% and the residual volume 26% ofpredicted.

GAS TRANSFER The values obtained for thetransfer factor (DL) and the correspondingmeasurements of 0 in each subject are shown inTable II, and the calculated values for the transferfactor (DL, O = 1), the membrane component(DM), and the pulmonary capillary volume (Vc)are given in Table III. In the patients withpulmonary fibrosis, the transfer factor (DL) wasmore than three standard errors below the normalfor the patient's age (Hamer, 1962). The membranecomponent (DM) was similarly reduced in allcases, but the capillary volume (Vc) was lessaffected, being in the normal range in two subjects.The patient (E.F.) with the largest capillaryvolume appeared to be less severely affected thanthe other patients in this group, as the radio-graphic changes were minimal. There was no clearrelationship between the changes in gas transferand the severity of the disease as judged from thereduction in lung volume. The two patients withdiffuse carcinoma had a gross reduction of bothcomponents of gas transfer.

t-L

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TABLE IIGAS TRANSFER MEASUREMENTS AND EFFECTIVE LUNG VOLUMES

PatientI 0

C.M. 0-660 640-66

R.G. 0-760-760 76

J.D. 1 10083

W. L. 0-96095

A.L. 0-83

M.G. 1-081-06

E.F. 0 95091

L.C. 0 74073

W.C. 071071

DL

9 5829 6

8 58-88 7

13 412 8

13 613 2

5. 2

15.115*5

14 514 3

4-84.9

8-48 1

Air Mixture

Effective Lung 'Volumes

T.L.C.(mI.)

1,8001,8601,800

3,2003,2903,090

R.V.(ml.)

740800760

1,6001,6501,530

5,700 1,9805,970 2,070

5,670 2,5505,700 2,600

Oxygen Mixture

Eflective Lung VolumesI O DL

r.L.C. R.V.(ml.) (ml.)

2-10 6 8 1,870 6702 04 6 3 1,840 7202-06 6 4 1,720 610

1-93 5 1 3,2201.91 48 3,140

2-33

261

2-382-36

9 6 . .l5,7607 1 6,040

8-9 5.5309 0 ',360

1,810 1,130 1*98 3 7 1,740

3,150 1,320 2-90 911 3,0703,070 1,360 2-81 8-9 2,920

5,460 1,970 2-76 10-7 5,5705,070 2,370 2-81 10 4 5,490

2,420 840 1-94 3-1 2,2602,420 750 1-74 3 1 2,230

2,520 7702,390 710

123 6-2 2,3301 22 66 2,170

1,6201,640

2,4302,000

2,4002,350

1,080

1,2301,210

1,8801,810

760590

570520

TABLE IIIRESULTS

Fffecti\ve Lung Volumes Gas Transfer Measurements

Patient T. L.C. R.V. D0 - I DmI (ml. mm. (ml. mm. '(ml. B.T.P.S.) % Predicted (ml. B.T.P.S.) °'gPredictedHgnm.)t{min.) (ml.)

C.M. 1,810 26 770 38 8 3 I I 33R.G. 3,180 48 1,610 89 7-5 18 13J.D. 5,880 89 2,120 71 13 1 21 30W.L. 3,090 45 2,480 83 13 2 20 38*A.L. 1,780 43 1,100 56 4 3 7 15M.G. 3,000 73 1,260 73 15 3 26 29E.F. 5,400 84 2,000 67 14 2 18 72*I.C. 2,330 39 730 30 4 2 8 10W.C. 2,350 34 650 21 7 0 13 15

* Within three standard errors of normal for age.

The average values in each group, together withthe average findings in 25 normal subjects (Hamer,1962) and in three groups of patients withpulmonary sarcoidosis (Hamer, 1963b), are shownin Table IV. The results of the present studyresemble those reported in the more severelyaffected patients with pulmonary sarcoidosis.Similar findings have been reported by McNeillet al. (1958) in five patients, and by Bates, Varvis,Donevan, and Christie (1960) in four patientsusing a slightly different technique.

PULMONARY CIRCULATION Cardiac catheterizationwas performed in four patients with diffuse

AVERAGE VALUES

TABLE IVFOR THF COMPONENTS OF GASTRANSFER

DLO 1I D Vc(ml./mm. (mil./mm. (ml.)Hg/min.) Hg/min.)

25 normal subjects(Hamer, 1962)! 29-4 52 75

Pulmonary sarcoidosis (Hamer,1963b)

Normal findings, 7 subjects .. 27-7 49 68Low Dm only, 16 subjects .. 166 24 55LowDmand Vc, 7 subjects .. 108 21 21

Present studyPulmonary fibrosis, 7 subjects 10 9 17 33Difluse carcinoma, 2 subjects 5-6 11 13

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TABLE VFINDINGS AT CARDIAC CATHETERIZATION

Effective Mean PulmonaryLung Arterial Cardiac P.A. Wedge Vascular Capillary Contact

Patient Diagnosis Capacity 02 Satn. Output Pressure Pressure Resistance Volume Time(%() (1. min.'m.2) (mm.Hg) (mm.Hg) (units.m. 2) (ml._m.2) (sec.)

predicted) * _

C.M. I.P.F. 26 84 3-0 30/20 I 8 20 0 4R.G. I.P.F. 48 97t 3 2 25/10 2 3 7 0.1A.L. I.P.F. 43 82 2-9 38/10 -3 7 10 0-2M.G. Systemic 73 93 3-7 75/25 2 11 20 0 3

sclerosisT.M. Sarcoid* 70 88 4-1 46'18 1 6 21 0-3R.R. Sarcoid 66 90 3-5 44/20 - 7 8 0.1G.W. Sarcoid 60 86 2 5 55i30 _ 17 10 0-2K.S. Sarcoid 80 86 4 1 44/19 _ 7 44 0-6

* Chest radiograph showed infiltration only. t 94 on effort. * Base line at mid chest. I.P.F.=Interstitial pulmzonary fibrosis.

pulmonary fibrosis and in four with sarcoidosis(Table V); the gas transfer measurements in thepatients with sarcoidosis have been reported else-where (Hamer, 1963b). There was only slightelevation of pulmonary artery pressures in mostof these patients, with a corresponding slightincrease in pulmonary vascular resistance. In twocases the pulmonary hypertension was appreci-able, and the resistance exceeded 10 units(expressed in terms of body surface area). Thecardiac output was normal or slightly reduced,and there was no evidence of cardiac failurethough some patients showed a prominent 'a'wave in the right atrial pressure-pulse. The arterialoxvtren saturation was reduced at rest in all butone patient, anfall in saturaticThere is no 4

the respiratorytion in effectiv

80-

60-

Uv40

20-

UpIII

nor,P!

FIG. 3. Relation)and pulmonarypatients with diffu

2S

changes. Although the pulmonary vascular resist-ance and capillary volume were abnormal in allbut two patients (R.G. and K.S. respectively) therewas no definite relation between these two factorswithin the group (Fig. 3). Similarly, changes in thecardiac output and the arterial oxygen saturationappeared to be independent of the other para-meters studied. The contact time was considerablyreduced in most patients but was largelydetermined by the changes in capillary volume, asthe pulmonary capillary blood flow was relativelyunchanged. The average contact time was 0.3 sec.

DISCUSSION

d in this subject there was a clear Idiopathic pulmonary fibrosis was first describedn on effort. in an acute form by Hamman and Rich (1944).correlation between the severity of Baldwin, Cournand, and Richards (1949) studieddisease, as judged from the reduc- the functional changes produced by pulmonary

re lung capacity, and the vascular fibrosis and found a reduction in the volume ofthe lungs, a low arterial oxygen saturation, andevidence of hyperventilation. Austrian et al. (1951)

)per * suggested that the abnormality in these patientsimit was due to 'alveolar-capillary block', i.e., impair-Mal ment of diffusion of gases from the alveoli to.R. the pulmonary capillaries. Subsequent work

extended the definition of idiopathic pulmonaryfibrosis to include chronic cases (Rubin and

Lower limit of normal Vc Lubliner, 1957; Scadding, 1960; Livingstone,* a Lewis, Reid, and Jefferson, 1964). It appeared to

a confirm the hypothesis of a diffusion defect(Marks, Cugell, Cadigan, and Gaensler, 1957)

* both in the idiopathic cases and in pulmonaryfibrosis due to sarcoidosis (Marshall, Smellie,Baylis, Hoyle, and Bates, 1958) or scleroderma

2 .0. . (Catterall and Rowell, 1963), and also in diffuse2 4 6 a 10 carcinomatous infiltration of the lungs (Baldwin

P.V.FCunits) et al., 1949).betweenpulmonary capillary volunme (VC) The suggestion that a diffusion defect wasvascular resistance (P.V.R.) in eight responsible for the low arterial oxygen saturation{se pulmonary fibrosis. in pulmonary fibrosis was first seriously

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challenged by Swiss workers (Rossier, Buhlmann,and Luchsinger, 1954; Luchsinger et al., 1957;Luchsinger, Katz, McCormick, Donohoe, andMoser, 1959). They pointed out that the hypox-aemia was associated with a rise in the pulmonaryvascular resistance and suggested that a criticalreduction in the pulmonary vascular bed wasresponsible for both changes. A small pulmonarycapillary bed in the presence of a normal cardiacoutput would be expected to reduce the contacttime between the red cells and the alveolar gasso that equilibrium could not be attained beforethe red cells reached the end of the capillary.The work of Roughton and Forster (1957) has

allowed a more accurate assessment of the import-ance of changes in the pulmonary capillary bed.They demonstrated the importance of the rate ofcombination of the gas with blood (0) and showedthat the capillary volume could be calculated usingcarbon monoxide. Unfortunately, the study ofoxygen transfer is more difficult as there is nosimple relation between 0 for oxygen and theoxygen tension (Staub, Bishop, and Forster, 1962).Recent calculations, however, confirm the import-ance of a reduction in the contact time in theproduction of low arterial oxygen saturations, andsuggest that in normal subjects equilibrium withalveolar gas is reached before the end of thecapillaries except on exercise breathing a hypoxicgas mixture (Staub, 1963). These estimates arebased on the assumption that the capillary volumecalculated using carbon monoxide is alsoapplicable to oxygen transfer. However, it hasbeen suggested (Turino, Bergofsky, Goldring, andFishman, 1963) that the capillary volume foroxygen may be smaller than for carbon monoxideas slow-moving oxygenated blood will take upcarbon monoxide but not oxygen. However, thiseffect is unlikely to be large enough to affect theargument, and Staub (1963) estimates that a reduc-tion in contact time to one fifth of normal isnecessary to produce any measurable differencein oxygen tension between alveolar gas and theblood at the end of the capillaries at rest.Measurements of the contact time in the presentstudy showed changes of this degree only in themore severely affected patients, suggesting thatrestriction of the pulmonary vascular bed is notthe major determinant of the low arterial oxygensaturation in pulmonary fibrosis, though it may bea contributory factor.Uneven distribution of ventilation and perfu-

sion in the lung is responsible for most of thedifference between alveolar and arterial oxygentensions in normal subjects (Briscoe, 1959;Asmussen and Nielsen, 1960 and 1961). These

effects are greatly accentuated in pulmonaryfibrosis by focal involvement of airways and bloodvessels, and many investigators have concludedthat the low arterial oxygen saturation in thiscondition can be accounted for by the distributiondisturbances (Motley, 1958; Holland and Blacket,1960; Finley et al., 1962; West, 1963). Thechanges in the components of gas transferreported here must be interpreted in the light ofthese findings. The single-breath method used tomeasure the transfer factor for carbon monoxideis influenced by uneven ventilation, and in addi-tion local variations in capillary volume areprobably produced by uneven blood flow in thelungs (Hamer, 1963b). These distribution effectsreduce the transfer factor by limiting the contactbetween alveolar gas and capillary blood (Burrows,Niden, Mittman, Talley, and Barclay, 1960). If theeffect is similar at all levels of oxygen tension,both the components of gas transfer (DM and Vc)will be similarly reduced. However, Burrows et al.(1960) suggest that the effect may be less at higheroxygen tensions. Breathing air, the carbonmonoxide concentration will fall to low levelsduring breath holding in alveoli with a rapiduptake. At higher oxygen tensions, the reduceduptake will maintain higher carbon monoxidelevels in these alveoli throughout breath holding,so the transfer factor will be greater than

DL DL Uneven VA:Qc DM25 Vc25/

0 15 DL6-37-/

~-DLB-3

10 0.10// Burrows effectZ_SA DM17 VCSO

L12/5 Li25

20j 005 Normal DM 50 Vc 50

DL 2540-

X

FIG. 4. Suggested mechanism by which a reduction in DMcan be produced by uneven distribution in the lungs. Ifdistribution effects are similar at all oxygen tensions, bothDM and Vc are reduced. However, ifthe effects are less athigher oxygen tension, as suggested by Burrows et al.(1960), only DM is affected.

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expected. If this mechanism reduces the changesdue to uneven distribution by approximately onethird at high oxygen tensions, the effects ofuneven distribution will be confined to themembrane component (DM) (Fig. 4).

In many patients with pulmonary sarcoidosisof relatively short duration (Hamer, 1963a), andin two patients with mild idiopathic pulmonaryfibrosis reported here, the membrane component(DM) was found to be significantly impaired butthe capillary volume (Vc) was normal. Thesefindings might at first sight be taken to indicateinterference with diffusion across the alveolar-capillary membrane, either by sarcoid deposits ordiffuse fibrosis, but they can also be explained onthe basis of uneven distribution of ventilation andperfusion. Even in normal subjects, measurementsof the membrane component (DM) probably over-estimate the resistance to diffusion across thealveolar-capillary membrane as uneven distribu-tion effects are included in the measurement.Experimental studies of the effect of anaemia onperfused dog lungs (Burrows and Niden, 1963)and of movement of gases of different molecularweights (Chinard, Enns, and Nolan, 1961) confirmthat there is in fact little resistance to diffusion.Although thickening of the alveolar walls inpulmonary fibrosis must greatly increase thediffusion pathway (Meessen, 1961 ; Schulz, 1962),Staub (1963) has estimated that the resistance todiffusion must be more than five times the normalvalue to produce any detectable fall in arterialoxygen tension. Changes in the membranecomponent (DM) of this order were frequent inthe present study but are probably in the main areflection of ventilation-perfusion disturbances. Itseems unlikely that thickening of the alveolar-capillary membrane is playing more than a minorpart in producing the low arterial oxygen satura-tions in these patients.The small capillary volume (Vc) found in most

patients with pulmonary fibrosis or longstandingsarcoidosis (Hamer, 1963b) may also in part bedue to distribution disturbances. However, thechanges in the membrane component (DM) aresimilar to those found in patients with a normalcapillary volume (Table IV), suggesting that theeffects of uneven distribution are not grosslydifferent in the two groups. A fall in themembrane component might be expected toaccompany a reduction in capillary volume as thearea available for diffusion is diminished. Therelative constancy of the membrane componentin these patients, and in physiological changes incapillary volume (Cotes, Snidal, and Shepard,1960), gives further support to the suggestion that

the resistance to diffusion does not play animportant part in determining the membranecomponent of gas transfer.

SUMMARY

The components of the pulmonary gas transfer(DL) were measured in seven patients with diffuseinterstitial pulmonary fibrosis and in two withcarcinomatous infiltration of the lungs.The membrane component of gas transfer (DM)

was considerably impaired in all cases. This isinterpreted as evidence of disturbances of distri-bution in the lungs rather than of a diffusiondefect.The pulmonary capillary volume (Vc) was also

markedly diminished in most of these patients.However, cardiac catheterization confirmed thatthe changes were not sufficient to produce aserious reduction in the contact time between theblood and the alveolar gas.The results are consistent with the suggestion

that the fall in arterial oxygen saturation in diffusepulmonary fibrosis is due to uneven distributioneffects. The concept of 'alveolar-capillary block'should be discarded.

I am most grateful to Dr. Clifford Hoyle for hisencouragement and for allowing me to study patientsunder his care.

REFERENCES

Asmussen, E., and Nielsen, M. (1960). Alveolo-arterial gas ex-change at rest and during work at different 02 tensions. Actaphysiol. scand., 50, 153.

-, - (1961). The contribution of the distribution factorto the A-a Po2 difference (a correction). Ibid., 51, 385.

Austrian, R., McClement, J. H., Renzetti, A. D., Donald, K. W.,Riley, R. L., and Cournand, A. (1951). Clinical and physiologicfeatures of some types of pulmonary diseases with impairmentof alveolar-capillary diffusion: the syndrome of "alveolar-capillary block". Amer. J. Med., 11, 667.

Baldwin, E. deF., Cournand, A., and Richards, D. W. (1949). Pul-monary insufficiency II. A study ofthirty-nine cases ofpulmonaryfibrosis. Medicine (Baltimore), 28, 1.

Bates, D. V., Varvis, C. J., Donevan, R. E., and Christie, R. V.(1960). Variations in the pulmonary capillary blood volumeand membrane diffusion component in health and disease.J. clin. Invest., 39, 1401.

Briscoe, W. A. (1959). Comparison between alveolo arterial gradientpredicted from mixing studies and the observed gradient. J.appl. Physiol., 14, 299.

Burrows, B. and Niden, A. H. (1963). Effects of anemia and hemorr-hagic shock on pulmonary diffusion in the dog lung. Ibid., 18,123.

--, , Mittman, C., Talley, R. C., and Barclay, W. R. (1960).Non-uniform pulmonary diffusion as demonstrated by thecarbonmonoxide equilibration technique. Experimental results inman. J. clin. Invest., 39, 943.

.Catterall, M., and Rowell, N. R. (1963). Respiratory function inprogressive systemic sclerosis. Tho,ax, 18, 10.

Chinard, F. P., Enns, T., and Nolan, M. F. (1961). Diffusion andsolubility factors in pulmonary inert gas exchanges. J. appl.Physiol., 16, 831.

Cotes, J. E. (1963). Terminology for exchange of gas in the lungs.Lancet, ii, 843.- Snidal, D. P., and Shepard, R. H. 01960). Effect of negative

intra-alveolar pressure on pulmonary diffusing capacity. J.appl. Physiol., 15, 372.

- Finley, T. N., Swenson, E. W., and Comroe, J. H. (1962). The causeof arterial hypoxemia at rest in patients with "alveolar-capillaryblock syndrome". J. clin. Invest., 41, 618.

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1-famer, N. A. J. (1962). The effect of age on the components of thepulmonary diffusing capacity. Clin. Sci., 23, 85.(1963a). Changes in the components of the diffusing capacityin pulmonary sarcoidosis. Thorax, 18, 275.

--(1963b). Changes in the absorption of carbon monoxide in thelungs after breathing oxygen. Clin. Sci., 25, 385.

Hamman, L., and Rich, A. R. (1944). Acute diffuse interstitialfibrosis of the lungs. Bull. Johns Hopk. Hosp., 74, 177.

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Jones, R. S., and Meade, F. (1961). A theoretical and experimentalanalysis of anomalies in the estimation of pulmonary diffusingcapacity by the single breath method. Quart. J. exp. Physiol.,46, 131.

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Livingstone, J. L., Lewis, J. G., Reid, L., and Jefferson, K. E. (1964).Diffuse interstitial pulmonary fibrosis. Quart. J. Med., 33, 71.

Luchsinger, P. C., Katz, S., McCormick, G. F., Donohoe, R. F.,and Moser, K. M. (1959). Cardiorespiratory studies in Hamman-Rich syndrome. Dis. Chest, 35, 52.Moser, K. M., Buhlmann, A., and Rossier, P. H. (1957). The

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Ogilvie, C. M., Forster, R. E., Blakemore, W. S., and Morton, J. W.(1957). A standardized breath holding technique for the clinicalmeasurement of the diffusing capacity of the lung for carbonmonoxide. J. clin. Invest., 36, 1.

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