ON (CLOSED...A. COURNAND, R. C. DARLING, J. S. MANSFIELD, AND D. W. RICHARDS, JR. lung contents are presumably measured and used in the calculation, contrasted with Sonne's studies

STUDIES ON THE INTRAPULMONARYMIXTURE OF GASES.II. ANALYSIS OFTHE REBREATHINGMETHOD(CLOSED

CIRCUIT) FOR MEASURINGRESIDUAL AIRBy ANDRECOURNAND,ROBERTC. DARLING, JAMESS. MANSFIELD,

AD DICKINSON W. RICHARDS, JR.(From the Research Service, First Division, Welfare Hospital, Department of Hospitals, New York

City,' and the Department of Medicine, College of Physicians and Surgeons,Columbia University, New York City)

(Received for publication March 12, 1940)

The closed rebreathing circuit has been widelyused for residual air measurement (1, 2, 3, 4, 5,and others). The essential features of the ap-paratus and procedure were the same in all. Aspirometer filled with high oxygen (or with ahydrogen-containing) gas mixture was attachedto the test subject. The carbon dioxide wasremoved with soda lime or other alkali in thecircuit and the subject breathed for a period oftime until the nitrogen (or hydrogen) was redis-tributed in the circuit. The residual lung gasvolume was calculated from the amount of redis-tributed gas.

In most of the work it was assumed that at theend of five or more minutes of quiet breathing thegas in lungs and spirometer was uniform in com-position, except for a slight excess concentrationof inert gases in the lungs. This excess wasassumed to be the same as that occurring duringthe breathing of room air. On the basis of theseassumptions, the net change in spirometer gasconcentration was considered the same as that inthe lungs during the rebreathing.

By actual measurement of the gas concentra-tion in the various parts of the spirometer systemand the alveolar gas, Lassen, Cournand, andRichards (6) concluded in the study of normalsubjects that these assumptions were not valid.Rather than an excess, they found a lower con-centration of nitrogen in the lungs than in thespirometer at the end of a breathing period.They explained these findings as due to the con-stantly increasing nitrogen concentration whichresulted from the steadily diminishing spirometervolume. This effect they called the "oxygenstorage" effect. To correct for it, they intro-duced alveolar air concentrations into the calcu-lation and found that this correction made a

1 Formerly Research Division, Metropolitan Hospital,Department of Hospitals, New York City.

difference of several hundred cubic centimetersin the residual air value in some subjects.

Other workers have found variable results intesting the need for this correction. Anthony(7), using a larger spirometer and a powerfulmotor blower, failed to find any need for alveolarmeasurements. The discrepancy from Lassen,Cournand, and Richards' finding seemed to beexplained by the difference in apparatus. Kalt-reider, Fray, and Hyde (8) believed from thestudy of six normal subjects that the correctiondue to the " oxygen storage " effect was negligiblysmall. Herrald and McMichael (9) confirmedthe presence of a significant "oxygen storage"effect and proposed a modified procedure inwhich the spirometer volume was kept constantby added oxygen.

In severe cases of pulmonary emphysema,Cournand, Lassen, and Richards (10) found nosuch predictable "oxygen storage" effect as innormal subjects. Moreover, they found extremevariability of results in these subjects on suc-cessive measurements. Some figures obtainedseemed improbably high, considering the ex-ternal chest measurements of the subjects.From this they suggested that in these subjectsthere was an unequal distribution of respiratorygases within the lungs. If this were true, thealveolar air as measured was not a true index ofaverage lung gases. Previously, Sonne and hiscoworkers (11, 12, 13) had shown this lack ofuniformity of the alveolar air not only in em-physema but also in some normal subjects. Byfractional analyses of alveolar air after breathinghydrogen, Roelsen (14, 15) has shown an evengreater factor of unequal distribution than wasevident in analyses of the normal respiratorygases. In the residual air measurements, it ispossible that this factor may be still more mag-nified in its effect, since here the entire gaseous

599

A. COURNAND,R. C. DARLING, J. S. MANSFIELD, AND D. W. RICHARDS, JR.

lung contents are presumably measured andused in the calculation, contrasted with Sonne'sstudies of the variations in that part of the lunggases which can be expired.

The purpose of the present investigation is todetect and quantitate the effect of imperfect dis-tribution on closed circuit residual air measure-ments, not only in order to test the reliability ofthe method, but also to detect poor mixing asone of the factors disturbing normal lung func-tion. The approach is necessarily indirect. Itis proposed to determine the residual air valuesby several modifications of the method, in which

poor mixing should give opposite effects. Con-clusions will be based on a comparison of thedifferent values so obtained.

Discussion of effect of poor mixing on standardmethod

Let us first consider the probable direction ofthe error due to this factor of unequal distribu-tion by noting the variables in the formula fromwhich the functional residual air 2 is calculated inthe standard method. This formula in itssimplest form is

F. R. A. = (N2 in spirometer system at end) - (N2 in spirometer system at start) _ (N2 excretionalv. a N2- alv. p N2 factor),

where alv. a N2 is the alveolar nitrogen concen-tration at the start, alv. p N2 that at the end ofthe breathing period.

It will be seen that the numerator of thefraction is the difference of two definitely meas-urable volumes, involving no assumptions. Inthe denominator, however, one or both of thevalues alv. a and alv. p may be in error if thereis imperfect distribution of gases within thelungs. Under these conditions, each alveolarspecimen will more likely represent the gas inthe relatively well aerated portions of the lung.

In the instance of the alv. a specimen takenon room air breathing, the gas in the poorly ven-tilated areas of the lung will show a relativenitrogen concentration, as long as these areas areperfused with blood from the pulmonary arteries.This arises from the fact that the R, Q. is nor-mally less than 1. Thus probably alv. a nitro-gen as measured is lower than the average lunggas concentration.

The likely error in alv. p is not so simple. Atthe start of the experiment the lungs are high innitrogen, the spirometer system low. The firstfew inspired breaths are low in nitrogen, thenrise as nitrogen from the lungs enters the spi-rometer. Furthermore, with the reduction involume of the spirometer gas due to oxygenused, the successive inspiratory samples increasein nitrogen concentration. If there is unequaldistribution, the alv. p specimen as measuredwill be more influenced by recent inspiratory gas

and less by more distant breathing mixtureswhich may be trapped in the poorly aeratedregions. One can enumerate three periods ofprevious breathing which may influence thegaseous content of the deeper regions whosecontents are not measured: (1) the high nitrogenof the original room air breathing, (2) the verylow nitrogen of the first few breaths of the ex-periment, and (3) the somewhat lower nitrogenof the immediately preceding spirometer samples,due to decreasing volume during the period ofalleged equilibrium. If the volume is keptconstant as in McMichael's work (9) and insome of ours, the third factor is eliminated. Thefirst factor will make alv. p as measured toolow, the second and third, too high. Thus theerror depends on the balance of these factors.Regardless of the direction of the resultant error,it will probably be less negative than that inalv. a, which is due to factor (1) alone. Thusthe difference between alv. p, a value either highor slightly low, and alv. a, which is definitely toolow, will also be too low. Substituting this inthe calculation, the F. R. A. value will be toohigh. Since the difference, alv. a - alv. p isusually less than 0.3 atmosphere, this error willbe magnified by the form of the calculation. Itshould be emphasized again that this conclusionis based on a series of assumptions of probability.There may be other sources of error which have

2Functional residual air is the volume of air in the lungsand air passages at the end of a normal quiet expiration.

600

INTRAPULMONARYMIXtURE OF GASES

not been considered, or there may be more can-cellation of errors than allowed for. Realizingthis, we may still take as a probability thepremise that the factor of imperfect lung gasmixture causes too high a value for residual airby the Christie procedure.

A reversed technique, its purpose, and the probableinfluence of poor mixing I

If the above arguments are valid as the ex-planation of errors in residual air determinationby the Christie method, then it should be pos-sible, by reversing the shift of nitrogen duringrebreathing, to reverse also the direction of signof the error. Specifically, if the lungs are firstfilled with pure oxygen, then a rebreathing of

nitrogen (or room air) is carried out, the resultantF. R. A. figure in subjects with imperfect distri-bution should be too low. Such a technique hasbeen devised: the subject is allowed to breatheoxygen for a prolonged period, then connectedto the spirometer filled with room air for therebreathing period. In such a procedure, thenet nitrogen shift is from spirometer to lung, incontradistinction to the Christie method wherethe nitrogen shift is from lung to spirometer.For brevity in future references, we shall call theoriginal method, that of decreasing lung nitrogen,Method I; and the new modification, that ofincreasing lung nitrogen, Method II.

The calculation formula of Method II is anal-ogous to that of Method I:

F. R. A. =(N2 in spirometer system at start) - (N2 in spirometer system at end) _ (N2 absorption

alv. p N2- alv. a N2 factor).

As before, all values are definitely measurablewithout assumptions, except those in the de-nominator of the formula. If these alveolarmeasurements represent true average lung gassamples, the F. R. A. value should be an accuratevolume measurement. However, if there isimperfect gas mixture in the lungs, either alv. aor alv. p or both will be in error. Under suchcircumstances, alv. a taken after pure oxygenbreathing may be too low in nitrogen, since itwill not measure the nitrogen still trapped inpoorly ventilated areas of the lung. As inMethod I, several factors may influence theaccuracy of alv. p: (1) too high in nitrogen dueto trapped oxygen from the previous oxygenbreathing; (2) too low due to very high nitrogenin the first few breaths of the rebreathing period;(3) too high due to lower nitrogen in spirometergas during the course of rebreathing. The netresult of these three factors is a probable positiveerror in alv. p. Thus the difference betweenalv. a (too low) and alv. p (too high) will showa probable positive error. From this, in the cal-culation F. R. A. will be smaller than the truevolume if the factor of unequal distribution isimportant. It should be noted from this dis-

J A preliminary report of this investigation was publishedin the Proceedings of the American Society for ClinicalInvestigation, 1938 (J. Clin. Invest., 1938, 17, 536).

cussion that a cancellation of errors is less likelyin this method than in the standard method.

As noted in the analysis of both methods, thefactor of diminishing volume in the system isone important feature contributing to the pos-sible errors due to poor intrapulmonary gasmixture. Herrald and McMichael (9) have re-moved this factor by continual replacement ofthe oxygen used during the rebreathing period.A similar procedure has been carried out in thiswork, not only in the usual Method I, but alsoin Method II, so that in subjects fully studied,the results of four separate procedures are pre-sented. In those instances where the volume isallowed to diminish, the methods are designatedas Ia and IIa; where the volume is kept constantby oxygen replacement, as Ib and IIb.

A comparison of figures obtained by all fourmethods or by-any pair of figures should givesome measure of the factor of imperfect gas dis-tribution within the lungs. If all agree in anysubject, the reliability of the method may beassumed, but poor distribution will not be en-tirely ruled out, since there may be a cancellationof errors. However, a difference between theresults by the different methods will be of posi-tive significance as an index of slow gas mixturewithin the lungs. This type of data, on the other

60i


hand, gives no information as to the true valuefor the residual lung volume.

METHODS

Method Ia (decreasing lung nitrogen, diminishingvolume)

This is the Christie method as modified by Lassen,Cournand, a.nd Richards (6) to include alveolar air meas-urements before and at the end of the rebreathing period.The apparatus shown in Figure 1 is fundamentally that ofa Benedict-Roth basal metabolism apparatus, with a fewadditions. The soda lime carbon dioxide absorber (S.L.)and the flutter valves (F1, F2) are inserted outside thespirometer. The chief addition is a valve (V1) adjacentto the mouthpiece (Mt), which can be turned either intothe spirometer circuit or into a side circuit fitted withsimilar flutter valves (F,, F4). In the expiratory side ofthis circuit are inserted the alveolar sampling tubes. Thedead space from mouthpiece to these tubes is approxi-mately 100 cc. A valve (V2) is inserted to close theinspiratory gas flow during alveolar sampling.

In preparing the apparatus for Method Ia, the deadspace was washed repeatedly with room air by raising and

lowering the spirometer bell. The water level in thespirometer was kept at a measured level. At this levelthe dead space of the spirometer system had been pre-viously determined (Christie). After washing, the valve(V1) was turned to the side circuit, thus closing thespirometer circuit. Oxygen was then admitted throughR.I., usually about 4000 cc. The actual amount was meas-ured on the graphic tracing after constant temperaturehad been reached. In practice, the amount of oxygenadded was varied, depending on the size of the residualair and the oxygen consumption expected. Ideally, itshould be such an amount that the final spirometer gasafter rebreathing should be slightly under 50 per centoxygen. The apparatus was tested for leaks by registeringa short period on the drum with a weight placed on thespirometer bell. A straight horizontal line should bedrawn.

The subject, preferably under basal conditions, theninserted the mouthpiece and applied the nose clip. Whenbreathing quietly through the side circuit, he was in-structed to exhale fully for an alveolar specimen whichwas taken at the end of three to five seconds of forcedexpiration. Quiet breathing was then resumed and con-tinued one to two minutes, or until the effect of the exertionof alveolar sampling had passed. With the drum moving,

Main circuit

Gas inlet

AIv. 5ide circuit

F.

FIG. 1. DIAGRAMOF CLOSEDCIRCUIT APPARATUSFORANALYSIS OF INTRAPULMONARYMIXTURE OF GASES

M, mouthpiece. Alv., set of three evacuated gas sampling tubes. V1, V2, three-way respiratory valves.F1, F2, F3, F4, one-way rubber flutter valves. B, rubber anesthesia bag. S.L., soda lime absorber for CO0.Sp., spirometer. R.I., side valve for sampling spirometer gases. D, recording drum.

602

INTRAPULMONARYMIXTURE OF GASES

the valve (VI) was then turned to the spirometer circuitas nearly as possible at the end of a quiet expiration.Quiet breathing was recorded for the standard time ofseven minutes, or a longer period, as desired in some datato be reported. Near the end of this period, the spirom-eter temperature was read. At the end of this time, thevalve (V1) was turned to the side circuit and simultane-ously the subject expired fully for alveolar sampling. Itwas not necessary that this valve shift occur at the endof a normal expiration. In fact, it was found better toturn it immediately after the start of the expiration. Thespirometer gas sample was then taken by placing a weighton the spirometer bell, opening R.I., allowing approxi-mately half the gas to escape, and then taking the sample.

There were three gases to be analyzed, the spirometerand two alveolar specimens, which we shall call alv. d andalv. p. For calculation, only the nitrogen percentageneeded to be measured as the difference between the totaland the combined oxygen and carbon dioxide. Actually,frequent analyses were made for carbon dioxide separately:on the spirometer to check the efficiency of the soda lime,and on the alveolar specimens to be sure that specimenswere not significantly diluted with dead space gas. Anal-yses were made with a Haldane apparatus in which theburette was calibrated for up to 50 per cent absorbablegases.

All volume measurements were made from the tracings,together with the previously measured dead space of theapparatus. The volume of added oxygen in the spirometerwas recorded at the time it was run in; the oxygen con-sumption during the experiment was measured from theslope of the tracing. The initial volume minus this con-surmption equals the final spirometer volume to which thedead space volume was added to obtain the final volume ofspirometer system.

The formula for the F.R.A. calculation is obtained froma mathematical statement that the nitrogen in the lungsand spirometer at beginning and end is equal (with acorrection for nitrogen excretion).Let Va= vol. N2 containing gas in spirometer system at

start (in this case= D.S., dead space).Vp=final spir. vol.+D.S.

Spir. p = analysis of spir. gas for N2 expressed as part of anatmosphere.

Alv. p =alveolar N2 analyses in same units.

F.R.A. =functional residual air in cc.Then:F.R.A.(alv. d) + Va(0.791)

= F.R.A.(alv. P) + Vp(Spir. p) -N2 excretion.Solving:

F.R.A. = Vp Spir. p- Va(0.791) - N2 excretionalv. a-alv. p

From Paper I of this series (16):excretion =alv. -alv.-N2exrto 0.80 X 220.

(For seven minutes' breathing time; 10 cc. added to220 cc. for each minute after seven, if longer period.)

Substituting:

F.R.A. = Vp Spir. p- Va(O. 791) 275.alv. a-alv pAll analyses with Haldane apparatus give proportions

of dry gas, so Vp and Va were corrected to dry gas at thetemperature of the experiment before substituting in theformula. The F.R.A. value then obtained may need aslight correction if the rebreathing period did not beginat the exact end of a normal expiration. Such a correctionwas determined from examination of the tracing. Afterthis correction the F.R.A. volume was corrected to 370 C.and saturation with water vapor.

Method Ib (decreasing lung nitrogen, constantvolume)

This procedure differed only in a few details from Ia.Immediately after the start of the rebreathing period, asteady flow of oxygen was begun through R.I. (Figure 1),equal to the resting oxygen consumption. This figure wasestimated from a previous tracing. For regulating theflow, a Forregger flow measuring valve was used with afine and coarse water manometer gauge. This flow ofoxygen was turned off fifteen seconds before the end ofthe rebreathing period.

The formula for calculation is unchanged. Va is stillthe D.S. (dead space). A base line, drawn on the tracingas in Ia, will be approximately horizontal. Vp will beD.S. +02 volume added at start 1 correction for any devia-tion of tracing from horizontal.

Method IIa (increasing lung nitrogen, dimin-ishing volume)

This method required the same apparatus with only oneaddition. On th.e inlet valve of the side circuit a rubberanesthesia bag (B) was attached. This in turn was con-nected with an oxygen tank fitted with reduction and flowmeasuring valves.

In preparing the apparatus, the spirometer and deadspace were washed with room air as before, then partlyfilled with room air and tested for leaks. The volume ofroom air admitted to spirometer was usually 2000 to3000 cc., but was conveniently made larger with subjectsof large F.R.A. and smaller with small subjects.

With V1 open to the side circuit and the oxygen flow inthat circuit maintained at 7 to 8 liters per minute, thesubject was then attached to mouthpiece and allowed tobreathe quietly for ten minutes. Oxygen flow was ad-justed to keep the anesthesia bag partly full. The ten-minute period was chosen because preliminary experimentsmeasuring alveolar nitrogen values at frequent intervalsduring oxygen breathing showed that in normals a lowplateau level for alveolar nitrogen was reached after threeto four minutes; in severe emphysema a slightly higherplateau level was reached in ten to twelve minutes.

At the end of ten minutes of oxygen breathing, analveolar specimen was taken with the inlet valve (V2)closed for the few seconds of the procedure. Oxygenbreathing was continued for two additional minutes toreach a resting level; then at the end of a normal expiration,

603


valve V1 was turned to the spirometer system. For sevenminutes or longer, spirometer breathing was recorded onthe drum and an alveolar specimen taken at the end, asin Method I. It was found advisable to partly wash outthe tubing of the side circuit with room air before takingthe alv. p specimen, in order that the high oxygen pre-viously there would not too greatly dilute the nitrogen ofthe alveolar air.

Using the same symbols as in Method I, the calculationformula is similarly derived:F.R.A.(alv. 4)+ Va(0.791)

=F.R.A.(alv. p) + Vp(Spir. p)+N2 absorbed.Solving:

F=V(0.791) - Vp(Spir. p) - N2 absorbedalv. p-alv. a

Substituting formula for N2 absorption:

F.R.A. = Vt(0.791) - Vp(Spir. p) _275alv. p-alv. ava in this case is the dead space plus the room air

added to system. Vp is this value minus the oxygenabsorbed during the rebreathing period. Corrections aremade as in Method I for inexact starting point, temperatureand for water vapor.

Method Ilb (increasing lung nitrogen, constantvolume)

This modification of Method II is exactly analogous tothe " b " modification of Method I. The volume was keptnearly constant by a steady flow of oxygen into R.I.during the rebreathing period, up to fifteen seconds beforethe end.

The calculation formula is likewise unchanged. Vp inthis case equals V&- any necessary correction for devia-tion from horizontal in the slope of the tracing.

Actually the Method IIb was used more frequentlythan Ila in those cases in which only a comparison ofresults by Methods I and II was desired. One reasonfor this was that in the "b" modification there is nochance of obtaining a final breathing mixture of less than21 per cent oxygen, as is possible in Ila.

RESULTS

The subjects for this work consisted of six nor-mal persons and ten patients with severe pulmon-ary emphysema. The normal subjects includedphysicians and ambulant hospital patients withnon-pulmonary diseases. In the patients withemphysema, the diagnosis was established by thephysical signs, the x-ray and the spirographictracings. All suffered from severe dyspnea; sixout of ten showed a reduced arterial oxygen satu-ration. Only one subject (Ant. C.) seemed to besuffering from some degree of cardiac failure, andin this case the pulmonary disturbance seemedpredominant. Two subjects who have since died

were examined at autopsy and the diagnosis ofemphysema confirmed. They also showed somedegree of bronchiectasis and it is probable thatsome of the living subjects also showed this com-mon complication of advanced obstructive em-physema. The group of abnormal subjects istherefore a picked group, chosen not as averagecases but as extreme and advanced cases.

Table I shows the results on the entire seriesby Methods Ta and Ilb. In addition, calculatedfigures for the Ia experiments are listed, using

TABLE I

Functional residual air determinations by closed system

NORMALSUBJECTS

Decreasing lung N2 Increasing lungmethod-Ia Nsmethod-IIb

Length Nm asnNmSubject Of Nu-ChristieLasnNmtest ber ac_et at. ber

Of lated~ calcu- Of Aver-deter aver- lated deter- agetions age age tions

minutesJ. D ......... 3 1225 1115 3 1065J. L.. 7 12 1420 1320 12 1300

12 3 1210A. C......... 7 2 1895 1745 3 1770

10 1 1735T. R......... 7 4 5500 4375 3 4460

10 1 4300D. W. R...... 7 3 4040 3540 2 2930

10 1 3470 1 3310R. C. D....... 7 5 3990 3250 6 2330

10 2 3810 2 2340

Mean of group 3010 2560 2310S.D 1740 1480 1370S.E.,,, 710 602 503.*.......... 0.5 0.3

SUBJECTS WITH PULMONARYEMPHYSEMA

M. K......... 4 4100 3320 4 2390J. O . 5 5180 4380 4 2530M. H 15 6060 5360 4 3845J. F.. 7 5 4760 4240 4 2280

12 1 5040 2 2085M. A 7 7490 5465 9 3320Ant. C 2 3490 3240 2 2850J. C. . 7 4 7210 6570 4 5430

12 2 6285 2 5470D. H 2 3365 3140 2 2530H. K... 7 3 3790 3835 3 2250

12 2 3765 2 1940F. H 1 3160 3020 1 1945

Mean of group 4860 4260 2960S.D 1680 1270 1120S.E.m 531 401 354

t*............ 0.9 2.4

*S.E. Difference of Means'

604

AM


the original Christie calculation and neglectingthe alveolar measurements. The average valueof a series of determinations is given for each ofthe three calculations. Results of Methods Iband IIa are omitted from this table, but will bepresented in a later detailed listing of results onfour subjects, together with an analysis of thevariations by each single method.

A comparison of columns 1 and 2 gives con-firmation to the findings of Lassen, Cournand,and Richards (6) on the influence of alveolarmeasurements in the calculation. Of the six nor-mal subjects, the Christie calculation gave largerresults in every instance, the difference varyingfrom 100 to 1125 cc. Of the ten emphysematoussubjects, nine showed higher results by theChristie calculation, the difference varying from140 cc. to almost 2000 cc. In one (H. K.) theChristie calculation gave practically identicalresults.

A comparison of columns 2 and 3 gives the evi-dence by which the factor of unequal distributionin the lungs may be discovered and roughlyquantitated.

Normal subjectsOf the six normal subjects, the two methods

give practically identical results in four. Ofthese four, three were subjects with functionalresidual air of less than 2000 cc. In the case ofthe other two normal subjects, both with ratherlarge functional residual air, there was a differ-ence of 600 cc. and 900 cc., respectivqly, in theaverage values by the two methods. It shouldbe mentioned that no abnormalities could befound clinically or by x-ray of the chest in thesetwo subjects. Thus it would seem that in thesetwo normal subjects there was indirect evidencethat the alveolar air as measured does not indi-cate the gas concentration throughout the lungs,under the conditions of the experiment.

Theoretically, this situation might be correctedby increasing the rebreathing time beyond theusual seven minutes. Such an experiment wascarried out on these two subjects. In a singlepair of ten-minute tests on one of them, thereappeared to be better agreement than in theseven-minute tests. In the case of the other sub-ject, however, no closer agreement could bereached.

Subjects with emphysema

In the experiments on the emphysematous sub-jects, it will be seen from Table I that there wasin every instance a significant difference betweenaverage results by Methods Ia and IIb. Thisdifference ranged from 400 cc. in the case of Ant.C. to 2000 cc. in the case of J. F. In seven out often cases, the difference was greater than 1000 cc.It would seem that these findings have similarsignificance to those in the case of the last twonormals, except that the degree of change is moremarked in the pathological cases. Evidently thealveolar air samples as obtained were in all casesa poor measurement of the average lung gases,even though the alveolar carbon dioxide level inthe gases analyzed was regularly above 5 per cent.The comparable findings in some normal subjectsand all emphysematous subjects would seem tofollow closely Sonne's findings of variations indifferent parts of the measurable alveolar air inthe same groups of subjects.

As in the case of the normal subjects, an at-tempt was made to repeat the experiments, usinglonger breathing periods. Such experiments aretechnically somewhat more difficult. In threecases, results of a twelve-minute breathing periodare presented in the same table (Table I). Itwill be seen that in no case was agreement ob-tained between the two values. Furthermore,there is no definite trend toward decreasing thedifference between them. In two there is actu-ally an increase in the difference; in the third, aslight decrease, probably not significant.

Table I also shows a statistical analysis of theseven-minute figures by the various methods.Such an analysis of small groups of subjects,however, introduces a large variable in the sizeof the chest within the group, so that the tests ofsignificance between the different methods are nomeasure of significant differences due to themethod alone. In spite of this unfavorable typeof comparison, it will be seen that in the group ofabnormal subjects there is a statistically signifi-cant difference between the means of results byMethods Ia and IIb.

To obtain a comparison of the groups in whichonly the factor of difference of method is in-volved, a second table is presented (Table II),expressing only the relative values by each

605


TABLE II

Relative mean values of functional residual air by closedcircuit methods

NORMALSUBJECTS

Decreasing lung N2 method-IaIncreasing

Subject lung N2Christie Lassen et at. method-IIb

calculation calculation

J. D............ 1.10 1.00 0.96J. L.. 1.07 1.00 0.98A. C............ 1.09 1.00 1.02T. R.. . 1.26 1.00 1.02D. W.R. 1.14 1.00 0.83R. C. D......... 1.23 1.00 0.72

Mean .. . 1.15 1.00 0.92S.D ........... 0.087 0.133S.E, ........... 0.034 0.054

............... 4.4 1.5

SUBJECTS WITH PULMONARYEMPHYSEMA

M. K........... 1.24 1.00 0.72J. 0............ 1.18 1.00 0.59M. H........... 1.13 1.00 0.72J. F... 1.12 1.00 0.54M. A........... 1.37 1.00 0.64Ant. C.......... 1.08 1.00 0.88D. H........... 1.21 1.00 0.81J. C............ 1.10 1.00 0.82H. K........... 0.99 1.00 0.59F. H............ 1.05 1.00 0.64

Mean ........... 1.15 1.00 0.70S.D ........... 0.115 0.121S.E.m ........... 0.036 0.038t............ .. 4.2 7.9

method, arbitrarily setting the value by MethodIa as unity in each subject. In this comparisonit will be seen that the Christie calculation givessignificantly higher values in both groups. Con-sidered as a group, Methods Ia and IIb are notsignificantly different among the normals. Inthe abnormal group, the striking difference of thetwo methods is clearly shown.

Table III presents the more complete data on

four subjects studied thoroughly: one normalsubject with small residual air, one normal sub-ject with large chest who showed discrepanciesbetween results by the contrasting methods, andtwo subjects with pulmonary emphysema. Sucha comparison is more valuable than analysis ofgroups since the subjects were picked as strik-ingly abnormal cases and, also, the evaluation ofany method may depend on its applicability tothe extreme and unusual case.

In the case of J. L., a small normal subject,it is evident that the results by all the methodsusing alveolar measurements are not significantlydifferent. Even here, however, the Christie cal-culation is significantly higher than that usingalveolar measurements. It should also be noted,in this small subject, that there is much less vari-ability of results by the same method than in theother three subjects.

The tabulation on R. C. D. merely repeatsin statistical form the results on this subject

TABLE III

Functional residual air values by closed circuit methods, statistical analyses on individual subjects

J. L. (Normal) R. C. D. (Normal) M. H. (Emphysema) M. A. (Emphysema)

Num- Num- Num- Num-ber of ber of ber of ber ofdeter- Mean S.D. S.E.n deter- Mean S.D. S.E.w deter- Mean S.D. S.E.w deter- Mean S.D. S.E.u,mina- mina- mina- mina-tions tions tions tions

Method laChristie Calculation... 12 1420 105 30 5 3990 442 198 15 6060 821 212 7 7490 1740 660Lassen et al. Calculation 12 1320 108 31 5 3250 359 160 15 5360 748 193 7 5465 553 209

Method lb ............. 6 1290 48 35 5 4630 105 47 5 4560 373 167Method IIa ............ 8 1230 82 29 8 3865 368 130 10 3475 170 .54Method lIb ........|.15 1270 79 20 6 2330 221 90 4 3845 316 158 9 3320 196 65

Values compared I t

Christie Calculation vs.Lassen et al. Calculation 2.3 2.9 2.4 2.9

Ia vs. Ib.0.6 3.7 3.4Ila vs. IIb.1.1 0.1 1.8Ia vs. Ib .1.3 5.0 6.1 10.2Ib vs. Ilb ..... 0.5 4.9 6.3

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in Table I. It will be seen that the comparisonto show the effect of "oxygen storage" and also thecomparison to show the possible effect of poor mix-ing both give statistically significant differences.

The figures on M. A. and M. H. are not onlyan analysis of those in Table I, but also includefigures by Method Ib (which is essentially themodification of McMichael), and by Method IIa.The results by Methods Ia and lIb are widelydivergent, as is evident from inspection. A com-parison of the values by Ia against Ib, and by Ilaagainst Ilb will show how far the maintenance ofconstant volume corrects the error due to imper-fect intrapulmonary gas mixture. In these twosubjects the values by lb were significantly lowerthan by Ia, yet there is even more difference be-tween either of these and Method II. Further-more, in the case of "a" and "b" modifications ofMethod II, there is no significant difference.

The findings in these two subjects are char-acteristic of several others so studied. In no casedid the maintenance of constant volume removethe evidence for error due to malmixture withinthe lungs.

DISCUSSION

These data not only give us some informationon the limitations of the rebreathing methods formeasuring residual air, especially in severe casesof emphysema, but they also furnish an indirectmeasure of imperfect gas mixture in the lungs.The reversed Christie procedure, Method II, wasdevised in such a way that, if uniform mixturewithin the lungs occurred, the two methodsshould give identical results. Furthermore, theprobable direction of the error in case of imper-fect mixture was predicted in each method, as-suming that there was gas trapped in the lungsfrom previous breathing which did not contributeto the alveolar air measured.

The uniform evidence of unequal distributionin the emphysematous subjects is not surprising.It has long been evident that such might be thecase from the anatomical changes in the lungs ofsuch subjects. Analysis of gas obtained by di-rect puncture from large emphysematous bullaehas shown very high nitrogen values (17).Sonne's fractional analyses of an alveolar sampleshowed directly a marked variability. Roelsenrepeated the fractional alveolar analyses follow-ing a single breath of hydrogen and deduced from

the results that the mixture was even more im-perfect than was evident from the carbon dioxideand oxygen analyses alone. This latter findingwith the use of hydrogen would seem to give theclue to the reason why the factor of maldistribu-tion has been so rarely appreciated. The frac-tional analyses of alveolar air for carbon dioxideand oxygen give evidence of unequal distributiononly if the poorly aerated lung regions are rela-tively well perfused with blood. If in the courseof disease the blood circulation in those areas di-minishes parallel to the drop in aeration, then thealveolar samples may be uniform and the alveolarcarbon dioxide tension may correspond well tothat in the arterial blood. This correspondencebetween alveolar and arterial blood carbon di-oxide tensions has been an important piece ofevidence and has been interpreted to signify uni-formity of gas mixture within the lungs.

In spite of the previous evidence that gas mix-ture is slow in emphysematous lungs, it has beenassumed that the seven-minute period was ade-quate to overcome difficulties arising from thisslow mixture. It seems likely from our data thatthe factor of poor mixture in the lungs is an im-portant source of error not only after seven min-utes' breathing, but also after ten to twelve min-utes. It seems doubtful whether increasing thetime further would remove the difficulty. Fur-thermore, the magnitude of the discrepancies dueto poor mixture in our data seems to indicate thatthis factor is a major one, not only for the meas-urement of residual air, but probably also for thegeneral problem of the pulmonary disturbance.

The finding of a factor of imperfect distribu-tion in certain normal subjects was somewhatmore surprising. Sonne's work showed that itexisted, but not that it was as large as the datahere indicate. Possibly our method is sensitiveto detect small degrees of maldistribution.

It is evident that our data give no conclusiveevidence as to the true residual air value in thecases showing different results by the variousmethods. The residual air volume has been con-sidered an important index in emphysema of thedegree of disability, usually expressed in relation-ship to the vital capacity or the total capacity.It is possible in these cases that the residual airvalue, as measured by the Christie method, isnot a true volume measurement, but represents

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the true volume plus an added value due to thefactor of poor gas mixture. In order to prove

this, it would be necessary to have anothermethod for comparison which minimizes or elimi-nates the effects of mixing.

A detailed consideration of the rebreathingmethod has shown why, in cases of poor mixing,

the chances of true equilibrium between lungsand spirometer are not good. Even keeping thevolume constant as in McMichael's work or our

Method Ib, there is a constantly changing breath-ing mixture for the first few minutes of the re-

breathing. If the volume is diminishing, thechanges are more complicated and the inspiratorygas mixture is always changing. Furthermore,the size of the usual spirometer is such that thechange in alveolar nitrogen is usually 0.2 to 0.3atmosphere. In the course of calculation, sucha small change leads to a three- to five-fold mag-

nification of error in the residual air value.Thus, a method which would allow a uniform

inspiratory gas mixture and would utilize a maxi-mumalveolar change should offer greater likeli-hood of reaching a true measure of residual air.Such a method will be presented in Paper III ofthis series (18).

SUMMARYAND CONCLUSIONS

1. Modifications of the Christie method of re-

sidual air measurement are presented which (1)keep the spirometer volume constant, (2) reverse

the shift in nitrogen and therefore reverse thedirection of error due to unequal distributionwithin the lungs.

2. Resultsarepresentedusingthedifferentmod-ifications and the original method on six normaland ten subjects with pulmonary emphysema.

3. These results give agreement by all methodsin four normal subjects only, three of whomhadsmall residual air volume.

4. In the remainder of the normal subjects andall the subjects with emphysema, there are widediscrepancies between the results by the differentmethods. Keeping the spirometer volume con-

stant does not correct the discrepancies. Thesedata give positive evidence of unequal gas dis-tribution within the lungs.

BIBLIOGRAPHY1. Van Slyke, D. D., and Binger, C. A. L., The deter-

mination of lung volume without forced breathing.J. Exper. Med., 1923, 37, 457.

2. Anthony, A. J., Zur Methode der Spirometrie. Beit r.z. Klin. d. Tuberk., 1927, 67, 711.

3. Christie, R. V., The lung volume and its subdivisions.I. Methods of measurement. J. Clin. Invest., 1932,11, 1099.

4. Sendroy, J., Jr., Hiller, A., and Van Slyke, D. D.,Determination of lung volume by respiration ofoxygen without forced breathing. J. Exper. Med.,1932, 55, 361.

S. Hurtado, A., and Boller, C., Studies of total pulmonarycapacity and its subdivisions; normal, absolute andrelative values. J. Clin. Invest., 1933, 12, 793.

6. Lassen, H. C. A., Cournand, A., and Richards, D. W.,Jr., Distribution of respiratory gases in a closedbreathing circuit. I. In normal subjects. J. Clin.Invest., 1937, 16, 1. %

7. Anthony, A. J., Ueber das Verhalten neutraler Gasebei Atmung an einem geschlossenen System.Ztschr. f. d. ges. Exper. Med., 1938, 104, 623.

8. Kaltreider, N. L., Fray, W. W., and Hyde, H. V.,Effect of age on total pulmonary capacity and itssubdivisions. Am. Rev. Tuberc., 1938, 37, 662.

9. Herrald, F. J. C., and McMichael, J., Determinationof lung volume: simple constant volume modifica-tion of Christie's method. Proc. Roy. Soc., Lon-don, Series B, 1939, 126, 491.

10. Cournand, A., Lassen, H. C. A., and Richards, D. W.,Jr., Distribution of respiratory gases in a closedbreathing circuit. II. Pulmonary fibrosis and em-physema. J. Clin. Invest., 1937, 16, 9.

11. Nielsen, E., and Sonne, C., Die Zusammensetzung derAlveolarluft. Ztschr. f. d. ges. Exper. Med., 1932,85, 46.

12. Sonne, C., Der respiratorische Luftaustausch in denLungen. Ztschr. f. d. ges. Exper. Med., 1934, 9413.

13. Roelsen, E., Ueber die Verteilung der Inspirationsluftin der Alveolarluft. Acta Med. Scandina v., 1934Suppl. 59, 356.

14. Roelsen, E., Fractional analyses of alveolar air afterinspiration of hydrogen as a method for the deter-mination of the distribution of inspired air in thelungs. Acta Med. Scandinav., 1938, 95, 452.

15. Roelsen, E., The composition of the alveolar air in-vestigated by fractional sampling. Comparativeinvestigations on normal persons and patients withbronchial asthma and pulmonary emphysema.Acta Med. Scandinav., 1939, 98, 141.

16. Darling, R. C., Cournand, A., Mansfield, J. S., andRichards, D. W., Jr., Studies on the intrapulmonarymixture of gases. I. Nitrogen elimination fromblood and body tissues during high oxygen breath-ing. J. Clin. Invest., 1940, 19, 591.

17. Kaltreider, N. L., and Fray, W. W., Pathologicalphysiology of pulmonary cysts and emphysematousbullae. Am. J. M. Sc., 1939, 197, 62.

18. Darling, R. C., Cournand, A., and Richards, D. W., Jr.Studies on the intrapulmonary mixture of gases.III. An open circuit method for measuring residualair. J. Clin. Invest., 1940, 19, 609.

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Documents

ON (CLOSED...A. COURNAND, R. C. DARLING, J. S. MANSFIELD, AND D. W. RICHARDS, JR. lung contents are presumably measured and used in the calculation, contrasted with Sonne's studies