Alterations of Ventilation to Perfusion Ratios Distribution

Transcription

1 Journl of Clinicl Investigtion Vol. 44, No. 9, 1965 Altertions of Ventiltion to Perfusion Rtios Distribution Associted with Successive Clinicl Stges of Pulmonry Emphysem * CLAUDE LENFANT t AND WILLIAM R. PACE, JR. (From the Institute of Respirtory Physiology, Firlnd Sntorium, nd the Deprtments of Medicine nd Physiology, University of Wshington School of Medicine, Settle, Wsh.) Studies reported by Briscoe nd co-workers (1) nd Finley (2) hve demonstrted the blood gs bnormlities of ptients with pulmonry emphysem to be minly the result of impired distribution of the ventiltion to perfusion (VA/Q) rtios throughout the lung. Finley provided no informtion bout the differences in clinicl severity of his subjects, however, nd Briscoe nd co-workers pprently studied ptients representing only one stge of the disese ccording to the clssifiction of Bldwin, Cournnd, nd Richrds (3). Thus, neither study estblished the ctul nture of chnges in VA/Q distribution tht develop s the disese progresses. Unnswered is the question of whether there occurs n increse of rnge,' of dispersion, or of both. Yet it is importnt to know wht modifictions develop s the disese worsens, becuse knowledge of these progressive chnges my led to better understnding of the bsic physiologicl impirments occurring with ge (4, 5). This pper is report of experiments tht were mde in n ttempt to ssess the nture of the differences in VA/Q distribution present in three groups of subjects selected c- * Submitted for publiction September 1, 1964; ccepted June 7, This work ws supported by the Ntionl Institutes of Helth, grnts H-8465 nd H t Address requests for reprints to Dr. Clude Lenfnt, Institute of Respirtory Physiology, Firlnd Sntorium, 174 N.E. 15th St., Settle 55, Wsh. 1 As used in this discussion, the terms "over-ll," "rnge," "dispersion," nd "frequency distribution" re defined s follows: "over-ll" refers to the whole lung (e.g., VAT/QT is the over-ll VA/Q; "rnge" is the intervl between the highest nd the lowest figures; "dispersion" is the vrition in size occurring mong the vrious items constituting the series, nd "frequency distribution" is defined s n rrngement of numericl dt ccording to size. cording'to the clinicl severity of their pulmonry emphysem. Methods Subjects Twenty-two hospitlized ptients hve been studied. Upon physicl exmintion, they ll hd symptoms nd findings consistent with some degree of obstructive bronchopulmonry disese. All hd chronic coughs nd some shortness of breth. Some hd pulmonry fibrosis in ddition to emphysemtous chnges, nd most of them hd tuberculosis when they were studied, or hd hd this disese t some time in the pst. In this study the subjects were clssified into three groups on the bsis of the severity of their clinicl symptoms nd the impirment of spirometriclly mesured ventiltory function. Group I comprised six ptients who did not complin of shortness of breth t rest, but who becme dyspneic with moderte exertion nd hd mximl expirtory flow (MEF) rtes greter thn 18 L per minute. Wheres some of the subjects in this group hd numericl vlues for MEF, or mximl brething cpcities (MBC) tht were borderline or even norml, these ptients hd forced expirtory spirogrms tht demonstrted slowing of the expirtory flow in some portion of the trcing. Group II ws composed of nine ptients, ech with recurring symptoms while resting, nd ech suffering from enough dyspne to prevent ny prolonged physicl ctivity. The mximl brething cpcities of these ptients vried from 34 to 76 L per minute, with men vlue of 55; men MEF mesurement for this group ws 113 L per minute, nd ll but one member hd MEF vlues between 7 nd 12. Group III comprised seven ptients with crippling brethlessness, MBC between 13 nd 52 L per minute, nd MEF between 5 nd 1 L per minute. These ptients were confined to bed most of the dy nd cpble of only miniml physicl ctivity. The ges, body surfce res, nd vilble results of routine ventiltory testing for these ptients re recorded in Tble I. Progressive incpcity is ccompnied by corresponding increse in obstructive nd restrictive ventiltory defects. Procedure The dy before the experiment, the ptient received preliminry detiled explntion from the investigtors 1566

2 VENTILATION TO PERFUSION RATIOS IN EMPHYSEMA 1567 TABLE I Sttisticl nd bsic respirtory dt for ll subjects Body Comprison Mximl Comprison Mximl Subject surfce Vitl to predicted* brethingt to predicted* expirtory no. Age re cpcity vlue cpcity vlue flow Group I yers M2 L % L/min % L/min Ment Group II Men Group III Men f * The predicted vlues of vitl cpcity nd of mximl expirtory flow were estblished from the stndrd vlues, given in reference 6. t The mximl brething cpcity ws not vilble for ll the subjects of group I. T = stndrd devition. who would crry out the procedure. After n rteril puncture, the subject ws seted in comfortble chir. His nose ws occluded with nose clmp, nd rubber mouthpiece ws fitted into his mouth nd checked for leks. The mouthpiece ws connected to two-wy plstic vlve, hving 3-ml ded spce. The subject first inspired n rgon-free gs in which the frctionl concentrtions of 2 nd N2 were comprble to those in room ir. After n dpttion period of 1 minutes, the expired gs ws collected while smple of rteril blood ws being withdrwn. The inspired gs ws then chnged to mixture of 9% 2 nd 1% N2 with no rgon. The subject brethed this mixture for 11 to 15 minutes before smples of rteril blood nd expired gs were gin collected simultneously. The subject then resumed brething the gs mixture simulting room ir; the finl blood nd gs smples were simultneously collected 1 to 15 minutes lter, Throughout the entire procedure, the concentrtions of expired CO2 nd N2 t mouth level were continuously monitored with n infrred CO2 nlyzer nd nitrogen meter, both of which were clibrted with stndrd gs mixtures before nd fter ech experiment. The concentrtion of 2 t ny moment ws clculted s the difference between 1% nd the sum of the CO2 nd N2 concentrtions. Expirtory flow nd integrted volume were constntly monitored with Godrt pneumotchogrph. In some experiments the pressure t mouth level ws recorded during inspirtion nd expirtion in order to clculte the resistnce of the system. The resistnce never exceeded.2 cm H2 per L per second. Beckmn O2 nd Severinghus CO2 electrodes were used to mesure Po2 nd Pco2 of the collected smples of rteril blood nd expired gs. The smples were tested within less thn 5 minutes fter collection. A dely of 5 minutes could cuse pproximtely 2 mm Hg underestim-

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4 VENTILATION TO PERFUSION RATIOS IN EMPHYSEMA 1569 tion of rteril oxygen pressure (PO2) during room ir brething, nd bout 14 mm Hg lowering of 2 tension of the high FIo22 smples; the overestimtion of Pco2 resulting from this short wit would be insignificntly smll (7). The electrodes were clibrted with tonometered smples of blood immeditely before nd fter ech nlysis. All mesurements were mde t 37.5 C. A portion of ech blood smple ws kept nerobiclly until the end of the experiment, when it ws nlyzed for PN2 with Beckmn CG2A gs chromtogrph. The nitrogen concentrtion in mixed expired smple ws clculted s the difference between 1% nd the sum of the 2 nd CO2 concentrtions. For the determintion of lveolr-rteril differences (A-D) in gs tensions, nd for plotting the wshout nd wshin, the concentrtions of end tidl expired gs were ssumed to represent the gs concentrtions in the lveoli. The mount of N2 eliminted from the tissues while the subject brethed 9% 2 ws determined ccording to the dt of Robertson, Siri, nd Jones (8), corrected for the subject's weight. Clcultions Totl lveolr ventiltion. Alveolr ventiltion (VA) ws determined s the product of the totl expired ventiltion (VE) nd the rtio of CO2 concentrtion in expired gs to tht in end tidl gs, ccording to the eqution: VA = VE(FECo2/FACO2). The results in Tble II re expressed in conditions BTPS.3 Wshout nd wshin curves. The method originlly described by Briscoe nd Cournnd (9) ws used in slightly modified form. On semilogrithmic pper, time ws expressed long the liner bsciss, nd the vlues of lveolr N2 concentrtion minus lveolr N2 concentrtion t infinity were expressed long the logrithmic ordinte ccording to the eqution: (FAt- FA,)/(FAo - FA,) = e-kt, where FA, FAt, nd FAX re, respectively, the mesured N2 concentrtions before the study, t time t during the study, nd fter infinite time, nd k is equl to the rtio of lveolr ventiltion to lung volume (VA/VL). The wshout nd wshin curves for ech subject were nlyzed into three exponentil components, corresponding to the lung comprtments hving different ventiltory rtes. The component representing the comprtment hving the poorest ventiltion ws esily derived in the usul mnner. Occsionl difficulty ws encountered in differentiting the best ventilted nd the intermedite comprtments, principlly with curves for subjects from group I. The ventiltion of ech comprtment ws clculted from the eqution: VAi/VA FAiO/FAT, nd the lveolr = ventiltion per unit of lung volume from the eqution: VAi/VLi = M/2.3. In these equtions, VAi nd VA re, respectively, the lveolr ventiltion per minute of ny comprtment nd of the whole lung; VLi is the volume in milliliters of tht comprtment, FAi is the nitrogen concentrtion in the sme comprtment t time zero; FAT is 2 Frctionl concentrtion of 2 in inspired gs. I Body temperture, pressure, sturted with wter. the mixed lveolr nitrogen concentrtion; M is the number of units of time in which single exponentil function flls to X of ny previous vlue, nd 2.3 is log. 1. The volume of ech comprtment ws determined from these equtions, nd the totl lung volume (VL) ws computed s the sum of the volumes of ll comprtments (VLi + - -VL.). For simplicity the three comprtments will be designted herefter by the numbers 1, 2, nd 3, referring, respectively, to the most ventilted, the intermeditely ventilted, nd'the lest ventilted comprtments, in reltion to their volumes. Determintion of Q. Assessment of the distribution of blood flow within the three comprtments required severl ssumptions, ech of which will be discussed in turn. ) VA/Q is ssumed to be the sme throughout (i.e., not distributed within) ech of the comprtments identified from the N2 wshout dt. This ssumption is necessry if the number of comprtments is to be kept within mngeble limits. b) VA/Q is ssumed to be lower in comprtments with less ventiltion per unit volume. In ny cse where this is not true, our interprettion is not vlid. In the ptients studied in these experiments, however, the wshout dt indicte tht those prts of the lung with lowest VA/VL rtios constitute significntly lrge frction of the totl lung volume, ccounting for 71% of the functionl residul cpcity (FRC) in group III nd 46% in group I. Our ssumption, then, is tht such lrge prt of the lung must be perfused by substntil portion of the crdic output. Hence, since its ventiltion is so much less thn tht of other prts of the lung, this lrger comprtment must hve the lowest VA/Q. Although this ssumption will be reviewed in detil in the Discussion, it must be kept in mind tht these comprtments, so defined, hve no sptil significnce whtsoever. The technique used in our experiments considers units with the sme functionl properties from ll over the lung s grouped together in ech comprtment. The findings, therefore, of regionl function studies (1-11), which, by contrst, group together in vrible proportions units with different chrcteristics, do not refute our ssumption. c) A-DN2 is considered s being determined exclusively by the group of low VA/Q units. This ssumption is not entirely ccurte, since the better ventilted spces lso mke smll contribution; where the ssumption is invlid, the resulting error would minimize the ventiltion to perfusion rtios of the slow spces. d) A-Dco2 is ssumed to be determined exclusively by the group of units with the highest VA/Q. If this postulte is not vlid, the estimtes of the VA/Q in the better ventilted spces re mximl vlues. e) Totl blood flow is ssumed to be S L per minute, nd the sme in ll subjects. Devitions from this estimte by 3% in either direction were found to cuse no pprecible difference in results from this system of interprettion. On the bsis of these ssumptions, the vlue of Q ws obtined by determining the blood flow necessry to produce the mesured A-DN2, when the lveolr ventiltion ws equl to VA3, s derived from the N2 wshout curve.

5 157 CLAUDE LENFANT AND WILLIAM R. PACE, JR. TABLE III Ventiltion* Subject VA/VAT VL/VLT VA/VL no. Comprtment VAT VLT VAT/VLT mi/min % ml % ml/ml/ m/mil/min min Group I 1 4, , , , , , , , , , , , Men 5, , , Group II 7 5, , , , , , , , , , , , , , , , , , Men 5, , , Group III 16 5, , , , , , , , , , , , , , Men 4, , p I-II NS.2.5 NS.1 NS.1 NS.5 NS NS.1 p II-III.1 NS.1 NS NS NS.2 p I-III NS NS.5.1 * Ventiltion (VA), lung volume (VL), nd ventiltion to lung volume rtio (VA/VL) for the totl lung (T), nd for ech Comprtment. It is obvious from Eqution 1, Q A-DN2 QT PA3N2 - PAN2' 1 tht Q3/QT will be smllest if there is no ctive ventiltion, since then PA3N2 would be s high s it cn possibly become. On the other hnd, PAIN2 decreses s ventiltion increses, so tht Q3/QT increses s function of the incresing ventiltion. It is not possible to clculte PAIN2 directly from the ctul ventiltion of the low VA/Q units, becuse mesurement of V2 is required for the lveolr ventiltion eqution. Therefore, the Q3 corresponding to VA3 ws clculted by somewht more lborious process. First, the vlue of Q3/QT t n rbitrrily selected vlue for PA3N2 ws determined by substituting the ltter nd the known vlues of A-DN2 nd PAN2 in Eqution 1. Then, the difference in 2 content between the mixed venous blood nd the cpillry blood of VL3 ws estimted from the 2-C2 digrm, in order to determine the 2 consumption of this prticulr group of units. With this informtion, vlue for VAs tht would correspond to the rbitrry vlue of PAIN2 could be clculted from the lveolr ir eqution. Repeting these steps with series of decresing vlues for PA3N2 provided plot of QO versus VA3, from which we could select vlue of Q3 corresponding to the ctul vlue of VA3. By somewht simpler process, Q1 ws clculted from A-DcO2. The prtil pressure of CO2 in VL1 (PAiCO2) ws clculted ccording to Eqution 2, VA1 A-DCO2 [2] VAT -PcO2 - ACO2 The CO2 content of the cpillry blood from comprtment 1 ws determined from the 2-CO2 digrm, on the ssumption tht the blood from this comprtment would be fully sturted with 2. Then Q' ws clculted from the eqution, Q1 = VA1 X PAICo2/.863(CVCo2 - ClCO2).

6 VENTILATION TO PERFUSION RATIOS IN EMPHYSEMA 1571 (CvCo2 = venous concentrtion of C2; C'C2 = rteril concentrtion of CO2 in comprtment 1.) Blood flow to comprtment 2 ws ssumed to be the difference between the totl blood flow nd the sum of perfusion of the other two comprtments: Q2 = QT -(Q + Q). Results Blood gses (Tble II). Significnt differences in men vlues for Po2 nd Pco2 for the three groups occurred when the subjects were brething the mixture simulting room ir. Although not s significnt, similr differences were observed between the men vlues for A-DO2, A-Dco2, nd A-DN2. After the chnge to 9% 2, the A-D incresed for ll gses, s would be expected. The mgnitude of this increse seemed to be closely relted to the size of A-D in the first phse of the experiment. Therefore, significnt differences in the men vlues for A-DO2, A-DcO2, nd A-DN2 persisted. Alveolr ventiltion. The vlues for the totl lveolr ventiltion listed in the first column of Tble III re mens for the lveolr ventiltion derived for the smpling period before the beginning nd t the end of the nitrogen wshout. In ll subjects, the ctul ventiltion vried throughout the wshout. Consequently, in view of the effect of ventiltion on the N2 clernce curve nd the slope of the three components derived from it, the men vlue for ventiltion ws felt to be tht most suitble for deriving other dt. The men vlues of VAT for groups I nd II were identicl, wheres this vlue ws significntly lower in group I I I, which consisted of hypercrbic ptients. Ventiltion ws unevenly distributed to the three comprtments in ll subjects. In ll three groups, comprtment 3 received the lowest proportion of VAT, lthough this frction ws highest for group III nd lowest for group I. Comprtments 1 nd 2 together lwys received the greter shre of ventiltion. In group I subjects, however, the ventiltion of comprtment 2 ws greter thn tht of comprtment 1. By contrst, ptients in groups II nd III hd more ventiltion of comprtment 1 thn of comprtment 2. Lung volume. Tble III shows noteworthy increse in totl lung volumes of ptients, progressing from group I through group III. Chnge in these vlues is pprent between ech group nd the next, in contrst to lveolr ventiltion, for which the men vlues of groups I nd II were identicl. The poorly ventilted comprtment ws the lrgest of the three in ll subjects, nd its size incresed progressively from group I through group III. Comprtment 2 ws the next lrgest in size in ll groups, but its size progressively decresed from groups I through III, corresponding to the increse in volume of comprtment 3. Comprtment 1 ws the smllest in ll three groups, nd its proportionl reltionship to the totl lung volume ws the sme in ll groups. Its bsolute size, however, becme progressively greter from group I through group III, in prllel with the increse in totl lung volume. These reltionships explin the prdoxicl distribution of VA to the different comprtments in the subjects of the three different ctegories, nd lso demonstrte the necessity for considering VA in reltion to VL. Turnover rte. The lveolr turnover rte for the whole lung ws lower by significnt mount for ech successive group from I through III. In group II this decrese ws function of the increse in lung volume. Between groups II nd III, chnges in VA s well s in VL were in the direction of leding to lower VA/VL. In ll groups, the lveolr units in comprtment 2 hd nerly norml turnover rte. Furthermore, in groups I nd II, the turnover rte in comprtment 2 (VA2/VL2) ws similr to tht of the whole lung (VAT/VLT). The discrepncy between VA2/VL2 nd VAT/VLT in group III resulted from n excessively lrge number of poorly ventilted units in these ptients. The significnce of this fctor will be discussed lter. The turnover rte of comprtment 3, which ws the lowest in ll three groups, decresed progressively, lthough modertely, from group I through group III. The mount of this decrese from one group to the next ws lessened, however, by the progressive ugmenttion of the comprtmentl ventiltion (VA3), which occurred even though the totl ventiltion (VAT) diminished progressively. The turnover rtes of comprtment 1 were not significntly different in the three groups.

7 1572 CLAUDE LENFANT AND WILLIAM R. PACE, JR. TABLE IV Perfusion* Subject Q/QT Q7VL VA/Q no. Comprtment QT/VLT VAT/QT %, ml/ml/min mi/milti/l /nl//ml/,inin ml/,nl /miz Group I Men Group II Men ( ( Group III Men or p I-II NS NS NS NS NS NS NS NS p II-III NS NS NS NS.1 NS NS.1 p I-III NS NS NS NS.5 * Perfusion (Q), perfusion to lung volume rtio (Q/VL), nd ventiltion to perfusion rtio (VA/Q) for the totl lung (T), nd for ech comprtment. Blood flow. Since the totl blood flow ws ssumed to be the sme in ll subjects, only the distribution of Q to the different comprtments is shown in Tble IV. Blood flow to comprtment 1 did not differ significntly from one group to nother. The men vlues for comprtment 2, however, progressively decresed while those for comprtment 3 correspondingly incresed. This increse in Q of comprtment 3 is similr to the increse in VA to tht comprtment. As in the cse of VA, however, these vritions in Q must be considered in reltion to the volumes of the different comprtments. Rtio of perfusion to lung volume. The fourth column in Tble IV shows QT/VLT decresing progressively from group I through group III. This is the direction in which this rtio would be expected to chnge, corresponding to the progressive increse in VLT. The Q/VL in comprtments 2 nd 3 tended to decrese from group I to group II I. The two components of the rtio, however, chnged in dissimilr fshion in the different comprtments. In comprtment 3, both Q nd VL incresed progressively from group I through group III, but the increse of VL ws greter thn tht of Q. In comprtment 2, Q decresed progressively, s did VL2, but the ltter decrese ws less rpid. There ws prcticlly no difference in Q1/VL1 in the successive groups, in spite of the increse in VL1. Ventiltion to perfusion rtio. The verge over-ll VA/Q decresed between groups I nd

8 VENTILATION TO PERFUSION RATIOS IN EMPHYSEMA I I I. As indicted in Tble IV, the VA/Q differed in the three comprtments. In ll three groups, VAT/QT ws higher thn either VA2/Q2 or VA3/Q3. Between groups, there were only insignificnt chnges in VA1/Q1 nd VA2/Q2. Discussion Comprison of Tbles I nd II shows good correltion between the degree of ventiltory impirment nd the disturbnces of Po2 nd Pco2 in the rteril blood. This grees with the generlly ccepted concept tht disordered blood gs tensions re, in this type of ptient, reflection of the impirment of the ventiltion to perfusion rtios distribution throughout the lung. To estimte whether the chnges in the frequency distribution of VA/Q resulted from n increse of rnge, or of dispersion, or of both, it ws necessry to divide the lung into mngeble number of uniform comprtments nd then to derive the comprtmentl ventiltion nd the comprtmentl perfusion. Most of these dt depend lrgely on the rte of nitrogen wshout, which ws estimted from the end tidl vlues of nitrogen. Prticulrly in disesed subjects, these vlues for N2 my not represent the mixed expired lveolr gs. Thus, s pointed out by Briscoe nd ssocites (1, 9), lthough the slope of the stright line into which the semilogrithmic plot is nlyzed is not ffected by which gs concentrtion is plotted (mixed expired, end tidl, or forced expirtory), the intercept of those stright lines with the ordinte, nd their derivtives, re. Consequently, the vlues of VA/VL given for ech comprtment in Tble II, which depend only on the slope of the line, re relible. On the other hnd, the use of end tidl vlues leds to overestimtion of VA3/VAT, nd to underestimtion of VAl/VAT nd VA2/VAT. For this reson, the derived vlues VA1, VA2, VA3, VL1/VLT, VL2/VLT, VL3/VLT, nd VLT re lso in error. Yet no effort ws mde to correct these determintions, whose vlues, s they stnd, led to minimizing the dispersion of VA/Q distribution. Although VA/VL should not be influenced by the nture of the gs concentrtion used in the semilogrithmic plot, other fctors might hve ffected our findings. Torres, Hung, nd Lyons hve reported n lmost instntneous decrese 1573 of lung complince, ccompnied by incresed venous dmixture when pure 2 is inspired (12). These findings nd Briscoe nd Cournnd's observtion (13) of incresed perfusion to the poorly ventilted comprtment during 2 brething suggest tht some lveoli collpse throughout the period of oxygen brething. If N2 wshin follows the N2 wshout, chnge in the slope for comprtment 3 should revel ny increse tht occurred in the number of closed lveoli when the subject begn brething 9% 2. Qudrnt D of Figure 1 compres the vlues of VA/VL in ech comprtment, mesured from the N2 wshout nd wshin plot. Although there is n importnt scttering, no significnt difference could be estimted between the two methods. These findings re consistent with results obtined by Briscoe nd ssocites (1), plotted in qudrnt C. The regression lines between the two sets of dt re not different, just s there is no vrince in qudrnts A nd B showing the sme kinds of dt obtined from ptients nd norml subjects brething n 2 concentrtion no different from tht of room ir (9). This evidence, in ddition to other dt (14), strongly refutes the concept tht high 2 concentrtion in the inspired gs cuses n immedite chnge in the number of closed or collpsed lveoli. The procedure used to clculte blood flow ws bsed on the severl postultes stted previously nd lso on the use of the end tidl vlues of the expired gses s the lveolr gses. The cse ginst such method is strong in ptients with disese likely to cuse or increse sequentil emptying of the lung. As shown by Mrshll, Btes, nd Christie (15), during the course of n expirtion there is n importnt increse of CO2 nd decrese of 2 in the expired gses. In our subjects, who were quietly brething, in opposition to forced or prolonged expirtion, monitoring of the expired CO2 nd N2 lso reveled consistently scending slope for both. The rtes of chnge were more pronounced in ptients of group III, compred to those of ptients in groups I nd II. However, the finl vlue in CO2 nd 2, s clculted from the difference between the totl pressure nd the sum of Pco2 nd PN2, remined within resonble limits. The mens for the subjects of groups

9 1574 CLAUDE LENFANT AND WILLIAM R. PACE, JR I VA/VL A / / WASHIN He VA/VL /. / WASHOUT He / I..I IA I I I A. VA/VL D / - ** 8.' 1 49, WASHOUT N2 /1 / 8 / / so* 6.,4;?. A/ 'VL WASHIN N2 t. I I I*,l I A I I VA/VL WASHiN He B / / o / /"%. / *e * / VA/VL WASHOUT He I. I.I.. I. _ VA/VL ~ / *t I C WASHOUT N2 VA/VL O / j -/ / WASHIN N2 1 I. I I.1... I I... / I FIG. 1. COMPARISON OF TURNOVER RATES (VA/VL) IN ALL COMPARTMENTS DETERMINED FROM THE WASHOUT CURVE WITH THAT DETERMINED FROM THE WASHIN CURVE IN THE PRESENT AND IN OTHER STUDIES. Qudrnts A (normls) nd B (ptients) show the dt of reference 8, qudrnt C corresponds to reference 1, nd qudrnt D represents the present series. The slopes of the regression lines re 1.3 in A,.99 in B,.85 in C, nd.93 in D. There is no significnt difference between those vlues nd between ech nd the line of identity represented by the dshed line in ech qudrnt. I, II, nd III were, respectively, for Pco2, 35.4, 34.5, nd 41.8 mm Hg, nd for Po2, 13.1, 14.9, nd 1.6 mm Hg. Although we recognize tht the choice of the end tidl smple s representtive of the lveolr gs is rbitrry, we feel tht, in these ptients, it my hve been not gretly different from the mixed lveolr gs. Also, it must be remembered tht, in our computtion, the lveolr gs tensions re used only in determining the lveolr-rteril differences. Since the chnges in perfusion mong the three groups of subjects result from the chnges in the A-DCO2 nd A-DN2, the role of the lveolr vlues must be estblished in comprison to the role of the rteril vlues. It is evident from Tble I I tht most of the chnges in A-D from group I to group III come from the differences in the rteril blood gs tensions mong the three groups, rther thn from the vritions in the end tidl vlues. Yet, insofr s the method used to select the lveolr gs tension is, to certin extent, incorrect, it follows tht PACO2 is overestimted, nd A-DcO2 is underestimted. This leds to miniml VA/Q in the better ventilted comprtment in reltion to its volume. Similrly, PAN2 is overestimted nd A-DN2 is underestimted, resulting in mximl vlue of VA/Q in the third comprtment.

10 VENTILATION TO PERFUSION RATIOS IN EMPHYSEMA The ssumption tht the comprtmentl distribution of VA/Q prllels the distribution of VA/VL is prtly substntited by the demonstrtion tht, when the lung is nlyzed into two comprtments, the comprtment with the lower turnover rte (VA/VL) lso hs the lower VA/Q (1, 2). The ssumption here, then, is tht VA/Q will continue to vry in the sme direction s VA/VL,. when the lung is further subdivided into three comprtments. Actully, some of our dt corroborte this hypothesis. If the units with the lowest VA/VL re lso the units with lowest VA/Q, VA3/VL3 should be relted to the rteril gs tension of 2, N2, or C2, since the lveoli with low VA/Q contribute the most to the ltertion of gs tensions of the mixed rteril blood. Figure 2 demonstrtes such reltionship between PO2 nd VA3/VL3, indicting tht those lung units with the poorest ventiltion in reltion to volume must lso hve the lowest VA/Q. Thus, evidence seems to confirm the ssumption tht comprtment 3, being the sme s the 1575 second comprtment described in the work of others, hs the lowest vlues for both VA/VL nd VA/Q. Somewht greter difficulty is encountered, however, in ttempting to corroborte the hypothesis tht, since VA1/VL1 > VA2/VL2, the reltionship VA1/Q1 > VA2/Q2 must lso be true. One might hope to demonstrte the existence of reltionship similr to tht between the rteril gs tension nd VA3/VL3 between the 8. P2 (mmhg) lveolr gs prtil pressures nd VA1/VL1, if comprtment 1, which hd the highest ventiltion to lung volume rtio, lso hd the lowest Q/VL. It would seem, from the shpe of VA/Q line plotted on the 2-CO2 digrm, tht the PACO, would be the lveolr gs prtil pressure to consider. Plotting VA1/VL1 ginst PAcO2 filed to significntly demonstrte such reltionship, however, nd plot of PACo, versus VA2/VL2 ws eqully inconclusive. This filure does not negte the hypothesis, however, since the vlues of VA1/VL1 in the three groups of sub-,- -_ ,, /.2 /I / /i / / /.3 -A L O.1 VA3/VL3 o o hypoxi hypoxi, dyspne hypoxi,dyspne, hypercpni (ml/r/ml).4.5 FIG. 2. RELATIONSHIP BETWEEN OXYGEN PRESSURE IN THE MIXED ARTERIAL BLOOD (PO2) AND THE TURNOVER RATE OF COMPARTMENT 3 (VA3/VL,3). The blck symbols represent the men of ech group. The dshed line is the best fitted line.

11 1576 jects my hve been too close together to permit grphic demonstrtion of such reltionship. Probbly the best support for the belief tht the units with the highest VA/Q units occur in comprtment 1 is the following resoning. The existence of bnormlly high A-DCO2 mkes it necessry to ssume tht, in these subjects, the scttering of Pco2 throughout the whole lung is greter thn norml, nd tht, therefore, there re units in their lungs with VA/Q tht is higher thn norml. The proportion of units with this high VA/Q must be reltively quite smll, however; otherwise, CO2 elimintion would be more efficient thn it is, becuse more blood would be flowing through better ventilted units. Thus, it seems most unlikely tht the units with the highest VA/Q occur in comprtment 2, which is lrger thn comprtment 1. Other investigtors who studied the reltionship between VA/Q nd VA/VL in the ntomicl divisions of the lung hve found high VA/Q nd low VA/VL in the upper lobe nd low VA/Q nd high VA/VL in the lower lobe (16, 17). These results might pper to weken our ssumption regrding the prllel distribution of VA/Q nd VA/VL to the comprtment, nd lso to contrst with the dt we used to corroborte it (1, 2). The resons for such discrepncy lie in the differences in the pproches; functionlly defined comprtment of ny orgn contining mny units does not necessrily refer to n ntomicl grouping of those units. With models it is possible to show tht this prdoxicl disgreement between the ntomiclly nd functionlly defined divisions of the lung depends upon the respective volume of ech lobe, the bsolute ventiltion of ech lobe, nd the fct tht the lobes re not uniform but contin both low nd high VA/Q units in different proportions. Thus the contrdiction in these findings is ctully only pprent, nd the two concepts cn be true t the sme time. The ssumptions regrding the types of VA/Q units cusing A-D for N2 nd CO2 hve two implictions tht my be questioned. First it is implied tht PN2 is the sme in ll units hving VA/Q higher thn, or equl to, the men VA/Q, wheres Pco2 is identicl in ll lveoli hving VA/Q lower thn, or equl to, the men VA/Q. Only under such conditions could A-DN2 result CLAUDE LENFANT AND WILLIAM R. PACE, JR. entirely from the low VA/Q units, nd A-DCO2 be cused exclusively by the high VA/Q units. As is evident from Rhn nd Frhi's discussion (18), this is not exctly the cse, lthough it cn be shown tht A-DN2 reflects primrily the presence of lveoli with low VA/Q rtios, wheres A-DCo2 describes lveoli with high VA/Q rtios. The second impliction is tht VA/Q of the middle comprtment (VL2) is not different from the men VA/Q, nd, therefore, does not contribute to rteriolveolr differences. This postultion, too, my not be entirely correct. The middle comprtment is not bsolutely uniform nd, consequently, must contribute to some extent to the A-D. Insofr s this postulte is incorrect, Q will be overestimted in VL1 nd VL3, nd underestimted in VL2. However, such n error tends to minimize, rther thn exggerte, the physiologiclly significnt findings of this study. Finlly, it ws ssumed tht the totl blood flow for ll subjects ws identicl nd lso tht it ws not ffected by the severity of the disese. The choice of 5 L per minute is obviously rbitrry, but this is n dmissble figure, since no subject hd signs of circultory or crdic filure t the time of the experiment. Actully, in the method of computtion used, differences in totl blood flow would not gretly ffect its distribution throughout the three lung comprtments, nor would it mrkedly chnge the increse in dispersion of Q from group I to group III. On the other hnd, the vlues of Q/VL nd VA/Q would be ffected, since they re clculted from the bsolute vlues of Q. If totl blood flow were higher thn 5 L per minute, Q/VL would be higher nd VA/Q would be lower thn clculted. A lower thn estimted blood flow would hve the opposite effects. It is not cler from the literture whether there is ny considerble chnge in blood flow in emphysemtous ptients before crdic decompenstion. Some published dt (19, 2) indicte decrese in crdic output, nother study (21) indictes no differences from norml, nd third group of dt (22, 23) indictes slight increse. In ny event the selected condition, no chnge in Q, hs the effect of minimizing the vritions in function within the lung. In ddition, it cn be redily shown tht ny vrition of Q not

12 VENTILATION TO PERFUSION RATIOS IN EMPHYSEMA 1577 TABLE V Comprison of present dt for group III with vlues clculted in other studies No. of lung comprt- Rnge* Author nd reference no. ments VL1 VL2 VL3 VAi/Q1 VA,/Q2 VAS/Q3 VA/Q Briscoe nd ssocites (1) Finley (2)t Klocke nd Frhi (24) 2.18 Briscoe nd Cournnd (13)t 2.25 Group III, present experiments * Rnge in VA/Q is expressed by the difference between VAI/Q, nd VA3/Q3. t The results for VA/Q re reltive vlues (% VA/% Q). t Results of the urinry nitrogen method. exceeding 3% will not invlidte the finl conclusions. Tble V lists the dt vilble in the literture relted to VA/Q in two comprtment representtion of the lung; these vlues re, wherever possible, correlted with the size of the comprtment. The men vlues for group III in the present study re included. This group lone ws selected, becuse these subjects hd symptomtology tht compred with tht of the ptients in the other reports. To mke comprison esier, our results hve been tbulted twice; they were nlyzed into both two nd three comprtments. On the bsis of the two comprtment system, the rnge nd bsolute vlues of VA/Q in the vrious studies re remrkbly similr. Our three comprtment representtion differs gretly, however, becuse of the discrepncy in the mgnitude of the high VA/Q units. This difference demonstrtes the importnce of dividing the lung into s mny comprtments s possible in ttempting to estimte ccurtely the functions of vrious prts of the lung. This incresed subdivision becomes especilly necessry if subjects with different clinicl stges of emphysem re to be compred. As shown in Tble II, deepening hypoxi nd hypercpni develop s emphysem worsens. Such disturbnces probbly result from severl different mechnisms. Tble IV shows tht, with incresing severity of disese, there is lowering of the over-ll VA/Q nd slight increse of the rnge of VA/Q. The chnge in over-ll VA/Q is ctully miniml nd my be explined s direct consequence of the hypoventiltion resulting from progressive obstruction of the irwys. A lowering in the over-ll VA/Q cn explin hypoxi nd eventully hypercrbi, but certinly not the existence of A-D if the VA/Q, regrdless of its bsolute vlue, is uniform throughout the lung. Therefore, n estimte of the lveolr nd rteril concentrtions of gs is importnt in the determintion of the scttering of VA/Q in the lung. The rnge of VA/Q incresed only between groups II nd III; this chnge resulted from decrese in VA/Q in comprtment 3 nd tendency for VA/Q in comprtment 1 to increse in those ptients with most dvnced disese. As result, the intervl between the highest nd the lowest VA/Q is twice s high in group III s in the first two groups of ptients. Undoubtedly, these chnges contribute in prt to the production of hypoxi nd hypercrbi nd prtly explin the lveolr-rteril differences in 2, C2, nd N2. There must be some further cuse for the A-D, however, since hypoxi deepened nd the A-D incresed between groups I nd II without ny demonstrble chnge in rnge of VA/Q. Furthermore, it cn be shown tht the moderte increse in vrince of VA/Q occurring in group III does not ccount entirely for the ugmenttion in the size of the A-D. These modifictions in the sizes of the different groups of lung units occurring during the course of the disese (Tble III) would indicte tht, with progression of the clinicl disorder, there is n initil increse in the number of low VA/Q units, which is followed by further increse in size of the low VA/Q comprtment nd simultneous lowering of VA3/Q3. Some-

13 1578 CLAUDE LENFANT AND WILLIAM R. PACE, JR GROUP 11 VLx VLT , VA,/ t.l ~~~.5 i.. FIG. 3. SCHEMATIC REPRESENTATION OF THE FRE- QUENCY DISTRIBUTION CURVE IN THE THREE GROUPS OF SUBJECTS. 1, 2, nd 3 refer to the three comprtments, nd VLX/VLT indictes the frction of lung volume of ech comprtment. The verticl rrow represents the over-ll men. wht comprble chnges occurred in the group of high VA/Q units but were not s pprent, becuse this comprtment is much smller. Its bsolute volume incresed, however, between ech ptient group, even though its VA/Q incresed only between groups II nd III. Two chnges in the frequency distribution curve of VA/Q occurred, in ddition to the increse in rnge. First, the shpe of the curve ws ffected; the skewness incresed, becuse more units were scttered wy from the men in both directions. As result, the dispersion lso incresed (Figure 3). Although the rnge of VA/Q is much lrger in our experiments thn it ws in those done by Briscoe nd ssocites (1), reltive compensting underperfusion of the poorly ventilted group of units ppered in our subjects s well s theirs. As pointed out by these uthors, this fctor is n importnt mens of mintining the VA/Q dispersion within reltively nrrow limits, ti thereby preventing further desturtion of rteril blood. This underperfusion occurs becuse the increse in size of comprtment 3 s the disese progresses is reltively greter thn the increse in blood flow to these poorly ventilted units. Obviously, greter perfusion of this comprtment would result in lower VA/Q, nd, in turn, lower Po2 nd higher Pco2 in the cpillry blood leving these units. This stte would result in n increse in both hypoxi nd the A-Do2. An overventilted, or high VA/Q, comprtment need not be present to explin the A-D for 2 nd N2, since most of the vrince in Po2 ppers between the normlly ventilted second nd poorly ventilted third comprtments. The ddition of the first, or highly ventilted, comprtment to the comprtmentl nlysis cuses only moderte increse in the rnge of Po2 nd PN2. Considertion of the reltionship between the different fctors leding to hypoxi mkes it pprent tht the reltive mount of perfusion to poorly ventilted comprtment is s importnt s its VA/Q. This sitution is somewht nlogous to the conditions ssocited with hypoxi resulting from true ntomicl shunt; the sme level of unsturtion of the mixed rteril blood cn be ttined with lrge shunt of modertely unsturted blood s with smller shunt of more desturted blood. A similr mechnism is involved in hypercrbi nd the A-DCO2. Figure 4 shows tht, between groups II nd III, the developing hypoventiltion ws ssocited with n incresed Pco2 in lveolr gs, nd, consequently, lso in the mixed rteril blood, since the over-ll VA/Q hd decresed. However, the incresed number of very low VA/Q units obviously resulted in n increse in the reltive mount of blood from these units being dded to the mixed rteril blood, thereby lso contributing to the elevtion of Pco2. The importnce of this fctor is borne out by the significnt increse in PcO2 between groups I nd II, even though the subjects in these groups hd the sme ventiltion. A difference between PAcO2 nd Pco2 cn be present only if some lveolr units hve Pco2 tht differs considerbly from tht of the rest of the lung; there is no other conceivble mechnism tht would produce n A-DCO2. The ctul Pco2

14 VENTILATION TO PERFUSION RATIOS IN EMPHYSEMA P 4 z EE VC2 ml STPD \ \ \ \ o h ypoxi & hypoxidyspne. hypoxi,dyspnehypercrb W C.) \ \ A\ k i ll \ 3 \ \ ' \STPSL \^\' \ ~~~VA \ N" LTPS FIG. 4. RELATIONSHIP BETWEEN MIXED ALVEOLAR CO2 PRESSURE (PACo2) AND TOTAL AL- VEOLAR VENTILATION (VA). The dshed lines re isolines for vrious rtes of CO2 elimintion. They were clculted with the eqution VA = Vco2 X.863/PAcO2. Vco2 = volume of CO2 per unit time; STPD = stndrd temperture, pressure, dry; BTPS = body temperture, pressure, sturted with wter. The blck symbols represent the men of ech group. is determined by the decrese in effective lveolr ventiltion nd by the rte of blood flow to the low VA/Q group of units, but the A-DCo2 hs to be produced by group of high VA/Q units tht cuse PAcO2 not to increse s much s Pco2. If the VA/Q in these units hd not been t the sme high level in groups II nd III, nd if the number of those units hd not been lrger in group III, the A-Dco2 could not hve incresed s gretly s it did, becuse there would hve been greter increse in PAcO2. As shown previously (25), the two fctors relted to the vlue of the difference between A-DO2 nd the sum of A-DcO2 + A-DN2 re the true ntomicl shunt, nd the effect of the 2 dissocition curve. While subjects brethe room ir, the effect of the shunt component on this vlue is smll; the effect of the dissocition curve is more importnt. The reverse is true for high Fi2. The bsence of ny very significnt difference in the vlues of A-Do2- (A-Dco2 + A-DN2) mong subjects of ll three groups suggests tht the size of the ntomicl shunt ws probbly the sme in ll. There probbly ws no importnt increse in the rnge of VA/Q, since chnge would hve occurred only if the effect of the 2 dissocition curve hd incresed. The increse in A-Do2 nd A-DN2 upon chnging from ir to 2 brething ws not unexpected, since it ws due primrily to the low VA/Q group of units (5). As true stedy stte obviously ws not reched in so short time, the vlues obtined for these A-D, which did not remin constnt, could not be considered s finl ones for the prticulr high Fio2 used (12). There is no generl greement on the mechnism for the increse in A-DcO2 consistently observed to follow chnge from brething ir to brething gs providing high Fio2. Some

15 158 CLAUDE LENFANT AND WILLIAM R. PACE, JR. P C2 (2) mm HIg / / / / / // & / / / / P C2 (ir) mmhg FIG. 5. COMPARISON OF CO2 PRESSURE IN MIXED ARTERIAL BLOOD (PCO2) DURING ROOM AIR BREATHING WITH THAT DURING THE HIGH 2 BREATHING PERIOD IN THE PRESENT AND IN OTHER STUDIES. The open symbols correspond to Pco2 lower thn 45 mm Hg, nd the blck, Pco2 higher thn 45 mm Hg during ir brething (A from reference 29, * from reference 1, from present series, group III, A from reference 29, nd from present series, groups 1 nd II). The plin line with 45 ngle represents the line of identity; the dshed line is the clculted regression line. The difference between those two lines demonstrtes tht the increse of Pco2 with 2 brething is relted to the originl Pco2. uthors hve suggested tht this increse is derived minly from chnge in VA/Q (26), or from the number of high VA/Q units (14), wheres others hve postulted tht it is result of the Hldne effect of the CO2 dissocition curve (27). Comprison of the Pco2 nd PACo2 before nd fter chnging from low to high Fio2 indictes the source of the chnge of A-DCo2 (28). In norml subjects nd those with only miniml disese, only decrese in the PACo2 occurs (14, 26). In ptients with dvnced emphysem nd hypercrbi, however, this sme directionl chnge in the PACo2 is ccompnied by n increse in Pco2 tht is of much greter significnce (Figure 5). This difference might be explined by Hldne effect occurring when these ptients' blood (the lrgest portion of which remins unsturted while the ptient brethes room ir) becomes sturted t the higher Fi2. Summry The physiologic chnges ssocited with the progression of disese in chronic pulmonry emphysem were exmined in comprtive study of the severl fctors relted to respirtory gs exchnge in 22 ptients t different stges of this disorder. Fctors considered included lveolr ventiltion, lung volume, blood flow, nd the reltionships of these to ech other in three comprtment system; the lveolr-rteril differences of ech of the three respirtory gses, 2, C2, nd N2; nd the distribution of the ventiltion to perfusion rtios (VA/Q) throughout the lung. Our findings confirm the fct tht chnges in the distribution of ventiltion to perfusion rtios pper to be the fctors minly responsible for progressive impirment of gs exchnge in ptients with emphysem grded ccording to ventiltory impirment. Although there is lowering of the over-ll VA/Q tht ccompnies worsening of the clinicl signs, this is ctully probbly not s significnt in the production of hypoxi nd hypercrbi s the chnges in distribution of units throughout the lung. These chnges include increses in the rnge of VA/Q, skewness of the frequency distribution curve, nd dispersion. In other words, s the clinicl disese dvnces, there ppers to be decrese in the number of lveolr units with norml ventiltion to blood flow rtio s more nd more units move wy from this ctegory in both directions; most become low units, while some others re becoming high VA/Q units t the sme time. The rte of blood flow, or percentge of totl blood flow, going to lveolr units with low VA/Q is eqully s importnt to the production of hypoxi nd CO2 retention s the ctul level of low VA/Q rtio vlue. Acknowledgments The uthors express their pprecition to Dr. C. J. Mrtin for helpful comments nd suggestions. They re indebted to Dr. W. Briscoe for his id nd constructive

16 VENTILATION TO PERFUSION RATIOS IN EMPHYSEMA 1581 criticism in the revision of this mnuscript. They lso cknowledge the proficient technicl ssistnce of C. Aucutt nd thnk Instrumenttion Assocites, Inc., for the generous lon of the Godrt pneumotchogrph. References 1. Briscoe, W. A., E. M. Cree, J. Filler, H. E. J. Houssy, nd A. Cournnd. Lung volume, lveolr ventiltion nd perfusion interreltionships in chronic pulmonry emphysem. J. ppl. Physiol. 196, 15, Finley, T. N. The determintion of uneven pulmonry blood flow from the rteril oxygen tension during nitrogen wshout. J. clin. Invest. 1961, 4, Bldwin, E. def., A. Cournnd, nd D. W. Richrds. Pulmonry insufficiency: III A study of 122 cses of chronic pulmonry emphysem. Medicine (Bltimore) 1949, 28, Rine, J. M., nd J. M. Bishop. A- difference in 2 tension nd physiologicl ded spce in norml mn. J. ppl. Physiol. 1963, 18, Lenfnt, C. Mesurement of ventiltion/perfusion distribution with lveolr-rteril differences. J. ppl. Physiol. 1963, 18, Bldwin, E. def., A. Cournnd, nd D. W. Richrds. Pulmonry insufficiency: I. Physiologicl clssifiction, clinicl methods of nlysis, stndrd vlues in norml subjects. Medicine (Bltimore) 1948, 27, Lenfnt, C., nd C. Aucutt. Oxygen uptke nd chnge in crbon dioxide tension in humn blood stored t 37 C. J. ppl. Physiol. 1965, 2, Robertson, J. S., W. E. Siri, nd H. B. Jones. Lung ventiltion ptterns determined by nlysis of nitrogen elimintion rtes; use of the mss spectrometer s continuous gs nlyzer. J. clin. Invest. 195, 29, Briscoe, W. A., nd A. Cournnd. Uneven ventiltion of norml nd disesed lungs studied by n open-circuit method. J. ppl. Physiol. 1959, 14, Bll, W. C., Jr., P. B. Stewrt, L. G. S. Newshm, nd D. V. Btes. Regionl pulmonry function studied with xenon". J. clin. Invest. 1962, 41, West, J. B., nd C. T. Dollery. Distribution of blood flow nd ventiltion-perfusion rtio in the lung, mesured with rdioctive C2. J. ppl. Physiol. 196, 15, Torres, G. E., C. T. Hung, nd H. A. Lyons. Increse in venous dmixture during brething 1%o oxygen. Physiologist 1963, 6, Briscoe, W. A., nd A. Cournnd. The degree of vrition of blood perfusion nd of ventiltion within the emphysemtous lung, nd some relted considertions in Cib Foundtion Symposium on Pulmonry Structure nd Function, A. V. S. de Reuck nd M. O'Connor, Eds. Boston, Little, Brown, 1962, p Lenfnt, C. Effect of high Fio2 on mesurement of ventiltion/perfusion distribution in mn t se level. Ann. N. Y. Acd. Sci. 1965, 121, Mrshll, R., D. V. Btes, nd R. V. Christie. Frctionl nlysis of the lveolr ir in emphysem. Clin. Sci. 1952, 11, Mrtin, C. J., nd A. C. Young. Lobr ventiltion in mn. Amer. Rev. Tuberc. 1956, 73, Young, A. C., C. J. Mrtin, nd W. R. Pce, Jr. Effect of expirtory flow ptterns on lung emptying. J. ppl. Physiol. 1963, 18, Rhn, H., nd L. E. Frhi. Ventiltion-perfusion reltionship in Cib Foundtion Symposium on Pulmonry Structure nd Function, A. V. S. de Reuck nd M. O'Connor, Eds. Boston, Little, Brown, 1962, p Blount, S. G. Crdic output in pulmonry emphysem in Pulmonry Circultion, W. Adms nd I. Veith, Eds. New York, Grune & Strtton, 1959, p Willims, J. F., nd R. H. Beknke. The effect of pulmonry emphysem upon crdiopulmonry hemodynmics t rest nd during exercise. Ann. intern. Med. 1964, 6, Kitchin, A. H., C. P. Lowther, nd M. B. Mtthews. The effects of exercise nd of brething oxygenenriched ir on the pulmonry circultion in emphysem. Clin. Sci. 1961, 21, Ferrer, M. I., nd R. M. Hrvey. Decompensted pulmonry hert disese with note on the effect of digitlis in Pulmonry Circultion, W. Adms nd I. Veith, Eds. New York, Grune & Strtton, 1959, p Woolf, C. R., R.W. Gunton, nd W. Pul. Crdic output nd blood volume in chronic cor pulmonle. Cnd. med. Ass. J. 1961, 85, Klocke, R. A., nd L. E. Frhi. Simple method for determintion of perfusion nd ventiltion-perfusion rtio of the underventilted elements (the slow comprtment) of the lung. Technicl documentry report no. AMRL-TDR (1), 1963, Lenfnt, C. Mesurement of fctors impiring gs exchnge in mn with hyperbric pressure. J. ppl. Physiol. 1964, 19, Lrson, C. P., Jr., nd J. W. Severinghus. Posturl vritions in ded spce nd CO2 grdients brething ir nd 2. J. ppl. Physiol. 1962, 17, Bryn, A. C., L. G. Bentivoglio, F. Beerel, H. Mc- Leish, A. Zidulk, nd D. V. Btes. Fctors ffecting regionl distribution of ventiltion nd perfusion in the lung. J. ppl. Physiol. 1964, 19, Lenfnt, C. Arteril-lveolr difference in Pco2 during ir nd 2 brething. In preprtion. 29. Sid, S. I., nd C. M. Bnerjee. Venous dmixture to the pulmonry circultion in humn subjects brething 1 per cent oxygen. J. clin. Invest. 1963, 42, 57.