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Journal of APPLIED PHYSIOLOGY VOLUME DECEMBER 2 1949 NUMBER in WARD S. FOWLER.2 From the Department of Physiology and Pharmacology, Graduate School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania V ~~10~s INVESTIGATORS, using fractional (1-4) or continuous (5) analysis of alveolar gas exhaled on a single expiration, have agreed that the lungs are not ventilated evenly in normal subjects, i.e. that inspired gas is not evenly distributed throughout the lung gas. The two principal explanations have been I) that the inspired gas is layered (stratified) in each unit of the lung so that there is a higher concentration of inspired gas in the alveolar ducts than unevenly in the alveolar sacs (I), and 2) that the inspired gas is distributed to different lobes or lobules of the lungs (2) ; regional differences in ventilation have been thought to arise because the per cent change in volume varies in different areas of the lung during inspiration (4). Roelsen found that patients with bronchial asthma and pulmonary emphysema showed greater variation in the composition of successive portions of expired alveolar gas than did normal subjects; he attributed this to a greater inequality of intrapulmonary (2). gas mixing Reinvestigation of this problem has been carried out to obtain quantitative data on this lack of uniformity of alveolar gas in normal subjects, to learn more concerning the mechanism by which this is produced, and to devise a test which might prove of value in the differentiation of normal intrapulmonary gas mixing from that occurring in patients with certain types of pulmonary disease. The studies to be reported confirm the presence of uneven lung ventilation in normal subjects, apparently on a regional basis. However, they indicate that preferential distribution of the dead space gas to certain areas of the Received for publication October 19, 1949. l This research was supported by a grant from the Commonwealth 2 National Institute of Health Postdoctorate Fellow. 283 Fund. Downloaded from http://jap.physiology.org/ by 10.220.33.3 on June 16, 2017 Ventihtzbn Lang Faction Stzcdies, III. Uneven Pdmonary Normud Szcsjects and in Patients with Pdmondry Disease1 6 WARD 284 S. FOWLER Volume 2 lungs may occur regularly and to some extent be responsible for the inequality. In addition, a ‘uniformity index’ is proposed for the measurement of intrapulmonary gas mixing; this index has been calculated for a group of normal subjects. Although not a direct quantitative measure, it has served to identify abnormal intrapulmonary gas mixing in patients. Since the test is objective, requires little cooperation on the part of the patient, and takes only a few minutes, it may be valuable as a ra.pid screening test for particular types of pulmonary disease. METHODS TABLE I .NORMALVARIATIONSINEXPIREDALVEOLARN~CONCENTRATIONAFTERMAXIMALINSPIRATION OF 02 MEAN POINTS zt S. D. COMPARED N2 Difference Index Uniformity % ah750 - ah260 ah750 - ah750 - 1 ah)TC o-79 2.4 zt 0.5 alvb 5.0 St 1.4 l S. D. and uniformity indices were approached the error of measuremenk not calculated, 0.852 0.725 since the variations A 0.040 * 0.066 (0.5 to I. 5% N2) gen meter (7), used in these studies, is not sensitive enough to detect accurately the slight changes in NZ concentration that occur in respired air during the respiratory cycle, when room air is breathed. However, when the inspired gas, to be mixed with alveolar gas (80~~ Nz), is not air, but O2 (o.& Nz), the effect of uneven mixing is magnified so as to be readily detected with this instrument. Studies were performed with the subjects in the sitting position, except when noted otherwise. At the beginning of each test, the subject breathed room air for several minutes through a mouthpiece attached to a J-way valve. During an expiration, the room air orifice was closed, so that O2was breathed on the following inspiration and thereafter. In special experiments (table 2), in addition to the routine measurements of expiratory volume flow, inspired volumes were measured from a 6-l. recording spirometer used as the source of Oz. For experiments in which positive expiratory pressure was developed by expiring against a water column, the flow meter calibration was calculated from direct spirometric measurement of total expired volume. Downloaded from http://jap.physiology.org/ by 10.220.33.3 on June 16, 2017 General. The method has been described previously (6). In brief it consists of continuous analysis and photographic recording of I> expiratory volume flow, and 2) N2 concentration of respired gases during and after the change from breathing room air to breathing 99.6 per cent Oz. The Lilly-Hervey nitro- Dectvn ber 1949 UNEVEN PULMONARY VENTILATION 285 i Fig. I. RECORD OF EXPIRATORY VOLUME FLOW (F) and Nz concentration hyperventilation. Read left to right. First, expiration after air breathing, then maximal expiration. For labels under arrows, see text. (N) during voluntary then inspiration of 02, uniform throughout the expiration and is assumed to be 80 per cent. Then O2 is inspired. On the next expiration, 20 to IOO ml. of undiluted O2 are expired, followed by several hundred milliliters of gas with a rapidly rising NZ content, and finally by gas with a relatively uniform N2 content. The first two phases represent washing out of the respiratory dead space, and the last phase, or plateau, is considered to represent ‘alveolar’ gas. These three phases are not readily identifiable in all individuals, especially those with pulmonary emphysema. However, when they are clearly separable (most normal subjects), the point on the curve representing the first pure alveolar gas can be located quickly by the following method. The point at which the S-shaped curve meets the alveolar plateau is selected by drawing a straight line on the photographic record along the top of the plateau; the N2 concentration at the point where the plateau line becomes tangent to the rising S-shaped curve is assumed to represent the first pure alveolar gas (alv,). When expired volume is large, the straight line is sometimes drawn along only the first half of the plateau, since the NZ curve in the later part of expiration may change its slope in relation to volume, or Downloaded from http://jap.physiology.org/ by 10.220.33.3 on June 16, 2017 Instrumental. The characteristics of the flow meter and NZ meter have been described previously (6). Measured points were separated in time by at least 0.5 second, which is at least 5 times the instrumental lag. The N2 concentrations were measured to the nearest 0.5 per cent, corresponding to about 0.5 mm. change on the record. On the basis of Roelsen’s data (8), we have assumed that, when the subject is breathing room air, the concentration of Nz in alveolar gas after a 65o-ml. expiration is 80 per cent and have calibrated each record on this basis. Measurement of Records. The uniformity index, to be described, compares the composition of alveolar gas at two different points during the first expiration following inhalation of Oz. The method of selecting these points is consequently a matter of importance for it is essential that both represent alveolar gas uncontaminated with dead space gas. Figure I, obtained upon a healthy adult, shows a typical record and the method of measurement. During the first part of the record, air is breathed, the N2 concentration appears to be 286 WARD S. FOWLER Volume 2 the terminal reduction in volume flow may change the slope of Nz increase in relation to time. The justification for this procedure follows. Since we are concerned with alveolar ventilation, a ventilator-y criterion is needed to define pure alveolar gas. In terms of ventilation, alveolar gas is ‘pure’ if it has no admixture of gas from the anatomical dead space. The presence of such admixture can be determined as follows. During inhalation of OS, the Ns concentration of alveolar gas is progressively reduced on successive breaths. This change in alveolar Nz concentration can be assumed to be expressed by the equation C,, = Coy%, For the first several breaths of 02, slight variations resulting from the presence of Nz (0.4~~) in the inspired gas and the elimination of blood Nz can be neglected. Thus log C, plotted against PZshould give a straight line, passing through 80 per cent Nz at rto, if the concentrations selected represent pure alveolar gas. When concentration points were selected from similar portions of the first part (02) of successive expired Na curves, Co was obviously zero (0.4~~). When the Nz concentrations were selected at about the midpoint of the S-shaped curve, Co was 40 per cent Nz. For Nz concentrations selected at the point at which the S-shaped curve meets the alveolar plateau, Co was 80 per cent Nz, and so meet this definition of alveolar gas. The equation is based on certain assumptions, including constancy of tidal, dead space and functional residual volumes. These results also apply only to the first several breaths of those normal individuals whose measured tidal volume was fairly constant, and are subject to the limits of accuracy of Nz measurement. In some cases Co varied somewhat from 80 per cent (78.5-81y0), but was the same for various points on the alveolar plateau; this indicates that early points on the plateau are as nearly pure alveolar gas as the end-tidal points. In patients with pulmonary disease and marked unevenness of gas mixing, alv, usually cannot be selected as above, as can be seen in figure 3. It is necessary that the expired volume preceding alv, be sufficient to wash out completely the anatomical dead space, so that alv, is uncontaminated with dead space gas. The wash-out volume has been found in normal subjects to have an average value of 325 ml. (S.D. + 65 ml.) during quiet breathing (6), or 526 ml. (S.D. + 118 ml.) during maximal inspiration and expiration (see the section on RESULTS). With maximal lung inflation the dead space and the volume required to wash it out on expiration are enlarged. Thus, on a patient’s record an expired volume of 750 ml. is marked on the flow record and the simultaneous point on the Nt record is considered to be alv,; 750 ml. is chosen because it represents approximately the mean normal wash-out volume plus Downloaded from http://jap.physiology.org/ by 10.220.33.3 on June 16, 2017 where Co = initial alveolar concentration, about 80 per cent Ns; c m = alveolar concentration after PZinhalations of 02; r = alveolar dilution ratio (9). December 1949 UNEVEN PULMONARY VENTILATION 287 SD. This method does not identify the first portion of pure alveolar gas, but statistically insures that 95 per cent of such points represent alveolar gas uncontaminated with anatomical dead space gas; when alv, is obtained in this way, it is identified as alv 750. The assumption that the volume required 2 TABLE 2. EFFECT OF RESPIRATORY VARIABLES ON UNIFORMITY OFEXPIRED ALVEOLAR GAS' A TYPE OF ,SUB EXPERIMENT Ja NO. OF ExPTS. INSP. VOL. INSP. TIME Total exp. (maximal Differences alvB and MAX. EXP. FLOW N2 2 3 2 2 Increasing inspired vol. normal pre-inspiratory lung volume Varying inspiratory breathholding Varying expira tory time by rate 240 sec. 1.6 l/ min. % Time Terminal exn. alveolar vol. Differences between alva and alvb - vol. in col. 2 Unif. Index 38 37 42 3-S 4-7s 3-S 1940 3020 32.50 4.8 8.0 3 2 2 I 825 830 830 3-O 70 76 76 72 6.5 187s 3-S 4-S 3.6 6.0 0.86 2 2 2 830 3-o 2.8 3.3 0.78 0.87 0.88 900 22.0 980 930 3.3 3.5 S-0 7-S 80 77 4.75 3.0 2.0 8.5 1825 1810 1850 none 89s 87s 87s added 1350 I 290 350 ml. added 1 All figures are average 2.5 2.0 I.9 4.5 3.8 1610 2.5 2.2j 1710 1350 3= 74 6.25 3.75 14.50 1440 4-o 2.5 0.66 0.77 20 80 4.2S I.75 1610 9-I 2.2 0.70 0.86 40 53 38 3.75 61 3-S 4-2s 55 0.80 4.3 4.4 0.89 0.93 1590 S-0 9.75 I-5 --- -- -- -- -- 790 74s 760 3.9 3.4 3.7 0.83 0.77 o-53 1430 4-o 4.6 0.84 o-77 1320 3-s 0.81 -- Added dead space; small inspira tory lung volume none added ISO ml. added 350 ml. added 4.8 s-0 $$kx - 0.63 0.70 3.75 6s 1940 1940 1940 3.5 2.75 2.1 2.6 4-o 2.5 0.47 0.67 0.78 0.80 0.80 o-79 0.84 770 1950 2450 13.0 3-o 2.7 2.6 3.0 3.5 4-o 2 2 I 950 sec. 840 9.50 9.50 950 0.47 0.67 0.69 0.70 6.5 85s ml- 3*0 2.7 3.8 5.0 2700 22.0 32.0 % sec. 840 950 2240 3100 3.9 13.0 Time - ??‘l. 1720 1-s Vol. 3-s 4-o 7.25 7-o 34 44 57 62 520 N2 -- values. to wash out the dead space is not greater in patients than in normar subjects is supported by experimental data. Other Ns concentrations, used for comparison with alv, or alv7ao, may vary according to the circumstances of the study. One such point can be the highest NB concentration on the plateau, found at or very near the end of expiration; this is called alvb. The volume of expired gas between alv, and alvt, can be variable; therefore in a few special studies (table 2)) the points 1 Downloaded from http://jap.physiology.org/ by 10.220.33.3 on June 16, 2017 ml. Vol. alv. vol. exp.) between alvb 288 WARD S. FOWLER Volume 2 CF- C i- initial Nfl concentration C F = final NS concentration V i= initial volume Va = added volume of 02. where Rearranging, V f = i example, V. i vi +%va C c c ’c F. This may be called the ‘dilution index’. For F if one liter (Va) of 02 is added to one liter (Vi) of gas containing 80-40 per cent Nz (c,), cF becomes 40 per cent and ______ = 1.0. 80 If only 600 cc. of 40 O2 is added to one liter of 80 per cent N2 gas, cF becomes 50 per cent so- 50 = 0.6. In both cases the magnitude of dilution is expressed quantitaso 50 tively by the dilution index. Comparison of dilution in two systems can be expressed as the ratio of the respective dilution indices, which may be called the uniformity 0.6 index. Here this is -, or the added O2 per unit of initial volume 1.0 in the second case has been only 0.6 of that in the first case. In RESULTS, dilution index of late expired gas In all cases, 80 per uniformity index = dilution index of early expired gas’ cent has been used as the initial concentration. A uniformity index can be computed for any two alveolar concentrations among those measured (alv,, alvYGO, etc.). However, for normal subjects, uniformity indices have not been calculated for alv, - alvb with quiet breathing, or alv750 - alvlzsO with hyper- Downloaded from http://jap.physiology.org/ by 10.220.33.3 on June 16, 2017 compared were alvb and a point at a measured volume preceding alvb. These points are designated as alvb minus the volume indicated (e.g. alvb - 1000). Many patients with cardiopulmonary disease have a reduced vital capacity an increased residual capacity, and cannot expel as large a fraction of their total lung capacity as normal subjects. It seemed advisable to have additional measurements on normal subjects which could be used for comparing similar fractions of the total lung gas. Two such measurements were made for the normal subjects who made maximal inspirations and expirations. The first was the NZ concentration at 125o-ml. expired volume (alv1260) ; most adult patients can expire 1250 ml. or more in the vital capacity procedure. N2 concentrations were also measured at a total expired volume equal to 50 per cent of the total lung capacity, estimated from age and vital capacity (IO) ; this point is called alv3Tc, and was at an average expired volume of 2760 ml. Cakulation of Results. In any system the dilution of contained Na by added O2 can be represented by the equation December I949 UNEVEN PULMONARY VENTILATION ventilation, since the differences in NZ concentration the error of measurement. were small and approach RESULTS Downloaded from http://jap.physiology.org/ by 10.220.33.3 on June 16, 2017 Uniformity of Expired Alveolar Gas in Normal Subjects. Records were obtained from 45 healthy while males, aged 19 to 38 years, who were breathing naturally. On the first expiration after O2 inhalation, the expired volume of 5 subjects was insufficient to wash out the dead space and the alveolar plateau therefore was not evident; measurements were made at alv, and alvb on the records of 40 subjects. The NZ plateau was approximately linear in 36 subjects, was wavy in 3 cases, and in one case showed a sudden step-like rise late in expiration without coincident change in volume flow. In all, the Nz concentration at alvb was equal to or greater than that at alv,; the average increase was 1.64 per cent with a standard deviation of ko.84 per cent. Both the slope of the plateau and volume of expired gas between the measured points were variable. Thirty measurements were also made on 18 healthy subjects (6 female, I 2 male, age I 7 to 73, average 33.7 years) during maximal expiration following maximal inspiration of 02; velocity of breathing was not controlled. These subjects were semi-reclining, with the head and trunk elevated 50-60 degrees above the bed. This position was selected because it is satisfactory for dyspneic as well as for normal subjects. Average values were: total expired volume, 4330 ml.; volume to a1v3Tc, 2760 ml.; volume to alv,, 526 ml.; S.D. AI 18 ml. (all BTPS). In every case the Nz concentration of the alveolar plateau increased almost linearly with respect to volume throughout most of the expiration, although during the last several hundred milliliters it increased more steeply in some and decreased slightly in others. The results of N2 measurement are given in table I. The uniformity indices were reproducible; the S.D. of differences between duplicate measurements (alvT50 - alvb) and their mean was 0.022 in 12 subjects. Factors In$uencing Uniformity of Expired A lveolar Gas. The increasing alveolar NZ concentration later in expiration indicates that inspired O2 is not evenly distributed throughout the functional residual gas and also that the relatively poorly ventilated areas of the lung empty proportionately more in late expiration. The following experiments were performed to determine the effect of varying volume, time and velocity of inspiration and expiration upon the uniformity of expired alveolar gas. The best controlled experiments are listed in table 2; column A gives the differences in y0 N2, volume and time between alv, and alvb; expirations were always maximal. Comparison of uniformity indices in column A is valid except for the experiments with increasing inspired volume, in which the uniformity indices in column B should be used, since the latter have been computed for 290 WARD S. FOWLER Volume 2 Downloaded from http://jap.physiology.org/ by 10.220.33.3 on June 16, 2017 equal volumes of gas expired at the same level of lung inflation. In 21 pairs of duplicate experiments on subject I, the S.D. of the differences between duplicate uniformity indices and their means was 0.023, and in the 14 pairs of duplicate experiments on subject z was 0.024. Thus a difference between the means of duplicate indices, as listed in table 2, must equal or exceed 0.05 to be significant. a) Inspiratory variables. It will be noted that as inspired volume increased, the uniformity of expired alveolar gas increased, i.e. the uniformity index approached unity (column B), although there was a diminishing effect with increasing volumes. As inspiratory time was prolonged by breathholding for IO to 30 seconds, the variation in N2 concentration decreased, but was still 2 to 3 per cent N2 Similar experiments were done by 5 after 20 to 30 seconds of breathholding. other subjects, comparison being made between uniformity indices of maximal and b) 20 seconds after inspiration. In expirations following a) immediately all, the uniformity index was greater after breathholding but did not reach unity. The mean increase was 0.154, with a significant t value of 4.3. Although inspired volume was not measured in these 5 subjects, the similarity of N2 concentrations and total expired volumes in .dicated that it had not varied by more than IOO to 200 cc. between the comparative experiments; peak expiratory flow was voluntarily controlled and found similar on measurement. Other inspiratory variables were tested without observing any significant effect. These included rate of inspiratory volume flow (8 experiments, 2 subjects); preinspiratory lung volume (12 experiments, 2 subjects); inspiratory flow and time (8 experiments, 2 subjects) ; and positive (8 cm. H20) inspiratory pressure (5 tests, 7 control experiments, I subject). b) Expiratory vareiables. When a maximal expiration was made evenly, alveolar N2 concentration increased almost linearly with respect to both time and expired volume during the major part of the expiration (fig. I). However, rapid expiration produced a more horizontal plateau than slow expiration (table 2). Experiments varying the rapidity of expiration were also done by 7 other subjects. With slow expiration the average peak expiratory flow was 34 l/minute, and with rapid expiration was I 15 l/minute. In all cases the uniformity index (alv, - alvb) was greater with a rapid expiration; the mean increase was 0.17, with a highly significant t value of 4.6. When a normal quiet expiration was followed immediately by a further forced expiration, as in giving an ‘end-expiratory’ alveolar sample, the N2 concentration no longer increased evenly in respect to volume, but increased rapidly early in the forced expiration, and then remained almost constant during the rest of the expiration. Such results were found in 6 of 9 normal subjects; in 3 the slope remained constant despite the interposed forceful expiration. In one subject, a small increase in uniformity was found with positive expira- December 1949 UNEVEN PULMONARY VENTILATION 291 Downloaded from http://jap.physiology.org/ by 10.220.33.3 on June 16, 2017 tory pressure (IO cm. HzO) ; the mean uniformity index 0.68 of 7 experiments was significantly greater than the mean index 0.65 of 7 control experiments. Cause of Nonuniformity of Expired Alveolar Gas. In addition to the explanations previously offered (‘stratification’ and ‘regional’ concepts) there is another way in which nonuniformity could arise, even though the per cent increase in volume during inspiration is equal in all sections of the lung. From experiments on one normal subject, Rauwerda concluded that certain areas of the lung fill mainly during the first part of inspiration, and other areas fill mainly during the latter part of inspiration. This process we shall call ‘sequential ventilation’. He also observed that the areas which fill during early inspiration are less well ventilated than the areas which fill later. On this basis the following possibility is suggested. It is certainly reasonable to believe that the dead space gas enters the alveolar spaces first, and the fresh inspired gas (OS in our studies) follows. If certain areas of the lung fill first, they may receive more of the dead space gas, while the areas which fill later receive more of the Oz. Then regional differences in alveolar gas composition will arise toward the end of inspiration even though the final percentage increase in volume is equal in all areas. This sequential filling process can be detected by examination of the expired alveolar gas only if there is also sequential emptying. The results above show that sequential emptying does occur, with relatively *poorly ventilated areas emptying preponderantly later in expiration. If the higher N2 concentration in these areas had resulted from preferential distribution of the dead space (Soy0 Nz) gas to them, it would be required that the areas which fill first on inspiration also empty last on expiration. This concept of sequential ventilation was tested by studies in which the sequence of inspired gases was reversed. Inhalations were made consisting of several hundred milliters of 02, followed without interruption by several hundred milliters of room air. When such inhalations began at the normal expiratory position, the usual rising N2 concentration late in expiration was found; however, when inspiration began at an extreme expiratory position, the slope of the alveolar plateau was reversed. Instead of the usual rising Nz, now a decreasing N2 concentration later in expiration was found; reversal of the alveolar Nz slope was obtained in duplicate experiments on 3 normal subjects. This confirms Rauwerda’s results and the ‘first-in, last-out’ possibility. When the gas that entered first contained 80 per cent N2 (dead space) and the gas that entered last was 02, a higher N2 concentration was found in the last expired gas. When the gas that entered first was mainly 02, and the gas that entered last contained 80 per cent NS, a lower Nz concentration was found in the last expired gas. This procedure was also used on 5 persons having pulmonary disease (asthma, chronic bronchitis, emphysema). Maximal inspira- 292 WARD S. FOWLER vozums 2 DISCUSSION In these studies, Nz concentration of expired gas always increased, with continued expiration, when O2 had been inhaled on the preceding inspiration. Before this finding can be interpreted validly in terms of alveolar ventilation, certain points require consideration. The phenomenon does not appear to be an artefact for the following reasons. a) The increase is much slower than the instrumental lag. b) After inhalation of room air, alveolar Nz content is approximately constant during normal or forced expiration. c) After breathing O2 for several minutes and then inhaling one breath of room air, the expired alveolar gas regularly shows a decreasing NZ content later in expiration. d) After a large inspiration of 02, the N2 concentration of 3000 ml. of expired alveolar gas may rise by 7 per cent; this would represent an addition of at least 105 ml. of N2 or 133 ml. of air, which is too large to have come from pulmonary venous blood, lung tissue or the oronasal cavities, or to be attributed to an R.Q. effect. The increasing NI content cannot represent a decreasing amount of admixture with O2 from the respiratory dead space, ‘pure’ alveolar gas being expelled only at the extreme end of expiration, as Armitage and Arnott suggest Downloaded from http://jap.physiology.org/ by 10.220.33.3 on June 16, 2017 tions and expirations were made (average 1790 ml.) ; inspired gas was either all 02, or the first half was O2 followed without interruption by room air. After inhalation of O2 alone, the plateaus showed considerable upward slope. However, after the Oz.-air inhalations, the plateaus in every case were more nearly horizontal. Uniformity indices, calculated from NZ concentrations at 750 ml. and end-expiration, were, with Os-air inhalations, increased an average of 0.196, with a highly significant t value of 7.8. These changes are of course similar in direction to those in normal subjects. If variations in the composition of alveolar gas were due solely to sequential filling, the volume of the dead space should limit the extent of variation, and greater variation would be expected when the dead space was increased. Experiments on 2 normal subjects were made in which dead space was added by interposing air-filled rubber tubing between the ,+-way valve and the source of Oz. When inspiration began at the normal expiratory level, the addition of 150 or 350 ml. of dead space did not affect the uniformity of expired alveolar gas; however, when inspiration began at a deep expiratory position, more variation in composition was found with added dead space (table 2). Eight subjects with chronic pulmonary disease made vital capacity inspirations and expirations (average 2580 ml.); inspired gas was, in each subject, either all 02, or 650 ml. dead space was added. Comparison of uniformity indices, calculated from NZ concentrations at 750 ml. and end-expiration, showed them to be smaller in all cases with added dead space. The mean decrease, 0.06, was highly significant, having a t value of 4.9. Decem her Ig4g UNEVEN PULMONARY VENTILATION 293 (I I), for reasons discussed under the section on METHODS. Furthermore, the addition of more than 400 ml. of O2 would be required, during a sooo-ml. expiration, to depress the plateau concentrations an average of 3.5 per cent N2 below that of the pure alveolar gas, represented by alvb. This volume, 400 ml., added to the 150 to 200 ml. of O2 expired prior to the plateau, is much greater than the volume of the respiratory dead space. Thus, one may conclude that the plateau represents alveolar gas and that the variations in expired alveolar Nz concentrations, by exclusion, must be TABLE BEFORE INSPIRATION Lower area lung 360 80 720 l See figure 80 AFTER INSPIRATION 2 MECHANISM DS -- 02 upper lower 40 320 80 640 upper lower 40 80 320 0” 2 n Expansion 20 340 LOO 1700 upper lower r20 240 720 N2 ml % 360 720 varies varies Uneven ventilation due to stratification 44-4 44*4 Even ventilation with uneven expansion 360 1800 42.2 26.0 Uneven ventilation due to different yO vol. change 360 720 53.3 40.0 Uneven ventilation due to preferential distribution of dead space gas 640 upper lower 0 MECHANISMS~ and text. attributed principally to unequal distribution of 02 throughout the functional residual gas. These studies confirm previous findings that the lungs are unevenly ventilated in most healthy subjects, even during a maximal inspiration. The average uniformity index, 0.725, is similar to the magnitude of variation in composition of expired alveolar gas reported by Roelsen and Mundt. However, the observed variations in Nz concentration during an expiration represent only the minimal variations which could have existed in the lungs at end-inspiration. For example, marked regional differences could exist in the composition of alveolar gas, but go unnoticed if the proportion of gas delivered to the expired gas from each region remained constant throughout expiration. Since the Na concentration does increase later in expiration, the proportion must be changing progressively in favor of poorly ventilated areas. However, the change Downloaded from http://jap.physiology.org/ by 10.220.33.3 on June 16, 2017 lung Vol. added N2 No. space Upper area OF VENTILATION INSPIRATION Vol. Dead 3. ILLUSTRATION WARD 294 Volume S. FOWLER 2 in proportion, or the relationship between the emptying of various areas can be altered. The sudden increase in NZ concentration with an interposed forceful expiration indicates that emptying of poorly ventilated areas is promoted to a greater degree than that of well ventilated areas. When the total expiration is more rapid, the increased gas uniformity suggests that poorly ventilated areas are emptied early in expiration to a greater extent than when expiration is quiet. Mundt’s failure to note the effect of changes in expiratory rate may have been due to the use of Hz, or to comparing only the differences in the last liter of a maximal expiration. The slope of Nz increase in the last liter is not always equal to that in alveolar gas expired earlier and may not show changes which are evident in the total expired alveolar gas; with this Rauwerda agrees. Open and closed circles represent N2 molecules. Central figure shows pre-inspiratory conditions in 2 lung areas and dead space. Figs. 14 correspond to conditions in table 3, after inspiration of a Nz-free gas (02). See text. 3 4 If analysis of the expired gas is used to determine whether end-inspiratory variations in alveolar gas composition can be changed, expiration must be controlled. Although the expiratory flow pattern is obviously an incomplete registration of the emptying process, similarity of flow patterns is at least some indication of a similar emptying process, and appears to be one of the requirements for reproducing the alveolar plateau. With such control, it appears that larger inspired volumes promote equality of alveolar ventilation. This is compatible with either of the theories of unequal ventilation. There are two main theories concerning the mechanism of uneven ventilation. The first states that the inspired gas is layered or stratified in each individual air unit throughout the lung so that there is a higher percentage of inspired gas in each duct and atrium than in the slightly more peripheral alveolar sacs; this might give rise to a progressive increase in Nz concentration throughout expiration (table 3, fig. 2, mechanism I.) However, Rauwerda believes this theory to be untenable, since his calculations showed that, within one second, diffusion would obliterate any differences existing within the unit consisting of an alveolar duct and its alveolar sacs. He showed that during 15 Downloaded from http://jap.physiology.org/ by 10.220.33.3 on June 16, 2017 2. VARIOUS MECHAOF PULMONARY VENTILA- Fig. NISMS TION. December 1949 UNEVEN PULMONARY VENTILATION 295 Downloaded from http://jap.physiology.org/ by 10.220.33.3 on June 16, 2017 to 30 seconds of breathholding after O2 inhalation, the differences in alveolar gas concentrations are reduced, but not eliminated; our results using similar periods of breathholding confirm this with respect to N2. He concludes that differences which disappear have done so by diffusion inside individual lobules or between adjacent lobules; the differences which do not disappear represent variations in the composition of gas in more widely separated areas of the lung. The second, and more likely, concept is that regional differences exist, namely that inspired gas is distributed unevenly to different lobes or lobules of the lung. In 1909 Keith (12) pointed out that the expansion of various parts of the lung may be unequal, since the lung is composed of elements of varying degrees of distensibility. The root zone, containing large bronchi and vessels and much fibrous tissue, offers greater resistance to a distending force than the peripheral subpleural zone. It must be remembered, however, that unequal expansion will produce unequal ventilation in different regions only when the percentage increase in volume varies in the different areas of the lung. In that case, non-uniformity of alveolar gas would occur (2, 4). These mechanisms are illustrated in figure 2, mechanismsz and 3. There is also another way in which regional diff erences in composition could arise, even though the percentage increase in volume was equal in all sections of the lung (fig. 2, mechanism 4). This results from sequential ventilation, which indicates that certain areas of the lung fill before, and empty after, other areas. When sequential filling occurs early in inspiration, the first gas entering the alveolar spaces (dead space gas) is distributed preferentially to those regions which expand first. Experimental evidence has been obtained which supports this mechanism as being a cause of uneven alveolar ventilation in both normal subjects and in patients with pulmonary disease. However, such evidence was obtained in normal subjects only when inspiration began at an extreme expiratory position, but not at the normal expiratory position. The cause of this difference is not apparent. The regional intrathoracic distribution of various forces interacting to cause gas flow in and out of the lungs is not well understood, either with respect to magnitude, time course, or variation at different levels of lung inflation. If variations in alveolar gas composition were due solely to inequality in the percentage increase in volume, it is not apparent why the variations should be affected by changing either the sequence of inspired gases or the volume of the dead space. It is possible that both mechanisms, unequal percentage changes in volume and sequential ventilation, occur. The uniformity of the composition of alveolar gas would then depend on the relative magnitude and spatial distribution of the two processes. When breathing air, the O2 content of alveolar gas depends on both the loss to the pulmonary blood (perfusion) and the gain from the inspired air (ventilation). Although the results above measure only the ventilation factor, 296 WARD Volume S. FOWLER 2 they suggest some of the variables which may be involved in obtaining reproducible Haldane-Priestley alveolar samples, a procedure which is well known to require considerable training. The marked variation present in a single alveolar expiration emphasizes that a single small sample of alveolar gas may not be representative of the total expired alveolar gas. Rahn and associates (13) found concentrationsof 02 in alveolar gas to decrease in order when samples were obtained 1) at the end of normal tidal volume, z) at the end of forced expiration begun at end-inspiration, and 3) at the end of forced expiration begun at end-expiration. The differences were attributed to the time required for the forced expiration. The significance of the differences between various types of alveolar gas samples is currently debatable. Barker et aZ. (14) found the pCOz to be lower in the end-tidal samples than in arterial blood, 3. RECORDS OF EX- (F) and N2 concentration (IV) during voluntary hyperventilation. First, expiration after air breathing, then (1-2) inspiration of 02, then expiration. N:! concentration at alv1250 exceeds alvvao in the normal record by I per cent, in the emphysema record by 9 per cent. VOLUME FLOW and Forssander and White (IS) believe that end-tidal samples are diluted with air from the dead space. However, Rahn (16) found close agreement between end-tidal and arterial tensions. The present studies indicate that end-tidal gas comes chiefly from well-ventilated alveoli. As Roelsen pointed out (8), alveolar gas samples at the end of a deep expiration come from relatively poorly ventilated alveoli. In such a terminal sample of expired gas, gas from poorly ventilated alveoli will be represented to a greater extent a) when the total expiraHaldane-Priestley samples than in tion is slower, and b) in end-expiratory end-inspiratory samples. The latter is because the normal tidal expiration empties mainly well ventilated alveoli; this gas is not available for admixture in the end-expiratory sample. The experimental procedure used in the study of normal subjects has been extended to an investigation of patients suspected of having abnormal alveolar ventilation. The patient is asked to make a maximal inspiration of 02 and Downloaded from http://jap.physiology.org/ by 10.220.33.3 on June 16, 2017 Fig. PIRATORY December 1949 UNEVEN PULMONARY VENTILATION 297 SUMMARY Continuous analyses were made of Nz concentration and volume flow of gas expired after one inspiration of 99.6 per cent Oz. A ventilatory criterion for identifying alveolar gas is given. After 02 inhalation, the Nz concentration of Downloaded from http://jap.physiology.org/ by 10.220.33.3 on June 16, 2017 follow this by a maximal expiration (vital capacity procedure). Nz concentrations are measured at alv 7Go,alv1250, and at alvb. Our studies confirm Roelsen’s finding that patients with bronchial asthma and pulmonary emphysema show much greater variation in the composition of alveolar gas than do normal subjects (fig. 3). In normal subjects, the difference between a1v1260and a1vT60 is not more than 2 per cent N2; this may increase to 3 to 4 per cent in patients with uncomplicated bronchial asthma and to IO per cent in patients with marked pulmonary emphysema. For reasons noted previously in the section on METHODS, these differences have not been expressed as uniformity indices. However in the range of Nz concentrations usually found, 20 to 50 per cent, the relationship between percentage N2 differences and uniformity indices is such that larger percentage Nz differences correspond roughly to smaller uniformity indices. The normal uniformity index, calculated for alvTboand alvb is 0.725 (SD. =t 0.066), and may decrease to 0.50 in some patients with asthma and to 0.25 in patients with severe emphysema. If the total lung capacity has been measured, the uniformity index calculated for alvTsoand alv*rc is useful, particularly in patients having slightly abnormal plateaus. Such patients may expel only 50 to 60 per cent of the total capacity and the uniformity index (alv760 - alvb) may be 0.65 to 0.75. Such values are compared better with the normal index for alv750 - alvfTC, which is 0.852 (SD. ~fi 0.04) than with the normal index for alvT50 - alvb (0.725 =t 0.066), which represents expulsion of about 80 per cent of total capacity. Detailed data upon patients will be presented elsewhere. Findings in patients such as these were attributed by Roelsen to increased variation of alveolar ventilation. However, variations in the composition of expired alveolar gas depend not only on uneven ventilation but also on the relations between the emptying of different areas of the lung. Thus the differences might not be solely the result of greater variations in alveolar ventilation, but be entirely or partially due to different emptying patterns; qualitatively, this is unlikely, since other evidence (9, 17) indicates the presence of abnormal ventilation in emphysema. However, at present this limits the validity of using the variations in compositions of expired alveolar gas as a quantitative measure of the uniformity of alveolar ventilation. Despite this, such measurements are useful clinically. With the continuous analysis method, they can be made rapidly and with a minimum of subject cooperation, and may be useful as a screening test for patients suspected of having abnormal pulmonary gas mixing. 298 WARD S. FOWLER Volume 2 The author wishes to thank Dr. J. H. Comroe, Jr., and Dr. S. S. Rety for valuable advice. REFERENCES I. 2. 3. 4. 5. 6. 7a. 7b. 8. 9. IO. I I. HROGH, A. AND J. LINDHARD. J. Physiol. 51: 59, 1917. ROELSEN, E. Acta med. Scandinav. 95: 452, 1938. ENGLEHARDT, A. Ztschr. f. Biol. IOI: 21, 1942. RAUWERDA, P. E. Unequal Ventilation of DiTerent Parts of the Lung. Groningen University, 1946. MUNDT, E., W. SCHOEDEL AND H. SCHWARZ. Arch. f. d. ges. Physiol. 244: 99, 1940. FOWLER, W. S., Am. J. Physiol. I 54: 405, 1948. LILLY, J. C. Federation Proc. 5: 64, 1946. LILLY, J. C. AND J. P. HERVEY. Science in WorZd War II. Boston: Little Brown & Co. 1948, Vol. I, p. 314. ROELSEN, E. Acta med. Scandinav. 98: 141, 1939. DARLING, R. C., A. COURNAND, D. W. RICHARDS, JR., AND B. DOMANSKI. J. Ch. Investigation 23: 55, 1944. BALDWIN, E. DEF., A. COURNAND AND D. W. RICHARDS, JR. Medicine 27: 243, 1948. ARMITAGE, G. H. AND W. M. ARNOTT. J. Physiol. 109: 70, 1949. Downloaded from http://jap.physiology.org/ by 10.220.33.3 on June 16, 2017 alveolar gas increased as expiration continued. During maximal ventilation the average increase in alveolar Na concentration was 5 per cent; the uniformity index was 0.725, which expresses the minimal variation in dilution of alveolar NB by inspired Oz. This finding indicates a) that inspired O2 is not evenly distributed throughout the functional residual gas, and b) that the relatively poorly ventilated areas of the lung empty predominantly later in expiration. Uniform end-inspiratory distribution of inhaled O2 is favored by larger inspired volumes and by breathholding. Uniformity of expired alveolar gas is affected by the rate and manner of expiration. The interpretation of data utilizing single alveolar gas samples is discussed. Experimental evidence was obtained against the stratification theory of uneven lung ventilation and favoring the regional concept. A new concept, with supporting evidence, has been advanced to explain uneven ventilation on a temporal basis; this sequential ventilation results in a preferential distribution of the respiratory dead space gas to those regions which fill first on inspiration. Both preferential distribution of the dead space gas and also variations in percentage volume changes may occur as explanations for uneven alveolar ventilation. Subjects with bronchial asthma and pulmonary emphysema showed greater variations in alveolar gas composition than did normal subjects. This difference makes the test useful in clinical diagnosis; measurements are made easily and rapidly. Their present limitations as a quantitative measure of intrapulmonary gas mixing are noted. December 1949 UNEVEN PULMONARY 12. HILL, L. F&her Advances iut Physiotogy. New p. 182. A. B. OTIS AND W. 0. 13. RAEXN, H., J. MOHNEY, 14. BARKER, E. S., R. G. PONTIUS, D. M. AVIADO, Proc. 8: 7, 1949. 15. FORSSANDER, C. A. AND C. WHITE. J. Applied 16. &lHN, H. Am. J. Physiol. 158: 21, 1949. 17. BIRATH, G. Acta med. Scandinav. Supplement, VENTILATION York: Longmans, 299 Green & Co., Igog, FENN. J. Aviation Med. 17 : 173, 1946. JR., AND C. J. LAMBERTSEN. Federation Physiol. 2: 110, 1949. 194. Downloaded from http://jap.physiology.org/ by 10.220.33.3 on June 16, 2017