Effects
of age on regional
residual
volume
RICHARD L. JONES, THOMAS R. OVERTON, DONNA M. HAMMERLINDL, AND BRIAN J. SPROULE Division of Pulmonary Disease, Department of Medicine, and Division of Biomedical Engineering, Faculty of Medicine, University of Alberta, Edmonton, Alberta T6G 2G3, Canada
JONES,RICHARD L. ,THOMAS R. OVERTONJONNA M. HAMMERLINDL, AND BRIAN J. SPROULE.E~~~C~S ofage OIZ regional residual volume. J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 44(Z): 195-199, 1978. -Forty-one normal nonsmokers between the ages of 20 and 80 were studied to determine if the increased residual volume, known to occur with aging, results from increased residual volume throughout, or only in specific regions of the lung. The subjects were divided into groups consisting of 20-29, 30-39, 40-49, 50-69, and 70+ yr. Measurements of regional residual volume to regional total lung capacity ratio (R&/TLC,) were made using xenon-133 and a multidetector analysis system in which five zones (from top to bottom) were analyzed in each lung. Closing volume was also measured. The subjects were in the sitting position for all studies. The results showed regardless of age, that R&/TLC, was higher at the top than at the bottom of the lung. In addition, the ratio of upper to lower R&/TLC, was not significantly different between any of the age groups. The results can be explained if airways throughout the lung close at higher volumes as age increases, or if altered emptying sequences within regions occur due to retarded emptying of highly compliant lung regions, closing volume;
xenon-133
AGING DECREASES THE ABILITY to empty the lungs resulting in increasing residual volume to total lung capacity ratio (RV/TLC). However, it is not known whether the entire lung or only a portion of the aging lung is responsible for increasing RV/TLC. Holland et al. (15) showed that subjects averaging 69 yr have a greater increase in regional RV/TLC (R&I TLC,) in the dependent than in the nondependent regions compared to subjects averaging 35 yr. However, four of the six subjects in Holland’s study were smokers for more than 40 yr which could have influenced the results. Engel et al. (10) showed at a lung volume slightly above RV, that airway closure could be detected up to 8 cm from the top of the lung in seated subjects averaging 33 yr. At RV it is possible that airway closure occurs throughout the lung even at this relatively young age, and that the loss in lung elastic recoil which accompanies aging (5, 27) may result in airways closing at higher volumes throughout the lung causing increased R&/TLC, in both dependent and nondependent regions. We used xenon-133 (l”“Xe) to measure the effects of age on R&/TLC, and to obtain information about the pattern of lung emptying. Our results indicate that aging increases R&/TLC, in all lung regions.
METHODS
Forty-one normal, life-time nonsmokers between the ages of 20 and 80 were separated into groups according to age. The groups consisted of 13 subjects 20-29 yr, 9 subjects 30-39 yr, 11 subjects 40-49 yr, 6 subjects 50-69 yr, and 2 subjects of 78 and 80 yr, respectively. Pulmonary function tests were conducted for all subjects and included lung volumes, forced expiratory volume in one second (FE&+,), and closing volume. Lung volumes were measured by helium dilution (19) with normal values for TLC and vital capacity (VC) obtained from the work of Boren et al. (7). Closing volume (CV) was measured by the single-breath oxygen method of Buist and Ross (8) with expiratory flow rates during the measurement kept below 0.5 l/s. At least two reproducible (VC differed by less than 5%) tracings were obtained on each subject with at least 5 min allowed between measurements. Closing capacity (CC), was measured by adding RV to CV and dividing this sum by TLC. The height of phase IV in the CV trace was measured according to the method of Siegler et al. (24) in which the change in nitrogen concentration is measured from the beginning of phase IV to its maximal concentration. In order to determine the takeoff point of phase IV a line of best fit was drawn through phase III omitting that portion of phase III lying within the first 30% of the exhaled vital capacity (9). RV,/TLC, was measured using l”“Xe and twenty scintillation detectors positioned over the chest of the seated subjects. Two colinear scintillation detectors (one anterior and one posterior) recorded count rates, which were integrated over 1.0-s intervals, from each of ten lung regions (five regions in each lung were analyzed). The upper detectors were centered approximately 5 cm from the top of the lungs and the centers of the lowest detectors were located 23 cm further down the lungs. The detector positions relative to the lungs are shown diagramatically in Fig. 1. The method used to measure R&/TLC, is illustrated in Fig. 2. The subjects were seated comfortably and the scintillation detectors positioned as described above. A seat belt was securely fastened around the pelvis to help the subjects maintain their position. A rubber mouthpiece was then inserted and a noseclip attached. The subjects breathed room air through a three-way valve (dead space 45 ml) during which time background counts were recorded from each of the 10 regions (Fig. 2, A). The valve was then turned so that the subject rebreathed from a closed circuit spirometer containing
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196
JONES, cm O--5---
11 ---
17---
22---
28---
FIG.
region
1. Approximate location of various regions studied. is analyzed by anterior as well as posterior detector.
2000
f 8 ii
Each
1
1ooo4
C-G=
l600
E-GRVr/TLCr
500
cps=
TLCr
cps-
RVr
= 5OO/I600=0.31
G
0 0
1 1
1 2
1 3
I 4
r 5
1 6
MINUVES
FIG.
single
2. Diagrammatic
region.
See text
example for details.
OVERTON,
HAMMERLINDL,
AND
SPROULE
of lx3Xe absorbed in the chest wall and lung parenchyma (Fig. 2, F). This linear portion was extrapolated to the beginning of the ls3Xe washout (20) to determine the count rate originating from lung and chest wall tissue during the two TLC breath holds (Fig. 2, G). The count rate represented by the difference E-G is proportional to RV, since any 133Xe remaining in the various regions after expiration to RV is simply diluted with inhaled room air. By making measurements of both TLC, and RV, with the subjects at TLC each region comprises similar lung units (20). Analysis of R&/TLC, in this manner requires that each detector has an output which is linearly related to changes in regional 133Xe concentration, and that the detectors “view” the same lung regions during the two TLC breath holds. To confirm this, the lungs of six additional normal subjects were equilibrated with five different 133Xe concentrations. At equilibrium, regional 13”Xe concentration is equal to 133Xe concentration in the spirometer (4). Each equilibration was done separately with complete f33Xe washout between procedures. After establishing an equilibrium the subjects inhaled to TLC and regional count rates were measured. Following this measurement the 133Xe was washed out of their lungs. The procedure was similar to that shown in Fig. 2 except RV, was not measured in these six subjects. When regional count rates at TLC were plotted against 133Xe concentration in the spirometer the linear regression coefficients ranged between 0. 94 a.nd 0.97 for all ten regions, thus confirming the linea rity of detector output and that a series of TLC breath holds can produce consistent detector-lung alignment Differences in RV,/TLC, between regions in a given age group were determined using the paired t-test while differences between corresponding regions of different age groups were determined using the unpaired t-test. Statistical analysis for the oldest group was not done since only two subjects comprised that group. l
of count
rate
vs. time
plot
from
approximately 0.5 mCi 13”Xe per liter room air. A series of deep breaths facilitated equilibration of lung gas with spirometer gas (Fig. 2, B). Oxygen was added and carbon dioxide was retioved to maintain a constant spirometer volume. After reaching equilibration the subjects were instructed to inhale to-TLC and hold their breath, with glottis open, for approximately 10 s so that a stable count rate could be recorded (Fig. 2, C). Following the TLC breath hold, instruction was given to exhale slowly (speed of expiration averaged 0.79 l/s) to RV (Fig, 2, D). Upon reaching RV the valve at the mouth was opened to room air and the subjects were instructed to inhale maximally to TLC and again hold their breath, with an open glottis, for 10 s (Fig. 2, E). A breath hold averaging 3.5 s occurred at RV to permit rotating the valve from the spirometer system containing 133Xe to room air. Following this procedure the subjects hyperventilated into an exhaust system to eliminate 133Xe from their lungs. A rapid 133Xe w.ashout is desirable, and to facilitate this all subjects inhaled a mixture of 5% carbon dioxide in room air during the washout phase so that a longer period of hyperventilation could be maintained. During the washout period the count rate from each region decreased rapidly due to elimination of 13”Xe from the ventilated air spaces, but after the initial rapid fal .l there was a linear decrease i.n count rate with time indicating eli .mination
RESULTS
Table 1 shows the pulmonary function results for each group. TLC and VC were at or slightly above the predicted values, and FEV, 0 was within the normal range. RV/TLC and CC/TLC increased with age with the regression equations being: RV/TLC = 6.54 + 0.48 (age), r = 0.81; CC/TLC = 13.79 + 0.57 (age), r = 0.85. Closing volume and the slope of phase III also increased with age with the regression equations being: CV/VC = 2.54 + 0.33 (age), r = 0.78; phase III slope (% NJl) = -0.48 + 0.05 (age), r = 0.74. Values of R&/TLC, from corresponding regions of right and left lungs (i.e., regions 1 and 6, Fig. 1) were not statistically different so the data from the two lungs were averaged. Figure 3 shows the R&/TLC, distributions for the various age groups. Adjacent regions within each group were significantly (P < 0.05) different from each other. It is clear that R&/TLC, increases with age in both the upper and lower lung regions. Statistically significant differences in RV,/ TLC, were found for the same regions between adjacent age groups. The age-related increase in R&/TLC, was
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EFFECTS
OF
AGE
ON
REGIONAL
RESIDUAL
TABLE 1. Pulmonary function for the different groups Age
TLC,
24.7 5 4.3
34.7 2 2.9
43.4 +- 2.1
60.0 k 6.1
79.0 k 1.4
All under
1
vc,
6.84 1.29 (115.6 + 14.5) 7.45 + 1.43 (116.8 2 11.9) 6.48 -t 1.32 (115.2 2 13.1) 5.92 + 1.25 (115.8 k 11.1) 4.94
2.0
results
1
FEV1,
5.61 * 1.04 (120.1 2 12.3) 5.6 1 0.98 (119.2 k 9.6) 4.69 k 0.94 (115.6 IL 12.5) 3.83 k 0.76 (114.3 + 15.2) 2.78 k 0.58 (95.5 z!z 0.7)
k 0.84 (98.5 Ifr 0.71)
197
VOLUME
1
RVITLC,
4.66 k 0.78 (83.6 5 5.7)* 4.40 k 0.57 (78.6 + 6.4) 3.61 ?I 0.74 (77.8 k 10.4) 2.78 k 0.52 (72.7 4 5.9) 1.93 Tk 0.11 (70.5 -t- 10.6)
values represent mean + 1 SD. TLC and VC represent % of predicted.
‘;r, CC/TLC,
17.8 k 7.7
1.0
23.7 + 5.3
U/L
33.0 k 4.2
0.5
27.3 + 5.6
38.3 k 7.4
0
24.7
34.7 MEAN
34.8 2 5.9
48.5 k 6.9
43.5 2 2.1
57.5 k 0.7
Values in parentheses * %VC.
0.7
o-6
1.5
9%
27.3 & 5.8
1
05
43.4 AGE
60.0
79.0
OF GROUPS
FIG. 4. Ratio of RVr/TLCr in upper (regions 1 and 6) to RVr/ TLCr in lower (regions 5 and 10) lung regions for different age groups. Values are expressed as mean k 1 SEM. There was no statistically significant difference between any groups.
tration difference between upper and lower lung regions. We found that the height of phase IV increased with age, the linear regression equation being: phase IV (%N2) = 2.93 + 0.09 (age, r = 0.50, P < 0.001. Presumably this reflects the age-related increase in nitrogen concentration gradient caused by the steadily increasing difference in R&/TLC, between upper and lower regions. Since airway closure is thought to occur primarily in the dependent lung regions during complete expiration (20) one might expect R&/TLC, in the lower regions to correlate better with closing capacity than R&/TLC, in the correlation bethe other lung regions. However, tween R&/TLC, and closing capacity was as good for the mid and upper lung regions as it was for the lowest region. The linear correlation coefficients ranged from 0.87 to 0.89.
0.3
DISCUSSION
RVr/ TLC r
0.2
0.1
0
r
T
1
T
1
1
5
10
15
20
25
30
Distance
From
Top
of
Lung
(cm)
3. RVr/TLCr for different regions in each age group. Values are expressed as mean k 1 SEM. Mean age of each group is shown next to values for lower regions. * Significant differences (P < 0.05) between specific regions of adjacent age groups. FIG.
similar in all lung regions. Figure 4 shows that the ratio of RVJTLC, in the upper region (U) to that in the lower region (L) was not statistically different between any of the age groups. These values for U/L are within the range reported by Engel et al. (12). Measurement of closing volume using the singlebreath oxygen technique relies on establishing a nitrogen concentration gradient between upper and lower lung regions. Siegler et al. (24) measured the height of phase IV to obtain an index of R&/TLC, distribution; this height is directly dependent on the nitrogen concen-
It is known that lung elastic recoil decreases with age (5, 27) and it has been proposed that this factor results in the lung parenchyma offering less support to the small airways leading to their instability and collapse at increasing lung volumes (3, 14, 25). Engel et al. (10) have shown that some airways in subjects 31-35 yr old do in fact close at low lung volumes and that closed airways can be found as high as 8 cm from the top of the lung at lung volumes of 4% VC. Since airway closure apparently begins in the most dependent regions and progresses upward with continued lung emptying (24) it is possible that even in young subjects airway closure is present in varying degrees at RV in all lung regions, including the uppermost regions. A uniform increase in R&/TLC, with age could result from airways in all lung regions closing at higher volumes due to decreased lung elastic recoil. The direct relationship between closing volume and age suggests that this is important in raising regional residual volume. Siegler et al. (24) found a decrease in the height of phase IV in asthmatics and interpreted this to indicate that regional residual volume is more evenly distributed between upper and lower lung regions. Our find-
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198 ings are compatible with this since the difference in R&/TLC, between upper and lower regions increased with age as did the height of phase IV. As the difference in R&/TLC, between upper and lower regions widens (despite constant U/L) the nitrogen concentration gradient increases, thus causing a higher phase IV. Although closed airways have been demonstrated to exist at lung volumes below the onset of phase IV (10, 13) it is co&dered by some (16) that the departure of from regions of low phase IV from phase III results nitrogen concentration reaching their flow limitation before other regions having higher nitrogen concentration. Pump (23) reported that aging is associated with emphysematous lesions within acini and that these lesions are distributed throughout the lung. These small units of differing mechanical properties could cause increased RVJTLC,, and in addition may play a role in producing phase IV. Martin et al. (18) have recorded phase IV’s from lung units as small as subsegments and they hypothesize that this occurs when flow from large poorly ventilated compartments increases relative to flow from other compartments. If such intraregional (within the individual detectors fields) areas of poor ventilation contribute to the production of phase IV, and also cause localized increases in R&/TLC, it is understandable why all regions in our study had a near-perfect correlation of closing capacity with RV,/ TLC,. Leith and Mead (17) proposed that in subjects less than 35 yr old RV is determined by the balance of forces be tween the chest wall and lun g, while in subjects over a-w 40, RV is determined by the inability to exhale completely due to expiratory flow limitations. It is possible that expiratory flow limitation, in addition to airway closure, could be responsible for increasing RV,/ TLC, with age. If flow limitation is an important factor then our data suggests that it affects lung emptying in all lung regions such that U/L remains constant. RVJTLC, distributio’n is dependent on the speed of expiration. Measurement of R&/TLC, following a fast expiration produces a larger R&/TLC, in the dependent regions than after a slow expiration (21). RV,/TLC, distribution obtained following a slow expiration to RV is similar to the value obtained if a breath hold follows a rapid expiration to RV. These data suggest that some air in dependent regions is trapped after a rapid expiration but if time is allowed for the trapped gas to escape, presumably via collateral channels, the true “static” RV,/TLC, is measured. Our results of R&/TLC, distribution likely represent the static situation since the expiratory flow rate to RV averaged a slow 0.79 l/s and, in addition, there was an average breath hold of 3.5 s at RV before the vital capacity inspiration of room air. It should be noted that Millette et al. (22) found no difference in the distribution of RV,/TLC, measured following expirations at 0.5 l/s and at maximal expiratory flow rate. Although our results show that aging increases RV,/ TLC, in all lung regions, Holland et al. (15) reported a greater increase in R&/TLC, in the lower than in the
JONES,
OVERTON,
HAMMERLINDL,
AND
SPRUULE
upper lung regions in a group averaging 69 yr when this group was compared with a group reported by Milk-Emili et al. (20) which averaged 35 yr. However, four of the six subjects studied by HO11and were smokers for more than 40 yr which reportedly affects airways in the lower lung regions primarily (Z), and this could have been responsible for the disproportionate increase in dependent R&/TLC,. Bigler and Renzetti (6) showed that R&/TLC, in a normal 71-yr-old female averaged 0.59 in the upper and 0.36 in the lower regions. These are similar to the values found in our oldest group. The single breath oxygen technique for measuring closing volume should become less sensitive with increasing age if there is a greater increase in RVJTLC, in the lower compared to the upper lung regions since the vertical gradient of nitrogen concentration would decrease and therefore make the departure of phase IV from phase III less distinct. However, Travis et al. (26) studied subjects of differing age and found that helium boluses introduced into the mouth at RV produced closing volumes which were not significantly different from those obtained using the single-breath oxygen technique. The helium bolus technique is thought to provide a greater concentration gradient from top to bottom and therefore make the departure of phase IV from phase III more distinct. The lack of difference between the two techniques suggests that the nitrogen concentration gradient developed by the single-breath oxygen technique is well preserved and that there is not a preferential increase in RV,/TLC, in the dependent lung regions with increasing age. It has been shown (11) that RVJTLC, becomes more uniform throughout the lungs after metacholine hydrochloride inhalation and that th .ebolus method for measuring closing volume produces a higher value than the single-breath oxygen method. Our results show that the height of phase IV increases with age. If R&/TLC, increased more in the lower than in the upper regions we would have expected the height of phase IV to decrease with age because of the smaller nitrogen concentration gradient which would have resulted. This, then, is added evidence that R&/TLC, does not increase more in the lower than in the upper regions wi th age. Although airway closure or expiratory flow limitations can explain the results of this study, the chest wall may also play an important role in determining RV (1). If expiratory muscle strength decreases or if the chest wall becomes less compressibl e with age then RV would naturally increa se and the increase would likely occur in all lung regions to a similar degree as found in this study. However, the closing volume data suggests that intrapulmonary rather than chest wall factors, are most important in determining RV and its distribution. This study was supported by the Canadian Thoracic Society Grant 55-03136. Address requests for reprints to: R. L. Jones, 6407, Clinical Sciences Building, University of Alberta, Edmonton, Alberta T6G 2G3, Canada. Received
for publication
7 February
1977.
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EFFECTS
OF
AGE
ON
REGIONAL
RESIDUAL
VOLUME
199
REFERENCES 1. AGOSTONI, E., AND G. TORRI. Diaphragm contraction as a limiting factor to maximum expiration. J. AppZ. Physiol. 17: 427428, 1962. 2. ANTHONISEN, N. R., H. BASS, A. ORIOL, R. E. G. PLACE, AND D. V. BATES. Regional lung function in patients with chronic bronchitis. C&z. Sci. 35: 495-511, 1968. 3. ANTHONISEN, N. R., J. DANSON, P. C. ROBERTSON, AND W. R. D. Ross. Airway closure as a function of age. Respiration Physiol. 8: 58-65, 1969, 4. BALL, W. C., P. B. STEWART, L. G. S. NEWSHAM, AND D. V. BATES. Regional pulmonary function studied with xenon. J. Clin. Invest. 41: 519-531, 1962. 5. BEGIN, R., A. D. RENZETTI, JR., A. H. BIGLER, AND S. WATANABE. Flow and age dependence of airway closure and dynamic compliance. J. Appl. PhysioZ. 38: 199-207, 1975. 6. BIGLER, A. H., AND A. D. RENZETTI, JR. Regional lung expansion using lsxXe: theory and methods. J. Appl. Physiol. 35: 770-777, 1973. 7. BOREN, H. G., R. C. KORY, AND J. C. SNYER. The Veterans Administration-Army cooperative study of pulmonary function. Am. J. Med. 41: 96-114, 1966. 8. BUIST, A. S., AND B. B. Ross. Predicted values for closing volume using a modified single breath nitrogen test. Am. Reu. Respirat. Diseases 107: 744-752, 1973. 9. BUIST, A. S., AND B. B. Ross. Quantitative analysis of the alveolar plateau in the diagnosis of early airway obstruction. Am. Rev. Respirat. Diseases 108: 1078-1087, 1973. 10. Engel, L. A., A. GRASSINO, AND N. R. ANTHONISEN. Demonstration of airway closure in man. J. Appl. Physiol. 38: 1117-1125, 1975. 11. ENGEL, L. A., L. LANDAU, L. TAUSSIG, AND P. T. MACKLEM. Influence of bronchomotor tone on airway closure. Am. Rev. Respirat. Diseases 111: 896, 1975. 12. ENGEL, L. A., L. LANDAU, L. TAUSSIG, R. R. MARTIN, AND G. SYBRECHT. Influence of bronchomotor tone on regional ventilation distribution at residual volume. J. AppZ. Physiol. 40: 411416, 1976. 13. FORKERT, L., S. DHINGRA, AND N. R. ANTHONISEN. The relationship of airway closure to lung volume (Abstract). Federation Proc. 36: 468, 1977.
14. HOEPPNER, V. H., D. M. COOPER, N. ZAMEL, A. C. BRYAN, AND H. LEVISON. Relationship between elastic recoil and closing volume in smokers and nonsmokers. Am. Reu. Respirat. Diseases 109: 81-86, 1974. 15. HOLLAND, J., J. MILIC-EMILI, P. T. MACKLEM, AND D. V. BATES. Regional distribution of pulmonary ventilation and perfusion in elderly subjects. J. Clin. Invest. 47: 81-92, 1968. 16. HYATT, R. E., G. C. OKESON, AND J. R. RODARTE. Influence of expiratory flow limitation on the pattern of lung emptying in man. J. Appl. Physiol. 35: 411-419, 1973. 17. LEITH, D. E., AND J. MEAD. Mechanisms determining residual volume of the lungs in normal subjects. J. AppZ. Physiol. 23: 221-227, 1967. 18. MARTIN, C. T., S. DAS, AND A. C. YOUNG. Terminal nitrogen rise. J. AppZ. Physiol. 41: 517-522, 1976. 19. MENEELY, G. R., AND N. L. KALTREIDER. Volume of the lung determined by helium dilution. J. C&z. Invest. 28: 129-139, 1949. 20. MILIC-EMILI, J., J. A. M. HENDERSON, M. B. DOLOVICH, D. TROP, AND K. KANEKO. Regional distribution of inspired gas in the lung. J. AppZ. Pbysiol. 21: 749-759, 1966. 21. MILIC-EMILI, J., AND F. RUFF. Effect of expiratory flow rate on closing capacity. CoZZoq. Inst. NatZ. Sante Rech. Med. 51: 395396, 1975. 22. MILLETTE, B., P. C. ROBERTSON, W. R. D. Ross, AND N. R. ANTHONISEN. Effect of expiratory flow rate on emptying of lung regions. J. AppZ. Physiol. 27: 587-591, 1969. 23. PUMP, K. K. The aged lung. Chest 60: 571-577, 1971. 24. SIEGLER, D., Y. FUKUCHI, AND L. ENGEL. Influence of bronchomotor tone on ventilation distribution and airway closure in Am. Rev. Respirat. Diseases 114: 123asyl *mptom atic asthma. 130 , 1976. 25. SLAGTER, B., AND H. HEEMSTRA. Limiting factors of expiration in normal subjects. Acta Physiol. PharmacoZ. NeerZ. 4: 419-421, 1955. 26. TRAVIS, D. M., M. GREEN, AND H. DON. Simultaneous comparison of helium and nitrogen expiratory “closing volume.” J. AppZ. Physiol. 34: 304-308, 1973. 27. TURNER, J. M., J. MEAD, AND M. E. WOHL. Elasticity of human lungs in relation to age. J. AppZ. PhysioZ. 25: 664-671, 1968.
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of age on regional
residual
volume
RICHARD L. JONES, THOMAS R. OVERTON, DONNA M. HAMMERLINDL, AND BRIAN J. SPROULE Division of Pulmonary Disease, Department of Medicine, and Division of Biomedical Engineering, Faculty of Medicine, University of Alberta, Edmonton, Alberta T6G 2G3, Canada
JONES,RICHARD L. ,THOMAS R. OVERTONJONNA M. HAMMERLINDL, AND BRIAN J. SPROULE.E~~~C~S ofage OIZ regional residual volume. J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 44(Z): 195-199, 1978. -Forty-one normal nonsmokers between the ages of 20 and 80 were studied to determine if the increased residual volume, known to occur with aging, results from increased residual volume throughout, or only in specific regions of the lung. The subjects were divided into groups consisting of 20-29, 30-39, 40-49, 50-69, and 70+ yr. Measurements of regional residual volume to regional total lung capacity ratio (R&/TLC,) were made using xenon-133 and a multidetector analysis system in which five zones (from top to bottom) were analyzed in each lung. Closing volume was also measured. The subjects were in the sitting position for all studies. The results showed regardless of age, that R&/TLC, was higher at the top than at the bottom of the lung. In addition, the ratio of upper to lower R&/TLC, was not significantly different between any of the age groups. The results can be explained if airways throughout the lung close at higher volumes as age increases, or if altered emptying sequences within regions occur due to retarded emptying of highly compliant lung regions, closing volume;
xenon-133
AGING DECREASES THE ABILITY to empty the lungs resulting in increasing residual volume to total lung capacity ratio (RV/TLC). However, it is not known whether the entire lung or only a portion of the aging lung is responsible for increasing RV/TLC. Holland et al. (15) showed that subjects averaging 69 yr have a greater increase in regional RV/TLC (R&I TLC,) in the dependent than in the nondependent regions compared to subjects averaging 35 yr. However, four of the six subjects in Holland’s study were smokers for more than 40 yr which could have influenced the results. Engel et al. (10) showed at a lung volume slightly above RV, that airway closure could be detected up to 8 cm from the top of the lung in seated subjects averaging 33 yr. At RV it is possible that airway closure occurs throughout the lung even at this relatively young age, and that the loss in lung elastic recoil which accompanies aging (5, 27) may result in airways closing at higher volumes throughout the lung causing increased R&/TLC, in both dependent and nondependent regions. We used xenon-133 (l”“Xe) to measure the effects of age on R&/TLC, and to obtain information about the pattern of lung emptying. Our results indicate that aging increases R&/TLC, in all lung regions.
METHODS
Forty-one normal, life-time nonsmokers between the ages of 20 and 80 were separated into groups according to age. The groups consisted of 13 subjects 20-29 yr, 9 subjects 30-39 yr, 11 subjects 40-49 yr, 6 subjects 50-69 yr, and 2 subjects of 78 and 80 yr, respectively. Pulmonary function tests were conducted for all subjects and included lung volumes, forced expiratory volume in one second (FE&+,), and closing volume. Lung volumes were measured by helium dilution (19) with normal values for TLC and vital capacity (VC) obtained from the work of Boren et al. (7). Closing volume (CV) was measured by the single-breath oxygen method of Buist and Ross (8) with expiratory flow rates during the measurement kept below 0.5 l/s. At least two reproducible (VC differed by less than 5%) tracings were obtained on each subject with at least 5 min allowed between measurements. Closing capacity (CC), was measured by adding RV to CV and dividing this sum by TLC. The height of phase IV in the CV trace was measured according to the method of Siegler et al. (24) in which the change in nitrogen concentration is measured from the beginning of phase IV to its maximal concentration. In order to determine the takeoff point of phase IV a line of best fit was drawn through phase III omitting that portion of phase III lying within the first 30% of the exhaled vital capacity (9). RV,/TLC, was measured using l”“Xe and twenty scintillation detectors positioned over the chest of the seated subjects. Two colinear scintillation detectors (one anterior and one posterior) recorded count rates, which were integrated over 1.0-s intervals, from each of ten lung regions (five regions in each lung were analyzed). The upper detectors were centered approximately 5 cm from the top of the lungs and the centers of the lowest detectors were located 23 cm further down the lungs. The detector positions relative to the lungs are shown diagramatically in Fig. 1. The method used to measure R&/TLC, is illustrated in Fig. 2. The subjects were seated comfortably and the scintillation detectors positioned as described above. A seat belt was securely fastened around the pelvis to help the subjects maintain their position. A rubber mouthpiece was then inserted and a noseclip attached. The subjects breathed room air through a three-way valve (dead space 45 ml) during which time background counts were recorded from each of the 10 regions (Fig. 2, A). The valve was then turned so that the subject rebreathed from a closed circuit spirometer containing
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196
JONES, cm O--5---
11 ---
17---
22---
28---
FIG.
region
1. Approximate location of various regions studied. is analyzed by anterior as well as posterior detector.
2000
f 8 ii
Each
1
1ooo4
C-G=
l600
E-GRVr/TLCr
500
cps=
TLCr
cps-
RVr
= 5OO/I600=0.31
G
0 0
1 1
1 2
1 3
I 4
r 5
1 6
MINUVES
FIG.
single
2. Diagrammatic
region.
See text
example for details.
OVERTON,
HAMMERLINDL,
AND
SPROULE
of lx3Xe absorbed in the chest wall and lung parenchyma (Fig. 2, F). This linear portion was extrapolated to the beginning of the ls3Xe washout (20) to determine the count rate originating from lung and chest wall tissue during the two TLC breath holds (Fig. 2, G). The count rate represented by the difference E-G is proportional to RV, since any 133Xe remaining in the various regions after expiration to RV is simply diluted with inhaled room air. By making measurements of both TLC, and RV, with the subjects at TLC each region comprises similar lung units (20). Analysis of R&/TLC, in this manner requires that each detector has an output which is linearly related to changes in regional 133Xe concentration, and that the detectors “view” the same lung regions during the two TLC breath holds. To confirm this, the lungs of six additional normal subjects were equilibrated with five different 133Xe concentrations. At equilibrium, regional 13”Xe concentration is equal to 133Xe concentration in the spirometer (4). Each equilibration was done separately with complete f33Xe washout between procedures. After establishing an equilibrium the subjects inhaled to TLC and regional count rates were measured. Following this measurement the 133Xe was washed out of their lungs. The procedure was similar to that shown in Fig. 2 except RV, was not measured in these six subjects. When regional count rates at TLC were plotted against 133Xe concentration in the spirometer the linear regression coefficients ranged between 0. 94 a.nd 0.97 for all ten regions, thus confirming the linea rity of detector output and that a series of TLC breath holds can produce consistent detector-lung alignment Differences in RV,/TLC, between regions in a given age group were determined using the paired t-test while differences between corresponding regions of different age groups were determined using the unpaired t-test. Statistical analysis for the oldest group was not done since only two subjects comprised that group. l
of count
rate
vs. time
plot
from
approximately 0.5 mCi 13”Xe per liter room air. A series of deep breaths facilitated equilibration of lung gas with spirometer gas (Fig. 2, B). Oxygen was added and carbon dioxide was retioved to maintain a constant spirometer volume. After reaching equilibration the subjects were instructed to inhale to-TLC and hold their breath, with glottis open, for approximately 10 s so that a stable count rate could be recorded (Fig. 2, C). Following the TLC breath hold, instruction was given to exhale slowly (speed of expiration averaged 0.79 l/s) to RV (Fig, 2, D). Upon reaching RV the valve at the mouth was opened to room air and the subjects were instructed to inhale maximally to TLC and again hold their breath, with an open glottis, for 10 s (Fig. 2, E). A breath hold averaging 3.5 s occurred at RV to permit rotating the valve from the spirometer system containing 133Xe to room air. Following this procedure the subjects hyperventilated into an exhaust system to eliminate 133Xe from their lungs. A rapid 133Xe w.ashout is desirable, and to facilitate this all subjects inhaled a mixture of 5% carbon dioxide in room air during the washout phase so that a longer period of hyperventilation could be maintained. During the washout period the count rate from each region decreased rapidly due to elimination of 13”Xe from the ventilated air spaces, but after the initial rapid fal .l there was a linear decrease i.n count rate with time indicating eli .mination
RESULTS
Table 1 shows the pulmonary function results for each group. TLC and VC were at or slightly above the predicted values, and FEV, 0 was within the normal range. RV/TLC and CC/TLC increased with age with the regression equations being: RV/TLC = 6.54 + 0.48 (age), r = 0.81; CC/TLC = 13.79 + 0.57 (age), r = 0.85. Closing volume and the slope of phase III also increased with age with the regression equations being: CV/VC = 2.54 + 0.33 (age), r = 0.78; phase III slope (% NJl) = -0.48 + 0.05 (age), r = 0.74. Values of R&/TLC, from corresponding regions of right and left lungs (i.e., regions 1 and 6, Fig. 1) were not statistically different so the data from the two lungs were averaged. Figure 3 shows the R&/TLC, distributions for the various age groups. Adjacent regions within each group were significantly (P < 0.05) different from each other. It is clear that R&/TLC, increases with age in both the upper and lower lung regions. Statistically significant differences in RV,/ TLC, were found for the same regions between adjacent age groups. The age-related increase in R&/TLC, was
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EFFECTS
OF
AGE
ON
REGIONAL
RESIDUAL
TABLE 1. Pulmonary function for the different groups Age
TLC,
24.7 5 4.3
34.7 2 2.9
43.4 +- 2.1
60.0 k 6.1
79.0 k 1.4
All under
1
vc,
6.84 1.29 (115.6 + 14.5) 7.45 + 1.43 (116.8 2 11.9) 6.48 -t 1.32 (115.2 2 13.1) 5.92 + 1.25 (115.8 k 11.1) 4.94
2.0
results
1
FEV1,
5.61 * 1.04 (120.1 2 12.3) 5.6 1 0.98 (119.2 k 9.6) 4.69 k 0.94 (115.6 IL 12.5) 3.83 k 0.76 (114.3 + 15.2) 2.78 k 0.58 (95.5 z!z 0.7)
k 0.84 (98.5 Ifr 0.71)
197
VOLUME
1
RVITLC,
4.66 k 0.78 (83.6 5 5.7)* 4.40 k 0.57 (78.6 + 6.4) 3.61 ?I 0.74 (77.8 k 10.4) 2.78 k 0.52 (72.7 4 5.9) 1.93 Tk 0.11 (70.5 -t- 10.6)
values represent mean + 1 SD. TLC and VC represent % of predicted.
‘;r, CC/TLC,
17.8 k 7.7
1.0
23.7 + 5.3
U/L
33.0 k 4.2
0.5
27.3 + 5.6
38.3 k 7.4
0
24.7
34.7 MEAN
34.8 2 5.9
48.5 k 6.9
43.5 2 2.1
57.5 k 0.7
Values in parentheses * %VC.
0.7
o-6
1.5
9%
27.3 & 5.8
1
05
43.4 AGE
60.0
79.0
OF GROUPS
FIG. 4. Ratio of RVr/TLCr in upper (regions 1 and 6) to RVr/ TLCr in lower (regions 5 and 10) lung regions for different age groups. Values are expressed as mean k 1 SEM. There was no statistically significant difference between any groups.
tration difference between upper and lower lung regions. We found that the height of phase IV increased with age, the linear regression equation being: phase IV (%N2) = 2.93 + 0.09 (age, r = 0.50, P < 0.001. Presumably this reflects the age-related increase in nitrogen concentration gradient caused by the steadily increasing difference in R&/TLC, between upper and lower regions. Since airway closure is thought to occur primarily in the dependent lung regions during complete expiration (20) one might expect R&/TLC, in the lower regions to correlate better with closing capacity than R&/TLC, in the correlation bethe other lung regions. However, tween R&/TLC, and closing capacity was as good for the mid and upper lung regions as it was for the lowest region. The linear correlation coefficients ranged from 0.87 to 0.89.
0.3
DISCUSSION
RVr/ TLC r
0.2
0.1
0
r
T
1
T
1
1
5
10
15
20
25
30
Distance
From
Top
of
Lung
(cm)
3. RVr/TLCr for different regions in each age group. Values are expressed as mean k 1 SEM. Mean age of each group is shown next to values for lower regions. * Significant differences (P < 0.05) between specific regions of adjacent age groups. FIG.
similar in all lung regions. Figure 4 shows that the ratio of RVJTLC, in the upper region (U) to that in the lower region (L) was not statistically different between any of the age groups. These values for U/L are within the range reported by Engel et al. (12). Measurement of closing volume using the singlebreath oxygen technique relies on establishing a nitrogen concentration gradient between upper and lower lung regions. Siegler et al. (24) measured the height of phase IV to obtain an index of R&/TLC, distribution; this height is directly dependent on the nitrogen concen-
It is known that lung elastic recoil decreases with age (5, 27) and it has been proposed that this factor results in the lung parenchyma offering less support to the small airways leading to their instability and collapse at increasing lung volumes (3, 14, 25). Engel et al. (10) have shown that some airways in subjects 31-35 yr old do in fact close at low lung volumes and that closed airways can be found as high as 8 cm from the top of the lung at lung volumes of 4% VC. Since airway closure apparently begins in the most dependent regions and progresses upward with continued lung emptying (24) it is possible that even in young subjects airway closure is present in varying degrees at RV in all lung regions, including the uppermost regions. A uniform increase in R&/TLC, with age could result from airways in all lung regions closing at higher volumes due to decreased lung elastic recoil. The direct relationship between closing volume and age suggests that this is important in raising regional residual volume. Siegler et al. (24) found a decrease in the height of phase IV in asthmatics and interpreted this to indicate that regional residual volume is more evenly distributed between upper and lower lung regions. Our find-
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198 ings are compatible with this since the difference in R&/TLC, between upper and lower regions increased with age as did the height of phase IV. As the difference in R&/TLC, between upper and lower regions widens (despite constant U/L) the nitrogen concentration gradient increases, thus causing a higher phase IV. Although closed airways have been demonstrated to exist at lung volumes below the onset of phase IV (10, 13) it is co&dered by some (16) that the departure of from regions of low phase IV from phase III results nitrogen concentration reaching their flow limitation before other regions having higher nitrogen concentration. Pump (23) reported that aging is associated with emphysematous lesions within acini and that these lesions are distributed throughout the lung. These small units of differing mechanical properties could cause increased RVJTLC,, and in addition may play a role in producing phase IV. Martin et al. (18) have recorded phase IV’s from lung units as small as subsegments and they hypothesize that this occurs when flow from large poorly ventilated compartments increases relative to flow from other compartments. If such intraregional (within the individual detectors fields) areas of poor ventilation contribute to the production of phase IV, and also cause localized increases in R&/TLC, it is understandable why all regions in our study had a near-perfect correlation of closing capacity with RV,/ TLC,. Leith and Mead (17) proposed that in subjects less than 35 yr old RV is determined by the balance of forces be tween the chest wall and lun g, while in subjects over a-w 40, RV is determined by the inability to exhale completely due to expiratory flow limitations. It is possible that expiratory flow limitation, in addition to airway closure, could be responsible for increasing RV,/ TLC, with age. If flow limitation is an important factor then our data suggests that it affects lung emptying in all lung regions such that U/L remains constant. RVJTLC, distributio’n is dependent on the speed of expiration. Measurement of R&/TLC, following a fast expiration produces a larger R&/TLC, in the dependent regions than after a slow expiration (21). RV,/TLC, distribution obtained following a slow expiration to RV is similar to the value obtained if a breath hold follows a rapid expiration to RV. These data suggest that some air in dependent regions is trapped after a rapid expiration but if time is allowed for the trapped gas to escape, presumably via collateral channels, the true “static” RV,/TLC, is measured. Our results of R&/TLC, distribution likely represent the static situation since the expiratory flow rate to RV averaged a slow 0.79 l/s and, in addition, there was an average breath hold of 3.5 s at RV before the vital capacity inspiration of room air. It should be noted that Millette et al. (22) found no difference in the distribution of RV,/TLC, measured following expirations at 0.5 l/s and at maximal expiratory flow rate. Although our results show that aging increases RV,/ TLC, in all lung regions, Holland et al. (15) reported a greater increase in R&/TLC, in the lower than in the
JONES,
OVERTON,
HAMMERLINDL,
AND
SPRUULE
upper lung regions in a group averaging 69 yr when this group was compared with a group reported by Milk-Emili et al. (20) which averaged 35 yr. However, four of the six subjects studied by HO11and were smokers for more than 40 yr which reportedly affects airways in the lower lung regions primarily (Z), and this could have been responsible for the disproportionate increase in dependent R&/TLC,. Bigler and Renzetti (6) showed that R&/TLC, in a normal 71-yr-old female averaged 0.59 in the upper and 0.36 in the lower regions. These are similar to the values found in our oldest group. The single breath oxygen technique for measuring closing volume should become less sensitive with increasing age if there is a greater increase in RVJTLC, in the lower compared to the upper lung regions since the vertical gradient of nitrogen concentration would decrease and therefore make the departure of phase IV from phase III less distinct. However, Travis et al. (26) studied subjects of differing age and found that helium boluses introduced into the mouth at RV produced closing volumes which were not significantly different from those obtained using the single-breath oxygen technique. The helium bolus technique is thought to provide a greater concentration gradient from top to bottom and therefore make the departure of phase IV from phase III more distinct. The lack of difference between the two techniques suggests that the nitrogen concentration gradient developed by the single-breath oxygen technique is well preserved and that there is not a preferential increase in RV,/TLC, in the dependent lung regions with increasing age. It has been shown (11) that RVJTLC, becomes more uniform throughout the lungs after metacholine hydrochloride inhalation and that th .ebolus method for measuring closing volume produces a higher value than the single-breath oxygen method. Our results show that the height of phase IV increases with age. If R&/TLC, increased more in the lower than in the upper regions we would have expected the height of phase IV to decrease with age because of the smaller nitrogen concentration gradient which would have resulted. This, then, is added evidence that R&/TLC, does not increase more in the lower than in the upper regions wi th age. Although airway closure or expiratory flow limitations can explain the results of this study, the chest wall may also play an important role in determining RV (1). If expiratory muscle strength decreases or if the chest wall becomes less compressibl e with age then RV would naturally increa se and the increase would likely occur in all lung regions to a similar degree as found in this study. However, the closing volume data suggests that intrapulmonary rather than chest wall factors, are most important in determining RV and its distribution. This study was supported by the Canadian Thoracic Society Grant 55-03136. Address requests for reprints to: R. L. Jones, 6407, Clinical Sciences Building, University of Alberta, Edmonton, Alberta T6G 2G3, Canada. Received
for publication
7 February
1977.
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EFFECTS
OF
AGE
ON
REGIONAL
RESIDUAL
VOLUME
199
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