- Email: [email protected]
Closing volume in healthy non-smokers
Brit. 3. Dis. Chest
CLOSING
(1973)
67,
Ig
VOLUME IN HEALTHY NON-SMOKERS
J. V. COLLINS, T. J. H. CLARK, S. MCHARDY-YOUNG, G. M. COCHRANE AND J. CRAWLEY Guy’s Hospital,
London
of FEV,, FVC and PEFR are easily made both in hospital and general practice and have proved useful in the assessment of disability and response to treatment in patients with chronic bronchitis, asthma and other diseases associated with airways obstruction. These tests have been found to be less suitable for detecting the early effects of disease or minimal loss of lung function and this can in part be explained by the fact that such tests are mainly influenced by changes in larger airways and lung elastic recoil (Pride 1971). Consequently these tests are not especially relevant to the early stages of disease, particularly if it begins in small airways which have a disproportionately small effect on total airway resistance and other tests have been designed to study the behaviour of distal airways. Frequency-dependence of pulmonary compliance is thought to reflect changes in small airways (Macklem 1972) but the measurement requires both sophisticated apparatus and investigators (Flenley et al. rg7 I). Recently a simple technique of expired gas analysis has been developed, which provides information about small airway behaviour. This ‘closing volume’ technique is thought to provide an indirect measurement of the lung volume at which airway closure begins and can therefore furnish evidence about the small airways which are likely to be the first to close at low lung volumes (Collins 1973). The technique is simple for the subject and operator and gives results with good reproducibility in health and some pathological states (Leblanc et al. 1970; Collins et al. 1972). It has been suggested that measurement of ‘closing volume’ may be a good epidemiological technique for screening large numbers of subjects for abnormal small airway behaviour (Buist & Ross 1972; Macklem 1972). A third technique which is believed to reflect changes in small airways has been developed, namely measurement of maximum mid-expiratory flow rate (McFadden & Linden 1972). This has slight advantages over measurement of ‘closing volume’ in simplicity of equipment and comfort for the patient but is believed to be a less sensitive indicator of small airway behaviour (Macklem I 972). We report the results of measurements of ‘closing volume’ under various conditions in a group of healthy non-smokers in the United Kingdom.
MEASUREMENTS
(Received
for publication
October
1972)
20
COLLINS
‘Closing
Volume’
ET
AL,
Technique
The ‘closing volume’ method makes use of the uneven distribution of ventilation which follows inspiration from residual volume (RV) (Milic-Emili et al. 1966) and is described in detail elsewhere (Dollfuss et al. 1967). It requires the use of a marker gas which in the original work was xenon-133 but may be another inert gas such as nitrogen, argon or helium. We have used xenon-133 for this study. The seated subject exhales to RV and is connected to a spirometer circuit containing room air. A bolus of O-I-0.3 mCi xenon-133 in 2 ml air is injected into the mouthpiece and the subject makes a slow steady vital capacity (VC)
TLC Volume of expirate FIG. I. Diagrammatic representation of the
RV 4 closing
volume
trace
inspiration to total lung capacity (TLC) at a rate of about 0.3-0.5 litres/sec. In normal subjects this results in a concentration gradient of the marker gas down the lungs so that the concentration in the upper zones is 5-10 times greater than in the lower zones (Anthonisen et al. 1970). The subject now exhales slowly at the same rate to RV and during expiration the concentration of xenon-133 is measured continuously at the mouth by a scintillation counter. The output from the counter is fed through a rate-meter and is displayed on the Y axis of an XY recorder. Simultaneously the volume of the expirate is measured by a potentiometer on the spirometer and this is recorded on the X axis of the XY recorder, This produces a characteristic trace represented diagrammatjcally in Fig. I. The trace has 4 phases : Phase I caused by emptying of the dead space of the trachea and apparatus, Phase 2 at the commencement of emptying of the lungs, Phase 3 the ‘alveolar plateau’ produced by mixing of air and xenon-r 33 from all lung regions and Phase 4, a rapid rise of the concentration of xenon-r 33 towards
CLOSING
VOLUME
IN
21
NON-SMOKERS
the end of the vital capacity expiration. This Phase 4 results from the emptying of the upper zones of the lungs when emptying has ceased from the rest of the lungs (Dollfuss et al. 1967). The junction between Phases 3 and 4 marks the lung volume at which small airway size begins to change. Results may be expressed as Phase 4, measured as a volume, related to vital capacity (Phase 4 volume/VC %). Alternatively, Phase 4 volume may be added to residual volume (RV), measured by other methods, and the sum referred to as ‘closing volume’ (CV), i.e. CV=Phase 4 volume +RV. Then CV is related to total lung capacity (CVjTLC %) . Patients
and Methods
Forty-one normal subjects (FEVJFVC greater than 75% with no change after a bronchodilator aerosol), all of whom were lifelong non-smokers with no history of respiratory or cardiac disease, were studied. There were 16 women and 25 men with ages ranging from I 7 to 6g years (mean age 36. I years). All subjects were studied seated erect and in all subjects the measurements were repeated after the inhalation of 200 pg of a /3-adrenergic bronchodilator aerosol (salbutamol). In 31 subjects the studies were also repeated with the subject supine before the use of the aerosol. Forced expiratory volume in I set (FEV,) and forced vital capacity (FVC) were measured under the same conditions using a water cannister spirometer. Total lung capacity (TLC) was measured erect in all subjects by the helium dilution method or derived from radiographic data (Lloyd et al. 1966). The radiographic volumes were corrected to helium volumes using a conversion factor employed in our laboratory. Residual volume was obtained by subtraction. For the ‘closing volume’ study the technique was explained to the subject and the manoeuvre practised without xenon- I 33 until the subject had perfected the control of flow rates required. Then 3-6 separate traces were recorded in each subject using xenon-133 before and after the use of the bronchodilator aerosol and a similar number in the supine studies. The volume of Phase 4 was measured from each trace by 2 independent observers, I of whom had not been present during the procedure and the mean value for the size of Phase 4 was calculated from the pooled measurements of both observers. To assess the reproducibility of Phase 4 in the individual subject 5 recordings before and 5 after the inhalation of the bronchodilator aerosol were made in each of IO subjects on I day. Coefficients of variation for Phase 4 before and after the bronchodilator were calculated for each subject and mean values were calculated for the group. In 31 subjects mean values for the ratio Phase 4 volume/VC y. for each subject were also obtained on 2 separate days for comparison. The mean value for Phase 4 volume for each day for an individual subject was calculated from the combined results obtained by 2 observers on that day. The observers were compared by correlating their results for the mean of Phase 4 in 31 subjects on the same day. At each stage of the studies in individual subjects FEV, and FVC were recorded 3 times, and the largest values were used each time.
22
COLLINS
ET
AL.
Each trace was recorded using 0.1-0.3 mCi of xenon-r 33 and the total time I inhalation/exhalation was approximately 30 seconds. If a total dose of 1-3 mCi of xenon-133 is used in each complete patient study (approximately IO traces) the absorbed dose for the lungs per subject is of the order of 14-42 mrads (Clark et al. 1967). for
Results In seated subjects the ratio of Phase 4 volume/VC yO showed a linear increase with age, the increase of Phase 4 each year being o*3go/o VC. Re-expressed as ‘closing volume’ the change with age of CV was 0*68O/~ TLC per year (Table I). TABLE REGRESSION
I.
RESULTS WITH
OF AGE
of
No. subjects
Position
Erect before salbutamol Erect after salbutamol
41
THE PRESENT OF PHASE 4/VC
STUDY
Phase 4/VC yO (_f1 SD)
IN
o/0 AND
HEALTHY
‘CLOSING
Tolerance limits
-z.6+0.3gxage
k10.8
Closing TLC%
Erect
31
Supine
31
volume/ (+I
SD)
II.g+o.68xage
Tolerance limits k22.0
(f5.5)
(f2.8)
41
NON-SMOKERS:
VOLUME’/TLC%
-2.l+o.38xage (f3.0)
k11.3
-o.46+o.35xage (k3.4) 1.3+0.34xage (53.3)
i ‘3’7
-
-
f ‘3’3
-
-
11.8+0.68xage
k2o.g
(k5.5)
For the SD and tolerance limits see Discussion and Bowden (I 966) In 31 subjects studied
erect and supine the increase in Phase 4 with age was 0*350/O VC/year erect and 0*34O/~ VC/year supine. These slightly lower values for the regression with age of Phase 4 may be due to the inclusion of more young subjects in this smaller group. After inhalation of salbutamol by aerosol there was no significant change in the size of the Phase 4 volume or ‘closing volume’ or the ratios Phase 4 volume/VC y. and CV/TLC y. and the regressions with age for these ratios were unaltered (Table I). The mean coefficients of variation for size of Phase 4 as a volume in IO subjects were I 1.5% before salbutamol and 10*20/O after. In 31 subjects the mean values for the ratio Phase 4 volume/VC o/o were compared on 2 separate days. The mean and standard deviation for the group were not significantly different (Day I : 10.6% VC ) 5.0; Day 2 : 10.1 y. VC ir 4.8) and the correlation coefficient was 0.88. The correlation coefficient for the 2 observers comparing their estimates of Phase 4/VC y. in 3 I subjects was o-91. Discussion As we have reported previously the ‘closing volume’ technique is simple for the operator and subject and shows good reproducibility in individual stibjects from
day
to day
both
in health
and
in patients
with
aortic
and
mitral
valve
CLOSING
VOLUME
IN
23
NON-SMOKERS
0
0 0 0
0
0
0
0 0
0 0 0 C 0
COO 0
0 0
800
00
oc cm
00
0
co8
IO
2. Results
FIG.
20
for
30
41 healthy
40 50 Age in years
subjects
for
Phase
60
4/VC
70
yO related
to age
, 0 l
0
’
I
30
I
40
I
50
.****** Anthonisen LeBlanc - - McCarthy --Collins
I
I
60
70
Age (years) FIG.
3. Regression
with
age of Phase 4/VC of present study with
yO in erect healthy subjects, three previous studies
comparison
of results
disease (Collins et al. 197 I, 1972). This is supported by the coefficients of variation reported in this study. The reproducibility of the measurement in individual subjects in our study is probably of a similar order to that reported
24
COLLINS
ET
AL.
previously (Anthonisen et al. 1969; Leblanc et al. 1970; McCarthy et al. 1972). However, this and other comparisons are complicated by apparent discrepancies in terminology among several authors. Thus ‘closing volume’ seems to have been used to mean Phase 4 volume alone and at other times to mean Phase 4 volume plus residual volume. For the purposes of comparison we have assumed that when previous authors relate ‘closing volume’ (CV) to vital capacity they have been using CV to mean Phase 4 volume. Similarly, no explanations have been provided for the derivation of the term ‘standard deviation’ of ‘closing volume’. We have recalculated the data provided by Leblanc et al. (1970) and McCarthy et al. (1972) and we find that standard deviation would seem to refer to the S, the square root of the residual mean square of Phase 4 volume/VC %. Comparing the present study with these previous studies (Fig. 3) we have found very similar values both for regression with age of Phase 4 volume/VC yO and standard deviation in erect subjects (Table 2). TABLE
2.
RESULTS FROM REGRESSIONS
Re@ort Anthonisen Leblance McCarthy Collins
Position
et al. 1967” et al. 1970” et al. et al.
1972
Ig72*
Erect? Erect? Supinet Erect Supinet Erect Supine
VARIOUS STUDIES IN WITH AGE OF PHASE
No.of subjects
840’ 2: Not stated 3’ 3’
HEALTHY 41 VC%
SUBJECTS:
of
Regression VC 0/o per year 0.55 0.42 0.56 0.36 0.56 0.35 0’34
s -
Tolerance limits -
f4.5 k4.0
f 1.3’3
f3.I
k11.3
f4.0 rfr3.4 -t3’3
k’3’7 f ‘3’3
-
-
* ‘Closing volume’/VC “/o has been assumed to refer to Phase 4 volume/VC %. t Subjects were mixed groups of smokers and non-smokers. 1 No separate values were given for the regression in erect studies in these groups.
In our study there was no difference in the ratio Phase 4 volume VC yO in individual subjects between erect and supine studies and the regression with age was almost identical in both positions. As we did not measure RV supine we do not know whether the regression with age for CV/TLC yO was different. The inhalation of a P-adrenergic bronchodilator aerosol did not alter the size of Phase 4 volume or ‘closing volume’ in our healthy subjects. The autonomic innervation of the bronchial tree is complex (Widdicombe & Sterling 1970) and such aerosols may not influence sympathetic tone in health. Changes in ‘closing volume’ after inhalation of such aerosols have been observed in patients with mitral and aortic valve disease (Collins et al. r 972) but the ‘closing volume’ technique may not be sufficiently sensitive to detect lesser changes which may occur in healthy subjects. It has been suggested that measurement of ‘closing volume’ may be a useful technique for population screening for early abnormalities of small airway behaviour (Buist & Ross 1972; McCarthy et al. 1972; Macklem 1972). While we have found Phase 4 to be reproducible in individual subjects we believe that
CLOSING
VOLUME
IN
NON-SMOKERS
25
the standard deviation as expressed by S does not take sufficient account of sampling error and is over optimistic in defining limits of ‘health’. We have calculated tolerance limits about our fitted lines using methods suggested by Bowden (1966) to enclose 95% of the population in our study in the age range 20-70 years with a confidence of 0.925 (Table I). Taking the example of our studies in seated erect subjects this gave a value of + 1043 for the range of Phase 4 volume VC y. at any age about our fitted regression line. This should be compared with the value for S which was 5 243. We have performed similar calculations for data from previous studies (Table 2). Controversy still surrounds the interpretation of the ‘closing volume’ trace. Dollfuss et al. (I 967) originally suggested that the change of slope from Phase 3 to Phase 4 resulted from closure of airways in the dependent zones of the lung. This explanation would account for the regional inhomogeneity of ventilation on inspiration from low lung volumes previously observed (Milic-Emili et al. I 966). In animal studies it has been shown that the gradient of pleural pressure down the lung, itself the result of gravity and the weight of the lung, would be sufficient to produce closure of small airways in the dependent zones. Histological techniques have been used to demonstrate closed airways in excised dog lungs in which conditions have been produced closely resembling those in the upright human lung (Hughes et al. 1970). The volume at which Phase 4 begins is known to vary with the expiratory flow rate such that increase in expiratory flow rate results in an increase in the size of the Phase 4 volume (Jones & Clarke 1969). This was confirmed by Hyatt and Okesen (197 I) using expiratory flow volume recordings. They showed that with increasing expiratory flow rate the size of the Phase 4 volume may rise from 15 to 50% VC in the same subject. They found that the start of Phase 4 coincides with a point on the flow/volume curve where flow limitation and a sharp rise in transpulmonary pressure begin. They suggested that this rise in transpulmonary pressure causes dynamic compression but not closure of airways in the dependent zones with a slowing of their rate of emptying. This would diminish the dilution effect of the dependent zone air on the air coming from the upper zones which is richer in marker gas and so result in a rising concentration of marker gas, i.e. Phase4. In the present study the inspiratory and expiratory flow rates were carefully controlled to rates below 0.5 litres per second and the size of the Phase 4 volume is independent of flow in this range (Travis et al. 1973). Whether the explanation of ‘closing volume’ is closure or dynamic compression of airways, our results confirm the findings of previous authors that when expiratory flow rates are kept low reproducible results are obtained in normal subjects that seem likely to reflect changes in small airways. The technique is being used to investigate a variety of diseases both in Europe and North America (Bjure et al. 1970; Ruff et al. 1971; Buist & Ross 1972; Collins et al. 1972 ; McCarthy et al. 1972 ; McFadden & Linden 1972) and it has been suggested that measurement of ‘closing volume’ may be useful for large scale epidemiological studies of early abnormalities in small airways in chronic bronchitis (Buist & Ross 1972 ; Macklem 1972). Our own experience with the 3
26
COLLINS
technique in patients with doubts we have expressed healthy subjects, suggest to before the technique could
ET
AL.
bronchial asthma (Clark IgTr), together with the about the tolerance limits of the measurement in us that further developmental studies are required be recommended for large-scale clinical use. Summary
‘Closing volume’, defined as that lung volume at which the dependent lung zones ceases expiration, was measured in 41 healthy non-smokers aged seventeen to sixty-nine years using xenon-r 33, Subjects were studied erect before and after inhalation of a /?-adrenergic bronchodilator aerosol and in 31 subjects the studies were repeated in the supine position. Results in individual subjects showed good reproducibility. The regression with age and standard deviation of the measurements were similar to previous reports and no change was observed after inhalation of bronchodilator. The relationship of Phase 4 to vital capacity was unaltered by change in posture. It is suggested that the use of standard deviation (i.e. f 2 SD) to define the limits of a normal range may be unduly optimistic. Tolerance limits to include 95% of healthy subjects calculated from studies of this size would provide unacceptably wide ranges for epidemiological purposes if the technique were introduced as a screening test for early disease of small airways. It is suggested that further developmental studies are required.
ACKNOWLEDGEMENTS
This research was carried whom we wish to thank advice, and to our willing Reprint
requests
out with for support. subjects.
to J. V.
Collins,
the
aid of a grant Our thanks are
Westminster
from the Chest and Heart also due to Frank House
Hospital,
London
Foundation for statistical
SWI.
REFERENCES
ANTHONISEN, N. R., DANSON, J., ROBERTSON, P. C. & Ross, W. R. D. (I 969) Airway closure as a function of age. Resp. Physiol., 8, 58. ANTHONISEN, N. R., ROBERTSON, P. C. & Ross, W. R. D. (1970) Gravity-dependent sequential emptying of lung regions. J. apjl. Physiol., 28, 589. BJURE, J., GRIMBY, G., KASALICICY, J., LINDH, M. & NACHEMSON, A. (1970) Respiratory impairment and airway closure in patients with untreated idiopathic scoliosis. Thorax, 25,
451. BOWDEN, D. C. (1966) Confidence band of uniform width for the regression line with a smaller than x smaller than b. J. Am. statist. Ass., 61, 182. BUIST, A. S. & Ross, B. B. (1972) ‘Closing volume’ as a simple, sensitive test for the detection of peripheral airway disease. 15th AsFen Conf. Proc., 34. CLARK, J. C., MATTHEWS, C. M. E., SILVESTER, D. J. & VONBERG, D. D. (I 967) Using cyclotonproduced isotopes at Hammersmith Hospital. Nucleonics, 25, 54. CLARK, T. J. H. (I 97 I) Assessment of airway closure using the closing volume method. Proc.
R. Sot. Med., 64, COLLINS,
J. V.
(1972)
1245.
Closing
volume-a
test
of small
airway
function.
Br. 3. Dis. Chest, 67, I.
CLOSING
VOLUME
IN
NON-SMOKERS
27
COLLINS, J. V.,
CLARK, T. J. H. & MCHARDY-YOUNG, S. (1972) Small airway closure in left heart failure. Thorax, 27, 260. COLLINS, J. V., CLARK, T. J. H., MCHARDY-YOUNG, S., CRAWLEY, J. & TURNER, J. (1971) Gravity-dependent peripheral airway closure in left heart failure. Clin. Sci., 40, 23P. DOLLFUSS, R. E., MILIC-EMILI, J. & BATES, D. V. (1967) Regional ventilation of the lung, studied with boluses of 133 xenon. Resp. Physiol., 2, 234. FLENLEY, D. C., GUYATT, A. R., SIDDORN, J. A. & BRASH, H. (1971) Frequency dependence of compliance. Proc. R. Sot. Med., 64, 1243. HUGHES, J. M. B., ROSENZWEIG, D. Y. & KIVITZ, P. B. (1970) Site of airway closure in excised dog lungs: histologic demonstration. J. a#$. Physiol., 29, 340. HYATT, R. E. & OKESEN, G. C. (1971) Expiratory flow limitation, the cause of so-called ‘airway closure’ or ‘closing volume’. Physiologist, 14, 166. JONES, J. G. & CLARKE, S. W. (1969) The effect of expiratory flow rate on regional lung emptying. Clin. Sci., 37, 343. LEBLANC, P., RUFF, F. & MILIC-EMILI, J. (1970). Effects of age and body position on ‘airway closure’ in man. 3. a@$. Physiol., 28, 448. LLOYD, H. M., STRING, T. & DUBOIS, A. B. (I 966) Radiographic and plethysmographic determination of total lung capacity. Radiology, 86; 7. MCCARTHY, D. S., SPENCER, R., GREENE, R. & MILIC-EMILI, J. (1972) Measurement of ‘closing volume’ as a simple and sensitive test for small airway disease. Am. 3. Med., 52, 747. MCFADDEN, E. R. & LINDEN, D. A. (1972) A reduction in maximum mid-expiratory flow rate: a spirographic manifestation of small airway disease. Am. 3. Med., 52, 725. MACKLERI, P. T. (1972) Obstruction in small airways-a challenge to medicine. Am. 3. Med., 52, 721. MILIC-EMILI, J., HENDERSON, J. A. M., DOLOVICH, M. B., TROP, D. & KANEKO, K. (1966) Regional distribution of inspired gas in the lung. 3. appl. Physiol., 21, 749. role of measurement of airways PRIDE, N. B. (1971) The assessment of airflow obstruction: resistance and tests of forced expiration. Br. 3. Dis. Chest., 65, 135. RUFF, F., HUGHES, J. M. B., STANLEY, N., MCCARTHY, D., GREENE, R., ARONOFF, A., CLAYTON, L. & MILIC-EMILI, J. (I 97 I) Regional lung function in patients with hepatic cirrhosis. 3. clin. Invest., 50, 2403. TRAVIS, D. M., GREEN, M. & DON, H. F. (1973) Relation between expiratory flow rate and closing volume by helium and nitrogen methods. Physiologist, in the press. WIDDICOMBE, J. G. & STERLING, G. M. (1970) The autonomic nervous system and breathing. Archs. int. Med., 126, 31 I.
CLOSING
(1973)
67,
Ig
VOLUME IN HEALTHY NON-SMOKERS
J. V. COLLINS, T. J. H. CLARK, S. MCHARDY-YOUNG, G. M. COCHRANE AND J. CRAWLEY Guy’s Hospital,
London
of FEV,, FVC and PEFR are easily made both in hospital and general practice and have proved useful in the assessment of disability and response to treatment in patients with chronic bronchitis, asthma and other diseases associated with airways obstruction. These tests have been found to be less suitable for detecting the early effects of disease or minimal loss of lung function and this can in part be explained by the fact that such tests are mainly influenced by changes in larger airways and lung elastic recoil (Pride 1971). Consequently these tests are not especially relevant to the early stages of disease, particularly if it begins in small airways which have a disproportionately small effect on total airway resistance and other tests have been designed to study the behaviour of distal airways. Frequency-dependence of pulmonary compliance is thought to reflect changes in small airways (Macklem 1972) but the measurement requires both sophisticated apparatus and investigators (Flenley et al. rg7 I). Recently a simple technique of expired gas analysis has been developed, which provides information about small airway behaviour. This ‘closing volume’ technique is thought to provide an indirect measurement of the lung volume at which airway closure begins and can therefore furnish evidence about the small airways which are likely to be the first to close at low lung volumes (Collins 1973). The technique is simple for the subject and operator and gives results with good reproducibility in health and some pathological states (Leblanc et al. 1970; Collins et al. 1972). It has been suggested that measurement of ‘closing volume’ may be a good epidemiological technique for screening large numbers of subjects for abnormal small airway behaviour (Buist & Ross 1972; Macklem 1972). A third technique which is believed to reflect changes in small airways has been developed, namely measurement of maximum mid-expiratory flow rate (McFadden & Linden 1972). This has slight advantages over measurement of ‘closing volume’ in simplicity of equipment and comfort for the patient but is believed to be a less sensitive indicator of small airway behaviour (Macklem I 972). We report the results of measurements of ‘closing volume’ under various conditions in a group of healthy non-smokers in the United Kingdom.
MEASUREMENTS
(Received
for publication
October
1972)
20
COLLINS
‘Closing
Volume’
ET
AL,
Technique
The ‘closing volume’ method makes use of the uneven distribution of ventilation which follows inspiration from residual volume (RV) (Milic-Emili et al. 1966) and is described in detail elsewhere (Dollfuss et al. 1967). It requires the use of a marker gas which in the original work was xenon-133 but may be another inert gas such as nitrogen, argon or helium. We have used xenon-133 for this study. The seated subject exhales to RV and is connected to a spirometer circuit containing room air. A bolus of O-I-0.3 mCi xenon-133 in 2 ml air is injected into the mouthpiece and the subject makes a slow steady vital capacity (VC)
TLC Volume of expirate FIG. I. Diagrammatic representation of the
RV 4 closing
volume
trace
inspiration to total lung capacity (TLC) at a rate of about 0.3-0.5 litres/sec. In normal subjects this results in a concentration gradient of the marker gas down the lungs so that the concentration in the upper zones is 5-10 times greater than in the lower zones (Anthonisen et al. 1970). The subject now exhales slowly at the same rate to RV and during expiration the concentration of xenon-133 is measured continuously at the mouth by a scintillation counter. The output from the counter is fed through a rate-meter and is displayed on the Y axis of an XY recorder. Simultaneously the volume of the expirate is measured by a potentiometer on the spirometer and this is recorded on the X axis of the XY recorder, This produces a characteristic trace represented diagrammatjcally in Fig. I. The trace has 4 phases : Phase I caused by emptying of the dead space of the trachea and apparatus, Phase 2 at the commencement of emptying of the lungs, Phase 3 the ‘alveolar plateau’ produced by mixing of air and xenon-r 33 from all lung regions and Phase 4, a rapid rise of the concentration of xenon-r 33 towards
CLOSING
VOLUME
IN
21
NON-SMOKERS
the end of the vital capacity expiration. This Phase 4 results from the emptying of the upper zones of the lungs when emptying has ceased from the rest of the lungs (Dollfuss et al. 1967). The junction between Phases 3 and 4 marks the lung volume at which small airway size begins to change. Results may be expressed as Phase 4, measured as a volume, related to vital capacity (Phase 4 volume/VC %). Alternatively, Phase 4 volume may be added to residual volume (RV), measured by other methods, and the sum referred to as ‘closing volume’ (CV), i.e. CV=Phase 4 volume +RV. Then CV is related to total lung capacity (CVjTLC %) . Patients
and Methods
Forty-one normal subjects (FEVJFVC greater than 75% with no change after a bronchodilator aerosol), all of whom were lifelong non-smokers with no history of respiratory or cardiac disease, were studied. There were 16 women and 25 men with ages ranging from I 7 to 6g years (mean age 36. I years). All subjects were studied seated erect and in all subjects the measurements were repeated after the inhalation of 200 pg of a /3-adrenergic bronchodilator aerosol (salbutamol). In 31 subjects the studies were also repeated with the subject supine before the use of the aerosol. Forced expiratory volume in I set (FEV,) and forced vital capacity (FVC) were measured under the same conditions using a water cannister spirometer. Total lung capacity (TLC) was measured erect in all subjects by the helium dilution method or derived from radiographic data (Lloyd et al. 1966). The radiographic volumes were corrected to helium volumes using a conversion factor employed in our laboratory. Residual volume was obtained by subtraction. For the ‘closing volume’ study the technique was explained to the subject and the manoeuvre practised without xenon- I 33 until the subject had perfected the control of flow rates required. Then 3-6 separate traces were recorded in each subject using xenon-133 before and after the use of the bronchodilator aerosol and a similar number in the supine studies. The volume of Phase 4 was measured from each trace by 2 independent observers, I of whom had not been present during the procedure and the mean value for the size of Phase 4 was calculated from the pooled measurements of both observers. To assess the reproducibility of Phase 4 in the individual subject 5 recordings before and 5 after the inhalation of the bronchodilator aerosol were made in each of IO subjects on I day. Coefficients of variation for Phase 4 before and after the bronchodilator were calculated for each subject and mean values were calculated for the group. In 31 subjects mean values for the ratio Phase 4 volume/VC y. for each subject were also obtained on 2 separate days for comparison. The mean value for Phase 4 volume for each day for an individual subject was calculated from the combined results obtained by 2 observers on that day. The observers were compared by correlating their results for the mean of Phase 4 in 31 subjects on the same day. At each stage of the studies in individual subjects FEV, and FVC were recorded 3 times, and the largest values were used each time.
22
COLLINS
ET
AL.
Each trace was recorded using 0.1-0.3 mCi of xenon-r 33 and the total time I inhalation/exhalation was approximately 30 seconds. If a total dose of 1-3 mCi of xenon-133 is used in each complete patient study (approximately IO traces) the absorbed dose for the lungs per subject is of the order of 14-42 mrads (Clark et al. 1967). for
Results In seated subjects the ratio of Phase 4 volume/VC yO showed a linear increase with age, the increase of Phase 4 each year being o*3go/o VC. Re-expressed as ‘closing volume’ the change with age of CV was 0*68O/~ TLC per year (Table I). TABLE REGRESSION
I.
RESULTS WITH
OF AGE
of
No. subjects
Position
Erect before salbutamol Erect after salbutamol
41
THE PRESENT OF PHASE 4/VC
STUDY
Phase 4/VC yO (_f1 SD)
IN
o/0 AND
HEALTHY
‘CLOSING
Tolerance limits
-z.6+0.3gxage
k10.8
Closing TLC%
Erect
31
Supine
31
volume/ (+I
SD)
II.g+o.68xage
Tolerance limits k22.0
(f5.5)
(f2.8)
41
NON-SMOKERS:
VOLUME’/TLC%
-2.l+o.38xage (f3.0)
k11.3
-o.46+o.35xage (k3.4) 1.3+0.34xage (53.3)
i ‘3’7
-
-
f ‘3’3
-
-
11.8+0.68xage
k2o.g
(k5.5)
For the SD and tolerance limits see Discussion and Bowden (I 966) In 31 subjects studied
erect and supine the increase in Phase 4 with age was 0*350/O VC/year erect and 0*34O/~ VC/year supine. These slightly lower values for the regression with age of Phase 4 may be due to the inclusion of more young subjects in this smaller group. After inhalation of salbutamol by aerosol there was no significant change in the size of the Phase 4 volume or ‘closing volume’ or the ratios Phase 4 volume/VC y. and CV/TLC y. and the regressions with age for these ratios were unaltered (Table I). The mean coefficients of variation for size of Phase 4 as a volume in IO subjects were I 1.5% before salbutamol and 10*20/O after. In 31 subjects the mean values for the ratio Phase 4 volume/VC o/o were compared on 2 separate days. The mean and standard deviation for the group were not significantly different (Day I : 10.6% VC ) 5.0; Day 2 : 10.1 y. VC ir 4.8) and the correlation coefficient was 0.88. The correlation coefficient for the 2 observers comparing their estimates of Phase 4/VC y. in 3 I subjects was o-91. Discussion As we have reported previously the ‘closing volume’ technique is simple for the operator and subject and shows good reproducibility in individual stibjects from
day
to day
both
in health
and
in patients
with
aortic
and
mitral
valve
CLOSING
VOLUME
IN
23
NON-SMOKERS
0
0 0 0
0
0
0
0 0
0 0 0 C 0
COO 0
0 0
800
00
oc cm
00
0
co8
IO
2. Results
FIG.
20
for
30
41 healthy
40 50 Age in years
subjects
for
Phase
60
4/VC
70
yO related
to age
, 0 l
0
’
I
30
I
40
I
50
.****** Anthonisen LeBlanc - - McCarthy --Collins
I
I
60
70
Age (years) FIG.
3. Regression
with
age of Phase 4/VC of present study with
yO in erect healthy subjects, three previous studies
comparison
of results
disease (Collins et al. 197 I, 1972). This is supported by the coefficients of variation reported in this study. The reproducibility of the measurement in individual subjects in our study is probably of a similar order to that reported
24
COLLINS
ET
AL.
previously (Anthonisen et al. 1969; Leblanc et al. 1970; McCarthy et al. 1972). However, this and other comparisons are complicated by apparent discrepancies in terminology among several authors. Thus ‘closing volume’ seems to have been used to mean Phase 4 volume alone and at other times to mean Phase 4 volume plus residual volume. For the purposes of comparison we have assumed that when previous authors relate ‘closing volume’ (CV) to vital capacity they have been using CV to mean Phase 4 volume. Similarly, no explanations have been provided for the derivation of the term ‘standard deviation’ of ‘closing volume’. We have recalculated the data provided by Leblanc et al. (1970) and McCarthy et al. (1972) and we find that standard deviation would seem to refer to the S, the square root of the residual mean square of Phase 4 volume/VC %. Comparing the present study with these previous studies (Fig. 3) we have found very similar values both for regression with age of Phase 4 volume/VC yO and standard deviation in erect subjects (Table 2). TABLE
2.
RESULTS FROM REGRESSIONS
Re@ort Anthonisen Leblance McCarthy Collins
Position
et al. 1967” et al. 1970” et al. et al.
1972
Ig72*
Erect? Erect? Supinet Erect Supinet Erect Supine
VARIOUS STUDIES IN WITH AGE OF PHASE
No.of subjects
840’ 2: Not stated 3’ 3’
HEALTHY 41 VC%
SUBJECTS:
of
Regression VC 0/o per year 0.55 0.42 0.56 0.36 0.56 0.35 0’34
s -
Tolerance limits -
f4.5 k4.0
f 1.3’3
f3.I
k11.3
f4.0 rfr3.4 -t3’3
k’3’7 f ‘3’3
-
-
* ‘Closing volume’/VC “/o has been assumed to refer to Phase 4 volume/VC %. t Subjects were mixed groups of smokers and non-smokers. 1 No separate values were given for the regression in erect studies in these groups.
In our study there was no difference in the ratio Phase 4 volume VC yO in individual subjects between erect and supine studies and the regression with age was almost identical in both positions. As we did not measure RV supine we do not know whether the regression with age for CV/TLC yO was different. The inhalation of a P-adrenergic bronchodilator aerosol did not alter the size of Phase 4 volume or ‘closing volume’ in our healthy subjects. The autonomic innervation of the bronchial tree is complex (Widdicombe & Sterling 1970) and such aerosols may not influence sympathetic tone in health. Changes in ‘closing volume’ after inhalation of such aerosols have been observed in patients with mitral and aortic valve disease (Collins et al. r 972) but the ‘closing volume’ technique may not be sufficiently sensitive to detect lesser changes which may occur in healthy subjects. It has been suggested that measurement of ‘closing volume’ may be a useful technique for population screening for early abnormalities of small airway behaviour (Buist & Ross 1972; McCarthy et al. 1972; Macklem 1972). While we have found Phase 4 to be reproducible in individual subjects we believe that
CLOSING
VOLUME
IN
NON-SMOKERS
25
the standard deviation as expressed by S does not take sufficient account of sampling error and is over optimistic in defining limits of ‘health’. We have calculated tolerance limits about our fitted lines using methods suggested by Bowden (1966) to enclose 95% of the population in our study in the age range 20-70 years with a confidence of 0.925 (Table I). Taking the example of our studies in seated erect subjects this gave a value of + 1043 for the range of Phase 4 volume VC y. at any age about our fitted regression line. This should be compared with the value for S which was 5 243. We have performed similar calculations for data from previous studies (Table 2). Controversy still surrounds the interpretation of the ‘closing volume’ trace. Dollfuss et al. (I 967) originally suggested that the change of slope from Phase 3 to Phase 4 resulted from closure of airways in the dependent zones of the lung. This explanation would account for the regional inhomogeneity of ventilation on inspiration from low lung volumes previously observed (Milic-Emili et al. I 966). In animal studies it has been shown that the gradient of pleural pressure down the lung, itself the result of gravity and the weight of the lung, would be sufficient to produce closure of small airways in the dependent zones. Histological techniques have been used to demonstrate closed airways in excised dog lungs in which conditions have been produced closely resembling those in the upright human lung (Hughes et al. 1970). The volume at which Phase 4 begins is known to vary with the expiratory flow rate such that increase in expiratory flow rate results in an increase in the size of the Phase 4 volume (Jones & Clarke 1969). This was confirmed by Hyatt and Okesen (197 I) using expiratory flow volume recordings. They showed that with increasing expiratory flow rate the size of the Phase 4 volume may rise from 15 to 50% VC in the same subject. They found that the start of Phase 4 coincides with a point on the flow/volume curve where flow limitation and a sharp rise in transpulmonary pressure begin. They suggested that this rise in transpulmonary pressure causes dynamic compression but not closure of airways in the dependent zones with a slowing of their rate of emptying. This would diminish the dilution effect of the dependent zone air on the air coming from the upper zones which is richer in marker gas and so result in a rising concentration of marker gas, i.e. Phase4. In the present study the inspiratory and expiratory flow rates were carefully controlled to rates below 0.5 litres per second and the size of the Phase 4 volume is independent of flow in this range (Travis et al. 1973). Whether the explanation of ‘closing volume’ is closure or dynamic compression of airways, our results confirm the findings of previous authors that when expiratory flow rates are kept low reproducible results are obtained in normal subjects that seem likely to reflect changes in small airways. The technique is being used to investigate a variety of diseases both in Europe and North America (Bjure et al. 1970; Ruff et al. 1971; Buist & Ross 1972; Collins et al. 1972 ; McCarthy et al. 1972 ; McFadden & Linden 1972) and it has been suggested that measurement of ‘closing volume’ may be useful for large scale epidemiological studies of early abnormalities in small airways in chronic bronchitis (Buist & Ross 1972 ; Macklem 1972). Our own experience with the 3
26
COLLINS
technique in patients with doubts we have expressed healthy subjects, suggest to before the technique could
ET
AL.
bronchial asthma (Clark IgTr), together with the about the tolerance limits of the measurement in us that further developmental studies are required be recommended for large-scale clinical use. Summary
‘Closing volume’, defined as that lung volume at which the dependent lung zones ceases expiration, was measured in 41 healthy non-smokers aged seventeen to sixty-nine years using xenon-r 33, Subjects were studied erect before and after inhalation of a /?-adrenergic bronchodilator aerosol and in 31 subjects the studies were repeated in the supine position. Results in individual subjects showed good reproducibility. The regression with age and standard deviation of the measurements were similar to previous reports and no change was observed after inhalation of bronchodilator. The relationship of Phase 4 to vital capacity was unaltered by change in posture. It is suggested that the use of standard deviation (i.e. f 2 SD) to define the limits of a normal range may be unduly optimistic. Tolerance limits to include 95% of healthy subjects calculated from studies of this size would provide unacceptably wide ranges for epidemiological purposes if the technique were introduced as a screening test for early disease of small airways. It is suggested that further developmental studies are required.
ACKNOWLEDGEMENTS
This research was carried whom we wish to thank advice, and to our willing Reprint
requests
out with for support. subjects.
to J. V.
Collins,
the
aid of a grant Our thanks are
Westminster
from the Chest and Heart also due to Frank House
Hospital,
London
Foundation for statistical
SWI.
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451. BOWDEN, D. C. (1966) Confidence band of uniform width for the regression line with a smaller than x smaller than b. J. Am. statist. Ass., 61, 182. BUIST, A. S. & Ross, B. B. (1972) ‘Closing volume’ as a simple, sensitive test for the detection of peripheral airway disease. 15th AsFen Conf. Proc., 34. CLARK, J. C., MATTHEWS, C. M. E., SILVESTER, D. J. & VONBERG, D. D. (I 967) Using cyclotonproduced isotopes at Hammersmith Hospital. Nucleonics, 25, 54. CLARK, T. J. H. (I 97 I) Assessment of airway closure using the closing volume method. Proc.
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volume-a
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function.
Br. 3. Dis. Chest, 67, I.
CLOSING
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NON-SMOKERS
27
COLLINS, J. V.,
CLARK, T. J. H. & MCHARDY-YOUNG, S. (1972) Small airway closure in left heart failure. Thorax, 27, 260. COLLINS, J. V., CLARK, T. J. H., MCHARDY-YOUNG, S., CRAWLEY, J. & TURNER, J. (1971) Gravity-dependent peripheral airway closure in left heart failure. Clin. Sci., 40, 23P. DOLLFUSS, R. E., MILIC-EMILI, J. & BATES, D. V. (1967) Regional ventilation of the lung, studied with boluses of 133 xenon. Resp. Physiol., 2, 234. FLENLEY, D. C., GUYATT, A. R., SIDDORN, J. A. & BRASH, H. (1971) Frequency dependence of compliance. Proc. R. Sot. Med., 64, 1243. HUGHES, J. M. B., ROSENZWEIG, D. Y. & KIVITZ, P. B. (1970) Site of airway closure in excised dog lungs: histologic demonstration. J. a#$. Physiol., 29, 340. HYATT, R. E. & OKESEN, G. C. (1971) Expiratory flow limitation, the cause of so-called ‘airway closure’ or ‘closing volume’. Physiologist, 14, 166. JONES, J. G. & CLARKE, S. W. (1969) The effect of expiratory flow rate on regional lung emptying. Clin. Sci., 37, 343. LEBLANC, P., RUFF, F. & MILIC-EMILI, J. (1970). Effects of age and body position on ‘airway closure’ in man. 3. a@$. Physiol., 28, 448. LLOYD, H. M., STRING, T. & DUBOIS, A. B. (I 966) Radiographic and plethysmographic determination of total lung capacity. Radiology, 86; 7. MCCARTHY, D. S., SPENCER, R., GREENE, R. & MILIC-EMILI, J. (1972) Measurement of ‘closing volume’ as a simple and sensitive test for small airway disease. Am. 3. Med., 52, 747. MCFADDEN, E. R. & LINDEN, D. A. (1972) A reduction in maximum mid-expiratory flow rate: a spirographic manifestation of small airway disease. Am. 3. Med., 52, 725. MACKLERI, P. T. (1972) Obstruction in small airways-a challenge to medicine. Am. 3. Med., 52, 721. MILIC-EMILI, J., HENDERSON, J. A. M., DOLOVICH, M. B., TROP, D. & KANEKO, K. (1966) Regional distribution of inspired gas in the lung. 3. appl. Physiol., 21, 749. role of measurement of airways PRIDE, N. B. (1971) The assessment of airflow obstruction: resistance and tests of forced expiration. Br. 3. Dis. Chest., 65, 135. RUFF, F., HUGHES, J. M. B., STANLEY, N., MCCARTHY, D., GREENE, R., ARONOFF, A., CLAYTON, L. & MILIC-EMILI, J. (I 97 I) Regional lung function in patients with hepatic cirrhosis. 3. clin. Invest., 50, 2403. TRAVIS, D. M., GREEN, M. & DON, H. F. (1973) Relation between expiratory flow rate and closing volume by helium and nitrogen methods. Physiologist, in the press. WIDDICOMBE, J. G. & STERLING, G. M. (1970) The autonomic nervous system and breathing. Archs. int. Med., 126, 31 I.