IV. INTRAPULMONARY
GAS
DISTRIBUTION
George R. DeMuth, M.D., and William F. Howatt, M.D.
Department of Pediatrics, University of Michigan, Ann Arbor
Supported by NIH Crant A-3575 from the National Institute of Arthritis and Metabolic Diseases.
PEDIATRICS, January, Part II, 1965
194
T
IIHEE TESTS of the distribution of gases within the lung (the nitrogenclear-ance, the single-breath oxygen, and the oxygen equilibration index) were included in a study of normal children. We wished
to determine normal values for the tests in children, to see the effect of growth in a longitudinal study, and to relate the results
to other lung function tests. Most of the usual tests of gas distribution were de-vised for adults and are not directly ap-plicable to children because of the differ-ences in lung volumes and in the rapidity
of turnover of the gases within the lung. Five methods of interpreting the nitrogen clearance test were evaluated to find the better modifications for children. Altera-tion of the calculation of the single-breath
oxygen test was also made to allow for the smaller lung volumes in children. This test was repeated in the second series to obtain
longitudinal data. The oxygen equilibra-tion index for children was devised in our laboratory. In this study we expressed the
change in equilibrating volume as a per-cent of the final equilibrating volume.
SUBJECTS AND METHODS
The children have been described previ-ously.1 The tests were performed on the subjects during the same testing period.
Nitrogen Clearance
The subjects sat upright, had their nasal airways occluded by nose clips, and
breathed through a two-way valve.0 At an end-tidal point two three-way valves were
turned so that oxygen was inhaled and the inspired gas was collected in a Tissot
#{176}Collins Plastic Valve.
Spirometer. The nitrogen concentration was continuously monitored at the mouth-piece by a Nitralyzer, Model 300 AR, whose
output was recorded on a Grass or an Off-ncr Dynograph Type R, 4-channel
re-corder.
The test was discontinued when the 1% nitrogen point was reached. The total
vol-ume exhaled was obtained from the Tissot Spirometer. Respiration was assumed to be even in the event that adjustment of vol-ume was needed because the 1% end point was passed. The number of breaths and
the time to reach the 1% end-tidal-concentra-tion were obtained from the recording. The peak nitrogen value of the breath nearest
the 2-minute time was also recorded. The clearance equivalent2 was obtained by di-viding the total volume breathed to reach
1% end-tidal nitrogen level by the
func-tional residual capacity. For tile FRC we
used the value obtained by helium equili-bration.1 The reported values are the means of duplicates.
The oxygen concentration in the in-spired gas was determined by mass
spec-trometric measurements. This varied from 99.6 to 99.7% oxygen.
Single-Breath Oxygen Test
The subject breathed through the mouth-piece and valve set-up as above. At an end of a tidal expiration the inlet valve was turned to permit a large inhalation of oxy-gen through a demand valve, and the ex-haled gas passed to the Krogh Spirometer.
The subject was instructed to exhale evenly and not too rapidly. The outputs of the nitrogen analyzer and of the spirometer were recorded on a Mosley X-Y recorder. Occasional unduiations in the “flat”
dc-Single-Breath Oxygen Clearance Eqniralent Oxygen Equili-bratio Index 0.078 -0.075 0.085 Vital Capacity 0.082 -0. 126 0.076 71=108. TABLE I
GAS DISTRIBUTION TESTS
Test Mean Sf Sf* 52* Sa2* Scx*
Correlation
with Height
Single-l)reath oxygen (1st Series) (‘2nd Series)
Oxygen equilibration index
Clearance equivalent Time to 1% Volumetol% Breathstol% %Nitrogenat2min 0.794 0.823 1.17 9.82 99.4 16.14 37.9 1.61 0.303 0.290 2.56 2.81 58.9 7.77 22.1 1.88 0.0916 0.0842 6.556 7.913 3472.8 60.356 490.07 3.518 0.0538 0.0372 4.296 6.093 378.2 7.617 81.33 0.862 0.0647 0.0657 4.408 4.867 3283.6 56.547 449.40 3.087 0.254 0.256 2.10 2.21 57.3 7.52 21.2 1.76 0.078 -0.117 -0.075 0.440 0.705 0.189 0.394
* See text.
termination of the slope in these cases a straight line was superimposed. As an in-dex we used the change in nitrogen per-centage between the points where the
sec-ond and third fifths of the subjects’ previ-ously measured vital capacity were ex-pired. This differs from that used in adults.’
Oxygen Equilibration Index
This test was performed as previously reported. In the original description the
change in the equilibrating lung volume was expressed in terms of volume per unit body weight. For this study we also
calcu-lated the change as a fraction of the final volume (FRC). The latter method appeared superior and was chosen for presenting the results. The values reported were the means of duplicates.
RESU LTS
In Table I are given the statistics of the
results of the gas distribution tests and the correlations of the results with height. The oxygen equilibration index results are ex-pressed as the fractional change
(percent-age) in the equilibrating lung volume dur-ing the second minute. No significant dif-ference nor consistent pattern of change between the first and second values of the duplicates was found for any of the tests. In Figure 1 is shown the relationship to
height of the end-tidal nitrogen concentra-tion after two minutes of oxygen breathing
(log-log).
In doing the 7-minute nitrogen clear-ance in adults, it is common to ask the sub-ject to force out the last breath, attempt-ing to empty out poorly ventilated por-tions. This was done in our subjects to con-firm the impression that little rise in end-tidal nitrogen values occurs in normal
chil-dren. In most subjects no appreciable rise occurred; in a few, a rise up to 0.5% was observed.
TABLE II
Height
Single-breath oxygen
Clearance equivalent
Oxygen equilibration index
CORRELATIONS OF SIZE ADJUSTED TESTS
HEIGHT IN CM
0/0
NI TROGEN
FIG. 1. The end-tidal nitrogen values after breathing oxygen for 2 minutes against height (log-log).
In Table II are given the correlations of
the results of the three tests which have in-herent volume adjustments with each
other and with height and vital capacity. The 95% confidence limits of the correla-tion coefficients include zero for each of
the pairs.
The OEI had previously been reported
as the milliliter change in the equilibrat-ing lung volume during the second minute
of rebreathing per kilogram body weight. The correlation of the results calculated by that method and those calculated as the
percentage change of the final volume was 0.95 (126 observations).
The correlation between the first and second SBO values of a set done at one time was 0.631 (95% confidence limits 0.54 to 0.71). The correlation between each subject’s values from the first and second
series was 0.375 (88 pairs, 95% confidence limits are 0.18 to 0.54).
COMMENT
In the nitrogen clearance test the nitro-gen in the lung is progressively diluted and washed out by breathing oxygen which results in a progressive fall in the end-tidal nitrogen values. The fall in re-spect to time is nearly exponential, or a series of exponentials, and can be analyzed as a series of compartments in parallel which are progressively washed out.
How-ever, the characterization of the lung by division into various compartments, each with its own clearance rate, is highly
im-precise, as well as laborious. Therefore, in adults it is common to use the value of the end-tidal nitrogen after a given time (7
minutes) as an index. In children the ni-trogen concentration falls much more rap-idly than in adults, the more so, the small-er the child. Children have a higher ratio of minute ventilation to functional residual
SUPPLEMENT
Five different ways of interpreting the nitrogen clearance were studied. Three of
these were measurements related to a fourth, the clearance equivalent. The
clearance equivalent was used by Vallbona and others to study 100 normal children.
Their results have been reported in part.6 Besides the effect of the intrapulmonary distribution of gases, the nitrogen concen-tration during the washout is determined by the volume to be cleared and the
amount of ventilation used to clear it. The clearance equivalent is the volume neces-sary to clear the nitrogen to a certain point,
1%, divided by the volume to be cleared.
This modification is valuable, for the val-ues obtained are nearly independent of age and body size. In performing this test we also looked at the time, number of breaths, and volume breathed to reach the
end point. The characteristics of these
re-sults have been included (Table I). None of the first three offers any clear advantage over the fifth way (the end-tidal nitrogen concentration at 2 minutes), and all four
have one disadvantage. Oxygen obtained
commercially may have small and varying amounts of nitrogen in it, which can
sig-nificantly alter the results of tests using 1%
nitrogen as the end point.
The fifth way of interpreting the nitro-gen clearance, the end-tidal nitrogen
con-centration after 2 minutes of oxygen breathing, is the simplest. It is similar to
that used in adults, except for a shortened time period. The test is short, easy for the
subject, and easy to calculate. These ad-vantages may outweigh its relative gross-ness. The normal values are size-depend-ent, as can be seen in Figure 1. Tile upper
line is two standard deviations above the regression line and includes 96.5% of the ac-tual values. The test results can be affected by changes in ventilation. Because moderate hyperventilation can be maintained for long periods of time, the end-tidal nitrogen value after a specified time, whether the time be 2 minutes or 7 minutes, may be reduced. Since
this may have occurred sporadically in
these children, some of the 2-minute end-tidal nitrogen values may have been
low-ered and the variation increased. Hypo-ventilation not due to disease is difficult
for the subject and is more so the longer the time period. Though this is more likely to be a factor in the 2-minute than in the 7-minute trials, it is doubtful if it has sig-nificantly raised the values.
The oxygen equilibration index is based
upon the delay in equilibration of the lungs with a bag of oxygen during rebreathing. It is sensitive, but somewhat tedious. As cur-rently reported it includes a correction based upon the volume of the lung. A previous report4 used the body weight as a correction.
Of the two corrections we feel that the one based on the lung volume is more pertinent and removes any false changes associated with nutritional variations. The correlation between the two was very high (0.95).
The single-breath oxygen test is the easiest and one of the most informative tests of gas distribution. It was necessary to modify the test for children because the set lung volume
points used in adults are greater than the
vital capacities in some children. Further, with different vital capacities different frac-tions are included if a fixed lung volume is used. The value of the chosen method is shown by the absence of any size dependence in the results. As an index we have used the change in nitrogen concentration over a
vol-ume change which is a constant fraction of the previously measured vital capacity. In the abnormal it might be well to use the
pre-dicted vital capacity to determine the value over which nitrogen concentration change is measured.
The population of normal values for the size-adjusted tests are of interest. The varia-bility in the two readings on an individual (the duplicates) allows us to obtain an esti-mate, Sd2, of the duplicability (or within) variance, #{248}d2.In addition, the sample vari-ance, S2, of the average of these readings is an estimate of cr02+ud2, where o.a2 refers to
compar-TABLE III
UPPER LIMITS OF NORMAL
(Size-Adjusted Tests)
Test Value %
Values Included Single-breath oxygen (233 tests) Clearance equivalent (125 tests)
Oxygen equilibration index
(119 tests) 1.5% 16 7.2% 97.8% 97.6% 97.5%
ing an individual’s average with the general average, the variance o.2 which is
esti-mated by
Satm = S22
-is also of some interest, since it indicates the “true” variability in the population, if meas-urement error were absent. For the OEI,
SBO, and clearance equivalent this variance is appreciably smaller than the sample vari-ance. These values are included in Table I. The ranges for normal children of each of these tests is only a small fraction at the lower end of the ranges seen with lung
dis-eases. In comparison to findings in patients,
gas distribution appears to be remarkably
uniform in normal people. Another charac-teristic of the normal values is that they tend to be positively skewed. This is in part because there is a theoretical floor or lower limit to the values. This is apparent in the f-minute end-tidal nitrogen values shown in Figure 1. The distribution would appear
even more deviant without the logarithmic transformation. Because of the skewness, it is recommended that the actual percentiles of the distribution be used to determine up-per limits of normality. The values which include at least 97.5% of our results are given in Table III. These arc slightly
greater than the mean plus 1.96 S. It is interesting that there was no signifi-cant correlation among the three tests which have volume adjustments. The highest cor-relation is between the OEI and SBO and is well within the limits to be expected by
chance alone. In patients with airway ob-structive diseases much more correlation is
found. This lack of correlation itt normal
subjects is probably due to the fact that, although each test assesses some aspect of
gas distribution, each (loes not measure the same one. Further, 110 aspect is too far from perfect. True correlations that are small may have been obscured by random variation.
Information about growth was obtained in two ways. The absence of a significant
corre-lation between the test results which are
adjusted for volume is of importance. This indicates that if we allow for the varying
lung volumes, there is 110 increase nor de-crease in the uniformity with which gases are distributed with changing size. Longi-tudinal information was obtained from tile single-breath oxygen test which was in-eluded in the second series. The 0.375 corre-lation between the means of the first and of the second trials on the individuals is
signifi-cant. This indicates that some of the varia-tion, even in this restricted normal range, is
due to a characteristic of the subject which persists during his growth. This quality is presumably the uniformity of composition of the airway conductance and lung elasticity in the different parts of the lung.
SUMMARY
1. Three tests of intrapulmonary gas dis-tribution (the nitrogen clearance, the sin-gle-breath oxygen, and the oxygen equili-bration index) were included in a study of normal children. Several adaptations for
children were made.
2. When the tests include lung volume adjustments, they show no correlation with changing body size, indicating no change in the uniformity of gas distribution with growth.
3. Values of the upper limits in normal subjects for four interpretations of the three tests are given.
4. No significant correlation among the three volume-adjusted tests was found in these normal subjects.
REFERENCES
1. DeMuth, C. R., Howatt, W. F., and Hill, B.:
The growth of lung function. Part I. Lung volumes. PEDIATRICS, 35:162, 1965.
2. Cohen, A. A., Hemingway, A., and Hemingway, C., Displacement of nitrogen from normal human lungs during oxygen breathing. J. Clin. Invest., 37:306, 1958.
3. Comroe, J. H., Jr., and Fowler, W. S.: Detection of uneven ventilation during a single breath of O. Amer. J. Med., 10:408, 1951.
4. DeMuth, C. R., Howatt, W. F., Talner, N. S.:
Intrapulmonary gas distribution in cystic
fibrosis. Amer. J. Dis. Child., 103:129, 1962. 5. Cournand, A., Baldwin, E. Dc F., Darling,
R. C., and Richards, D. W., Jr. Studies on
intrapulmonary mixture of gases. IV. The significance of the pulmonary emptying rate
and a simplified open circuit measurement of
residual air. J. Clin. Invest., 20:681, 1941.
6. Vallbona, C., Spencer, W. A., and Jackson,
R. R.: Quantitative studies of the mixing and distribution of inspired air in the lungs of
one-hundred healthy children. Amer. J. Dis.
