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* From the Departments of Medicine (Drs. Yamaguchi and Soejima) and Radiology (Drs. Koda and Sugiyama), School of Medicine, Keio University, Tokyo, Japan.
Correspondence to: Kazuhiro Yamaguchi, MD, FCCP, Department of Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; e-mail: yamaguc{at}cpnet.med.keio.ac.jp
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Abstract |
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 TOP Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Participants: Nonsmoking control subjects (n = 28) and patients with smoking-induced COPD (n = 47).
Measurements and results: Changes in lung CT densities were examined by HRCT while the subjects inhaled a gas mixture consisting of 21% O2 in SF6 or 21% O2 in He. HRCT images of the right upper and lower lung fields were obtained at the end of inspiration and expiration of the second and 60th breaths after the start of each gas. Introducing mean lung density (MLD) and relative area with low CT attenuation (%LAA), we analyzed the differences in acinar SF6 and He distribution in the early phase (second breath) and in the equilibrium state (60th breath). We found that the differences in inspiratory MLD between the SF6 and He images at the 60th breath were qualitatively consistent with the differences predicted from the physical properties of these gases. However, the differences in inspiratory MLD between the SF6 and He images taken at the second breath were smaller than those at the 60th breath, especially in the smoking group with COPD. These differences in second-breath inspiratory MLD in the smoking group were smaller in the upper lung field than in the lower lung field. The differences in MLD between the two gases were not detected at end-expiration at the time of either the second or 60th breaths. The %LAA values did not differ between the SF6 and He images in either the nonsmoking group or the smoking group.
Conclusions: SF6/He-associated HRCT images obtained at end-inspiration, but not at end-expiration, in the early breathing phase are useful for predicting acinar gas distribution abnormalities in patients with COPD.
Key Words: acinus • helium • high-resolution CT • smoking • sulfur hexafluoride • ventilation inhomogeneity
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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HRCT Data Acquisition
Subjects were put in a supine position and allowed to breathe
room air until stable respiration was achieved through a two-way
nonrebreathing valve that isolated inhaled gas from exhaled gas. The
inspiratory port was attached to a three-way valve, letting the subject
breathe a certain gas mixture from a 200-L reservoir bag. The
instrumental dead space volume between the reservoir bag and the mouth
amounted to 250 mL. Respiratory frequencies during measurements were
compulsorily adjusted to 12 breaths/min with 1-s pause at the end of
inspiration and expiration using a special metronome. Before HRCT
measurements, the subjects were trained several times to maintain a
well-regulated breathing pattern following the metronome. This maneuver
allowed us to obtain HRCT images at both ends of the respiratory cycle
without the prolonged breath holding.
HRCT was conducted with the subjects in a supine position (ProSeed; GE Yokogawa Medical Systems; Tokyo, Japan) at the end of inspiration or expiration. The positions of end-inspiration and end-expiration were determined by monitoring of lung CT density changes on the screen. CT images of the upper lung field defined as the position of the mid-intrathoracic trachea and the lower lung field positioned 1 cm above the diaphragm, each section 2.0-mm thick, were obtained at both ends of the respiratory cycle. Scanning was performed with kilovoltage/milliampere settings of 120/200, 1-s scan time, 2-mm collimation, 35-cm reconstruction circle (field of view), and 512 x 512 matrix, thus yielding a pixel size of 0.7 mm, which is about 10 times smaller than the pulmonary acinus, the diameter of which averages 7 mm in the case of human lung.14 Scan data were reconstructed using a high-spatial frequency algorithm.14 16 17 18 19 20 Images thus obtained were photographed at levels of - 500 Hounsfield units (HU), and window widths of 1,500 HU to visually assess lung parenchyma abnormalities.
Conventional HRCT images were obtained in the right upper and lower lung fields at both ends of the respiratory cycle 5 min after the subjects had reached stable respiration with room-air breathing. To analyze the transitional changes in gas distribution in a given lung field, however, inspiratory or expiratory HRCT images were obtained at the time of the second and 60th breaths after the start of breathing the gas mixture containing He or SF6. To accomplish these measurements, the subject was administered a mixture of either 21% O2 in 79% He or 21% O2 in 79% SF6 to inhale for 6 min through the nonrebreathing valve, and HRCT images of the right upper lung field were obtained at the end of inspiration and expiration of the second and 60th breaths. The inhaled gas was then changed to room air for 20 min to eliminate He or SF6 from the lung. Thereafter, the gas inhaled was switched to the other gas mixture containing either SF6 or He (whichever was not used in the first series of measurements), and inhalation of this gas mixture was continued for 6 min more for inspiratory or expiratory HRCT examination in the upper lung field. These procedures were repeated to obtain inspiratory and expiratory HRCT images of the right lower lung field during inhalation of the He or SF6 gas mixture. The sequence of inhaled gas, whether the He or SF6 mixture was inhaled first, was not fixed but varied randomly for each subject.
Quantitative HRCT Parameters
The lung periphery gas distribution was quantified in each CT
section of the right lung field by calculating two objective CT indexes
including mean lung density (MLD) and relative area with low CT
attenuation (%LAA) at the end of inspiration, but only MLD at the end
of expiration. Excluding large vessels and airways visible in each lung
section, the above-mentioned parameter values were calculated applying
an attenuation mask program.16
MLD indicates the CT
density obtained by averaging the CT values of all pixels in a given
lung section from which visibly large vessels and airways are excluded.
Thus, MLD is an approximate but reliable measure of the averaged
density in the lung periphery produced by various substances making up
the acinar structure.
Although several threshold CT values defining LAA during room-air breathing have been reported in the literature,16 17 18 19 21 22 23 these values were not applicable in the present study because the subject was compelled to inhale a gas mixture containing He or SF6, both of which were expected to cause a small but significant difference in the lung CT density as compared to that estimated in the case of room-air breathing. Preliminary examinations revealed that the CT density of a balloon filled with room air (21% O2 in N2) was - 997 ± 1 HU (n = 20), while that of a balloon filled with 21% O2 in He was - 998 ± 1 HU (n = 25), showing no statistical difference between the two. The CT density of gas mixture consisting of 21% O2 in SF6 was found to be - 991 ± 1 HU (n = 25), being more positive than that in the case of room air or the He gas mixture. To obtain the threshold CT value for defining LAA under the conditions of inhalation of each different gas mixture, we examined the 95% confidence limit of CT densities in the right upper and lower lung fields in nonsmoking healthy young volunteers (mean ± SD age, 22 ± 2.5 years old; n = 18) at end-inspiration under the conditions of inhalation of each gas mixture for 10 min. The nonsmoking subjects assigned to the C group were not included in this analysis because the average age of these subjects was 62 years (Table 1) . That is, we attempted to determine the cutoff CT values defining LAA, with the effects of smoking and aging nearly removed. The lower 95% confidence limit (ie, mean, - 2 SD) of inspiratory CT density in the right lung was thus confirmed to be - 907 HU for room air and - 910 HU for the He gas mixture, but - 898 HU for the SF6 gas mixture. Based on these findings, we defined the areas having an inspiratory CT value of < - 907 HU during room-air breathing as LAA. Similarly, the areas with inspiratory CT values of < - 910 HU and - 898 HU were taken as LAA for He gas and SF6 gas mixture breathing, respectively. Although inspiratory LAA has been used as an objective measure indicating the extent of airspace enlargement and/or destruction including emphysematous changes in each slice,16 17 18 19 20 21 the pathologic significance of expiratory LAA has not been conclusively decided.18 23 24 25 We, therefore, refrained from analyzing expiratory LAA in the present study.
To lessen the time consumed for estimation, we evaluated MLD and LAA only in the right lung field but not in the left lung field. Preliminary examinations demonstrated that the lung CT density in the left lung field did not differ significantly from that in the right lung field on inhalation of a given inert gas. Based on these findings, we assumed that the analytical results obtained for the right lung would hold true for the left lung as well.
Attainment of a Plateau in Lung CT Density Breathing
SF6 Gas
To examine the equilibration process during the period of
inhalation of inert gas, changes in MLD in the right upper lung field
were preliminarily measured for six subjects while breathing the gas
mixture consisting of 21% O2 in
SF6. These six subjects were selected because
they approved the additional examination in determining the
equilibration process during inhalation of SF6
gas. Three of the subjects belonged to the nonsmoking control group,
and the other three subjects were habitual smokers having conspicuous
emphysema in association with a marked reduction in
FEV1% (32 ± 2%). The MLD was measured at
end-inspiration at the time of the second, fifth, 10th, 20th, 30th,
40th, or 60th breaths after switching the inhaled gas from room air to
that containing SF6. The asymptotic MLD (D) was
calculated based on the assumption that equilibrium of the inert gas
with extremely low solubility would be approximated by the exponential
function, (Df - D0) = (D - D0) x (1 - e-kf), where D0 is
the MLD in the case of room-air breathing. Df and D are, respectively,
the MLD at breath number f and infinity during the period of inhaling
SF6 gas, while k is the rate constant for
equilibration.26
In the nonsmoking control subjects, the
inspiratory MLD averaged - 815 HU immediately before switching the
inhaled gas from room air to SF6 gas. The MLD was
then enhanced as the breath number increased, reaching 95% of the
asymptote within 10 breaths, and 99% of the asymptote within 20
breaths, inhaling SF6 gas (Fig 1
). In smoking subjects with COPD, 95% or 99% of the asymptote was
attained within 30 breaths or 40 breaths, respectively, after the start
of breathing the SF6 gas mixture (Fig 1)
.
Although the MLD equilibration was significantly delayed in the smoking
subjects with COPD, their MLD values measured at the 60th breath,
inhaling SF6 gas, appeared to be not different
from the corresponding asymptotes. Based on these findings, we assumed
that inspiratory HRCT parameters obtained for the lung periphery at the
second breath would reflect the transitional distribution of a given
inert gas, while those at the 60th breath would approximate the gas
distribution in a state of equilibrium. We did not measure transitional
changes in MLD reaching a plateau after introducing the He gas, because
the difference in MLD between air breathing and He-gas breathing was
small.
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Statistical Analysis
Whenever possible, data obtained from the two groups when
subjects inhaled the same gas mixture were compared by the unpaired
t test. If the data did not show equal variance, however, we
applied the Mann-Whitney test to assess statistical significance.
Differences in HRCT data obtained during the periods of breathing the
gas mixtures, comparing the results for the He-containing and
SF6-containing gas mixtures in each group, were
estimated by the paired t test or the Wilcoxon test. A p
value < 0.05 was considered statistically significant. Values are
presented as means ± SD.
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The %LAA values in the nonsmoking control subjects did not differ between SF6 gas and He gas breathing irrespective of the lung field in which the HRCT images were obtained (Table 2) . The same held true for the smoking group. The %LAA values estimated from SF6 or He images taken at the 60th breath, inhaling each gas mixture, differed little from those obtained during room-air breathing in both the nonsmoking and smoking groups.
HRCT Data at Second Breath Inhaling SF6 or He Gas
In the nonsmoking control group, upper lung inspiratory MLD
estimated at the second breath was more positive in the
SF6 image than that in the He image, and the
disparity in MLD between the two images was 25 ± 9 HU (Fig 2
). This value tended to be smaller than that observed at the 60th
breath, but the difference was not statistically significant
(p = 0.09). The same tendency was observed for inspiratory images in
the lower lung field of the nonsmoking control subjects, ie,
the difference in the lower lung MLD between the
SF6 and He images were 21 ± 10 HU at the
second breath and 27 ± 12 HU at the 60th breath. Although there was
no statistical difference between them, the former appeared to be
smaller than the latter (p = 0.07). In the control group, the
disparity in expiratory MLD estimated at the second breath in either
the upper or lower lung field in the SF6 and He
images did not differ from that estimated at the 60th breath (Fig 2)
.
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Discussion |
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Extensive studies5 6 7 8 9 10 11 12 have demonstrated that ventilation inhomogeneities in the lung periphery are mainly elicited by diffusion/convection-dependent inhomogeneities due to the interaction of diffusion and convection in the asymmetric airway branching within the acinus. These investigators5 6 7 8 9 10 11 12 have suggested that comparison of gas data collected at the mouth during single-breath or multiple-breath washout of He and SF6 at near-tidal ventilation provides valuable information on gas mixing in acinar regions. Because of its lower diffusivity, the front of SF6 is situated more distally than that of He, allowing SF6 to penetrate into more peripheral parts of the acinus in which inhomogeneity in ventilation distribution is expected to be augmented due to increasing airway branching asymmetry.6 7 12 He gas distribution may be less influenced by inhomogeneous ventilation distribution in the acinar regions, because He diffusion front is at the more proximal regions of the acinus where airway asymmetry is less. Furthermore, He concentration inhomogeneities, if any, are also more easily removed due to its higher diffusivity.6 7 These facts elucidated in studies in the physiologic field may indicate that SF6 gas data are valuable in evaluating abnormalities in acinar structures when they are compared with He gas data as the standard. Crawford and colleagues28 have demonstrated that differences in sloping alveolar plateaus of SF6 and He divided by their concentrations increase during the first five breaths of wash-in of these two gases and remain constant thereafter, leading them to conclude that the contribution of acinar structures to inhomogeneities in ventilation distribution in the lung periphery can only be assessed from SF6 gas and He gas data obtained within the first five breaths. Given these facts, we measured the disparity in lung CT density represented by MLD at the time of the second breath of SF6 or He gas inhalation, and we attempted to analyze the effect of acinar structures on ventilation distribution in different lung regions. Although the first breath was expected to include much information concerning the contribution of acinar structures to inhomogeneous ventilation distribution,29 we refrained from obtaining CT images at the time of the first breath, because the present system had a 250-mL instrumental dead space in the inspiratory gas route, which might invalidate the significance of the first breath. Furthermore, in order to reduce the total quantity of x-ray exposure for the subjects, CT images were not obtained at either third, fourth, or fifth breaths after the start of breathing a given gas mixture. SF6 and He images obtained at the 60th breath were used for analyzing the steady-state distribution of these two gases in the lung periphery because the lung CT density at the 60th breath while breathing the gas mixture containing SF6 did not differ from the predicted asymptote of SF6-associated MLD (Fig 1) . Although there was no discernible disparity in the lung CT density between He and room-air breathing (Table 2) , we did not adopt the HRCT measurements for room-air breathing as the companion data for SF6 images because it was anticipated that much difficulty would be encountered with respect to the wash-in of room air in comparison with that in the case of foreign inert gases such as SF6 or He.
It may be difficult to judge theoretically whether the differences in the lung peripheral CT density between SF6 and He images increase or decrease when acinar ventilation inhomogeneities become evident. However, we showed that the MLD differences in SF6 and He images obtained at end-inspiration at the time of second breath in the case of smoking subjects with COPD were significantly smaller than those in the steady state (Table 2 ; Fig 3 ). These findings may indicate the following. Firstly, disparities in SF6-associated and He-associated MLD estimated at end-inspiration at the time of second breath are useful for prediction of ventilatory inhomogeneities occurring in abnormal acini. This is highly consistent with the physiologic conclusion obtained by Crawford et al.28 Secondly, with respect to the differences in lung CT densities when SF6 and He are used for analysis, they become smaller than those expected on the basis of the physical properties of these gases under conditions with augmented ventilation inhomogeneities in acinar regions. This suggests that the increase in differences in sloping alveolar plateaus of SF6 and He divided by their concentrations observed in physiologic studies focusing on disease conditions in which abnormalities in acinar structures are augmented8 10 11 is reflected as a decrease in the differences in MLD of the two gases in the present CT method.
Importance and Limitations of SF6-Associated and
He-Associated HRCT Images as a Tool for Detecting Acinar Abnormalities
As compared with classical physiologic methods, the CT method
proposed in the present study may have both advantages and
disadvantages. Although important information regarding gas mixing
governed by acinar diffusion/convection-dependent inhomogeneities is
expected to be included in inert gas data obtained at
end-inspiration,6
12
such information is not directly
obtained by physiologic methods. This CT method, however, allows us to
separately measure the difference in SF6 gas and
He gas behavior at both ends of the respiratory cycle (Fig 2
, 3)
.
Although we only estimated disparities of
SF6-associated and He-associated lung CT
densities in the upper and lower lung fields, it is possible to use the
CT method to analyze them reliably in many lung regions along the
horizontal or vertical direction. This is a very important issue when
attempting to detect abnormalities in acinar structures, because they
may vary from region to region in various kinds of diffuse diseases of
the lung. On the other hand, the CT method has two undesirable
problems. One is the x-ray exposure, and the other is the complexity of
the examination. Effective dose of x-ray exposed to the subject is 8
millisieverts for taking one HRCT image.14
Since 12 HRCT
images were generally obtained, the total dose of x-ray exposure
amounted to 96 millisieverts for accomplishing a series of necessary
examinations. Furthermore, the examination procedures are complicated,
ie, inhaled gas should be changed several times and HRCT
images should be obtained at the end of inspiration and expiration at
the second and 60th breaths while inhaling the gas containing either
SF6 or He. These measurements should be repeated
for the different lung fields. Although such complexity may not allow
us to routinely use the current CT method as a diagnostic tool for
screening, we believe that the CT method is certainly useful for a
close examination with the intention of detecting regional differences
in acinar ventilation inhomogeneities.
Sensitivity of the CT Method in Detecting Ventilation
Inhomogeneities in Intact Acini
Although the differences in inspiratory MLD in
SF6 and He images at the second breath tended to
be smaller than those observed under steady-state conditions in
nonsmoking control subjects, the differences were not statistically
significant in either the upper or lower lung field (Fig 2)
. This
suggests that the diagnostic sensitivity of the CT method is not
sufficiently high for detection of subtle ventilation inhomogeneities
occurring in almost intact acini. At variance with the findings
regarding inspiratory MLD, expiratory MLD disparities in
SF6 and He images at the second breath analyzed
for upper and lower lung fields did not differ from those obtained in
the state of equilibrium in either the nonsmoking group or the smoking
group (Table 2
; Fig 2
, 3
). This may not necessarily indicate that
acinar ventilation inhomogeneities are fully removed at the end of
expiration even in the case of smokers with COPD manifestations.
Alternatively, it may be interpreted as one of the limitations of the
CT method. The disparity in MLD between SF6 and
He images becomes much smaller at end-expiration than that at
end-inspiration because of the relative increase in the contribution of
lung tissue components to MLD at end-expiration. Thus, we cannot
eliminate the possibility that such disparity is attributable to an
enhanced contribution of the lung tissue rather than diminution of
acinar ventilation inhomogeneities at the end of expiration. However,
further studies are absolutely necessary to know the definite reason
why the disparity in MLD between SF6 and He
becomes small at end-expiration in comparison with that at
end-inspiration.
Acinar Ventilation Inhomogeneities in Smokers With COPD Predicted
From SF6-Associated and He-Associated HRCT Images
The important CT findings for smoking subjects with COPD (Table 2 ;
Fig 3
) can be summarized as follows: (1) the differences in inspiratory
MLD of SF6 and He images at the second breath in
both lung fields are much smaller than those estimated under
steady-state conditions (ie, the 60th breath after the start
of breathing the inert gas); (2) the difference in second-breath
inspiratory MLD in the upper lung field is small in comparison with
that in the lower lung field; and (3) the %LAA estimated for
SF6 and He in either lung field does not differ
from the corresponding %LAA during room-air breathing. These findings
suggest that SF6/He-associated HRCT images are
unnecessary for quantitation of emphysematous lesions caused by almost
complete destruction of acinar structures forming LAA, but useful for
appraising the augmentation in asymmetrical airway branching at the
acinar level in various regions of the lung in COPD patients.
Furthermore, the experimental data on differences in second-breath
inspiratory MLD may indicate that incomplete destruction of acinar
structures including augmented asymmetry in acinar airway branching is
more evident in the upper lung field than in the lower lung field,
though the extent of complete destruction of acinar structures
represented by LAA does not differ between the two fields of smoking
patients with COPD.
In conclusion, (1) the most important message derived from the present study is that the quantitative difference in SF6 and He gas distribution over the lung periphery can be examined directly by means of HRCT images obtained at end-inspiration but not at end-expiration; (2) SF6-associated and He-associated HRCT images obtained at the time of end-inspiration of the second breath, but not in the steady state, appear to be promising for estimating abnormalities in airway branching due to incomplete destruction of acinar structures in various regions of the lung in COPD patients; (3) however, the second-breath SF6/He images at end-inspiration may not sensitively predict fine abnormalities in acinar airway branching in the intact lung; (4) furthermore, the usefulness of SF6/He images for detecting emphysematous changes on the basis of LAA does not surpass that of conventional HRCT during room-air breathing; and (5) in smoking subjects with COPD, incomplete destruction of acinar structures leading to enhanced asymmetry in airway branching appears to develop predominantly in the upper lung field in disproportion to the extent of emphysematous changes.
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Footnotes |
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Received for publication November 30, 2000. Accepted for publication May 23, 2001.
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References |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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This article has been cited by other articles:
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  G. H. Mills, J. M. Wild, B. Eberle, and E. J. R. Van Beek Functional magnetic resonance imaging of the lung Br. J. Anaesth., July 1, 2003; 91(1): 16 - 30. [Full Text] [PDF]
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; n = 3) and smokers with COPD
(•; n = 3) while breathing the gas with SF6. Error bars
are omitted for clarity because the standard deviation is very small at
each data point. 
= asymptomatic for nonsmoking control subjects
(- 782 ± 8 HU). 
= asymptomatic for smokers with COPD
(- 816 ± 12 HU).
MLD) between
SF6 and He gas breathing at the end of inspiration and
expiration of the second and the 60th breaths obtained for the
nonsmoking control group. Values are means ± SD. Top,
A: inspiration; bottom, B:
expiration. 2B = the second breath inhaling SF6 or He
gas; 60B = the 60th breath inhaling SF6 or He gas;
UL = upper lung field; LL = lower lung field.