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Clinical Investigations: SMOKING |

Inhaling Gas With Different CT Densities Allows Detection of Abnormalities in the Lung Periphery of Patients With Smoking-Induced COPD* FREE TO VIEW

Kazuhiro Yamaguchi, MD, FCCP; Kenzo Soejima, MD; Eiichi Koda, MD; Noriaki Sugiyama, PhD
Author and Funding Information

*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@cpnet.med.keio.ac.jp



Chest. 2001;120(6):1907-1916. doi:10.1378/chest.120.6.1907
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Study objectives: To establish a novel method allowing detection of regional abnormalities in gas distribution at the acinar level by high-resolution CT (HRCT).

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.

Figures in this Article

To assess the gas distribution in the lung periphery, He and SF6 have generally been used as indicator gases in the field of pulmonary physiology because of their extremely low solubility in blood,12 eliminating the effects of gas absorption into the alveolar capillaries. The physical properties of He and SF6 differ greatly, eg, the density of SF6 gas is 34 times greater than that of He gas but the viscosity is 0.8 times lower.4 The molecular mass weight of SF6 is 37 times that of He, reducing SF6 diffusivity in a gaseous medium to one sixth of that of He.,35 Extensive studies511 done in the field of pulmonary physiology have demonstrated that ventilation inhomogeneities at the periphery of diseased lungs during tidal breathing are mainly elicited by airspace destruction in association with enhanced asymmetry in airway branching within the acinus. Based on model calculations with asymmetrical acinar airway branching taken into account or based on actual measurements at the airway opening, many investigators513 have confirmed that 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 the acinar regions. To the best of our knowledge, however, physiologic studies have not shown immediately that He and SF6 are actually distributed differently in the lung periphery, particularly in the acini, based on the physical properties of the gases. Recent major progress in CT, including high-resolution CT (HRCT), however, appears to enable direct analysis of He and SF6 distribution at the acinar level, because current CT scanners can provide scan data with a spatial resolution of < 0.5 mm,14 one order magnitude less than the diameter of a single acinus. Since He and SF6 gas densities differ by a factor of 30,,34 we hypothesized that CT values for these gases might differ and high-precision CT scanners could detect disparities in their distribution in the acinar regions. Furthermore, HRCT may serve as a means of determination of different-density-gas acinar distributions in different lung fields. In the present study, we attempted to shed light on the following issues by measuring CT density in the lung periphery when gas containing He or SF6 was inhaled: (1) whether distributional differences in He and SF6 in different lung fields are detected by HRCT; (2) what the best timing is for SF6/He-associated HRCT imaging for predicting acinar abnormalities; and (3) what aspects are seen in He and SF6 distributions in the acinar regions in nonsmoking normal subjects without pulmonary disorders and in smoking subjects with chronic airflow obstruction.

Patient Selection

The institutional review board for human studies approved the protocol for this study, and informed consent was obtained from all subjects. We studied 75 male subjects; of these, 28 nonsmoking volunteers free of pulmonary disorders were adopted as nonsmoking control subjects (C group). The remaining 47 subjects (S group) were current smokers or ex-smokers with significantly long smoking histories but no marked abnormalities, such as giant bulla, bronchial asthma, bronchiectasis, pneumonia, pulmonary fibrosis, pulmonary vascular disease, or lung cancer, compromising pulmonary function. There were no differences in age, height, or weight between the C group and the S group (Table 1 ). All of the subjects in the S group showed a ratio of FEV1 to FVC (FEV1%) below the 95% confidence limit of values predicted from data on age-matched nonsmoking Japanese volunteers,15 indicating that subjects belonging to the S group suffered from chronic airflow obstruction. Therefore, they were regarded as patients having COPD. Four of 47 subjects in the S group were ex-smokers, and lifelong cigarette consumption in these ex-smokers was > 40 pack-years.

Pulmonary Function Tests

Pulmonary function was tested within a week before or after the HRCT examination. As ventilatory indicators, we measured vital capacity, FVC, and the expiratory flow-volume curve using an electronic spirometer (MFR-8200; Nihon Kohden; Tokyo, Japan). Respiratory impedance was measured using oscillation (MZR-4000; Nihon Kohden). Lung volumes, including functional residual capacity, residual volume, and total lung capacity, were examined by means of He dilution (Chestac-55V; Chest; Tokyo, Japan). Pulmonary diffusing capacity for carbon monoxide was estimated using 10-s breath holding (Chestac-55V; Chest).

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 × 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.14,1620 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,1619,2123 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,,1621 the pathologic significance of expiratory LAA has not been conclusively decided.18,2325 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) × (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.

To determine the time necessary for thoroughly expelling SF6 accumulated in the lung, we preliminarily examined changes in MLD in the right upper lung field at end-inspiration after switching the inhaled gas containing SF6 to room air (n = 3 for nonsmoking control subjects, and n = 3 for smokers with a marked reduction in FEV1%). The inspiratory MLD sharply decreased after initiating room air and reached, within 15 min, the value consistent with that observed for breathing solely room air in both nonsmoking control subjects and smokers. Based on these facts, we assumed that 20-min room-air breathing would be practically sufficient for eliminating SF6 (or He) from the lung even in the subject with severe COPD.

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.

HRCT Findings in the Case of Room-Air Breathing

%LAA values for both the upper and lower lung fields during room-air breathing were very low in the nonsmoking control group (Table 2 ). HRCT parameter values in the smoking group were, however, abnormal compared to those observed in the control group. Both inspiratory and expiratory MLD in the upper lung field shifted more negatively in the smoking group than in the control group. Although there was little difference in inspiratory MLD in the lower lung field between the two groups, expiratory MLD values for the lower lung field were more negative in the case of the smoking group. In addition, %LAA increased in the smoking group, averaging 21% for each lung field. Neither inspiratory nor expiratory MLD differed significantly between the upper and lower lung fields in the groups studied. %LAA showed qualitatively the same tendency as MLD. Comparing inspiratory and expiratory CT images, MLD in both lung fields became more positive in the expiratory phase in the control group. The extent of change in lung CT density between inspiration and expiration was 180 HU in the control group, while that seen in the case of the smoking group was only 60 HU (p = 0.01 vs control group).

HRCT Data at the 60th Breath Inhaling SF6 or He Gas

The disparity in upper lung MLD between the SF6 and He images estimated at end-inspiration at the 60th breath averaged 32 HU in the case of nonsmoking control subjects and 33 HU in the case of smoking patients with COPD, and the difference was not significant (Table 2). Qualitatively, the same tendency was observed for inspiratory MLD in the lower lung field in both groups. However, the situation was quite different for expiratory MLD. The MLD disparity at end-expiration during SF6 and He gas breathing was 10 HU in the upper lung field and almost zero in the lower lung field in either group.

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).

The differences in inspiratory MLD between the SF6 and He images estimated at the second breath in the case of the smoking group were 6 ± 1 HU in the upper lung field and 15 ± 3 HU in the lower lung field (Fig 3 ). These differences were much smaller than those seen at the 60th breath in both lung fields. In addition, the difference in MLD at the second breath in the case of the smoking group was smaller in the upper lung field than in the lower lung field. On the other hand, the MLD disparities at the second breath in the expiratory SF6 and He images did not differ from those observed at the 60th breath in the smoking group (Fig 3). %LAA was not calculated for SF6 and He images obtained at the second breath because the significance of LAA estimated from data reflecting transitional changes in lung CT density was not clear.

Methodology Critique

In the human lung, the airspace volume is about 80% of the total lung volume, whereas the parenchymal tissue accounts for 7% and the capillary network accounts for 5%.27 In addition,> 95% of the lung volume is peripheral to the respiratory bronchioles, that is, > 95% of the gas in the lung is within the acini.12,27 Therefore, the density represented by the CT value in the lung field mainly reflects the density of the gas in the acini rather than that of the lung tissue. This is more noticeable at end-inspiration than at end-expiration, because the lung is expanded more at the end of inspiration at which point the ratio of gas volume to lung tissue volume in the region of interest is increased. This suggests that HRCT measurements on inspiration are useful in appraising the intra-acinar gas distribution. Although HRCT measurements at end-expiration may be unsuitable for analyzing the gas distribution in the lung periphery due to an appreciable increase in the relative lung tissue contribution to the overall CT density, they may be important in estimating the extent of air trapping.18,2325

Extensive studies512 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 investigators512 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.,67,12 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.67 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 colleagues,28have 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 augmented,8,1011 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.

Abbreviations: FEV1% = ratio of FEV1 to FVC; HRCT = high-resolution CT; HU = Hounsfield unit; %LAA = relative area with low CT attenuation; MLD = mean lung density

Table Graphic Jump Location
Table 1. Basic Subject Data*
* 

Data are presented as mean ± SD. %VC = measured vital capacity/predicted vital capacity; V̇50 = expiratory flow rate at 50% of vital capacity; TLC = total lung capacity; FRC = functional residual capacity; RV = residual volume; Dlco = diffusing capacity of the lung for carbon monoxide; C group = nonsmoking control group; S group = smoking group.

 

Significantly different from the C group.

Figure Jump LinkFigure 1. Transitional changes in upper lung inspiratory MLD for nonsmoking control subjects (○; 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).Grahic Jump Location
Table Graphic Jump Location
Table 2. Quantitative HRCT Image Data Obtained at the Time of the 60th Breath, Inhaling Room Air, He, or SF6 Gas Mixture*
* 

Data are presented as mean ± SD.

 

Significantly different from the C group.

 

Differing from the values in the case of room air or He gas mixture.

§ 

Differing from the inspiratory values.

Figure Jump LinkFigure 2. Differences in MLD (ΔMLD) 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.Grahic Jump Location
Figure Jump LinkFigure 3. Differences in MLD between SF6 and He gas breathing at the end of inspiration and expiration of the second and the 60th breaths, obtained for the smoking group with COPD. Values are means ± SD. Top, A: inspiration; bottom, B: expiration.* = Significantly different from the value estimated at the 60th breath; + = significantly different from the value estimated for the upper lung field. See Figure 2 legend for expansion of abbreviations.Grahic Jump Location
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Braker W, Mossman AL. Helium. In: Matheson gas data book. 6th ed. Lyndhurst, NJ: Matheson, Division of Searle Medical Products USA, 1980; 344–349.
 
Braker W, Mossman AL. Sulfur hexafluoride. In: Matheson gas data book. 6th ed. Lyndhurst, NJ: Matheson, Division of Searle Medical Products USA, 1980; 649–654.
 
Lauzon, A, Prisk, GK, Elliot, AR, et al Paradoxical helium and sulfur hexafluoride single-breath washouts in short-term vs. sustained microgravity.J Appl Physiol1997;82,859-865. [PubMed] [CrossRef]
 
Paiva, M, Engel, JA Theoretical studies of gas mixing and ventilation distribution in the lung.Physiol Rev1987;67,750-796. [PubMed]
 
Verbanck, S, Paiva, M Model simulations of gas mixing and ventilation distribution in the human lung.J Appl Physiol1990;69,2269-2279. [PubMed]
 
van Muylem, A, de Vuyst, P, Yernault, JC, et al Inert gas single breath washout and structural alteration of respiratory bronchioles.Am Rev Respir Dis1992;146,1167-1172. [PubMed]
 
Verbanck, S, Weibel, ER, Paiva, M Simulations of washout experiments in postmortem rat lungs.J Appl Physiol1993;75,441-451. [PubMed]
 
van Muylem, A, Antoine, M, Yernault, JC, et al Inert gas single-breath washout after lung transplantation.Am J Respir Crit Care Med1995;152,947-952. [PubMed]
 
Rubio, ML, Sanchez-Cifuentes, MV, Peces-Barba, G, et al Intrapulmonary gas mixing in panacinar- and centriacinar-induced emphysema in rats.Am J Respir Crit Care Med1998;157,237-245. [PubMed]
 
Paiva, M, Engel, LA Gas mixing in the lung periphery. Chang, HK Paiva, M eds.Lung biology in health and disease (vol 40): respiratory physiology1989,245-276 Marcel Dekker. New York, NY:
 
Shaidel, GM, Lewis, SM Distribution of ventilation. Chang, HK Paiva, M eds.Lung biology in health and disease (vol 40): respiratory physiology1989,195-243 Marcel Dekker. New York, NY:
 
Webb, WR, Müller, NL, Naidich, DP Technical aspects of HRCT. Webb, WR Müller, NL Naidich, DP eds.High-resolution CT of the lung 2nd ed.1996,1-21 Lippincott-Raven Publishers. Philadelphia, PA:
 
Japan Society of Chest Diseases.. Standard values for pulmonary function tests in Japan.Jpn J Thorac Dis1991;31(suppl),1-25
 
Müller, NL, Staples, CA, Miller, RR, et al “Density Mask”: an objective method to quantitate emphysema using computed tomography.Chest1988;94,782-787. [PubMed]
 
Kinsella, M, Müller, NL, Abboud, RT, et al Quantitation of emphysema by computed tomography using “Density Mask” program and correlation with pulmonary function tests.Chest1990;97,315-321. [PubMed]
 
Knudson, RJ, Standen, JR, Kaltenborn, WT, et al Expiratory computed tomography for assessment of suspected pulmonary emphysema.Chest1991;99,1357-1366. [PubMed]
 
Gevenois, PA, de Maertelaer, V, de Vuyst, P, et al Comparison of computed density and macroscopic morphometry in pulmonary emphysema.Am J Respir Crit Care Med1995;152,653-657. [PubMed]
 
Yamaguchi, K, Soejima, K, Matsubara, H, et al Normal predicted values of CT indices reflect emphysematous alterations in the lung.J Jpn Respir Soc1997;35,1060-1066
 
Gierada, DS, Slone, RM, Bae, KT, et al Pulmonary emphysema: comparison of preoperative quantitative CT and physiological index values with clinical outcome after lung volume reduction surgery.Radiology1997;205,235-242. [PubMed]
 
Soejima, K, Yamaguchi, K, Kohda, E, et al Longitudinal follow-up study of smoking induced lung-density changes by high-resolution computed tomography.Am J Respir Crit Care Med2000;161,1264-1273. [PubMed]
 
Mitchell, AW, Wells, AU, Hansell, DM Changes in cross-sectional area of the lung on end expiratory computed tomography in normal individuals.Clin Radiol1996;51,804-806. [PubMed]
 
Gevenois, PA, de Vuyst, P, Sy, M, et al Pulmonary emphysema: quantitative CT during expiration.Radiology1996;199,825-829. [PubMed]
 
Arakawa, H, Webb, WR Expiratory high-resolution CT scan.Radiol Clin North Am1998;36,189-209. [PubMed]
 
Murphy, DM, Nicewicz, JT, Zabbatino, SM, et al Local pulmonary ventilation using nonradioactive xenon-enhanced ultrafast computed tomography.Chest1989;96,799-804. [PubMed]
 
Burri, PH Development and growth of the human lung. Fishman, AL Fisher, AR eds.Handbook of physiology, section 3: the respiratory system (vol 1); circulation and nonrespiratory functions1985,1-46 American Physiological Society. Bethesda, MD:
 
Crawford, ABH, Makowska, M, Paiva, M, et al Convection- and diffusion-dependent ventilation maldistribution in normal subjects.J Appl Physiol1985;59,838-846. [PubMed]
 
Verbanck, S, Schuermans, D, Muylen, AV, et al Convective and acinar lung-zone contributions to ventilation inhomogeneity in COPD.Am J Respir Crit Care Med1998;157,1573-1577. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Transitional changes in upper lung inspiratory MLD for nonsmoking control subjects (○; 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).Grahic Jump Location
Figure Jump LinkFigure 2. Differences in MLD (ΔMLD) 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.Grahic Jump Location
Figure Jump LinkFigure 3. Differences in MLD between SF6 and He gas breathing at the end of inspiration and expiration of the second and the 60th breaths, obtained for the smoking group with COPD. Values are means ± SD. Top, A: inspiration; bottom, B: expiration.* = Significantly different from the value estimated at the 60th breath; + = significantly different from the value estimated for the upper lung field. See Figure 2 legend for expansion of abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Basic Subject Data*
* 

Data are presented as mean ± SD. %VC = measured vital capacity/predicted vital capacity; V̇50 = expiratory flow rate at 50% of vital capacity; TLC = total lung capacity; FRC = functional residual capacity; RV = residual volume; Dlco = diffusing capacity of the lung for carbon monoxide; C group = nonsmoking control group; S group = smoking group.

 

Significantly different from the C group.

Table Graphic Jump Location
Table 2. Quantitative HRCT Image Data Obtained at the Time of the 60th Breath, Inhaling Room Air, He, or SF6 Gas Mixture*
* 

Data are presented as mean ± SD.

 

Significantly different from the C group.

 

Differing from the values in the case of room air or He gas mixture.

§ 

Differing from the inspiratory values.

References

Bartels, H (1971) Solubility coefficients of gases. Altman, PL Dittmer, DS eds.Biological handbooks: respiration and circulation,16-20 Federation of American Societies for Experimental Biology. Bethesda, MD:
 
Yamaguchi, K, Mori, M, Kawai, A, et al Effects of pH and So2on solubility coefficients of inert gases in human whole blood.J Appl Physiol1993;74,643-649. [PubMed]
 
Braker W, Mossman AL. Helium. In: Matheson gas data book. 6th ed. Lyndhurst, NJ: Matheson, Division of Searle Medical Products USA, 1980; 344–349.
 
Braker W, Mossman AL. Sulfur hexafluoride. In: Matheson gas data book. 6th ed. Lyndhurst, NJ: Matheson, Division of Searle Medical Products USA, 1980; 649–654.
 
Lauzon, A, Prisk, GK, Elliot, AR, et al Paradoxical helium and sulfur hexafluoride single-breath washouts in short-term vs. sustained microgravity.J Appl Physiol1997;82,859-865. [PubMed] [CrossRef]
 
Paiva, M, Engel, JA Theoretical studies of gas mixing and ventilation distribution in the lung.Physiol Rev1987;67,750-796. [PubMed]
 
Verbanck, S, Paiva, M Model simulations of gas mixing and ventilation distribution in the human lung.J Appl Physiol1990;69,2269-2279. [PubMed]
 
van Muylem, A, de Vuyst, P, Yernault, JC, et al Inert gas single breath washout and structural alteration of respiratory bronchioles.Am Rev Respir Dis1992;146,1167-1172. [PubMed]
 
Verbanck, S, Weibel, ER, Paiva, M Simulations of washout experiments in postmortem rat lungs.J Appl Physiol1993;75,441-451. [PubMed]
 
van Muylem, A, Antoine, M, Yernault, JC, et al Inert gas single-breath washout after lung transplantation.Am J Respir Crit Care Med1995;152,947-952. [PubMed]
 
Rubio, ML, Sanchez-Cifuentes, MV, Peces-Barba, G, et al Intrapulmonary gas mixing in panacinar- and centriacinar-induced emphysema in rats.Am J Respir Crit Care Med1998;157,237-245. [PubMed]
 
Paiva, M, Engel, LA Gas mixing in the lung periphery. Chang, HK Paiva, M eds.Lung biology in health and disease (vol 40): respiratory physiology1989,245-276 Marcel Dekker. New York, NY:
 
Shaidel, GM, Lewis, SM Distribution of ventilation. Chang, HK Paiva, M eds.Lung biology in health and disease (vol 40): respiratory physiology1989,195-243 Marcel Dekker. New York, NY:
 
Webb, WR, Müller, NL, Naidich, DP Technical aspects of HRCT. Webb, WR Müller, NL Naidich, DP eds.High-resolution CT of the lung 2nd ed.1996,1-21 Lippincott-Raven Publishers. Philadelphia, PA:
 
Japan Society of Chest Diseases.. Standard values for pulmonary function tests in Japan.Jpn J Thorac Dis1991;31(suppl),1-25
 
Müller, NL, Staples, CA, Miller, RR, et al “Density Mask”: an objective method to quantitate emphysema using computed tomography.Chest1988;94,782-787. [PubMed]
 
Kinsella, M, Müller, NL, Abboud, RT, et al Quantitation of emphysema by computed tomography using “Density Mask” program and correlation with pulmonary function tests.Chest1990;97,315-321. [PubMed]
 
Knudson, RJ, Standen, JR, Kaltenborn, WT, et al Expiratory computed tomography for assessment of suspected pulmonary emphysema.Chest1991;99,1357-1366. [PubMed]
 
Gevenois, PA, de Maertelaer, V, de Vuyst, P, et al Comparison of computed density and macroscopic morphometry in pulmonary emphysema.Am J Respir Crit Care Med1995;152,653-657. [PubMed]
 
Yamaguchi, K, Soejima, K, Matsubara, H, et al Normal predicted values of CT indices reflect emphysematous alterations in the lung.J Jpn Respir Soc1997;35,1060-1066
 
Gierada, DS, Slone, RM, Bae, KT, et al Pulmonary emphysema: comparison of preoperative quantitative CT and physiological index values with clinical outcome after lung volume reduction surgery.Radiology1997;205,235-242. [PubMed]
 
Soejima, K, Yamaguchi, K, Kohda, E, et al Longitudinal follow-up study of smoking induced lung-density changes by high-resolution computed tomography.Am J Respir Crit Care Med2000;161,1264-1273. [PubMed]
 
Mitchell, AW, Wells, AU, Hansell, DM Changes in cross-sectional area of the lung on end expiratory computed tomography in normal individuals.Clin Radiol1996;51,804-806. [PubMed]
 
Gevenois, PA, de Vuyst, P, Sy, M, et al Pulmonary emphysema: quantitative CT during expiration.Radiology1996;199,825-829. [PubMed]
 
Arakawa, H, Webb, WR Expiratory high-resolution CT scan.Radiol Clin North Am1998;36,189-209. [PubMed]
 
Murphy, DM, Nicewicz, JT, Zabbatino, SM, et al Local pulmonary ventilation using nonradioactive xenon-enhanced ultrafast computed tomography.Chest1989;96,799-804. [PubMed]
 
Burri, PH Development and growth of the human lung. Fishman, AL Fisher, AR eds.Handbook of physiology, section 3: the respiratory system (vol 1); circulation and nonrespiratory functions1985,1-46 American Physiological Society. Bethesda, MD:
 
Crawford, ABH, Makowska, M, Paiva, M, et al Convection- and diffusion-dependent ventilation maldistribution in normal subjects.J Appl Physiol1985;59,838-846. [PubMed]
 
Verbanck, S, Schuermans, D, Muylen, AV, et al Convective and acinar lung-zone contributions to ventilation inhomogeneity in COPD.Am J Respir Crit Care Med1998;157,1573-1577. [PubMed]
 
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