Loss of lung elastic recoil causing hyperinflation with increased TLC and decreased diffusing capacity and expiratory airflow are physiologic hallmarks of emphysema. We studied lung mechanics in 10 patients (seven men and three women) aged 69 ± 9 yr (mean ± SD) who had fixed, severe expiratory airflow limitation with a mean FEV1 = 0.73 ± 0.1 L (mean ± SD) (32 ± 7% predicted) and lung computed tomographic picture grade score ⩽ 20, indicating no or trivial emphysema. Three patients died, in whom whole-lung emphysema scores were 15 each and small airways were abnormal. Marked hyperinflation was present in all 10 patients studied, with TLC 7.3 ± 1.1 L (140 ± 12% predicted); FRC 5.6 ± 0.8 L (177 ± 30% predicted); and RV 5.2 ± 0.8 L (242 ± 28% predicted). Diffusing capacity of carbon monoxide (Dl CO was reduced, at 12 ± 6 ml/min/mm Hg (61 ± 29% predicted). The pressure–volume curves of the lung were markedly abnormal. Pst(L) at TLC was 11.6 ± 1.4 cm H2O. Transdiaphragmatic pressure (Pdi) in five patients was 66 ± 13 cm H2O. These results indicate that severe small-airways disease with no or trivial emphysema may cause a spurious reduction in diffusing capacity as well as severe loss of lung elastic recoil resulting in marked hyperinflation, increased TLC, and decreased Pdi and expiratory airflow.
This report addresses the spurious physiologic diagnosis of emphysema in symptomatic patients with severe expiratory airflow limitation due to chronic small-airways disease (SAD).
The American Thoracic Society (ATS) defines emphysema as “a condition of the lung characterized by abnormal, permanent enlargement of the air spaces distal to the terminal bronchiole, accompanied by destruction of their walls” (1). A previous radiologic–pathologic correlative study noted that the more severe the extent and distribution of anatomic emphysema, the more likely the chest roentgenogram will be abnormal, especially if there is airflow limitation causing clinical symptoms (2). The effects of such severe emphysema include hyperinflation, peripheral arterial deficiency, and increased markings, especially in patients with cor pulmonale (2). However, lung computed tomography (CT), especially when done with thin-section, high-resolution techniques to detect areas of abnormally low attenuation, has been shown to be the best way of detecting the extent and severity of emphysema (3).
Although there may be normal lung function in patients with mild emphysematous lung destruction (mean anatomic score < 24) (4, 5) a physiologic consequence of moderate to severe emphysematous lung destruction (anatomic score 25 to 50) is loss of lung elastic recoil causing expiratory airflow limitation even in cases of subclinical disease in which the FEV1 is normal or borderline (4, 6). Additionally, the diffusing capacity of carbon monoxide (Dl CO), a marker of the integrity of the alveolar capillary surface area, is also reduced (2, 4-6). Alternatively, primary intrinsic small-airways inflammation of varying extent causes mild to severe expiratory airflow limitation and abnormalities in gas exchange, although there is a normal Dl CO and normal lung elastic recoil in the absence of lung parenchymal destruction (4–10).
Because emphysema most often occurs in chronic cigarette smokers, it is common to find accompanying morphologic evidence of small-airways (< 3 mm I.D.) inflammation (4-6, 8, 9, 11, 12). However, although it is uncertain whether the small-airways abnormalities lead to or complicate emphysema, the small airways are the predominant anatomic sites of expiratory airflow limitation (12-14).
The present study investigated the physiologic abnormalities in symptomatic patients with severe expiratory airflow limitation, but with no or trivial morphologic evidence of emphysema and/or indications of emphysema on CT scans of the lung. The results indicated loss of lung elastic recoil causing hyperinflation with increased TLC, and that a reduced Dl CO and transdiaphragmatic pressure (Pdi) may also be physiologic consequences of severe expiratory airflow limitation resulting from severe small-airways inflammatory disease. These abnormalities may not be specific physiologic hallmarks of emphysematous parenchymal destruction.
We had previously studied 116 adult patients (62 men and 54 women), aged 68 ± 7 yr (mean ± SD), who had fixed expiratory airflow limitation and were seen consecutively in an outpatient clinic (11, 15). All but five of the patients were former long-term, regular cigarette smokers, with a mean smoking history of 53 ± 20 pack-yr (mean ± SD). As previously reported (11, 15), and as approved by the Institutional Review Board for Human Investigation, we conducted pulmonary-function studies and high-resolution, thin-section (2 mm) CT scans of the lungs in all patients. In only 24 of the 81 patients (30%) who had an FEV1 of less than 50% predicted was the CT emphysema score ⩾ 60, indicating severe emphysema (11). Alternatively, 35 of the 81 (43%) patients with an FEV1 of less than 50% predicted had CT emphysema scores ⩽ 20, indicating no or trivial emphysema (11). We were interested in conducting additional lung-function studies, including measurements of elastic recoil, in all patients who had an FEV1 of 35% predicted or less, with a lung-CT emphysema score ⩽ 20. Twelve of the 35 patients originally studied met this criterion. Two patients subsequently died, and neither measurement of lung elastic recoil nor autopsy material was obtained for these patients although both patients had an increased TLC. We report here the individual physiologic data obtained for 10 patients who had agreed to undergo additional lung studies. Also, there are correlative morphologic data for three of these patients who died and were autopsied. The data reported here have not been previously published. The results reported for the 10 patients are compared with those for 12 patients with severe emphysema who underwent lung-volume-reduction surgery (16). These 12 patients had a similar extent of expiratory airflow limitation (FEV1) to that of the 10 patients describved previously, but lung CT scores > 60.
As previously reported (6, 11, 15, 16), we obtained informed consent and measured lung function, including maximum inspiratory and expiratory flow–volume (MIEFV) loops, thoracic gas volume (TGV), airway resistance, single-breath Dl CO and static lung elastic recoil when the patients were clinically stable, using a pressure-compensated flow plethysmograph (Model 6200 Autobox; SensorMedics Inc., Yorba Buena, CA), and compared the results with predicted values (16). The panting frequency was set at ⩽ 1 Hz, to avoid mouth pressure from spurious underestimation of the alveolar pressure (17, 18). When necessary, the limits on panting frequency were supported during panting. TGV was measured on two separate occasions at least 6 mo apart, and the values were averaged. All studies were done after three inhalations (670 μg) of aerosolized albuterol, and the increase in FEV1 was < 200 ml in every patient.
As previously noted (4, 6, 7, 16), measurements of static lung-elastic-recoil pressures were obtained in the open plethysmograph with the patient in a sitting position, after placement of a 10-cm-long balloon inflated with 0.5 ml air in the lower third of the esophagus. After at least two inspirations to TLC, static transpulmonary (mouth-esophageal) pressures were recorded following stepwise, 3-s interruptions of exhalation against a closed shutter at different lung volumes. A minimum of five deflation curves were obtained for each patient, and a plot of best visual fit of the pooled data was drawn.
Maximal negative inspiratory mouth pressure was measured at RV (19).
A 5-cm-long balloon inflated with 1.0 ml air was positioned in the stomach to record gastric pressure (Pg). In five patients, we measured both Pg and esophageal pressure (Pes) during a maximal inspiratory sniff from end-tidal expiration without a nose clip or occluded airway. This technique has been previously reported to measure Pdi (Pdi = Pg − Pes). Normal male values for sniff Pdi are 148 ± 24 cm H2O (mean ± SD), and for sniff Pes 105 ± 26 cm H2O. Normal female values for sniff Pdi are 121 ± 25 cm H2O and for sniff Pes 92 ± 22 cm H2O.
As reported earlier (4, 6, 16) to determine the mechanism of expiratory airflow limitation in chronic obstructive lung disease, we plotted maximum expiratory airflow obtained from the MEFV loop against static lung-elastic-recoil pressure at corresponding lung volumes and constructed maximum-expiratory-airflow–static lung-elastic-recoil-pressure curves (MFSR). The slope of the MFSR curve between 50% and 30% of the FVC represents the conductance of the S airway segment (GS). Normal values were obtained previously in seven healthy subjects aged 61 to 74 yr, in whom GS = 0.6 ± 0.1 lps/cm H2O (mean ± SD) (4, 6).
Comparisons of differences between the two study-patient groups were made with the two-tailed paired t test, with values of p < 0.05 being considered significant.
Using a high-spatial-frequency reconstruction algorithm and 2-mm collimation, we obtained high-resolution CT scans of patients in the prone position, as previously decribed (3, 11, 15), with a Picker 1200SX scanner (Cleveland, OH). We used seven slices, from the lung apex to the base, at approximately 3-cm intervals, at end inspiration. Areas of low attenuation and vascular obliteration were graded for emphysema, using a picture-based 0 to 100 severity-grading system adapted for CT (3, 11, 15), with independent readings, by two radiologists (M.J.S., N.L.M.). Neither radiologist was aware of the clinical, anatomic, or physiologic results for any patient. Average scores were used in the data analysis.
Whole lungs, obtained at autopsy after inflation to 30 cm H2O, were prepared and cut into multiple transaxial slices similar to those scanned with CT, and were graded by a pathologist (J.C.H.) for gross emphysema score, using a modification of the picture-grading technique of Thurlbeck and colleagues (2, 3, 5, 11). The extent and severity of the abnormalities in the small membranous bronchioles (< 3 mm I.D.) and respiratory bronchioles were evaluated by a pathologist (J.C.H.) who was not aware of the clinical, radiographic, or physiologic results, using previously described techniques (5). From three to six stratified random blocks of lung tissue were obtained from the medial and lateral parts of lung slices without pneumonia, using a template that allowed for tissue shrinkage during paraffin processing. Five-micrometer-thick sections were cut, mounted on glass slides, and stained with hematoxylin and eosin (H&E), Masson trichrome, and periodic acid–Schiff (PAS) stains. The extent and severity of the disease in the small membranous and respiratory bronchioles were evaluated with a standard set of photomicrographs to grade epithelial changes, inflammatory cellular infiltration, connective tissue, and carbon-pigment deposition (5). Normal values for nonrespiratory bronchioles are 118 ± 47 (mean ± SD), and for respiratory bronchioles 83 ± 37.
In Table 1 are the results of lung-function studies in the 10 patients (seven men and three women, aged 69 ± 9 yr [mean ± SD]) with severe expiratory airflow limitation who had a lung-anatomic and/or CT emphysema score ⩽ 20 (mean CT score: 9 ± 7). TLC, RV, FRC, and RV/TLC (%) were significantly increased. For the 10 patients as a group, Dl CO was also reduced, although it was normal in three patients, and Dl CO/alveolar volume was normal in five patients. Values for TGV obtained on two separate occasions for each patient differed by < 10%. Patients with severe emphysema, despite similar FEV1 valves to those of the 10 patients described previously, had a greater reduction in Dl CO and lung recoil, causing greater hyperinflation and TLC (Table 1 and Figure 1).
|FVC, L*||2.0 ± 0.5 (50 ± 17)||2.5 ± 0.5 (62 ± 8)*|
|FEV1, L||0.73 ± 0.13 (32 ± 7)||0.69 ± 0.3 (29 ± 7)|
|TLC, L||7.3 ± 1.1 (140 ± 12)||9.3 ± 1.1 (156 ± 17)*|
|FRC, L||5.6 ± 0.8 (177 ± 30)||7.3 ± 1.0 (204 ± 28)*|
|RV, L||5.2 ± 0.8 (242 ± 28)||6.7 ± 1.0 (288 ± 38)*|
|SGaw, lps/cm H2O/L||0.04 ± 0.01 (19 ± 4)||0.02 ± 0.01 (10 ± 4)|
|Dl CO, ml/min/mm Hg||12 ± 6 (61 ± 29)||2.7 ± 2.1 (9 ± 9)*|
|Dl CO/Va, L||2.7 ± 0.7 (76 ± 19)||0.9 ± 0.9 (17 ± 10)*|
|RV/TLC, %||71 ± 6 (175 ± 18)||72 ± 6 (177 ± 19)|
|Pst(L) TLC, cm H2O||11.6 ± 1.4||10.3 ± 1.7|
|Pst(L) FRC, cm H2O||2.2 ± 1.0||1.3 ± 0.6*|
|Pst(L) TLC/TLC||1.6 ± 0.3||1.1 ± 0.3*|
|GS, lps/cm H2O||0.18 ± 0.03||0.20 ± 0.03|
|Pdi, cm H2O||66 ± 13|
|Pes, cm H2O||53 ± 15|
|Pg cm H2O||14 ± 5|
|MIP, cm H2O||58 ± 10|
|CT score||9 ± 7||74 ± 8*|
Results of static lung-elastic-recoil-pressure–volume curves for each patient are shown in Figure 1. In every case, the curve is shifted markedly to the left of that of normal age-matched controls (4, 16), indicating severe loss of lung elastic recoil. However, the loss of lung elastic recoil is not as severe as in the emphysema patients with a comparable reduction in FEV1 (16). The reduction in lung elastic recoil could not completely account for expiratory airflow limitation, and the small-airway conductance of the S segment (GS) was reduced in every case (see Table 1). All of these physiologic abnormalities are indistinguishable from those of patients with a similar extent of expiratory airflow limitation and documented emphysema (16).
Maximum inspiratory mouth pressures, and maximum sniff Pes and Pdi, were reduced as compared with normal valves (Table 1).
Results of lung-CT, airway-morphology, and whole-lung-macroscopic emphysema scores appear in Table 2. In the three cases available for study, there was close correlation between lung-CT and whole-lung-anatomic scores for emphysema. Membranous-bronchiole and respiratory-bronchiole scores were markedly abnormal. Correlation for scoring of lung CT scans between the two radiologists (N.L.M. and M.J.S.) was good (r = 0.91, p < 0.001).
|Case 1||Case 2||Case 3|
|Age, yr/sex||71 M||67 M||69 M|
|Lung CT emphysema score||20||15||20|
|Lung anatomic emphysema score||15||15||15|
|Membranous bronchiole score||333||244||305|
|Respiratory bronchiole score||266||211||200|
|TLC (L), % pred||6.6 (124)||7.8 (139)||9.5 (125)|
|Pst(L) TLC, cm H2O||12||15||12|
The present report, based on 10 selected symptomatic patients with severe expiratory airflow limitation, documents that marked loss of lung elastic recoil, causing hyperinflation with increased TLC and reduction in Dl CO and Pdi can be present despite the absence of or only trivial emphysema on lung CT scans and in morphologic studies. We attribute these physiologic abnormalities to chronic, severe SAD.
In 24 patients previously studied, we noted a strong correlation for detection of emphysema between lung CT findings and whole-lung morphology (r = 0.86, p < 0.001) (11). On the basis of these and similar results from other investigators (3), we believe that high-resolution , thin-section lung CT scanning is a reliable noninvasive surrogate technique for identifying the extent, severity, and distribution of macroscopic emphysema.
In a previous study of 14 patients with moderately severe expiratory airflow limitation (i.e., FEV1 = 1.2 ± 0.5 L [mean ± SD], or 45 ± 16% predicted), we found a close positive correlation between values for Dl CO and lung elastic recoil (13). However, we recently reported spuriously low values for DLco in patients with severe airflow limitation (i.e., FEV1 < 1 L, or < 40% predicted) who had no or only trivial emphysema according to lung-CT and/or morphologic criteria (11, 15). Similar observations were noted by Macklem and coworkers (8) in five of seven patients with severe airflow limitation caused by SAD, with no or mild morphologic emphysema and normal lung elastic recoil.
We have previously noted that inhomogeneity of ventilation and increased physiologic dead space in severe obstructive lung disease could lead to errors in measuring Dl CO from uneven sampling of regions of lung with varying washout-time constants (15). Furthermore, differences in breath-holding time, washout volume, or alveolar sample size could not explain spurious reductions in Dl CO (11, 15). The abnormal Dl CO values found in the present study may have been related to poorly ventilated lung units.
In the presence of clinically significant expiratory airflow limitation, whether it results from loss of lung elastic recoil and/or intrinsic small-airways obstruction, it would be anticipated that FRC and RV would be increased. However, only an increase in pressure generated by the inspiratory muscles, or a concurrent decrease in lung and/or chest-wall elastic recoil pressure, will increase TLC when the opposing pressures are equal (21).
Although we did not measure the elastic recoil of the relaxed chest wall in the present study, we (22) and Sharp and coworkers (23) have previously reported it to be decreased in patients with severe expiratory airflow limitation due to emphysema. Moreover, the very compliant chest wall facilitates the accommodation of the hyperinflated lung.
Measurements of inspiratory muscle pressure at FRC (Pi max) in patients with COPD are reduced (less negative) as compared with those of normal subjects at normal FRC (24). However, it has been shown that Pi max and maximal Pdi at FRC and RV in patients with stable COPD are actually normal or greater than those of normal subjects as a function of predicted lung volume (25). Similar results were observed in the present study.
Numerous investigators have repeatedly observed reversible hyperinflation and increased FRC, and sometimes increased TLC, with transient loss of lung (26-31) and chest-wall elastic recoil (29) and increased maximal inspiratory muscle pressure (26, 29, 30) in patients recovering from acute attacks of spontaneous asthma, and inconsistently after induced asthma (26, 29, 30). Furthermore, fixed hyperinflation and increased TLC has also been noted in chronic asthma (32). However, the mechanism responsible for these effects remains speculative (26-32) with respect to changes in lung-surface and/or tissue forces and stress relaxation following hyperinflation and asthma (28, 29, 32, 33).
In the present study, we did not measure the mean linear intercept (LM), which estimates the average distance between alveolar units. However, any increase in LM would not distinguish true emphysema from hyperinflation from other causes. Osborne and associates (34) have previously shown that loss of lung elastic recoil correlates better with LM than does the presence of macroscopic emphysema. However, it is unlikely that diffuse microscopic emphysema was present and contributed to loss of lung elastic recoil in our study. Previous measurements of LM in patients with an emphysema score of 29 ± 17 (mean ± SD) and FEV1 of 50 to 59% predicted yielded values similar to those obtained in patients with normal lung function, including a normal lung-elastic-recoil pressure at TLC and minimal morphologic emphysema (5). Furthermore, there was no loss of alveolar attachments/per millimeter of external perimeter of nonrespiratory bronchioles (5).
Determination of lung volume using lung-CT-gated spirometry was not done in the present study. However, a recent report noted a close correlation (r = 0.95) between lung CT and plethysmographic techniques for calculating TLC in normal subjects and in patients with obstructive lung disease (35).
We suspect that in patients with severe, fixed expiratory airflow limitation due to intrinsic SAD, chronic “smoldering” obstruction and/or bronchoconstriction causing dynamic hyperinflation and air trapping can lead to chronic loss of lung elastic recoil through unknown mechanisms despite the absence of significant macroscopic emphysema. This causes hyperinflation with increased TLC, which may be mistaken for emphysema, especially when the Dl CO is spuriously reduced (11, 16). The use of high-resolution lung CT scanning will help in clarifying the source of lung hyperinflation and increased TLC. It has previously been shown to be helpful for distinguishing hyperinflation in patients with chronic asthma from that in patients with emphysema (32).
The authors thank Jozef Kollin, M.D., and Robert Green, M.D., for autopsy studies; Randy Newsom, CPFT/RCP for technical services; W. Mark Elliott, Ph.D., for histopathologic studies; and Jay A. Nadel, M.D., for stimulating physiologic discussions that led to the present study.
|1.||American Thoracic SocietyDefinitions and classification of chronic bronchitis, asthma, and pulmonary emphysema. Am. Rev. Respir. Dis.851962762767|
|2.||Thurlbeck W. M., Henderson J. A., Frasser R. G., Bates D. V.Chronic obstructive lung disease: a comparison between clinical, roentgenologic, functional and morphologic criteria in chronic bronchitis, emphysema, asthma and bronchiectasis. Medicine49197081145|
|3.||Thurlbeck W. M., Müller N. L.Benjamin Felson Lecture. Emphysema: definition, imaging and quantification. Am. J. Roentgenol.163199410171025|
|4.||Gelb A. F., Gold W. M., Wright R. R., Bruch H. R., Nadel J. A.Physiologic diagnosis of subclinical emphysema. Am. Rev. Respir. Dis.10719735063|
|5.||Hogg J. C., Wright J. L., Wiggs B. L., Coxson H. O., Saez A. O., Pare P. D.Lung structure and function in cigarette smokers. Thorax491994473478|
|6.||Zamel N., Hogg J., Gelb A. F.Mechanisms of maximal expiratory flow limitation in clinical unsuspected emphysema and obstruction of the peripheral airways. Am. Rev. Respir. Dis.1131976337345|
|7.||Gelb A. F., Zamel N.Simplified diagnosis of small airway obstruction. N. Engl. J. Med.2881973395398|
|8.||Macklem P. T., Thurlbeck W. M., Fraser R. G.Chronic obstructive disease of small airways. Ann. Int. Med.741971167177|
|9.||Cosio M., Ghezzo H., Hogg J. C., Corbin R., Loveland M., Dosman J., Macklem P. T.The relations between structural changes in small airways and pulmonary function tests. N. Engl. J. Med.298197812771281|
|10.||McFadden E. R., Ingram R. H.Peripheral airway obstruction. J.A.M.A2351976259260|
|11.||Gelb A. F., Hogg J. C., Müller N. L., Schein M. J., Kuei J., Tashkin D. P., Epstein J., Kolin J., Green R. H., Zamel N., Elliott W. M., Hadjiaghia M. S.Contribution of emphysema and small airways in COPD. Chest1091996353359|
|12.||Hogg J. C., Macklem P. T., Thurlbeck W. M.Site and nature of airway obstruction in chronic obstructive lung disease. N. Engl. J. Med.278196813551360|
|13.||Gelb A. F., Gobel P. H., Fairshter R., Zamel N.Predominant site of airway resistance in chronic obstructive lung disease. Chest791981273276|
|14.||Leaver D. G., Tattersfield A. E., Pride N. B.Contribution of loss of lung recoil and of enhanced airways collapsibility to the airflow obstruction in chronic bronchitis and emphysema. J. Clin. Invest.52197321172128|
|15.||Gelb A. F., Schein M., Kuei J., Tashkin D. P., Müller N. L., Hogg J. C., Epstein J. D., Zamel N.Limited contribution of emphysema in advanced chronic obstructive pulmonary disease. Am. Rev. Respir. Dis.147199311571161|
|16.||Gelb A. F., Zamel N., McKenna R. J., Brenner M.Mechanism of short-term improvement in lung function following emphysema resection. Am. J. Respir. Crit. Care Med.1541996945951|
|17.||Stanescu D. C., Rodenstein D., Cauberghs M., Van de Woestljne K.Failure of body plethysmography in bronchial asthma. J. Appl. Physiol.521982939948|
|18.||Brown R., Ingram R. H., McFadden E. R.Problems in plethysmographic assessment of changes of total lung capacity in asthma. Am. Rev. Respir. Dis.1181978685692|
|19.||Black L. F., Hyatt R. E.Maximal respiratory pressures: normal values and relationship to age and sex. Am. Rev. Respir. Dis.991969696702|
|20.||Miller J. M., Moxham J., Green M.The maximal sniff in the assessment of diaphragm function in man. Clin. Sci.6919859196|
|21.||Agostoni, E., and R. E. Hyatt. 1986. Static behavior of the respiratory system. In P. T. Macklem and J. Mead, editors. Handbook of Physiology. Section 3, Vol. 3, Part 1. The Respiratory System: Mechanics of Breathing. American Physiological Society. Bethesda, MD. 113–130.|
|22.||Gelb A. F., McKenna R. J., Brenner M., Fischel R., Baydur A., Zamel N.Contribution of lung and chest wall mechanics following emphysema resection. Chest11019961117|
|23.||Sharp J. T., van Lith P., Nuchprayoon C. V., Briney R., Johnson F. N.The thorax in chronic obstructive lung disease. Am. J. Med.4419683946|
|24.||Byrd R. B., Hyatt R. E.Maximal respiratory pressures in chronic obstructive lung disease. Am. Rev. Respir. Dis.981968848856|
|25.||Similowski T., Yan S., Gauthier A. P., Macklem P. T., Bellmare F.Contractile properties of the human diaphragm during chronic hyperinflation. N. Engl. J. Med.3251991917923|
|26.||Müller N., Bryan A. C., Zamel N.Tonic inspiratory muscle activity as a cause of hyperinflation in asthma. J. Appl. Physiol. (Respir. Environ. Exerc. Physiol.)501981279282|
|27.||Woolcock A. J., Rebuck A. S., Cade J. F., Read J.Lung volume changes in asthma measured concurrently by two methods. Am. Rev. Respir. Dis.1041971703709|
|28.||Gold W. M., Kaufman H. S., Nadel J. A.Elastic recoil of the lungs in chronic asthmatic patients before and after therapy. J. Appl. Physiol.231967433438|
|29.||Peress L., Sybrecht G., Macklem P. T.The mechanism of increase in total lung capacity during acute asthma. Am. J. Med.611976165169|
|30.||Müller N., Bryan A. C., Zamel N.Tonic inspiratory muscle activity as a cause of hyperinflation in histamine-induced asthma. J. Appl. Physiol. (Respir. Environ. Exerc. Physiol.)491980869874|
|31.||Blackie S. P., Al-Majed S., Staples C. A., Hillam C., Paré P. D.Changes in total lung capacity during spontaneous asthma. Am. Rev. Respir. Dis.14219907983|
|32.||Kinsella M., Müller N. L., Staples C., Vedal S., Chan-Yeung M.Hyperinflation in asthma and emphysema: assessment by pulmonary function testing and computed tomography. Chest941988286289|
|33.||Buhain W. J., Brody J. S., Fisher A. B.Effect of artificial airway obstruction on elastic properties of the lung. J. Appl. Physiol.331972589594|
|34.||Osborne S., Hogg J. C., Wright J. L., Coppen C., Paré P. D.Exponential analysis of the pressure–volume curve. Am. Rev. Respir. Dis.137198810831088|
|35.||Brown, M. S., M. F. McNitt-Gray, J. G. Goldin, and D. R. Aberle. 1997. Automated measurement of split and total lung volume from helical CT. Annual Meeting, Radiologic Society of North America, Chicago, IL (abstract).|