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(Chest. 2002;122:2009-2014.)
© 2002 American College of Chest Physicians

Inspiratory Capacity and Decrease in Lung Hyperinflation With Albuterol in COPD*

Roberto Duranti, MD; Mario Filippelli, MD; Roberto Bianchi, MD; Isabella Romagnoli, MD; Riccardo Pellegrino, MD; Vito Brusasco, MD and Giorgio Scano, MD, FCCP

* From the Dipartimento di Medicina Interna (Drs. Duranti and Scano), Università di Firenze, Firenze; Fondazione Don C. Gnocchi "ONLUS" (Drs. Filippelli, Bianchi, and Romagnoli), UOF di Riabilitazione Respiratoria, Firenze; Fisiopatologia Respiratoria (Dr. Pellegrino), Azienda Ospedaliera S. Croce e Carle, Cuneo; and Dipartimento di Medicina Interna (Dr. Brusasco), Università di Genova, Genova, Italy.

Correspondence to: Roberto Duranti, MD, Dipartimento di Medicina Interna, Sezione di Immunoallergologia e Malattie dell’Apparato Respiratorio, Università di Firenze, Viale G. B. Morgagni, 85, 50134 Firenze, Italy; e-mail: r.duranti{at}dmi.unifi.it


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: Inspiratory capacity (IC) has been proposed as a simple method to assess acute changes in functional residual capacity (FRC) with bronchodilation, assuming that total lung capacity (TLC) is unchanged. This assumption is based on studies using body plethysmography, which may not accurately measure TLC in severely obstructed subjects. The aim of this study is to validate the use of IC measured by optoelectronic plethysmography (OEP) [ICOEP], a noninvasive technique capable of computing changes in absolute lung volumes with great accuracy.

Methods and measurements: We studied 13 subjects with COPD in clinically stable condition at baseline and after 200 µg of inhaled albuterol. Changes in lung volumes were obtained from changes in chest wall volume (Vcw) measured by OEP and were compared with those measured by standard techniques.

Results: Albuterol treatment caused a small but significant increase in FEV1 and FVC, a significant decrease of Vcw at FRC (VcwFRC), but no changes of Vcw at TLC (VcwTLC) and breathing pattern variables. The reduction of VcwFRC was not correlated with either spirometric or breathing-pattern variables. IC measured with a pneumotachograph was highly correlated with and not significantly different from ICOEP (p < 0.001).

Conclusions: A single dose of inhaled albuterol does not significantly modify VcwTLC in subjects with COPD, thus validating the use of IC to measure changes of FRC in the assessment of reversibility of airway obstruction.

Key Words: bronchodilation • functional residual capacity • optoelectronic plethysmography • total lung capacity


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The American Thoracic Society (ATS) and the European Respiratory Society suggest that the effects of the ß2-agonists on lung function in patients with COPD be assessed by measuring the FEV1 and FVC.1 2 Studies in the last decade have, however, stressed the importance of measurement of the operational lung volumes, with special reference to functional residual capacity (FRC) in addition to forced expiratory flows in evaluating the acute bronchodilator response.3 The decrease of the degree of lung hyperinflation, which is defined in the present article as a decrease in FRC, has been demonstrated to be critically associated with decrease of elastic work of breathing4 and breathlessness.5

Direct measurement of FRC needs sophisticated techniques that are not always available in every pulmonary function testing (PFT) laboratory. In contrast, inspiratory capacity (IC), ie, the difference between total lung capacity (TLC) and FRC, can be easily measured even with a simple spirometer, and may accurately track the changes in FRC after bronchodilatation if TLC remains constant. Thus, IC has been proposed for inclusion in the criteria for reversibility of airway obstruction.3 6 7 8 Nevertheless, accurate physiologic validation of IC for this use has never been done, probably due to the technical difficulties to prove that TLC is stable with the bronchodilator agents. Indeed, even with the best available techniques, such as body plethysmography, TLC cannot be accurately estimated especially when airflow obstruction is severe.9

Optoelectronic plethysmography (OEP) is a new noninvasive technique capable of computing with great accuracy and precision changes in absolute lung volumes of the entire chest wall by monitoring the three-dimensional movements of markers placed on the chest and abdominal walls.10 Its versatility to measure lung volumes under a variety of functional conditions prompted us to turn to this technique with the specific purpose to validate IC for the bronchodilator tests in clinical practice in subjects affected by chronic airflow obstruction.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
We studied 13 subjects affected by COPD, as defined by the criteria of the ATS.11 Their anthropometric and functional respiratory characteristics are presented in Table 1 . All subjects were very well familiar with pulmonary function techniques. To enter the study, the subjects had to be in clinically stable condition for at least 4 weeks before the study, to abstain from bronchodilators for at least 8 h before the study, and to show an arbitrary increase of FEV1 with albuterol treatment of at least 50 mL. None of the subjects were receiving long-acting bronchodilators. The protocol was approved by our ethics committee, and informed consent was approved prior to the study.


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  		Table 1. Anthropometric Data and Baseline Lung Function

 
Measurements
Standard spirometry prior to the study was obtained by a water-sealed spirometer (Pulmonet III; SensorMedics; Yorba Linda, CA). FRC was measured by helium-dilution rebreathing technique. Residual volume (RV) was computed by subtracting expiratory reserve volume from FRC, and TLC was computed by adding vital capacity to RV. All the tests were done according to the standards recommended by the ATS.1 The reference values for spirometry and lung volumes are from Quanjer et al.2

Chest wall volume (Vcw) was computed by using the OEP system. Details of the technique are reported elsewhere.10 In brief, four cameras (two cameras placed 4 m in front of the subject, and two cameras placed 4 m behind the subject) tracked the three-dimensional movements of 89 small surface markers attached to the skin of the trunk with double-sided adhesive tape and lit by infrared light-emitting diodes coaxial with the lenses of the cameras. The markers, 5-mm hemispheres coated with reflective paper, were positioned along seven horizontal and vertical lines both anteriorly and posteriorly to the chest wall and abdomen. The OEP data were recorded at a sampling frequency of 25 Hz. The coefficient of variation of the difference between changes in lung volumes measured with OEP method and with spirometry is < 3.5%.10

Flow at the mouth was measured by a Fleisch No. 3 pneumotachograph connected to a pressure transducer (± 2 cm H2O; Validyne Engineering; Northridge, CA). Volume was electrically integrated from the flow signal. Flow and volume signals were synchronized to the kinematic signals of the OEP and sent to a personal computer through an RTI 800 analog-to-digital card for subsequent analysis (Analog Devices; Norwood, MA).

Protocol
Standard spirometry and absolute lung volume measurements were obtained prior to the study. On the study day, the subjects attended the PFT laboratory in the midmorning after avoiding short-acting bronchodilators for at least 8 h and long-acting bronchodilators for 24 h. The preparatory procedures consisted of explanation of the technical aspects of the study to the subjects and positioning of the 89 reflective markers on the surface of the trunk. Then, the subjects seated on a stool in the center of the designated area with the cameras in front and in the back and were requested to breathe regularly. Approximately 10 min later, tidal breathing pattern was recorded for a duration of 4 min on two random occasions. On the first occasion, the subjects wore a nose clip and were connected to a pneumotachograph through a mouthpiece. The measurements were made when the subjects felt comfortable and well adapted to the mouthpiece and nose clip. Breathing signals were simultaneously collected by the pneumotachograph and the OEP system. Then, after four to six regular tidal breaths, the subjects were asked to take a deep breath to TLC in order to have IC measured by the pneumotachograph (ICPN) and IC measured by OEP (ICOEP). On the second occasion, the measurements were performed by OEP without nose clip, mouthpiece, and pneumotachograph. All the IC maneuvers were always performed in triplicate.

Forced expiratory flows were measured at least in triplicate during a forced expiration initiated from end-tidal inspiration and terminated to RV (partial forced expiratory maneuver) and from TLC to RV (maximum forced expiratory maneuver) soon after taking a maximum and fast inspiration. The reason for measuring partial flow is that it is more sensitive than maximal flows to detect changes in airway caliber after bronchodilatation than maximal flows.6 7 12 13 The same measurements were repeated 20 min after inhalation of albuterol, 200 µg, by a metered-dose inhaler with spacer device during a full inspiratory maneuver from RV.

Data Analysis and Statistics
Only regular breaths were used for analysis of breathing pattern. Tidal volume (VT), inspiratory time, and expiratory time were measured breath by breath and averaged over at least 30 breaths. Minute ventilation (E), breathing frequency (BF), and ratio of inspiratory time to total respiratory cycle duration were computed. Also measured was forced expiratory flow at 30% of FVC from a partial flow-volume curve (p30). The differences between ICPN and ICOEP were analyzed by the method of Bland and Altman.14 Differences between values were tested by the Student paired t test or repeated-measure analysis of variance, whenever appropriate. Correlations were assessed by the Pearson test. Data are presented as mean ± SD. p< 0.05 was considered statistically significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Airflow obstruction was of severe entity and significantly associated with lung hyperinflation (Table 1) . FRC as percentage of predicted was inversely correlated with FEV1 percent predicted (r = - 0.68, p < 0.02) and FVC percent predicted (r = - 0.71, p < 0.01). Within-patient coefficients of variation of ICOEP, Vcw at TLC (VcwTLC), and Vcw at FRC (VcwFRC) at control were 2.2 ± 1.3%, 0.19 ± 0.14%, and 0.18 ± 0.08%, respectively, and after albuterol treatment were 1.35 ± 0.65%, 0.11 ± 0.07%, and 0.13 ± 0.08%, respectively.

The response to albuterol was consistent with mild-to-moderate bronchodilatation, as documented by small but significant increments of FEV1, FVC, and p30 (Table 2 ). Only four patients had an increase in FEV1 > 12% of control and 200 mL. Individual values of FEV1, FVC, p30, ICPN, and ICOEP before and after albuterol treatment are reported in Table 3 . Control VcwTLC (38.5 ± 7.6 L) was on average unchanged after albuterol treatment (38.4 ± 7.5 L) [Fig 1 ]. No correlation was found between the difference of VcwTLC at control and after albuterol treatment and FEV1 as percentage of predicted. In contrast, VcwFRC decreased with bronchodilatation by 0.27 ± 0.32 L (p < 0.01), thus indicating decrease in lung hyperinflation. After albuterol treatment, ICPN and ICOEP increased significantly by 0.18 ± 0.20 L and 0.23 ± 0.24 L, respectively (p < 0.02 for both). ICPN and ICOEP were strongly correlated both before and after albuterol treatment (r = 0.90, p < 0.001, and r = 0.98, p < 0.001, respectively), and their differences were independent of the average values (Bland and Altman14 test; Fig 2 ). There were no correlations between the changes of ICOEP or ICPN with bronchodilatation and changes in FEV1 and FVC, with the exception of a tendency with p30 (r = 0.61, p = 0.06).


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  		Table 2. Absolute Changes in Main Spirometric Parameters Induced by Albuterol

 

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  		Table 3. Individual Spirometric Data at Control and After Albuterol Treatment*

 


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  		Figure 1. VcwTLC (@TLC) and VcwFRC (@FRC) at baseline and after albuterol treatment. IC is the difference between the two volumes and is represented by the hatched columns. NS = not significant.

 


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  		Figure 2. Bland and Altman14 plot comparing ICOEP (ICoep) and ICPN (ICpn). Differences between ICs are plotted against average values. Dotted-dashed line is the mean difference; dashed lines define 2 SDs above and below the mean.

 
Breathing-pattern variables recorded either with or without the mouthpiece, and the pneumotachograph did not significantly change after albuterol treatment. However, E and VT were slightly but significantly higher with than without the mouth apparatus either at control (E, + 16 ± 12% [p < 0.01] and VT, + 18 ± 11% [p < 0.001], respectively) or after albuterol treatment (E, + 16 ± 21% [p < 0.02] and VT, + 18 ± 31% [p < 0.02], respectively), whereas BF remained unmodified. With mouthpiece and pneumotachograph, the higher VT was sustained by an increase in Vcw at end-inspiratory lung volume, as documented by not significant differences between VcwFRC with and without mouth apparatus either at control (36.13 ± 7.49 L and 36.08 ± 7.44 L, respectively) or after albuterol treatment (35.86 ± 7.23 L and 35.75 ± 7.22 L, respectively). No significant differences were observed in BF and the ratio of inspiratory time to total respiratory cycle duration between with and without mouthpiece.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The main findings of this study are as follows: (1) the increment of IC with bronchodilatation accurately reflects the decrement of FRC, for VcwTLC does not vary with a single dose of albuterol, 200 µg; and (2) the decrement in VcwFRC with bronchodilatation is independent of changes in spirometric and breathing pattern indexes. Although IC has been increasingly used over the last decade with the purpose to assess the changes in FRC with bronchodilatation, its physiologic validation in clinical practice has always been based on studies that demonstrated no decrease15 or little decrease in TLC measured by plethysmographic technique12 13 in subjects with moderate airflow obstruction. It must be acknowledged, however, that in severe airflow obstruction, measurement of mouth pressure during panting maneuvers against a closed valve tends to be underestimated due to the poor transmission of alveolar pressure through flow-limited or closed airways,9 thus inevitably leading to an overestimation in lung volume. With bronchodilatation and opening of previously closed or flow-limited airways, alveolar pressure is better transmitted to the mouth, so that lung volume may be more properly estimated. This fact may likely help explain the frequent clinical observation that the decrease in FRC observed with bronchodilatation as assessed by plethysmography is generally greater than the increase in IC (unpublished observation from our laboratory). With the OEP system, we documented that VcwTLC was the same before and after albuterol treatment, thus strongly suggesting that thoracic gas volume at maximum lung inflation remained stable with acute bronchodilatation. Therefore, the changes in ICPN with bronchodilatation accurately tracked the changes in FRC, as supported by the Bland and Altman14 and linear regression analysis of the variations of ICPN and ICOEP. In addition, the lack of correlation between the differences of VcwTLC before and after albuterol and the FEV1 as percentage of predicted strengthens the validity of IC in evaluating the changes of FRC with bronchodilatation within the entire range of severity of the disease. Implicit with this assertion is that the decrease in TLC after bronchodilatation reported in studies with plethysmography is more likely a technical artifact than a physiologic pattern.9

In the same line with previous studies,7 16 the decrease in lung hyperinflation as assessed by the increase in ICPN was essentially independent of the changes of any classical spirometric parameters. This apparent discrepancy among spirometric parameters may have technical and physiologic reasons. For example, FEV1 and FVC cannot necessarily represent the functional conditions of airflow obstruction in the range of tidal breathing, even because of technical artifacts, such as thoracic gas compression volume and the volume history effects of the breath preceding the forced expiration. When the latter was taken into account in our study, the relationship between increases in ICPN and p30 became almost significant. In addition, even though there seems to be a tight link between expiratory flow limitation and regulation of FRC,17 FRC may be totally independent of any increase of forced expiratory flow if it is primarily regulated by the static properties of the respiratory system. On this basis, we believe that IC, a parameter easy to measure in any PFT laboratory, may be very useful in clinical practice to assess the effects of bronchodilators on lung function together with the FEV1 and FVC. An increase of it after a bronchodilator beyond the natural variability threshold (9% of control and 220 mL)7 could be interpreted as a result of the beneficial effects of the medication on bronchial tone and thus lung hyperinflation.

Even though ventilation was not modified by albuterol treatment, it was slightly but significantly greater when the mouthpiece and pneumotachograph were used. More specifically, the increase in E was sustained by an increase in VT due in turn to an increase in end-inspiratory lung volume while FRC remained constant. This ventilatory reaction to the mouthpiece and pneumotachograph could be due to the following: (1) an increase in dead space with the mouth apparatus,18 (2) neural stimuli arising from the physical contact of the mouthpiece with the oral cavity,18 (3) shift of ventilatory route from unrestricted nose to mouth,19 20 and (4) awareness of the recording of breathing.21 From a practical point of view, these findings suggest that caution be used when breathing pattern is investigated with different methods.

In conclusion, the present study supports the validity of IC in the assessment of the decrease in lung hyperinflation after acute bronchodilatation in subjects with COPD even when airflow obstruction is severe, because TLC remains stable with a usual dose of albuterol. Together with the lack of relationship between the changes in IC and the changes in FEV1 and/or FVC with bronchodilatation, the present data also strongly suggest that IC be added to the list of the traditional respiratory parameters for a comprehensive evaluation of the acute bronchodilator response.


   Footnotes
 
Abbreviations: ATS = American Thoracic Society; BF = breathing frequency; FRC = functional residual capacity; IC = inspiratory capacity; ICOEP = inspiratory capacity measured by optoelectronic plethysmography; ICPN = inspiratory capacity measured by a pneumotachograph; OEP = optoelectronic plethysmography; PFT = pulmonary function testing; RV = residual volume; TLC = total lung capacity; Vcw = chest wall volume; VcwFRC = chest wall volume at functional residual capacity; VcwTLC = chest wall volume at total lung capacity; E = minute ventilation; p30 = forced expiratory flow at 30% of FVC from a partial flow-volume curve; VT = tidal volume

Received for publication November 28, 2001. Accepted for publication July 10, 2002.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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