Abstract
OBJECTIVE:
Recent work has suggested that within-breath respiratory impedance measurements performed using the forced oscillation technique may help to noninvasively evaluate respiratory mechanics. We investigated the influence of airway obstruction on the within-breath forced oscillation technique in smokers and chronic obstructive pulmonary disease patients and evaluated the contribution of this analysis to the diagnosis of chronic obstructive pulmonary disease.
METHODS:
Twenty healthy individuals and 20 smokers were assessed. The study also included 74 patients with stable chronic obstructive pulmonary disease. We evaluated the mean respiratory impedance (Zm) as well as values for the inspiration (Zi) and expiration cycles (Ze) at the beginning of inspiration (Zbi) and expiration (Zbe), respectively. The peak-to-peak impedance (Zpp=Zbe-Zbi) and the respiratory cycle dependence (ΔZrs=Ze-Zi) were also analyzed. The diagnostic utility was evaluated by investigating the sensitivity, the specificity and the area under the receiver operating characteristic curve. ClinicalTrials.gov: NCT01888705.
RESULTS:
Airway obstruction increased the within-breath respiratory impedance parameters that were significantly correlated with the spirometric indices of airway obstruction (R=−0.65, p<0.0001). In contrast to the control subjects and the smokers, the chronic obstructive pulmonary disease patients presented significant expiratory-inspiratory differences (p<0.002). The adverse effects of moderate airway obstruction were detected based on the Zpp with an accuracy of 83%. Additionally, abnormal effects in severe and very severe patients were detected based on the Zm, Zi, Ze, Zbe, Zpp and ΔZrs with a high degree of accuracy (>90%).
CONCLUSIONS:
We conclude the following: (1) chronic obstructive pulmonary disease introduces higher respiratory cycle dependence, (2) this increase is proportional to airway obstruction, and (3) the within-breath forced oscillation technique may provide novel parameters that facilitate the diagnosis of respiratory abnormalities in chronic obstructive pulmonary disease.
Respiratory Impedance; Chronic Obstructive Pulmonary Disease; Airway Obstruction; Forced Oscillation Technique; Within-Breath Analysis, Chronic Obstructive Pulmonary Disease Diagnostics
INTRODUCTION
The mechanical changes due to chronic obstructive pulmonary disease (COPD) are
associated with a progressive increase in airflow obstruction (11. GOLD. Global Initiative For Chronic Obstructive Lung Disease -
UPDATE (2013). “Global Strategy for the Diagnosis, Management, and
prevention of Chronic Obstrutive Pulmonary Disease.” http://www.goldcopd.com: NHLBI/WHO; 2013.
http://www.goldcopd.com...
), which is usually evaluated by spirometric tests. However,
these tests are highly dependent on patient cooperation and effort, which may be a
limitation in older people and in patients in the advanced stages of the disease
(22. Kubota M, Shirai G, Nakamori T, Kokubo K, Masuda N, Kobayashi H.
Low frequency oscillometry parameters in COPD patients are less variable during
inspiration than during expiration. Respir Physiol Neurobiol. 2009;166(2):73-9,
10.1016/j.resp.2009.01.007.
http://dx.doi.org/10.1016/j.resp.2009.01...
).
The forced oscillation technique (FOT) offers a simple and detailed approach to
investigating the mechanical properties of the respiratory system (33. Oostveen E, MacLeod D, Lorino H, Farre R, Hantos Z, Desager K, et
al. The forced oscillation technique in clinical practice: methodology,
recommendations and future developments. Europ Respir J. 2003;22(6):1026-41.,
doi: 10.1183/09031936.03.00089403.
10.1183/09031936.03.00089403...
–55. Kaczka DW, Dellaca RL. Oscillation mechanics of the respiratory
system: applications to lung disease. Crit Rev Biomed Eng. 2011;39(4):337-59,
10.1615/CritRevBiomedEng.v39.i4.
http://sx.doi.org/10.1615/CritRevBiomedE...
). In practice, sinusoidal excitations are superimposed on spontaneous
breathing at the airway opening using a loudspeaker. The resulting oscillations in
airflow and pressure are recorded and used to estimate the mechanical impedance of
the respiratory system. These features make this technique potentially suitable for
the routine evaluation of respiratory function in COPD (66. Di Mango AM, Lopes AJ, Jansen JM, Melo PL. Changes in respiratory
mechanics with increasing degrees of airway obstruction in COPD: detection by
forced oscillation technique. Resp Med. 2006;100(3):399-410,
10.1016/j.rmed.2005.07.005.
http://dx.doi.org/10.1016/j.rmed.2005.07...
).
An interesting characteristic of this method is its excellent time resolution,
allowing for the analysis of changes within the respiratory cycles. This is an
important advantage for pathophysiological research, as it provides a detailed
characterization of the patient’s respiratory mechanics. In recent years,
strong evidence has emerged supporting the utility of within-breath FOT (WbFOT)
measurements in several contexts. This method has been successfully applied to
undertake difficult studies, including studies on sleep disorders (77. Farre R, Montserrat JM, Navajas D. Noninvasive monitoring of
respiratory mechanics during sleep. Eur Respir J. 2004;24(6):1052-60,
10.1183/09031936.04.00072304.
http://dx.doi.org/10.1183/09031936.04.00...
,88. Lemes LN, Melo PL. Forced oscillation technique in the sleep
apnoea/hypopnoea syndrome: identification of respiratory events and nasal
continuous positive airway pressure titration. Physiol Meas. 2003;24(1):11-25,
10.1088/0967-3334/24/1/302.
http://dx.doi.org/10.1088/0967-3334/24/1...
) and
studies evaluating pediatric (99. Schweitzer C, Ben Abdelkrim I, Ferry H, Werts F, Varechova S,
Marchal F. Airway Response to Exercise by Forced Oscillations in Asthmatic
Children. Pediatr Res. 2010;68(6):537-41,
10.1203/PDR.0b013e3181f851d2.
http://dx.doi.org/10.1203/PDR.0b013e3181...
) and elderly
(1010. Aarli BB, Eagan TM, Ellingsen I, Bakke PS, Hardie JA. Reference
values for within-breath pulmonary impedance parameters in asymptomatic elderly.
Clin Respir J. 2013;7(3):245-52, 10.1111/crj.2013.7.issue-3.
http://dx.doi.org/10.1111/crj.2013.7.iss...
) subjects. A detailed analysis of the
expiratory flow limitation (EFL) (1111. Dellaca RL, Santus P, Aliverti A, Stevenson N, Centanni S,
Macklem PT, et al. Detection of expiratory flow limitation in COPD using the
forced oscillation technique. Eur Respir J. 2004;23(2):232-40.,1212. Dellaca RL, Duffy N, Pompilio PP, Aliverti A, Koulouris NG,
Pedotti A, et al. Expiratory flow limitation detected by forced oscillation and
negative expiratory pressure. Eur Respir J. 2007;29(2):363-74,
10.1183/09031936.00038006.
http://dx.doi.org/10.1183/09031936.00038...
) and the response to salbutamol (1313. Dellaca RL, Pompilio PP, Walker PP, Duffy N, Pedotti A,
Calverley PM. Effect of bronchodilation on expiratory flow limitation and
resting lung mechanics in COPD. Eur Respir J. 2009;33(6):1329-37,
10.1183/09031936.00139608.
http://dx.doi.org/10.1183/09031936.00139...
) in COPD patients was also recently
performed. Previous studies have obtained promising results using the WbFOT to
evaluate abnormal respiratory mechanics in asthma patients (1414. Veiga J, Lopes AJ, Jansen JM, Melo PL. Within-breath analysis of
respiratory mechanics in asthmatic patients by forced oscillation. Clinics.
2009;64(7):649-56, 10.1590/S1807-59322009000700008.
http://dx.doi.org/10.1590/S1807-59322009...
–1616. Shirai T, Mori K, Mikamo M, Shishido Y, Akita T, Morita S, et
al. Usefulness of Colored 3D Imaging of Respiratory Impedance in Asthma.
Allergy, asthma & immunology research. Allergy Asthma Immunol
Res.2013;5(5):322-8, 10.4168/aair.2013.5.5.322.
http://dx.doi.org/10.4168/aair.2013.5.5....
), smokers
(1717. Shinke H, Yamamoto M, Hazeki N, Kotani Y, Kobayashi K, Nishimura
Y. Visualized changes in respiratory resistance and reactance along a time axis
in smokers: a cross-sectional study. Respir Investig. 2013;51(3):166-74,
10.1016/j.resinv.2013.02.006.
http://dx.doi.org/10.1016/j.resinv.2013....
), COPD patients (1818. Kanda S, Fujimoto K, Komatsu Y, Yasuo M, Hanaoka M, Kubo K.
Evaluation of Respiratory Impedance in Asthma and COPD by an Impulse Oscillation
System. Internal Med. 2010;49(1):23-30,
10.2169/internalmedicine.49.2191.
http://dx.doi.org/10.2169/internalmedici...
) and interstitial lung disease patients
(1919. Sugiyama A, Hattori N, Haruta Y, Nakamura I, Nakagawa M,
Miyamoto S, et al. Characteristics of inspiratory and expiratory reactance in
interstitial lung disease. Resp Med. 2013 ;107(6):875-82,
10.1016/j.rmed.2013.03.005.
http://dx.doi.org/10.1016/j.rmed.2013.03...
). In particular, a recent study from
our group provided evidence that WbFOT measurements may improve our understanding of
COPD pathophysiology and simplify the diagnosis of respiratory alterations in COPD
(2020. Silva KK, Lopes AJ, Jansen JM, de Melo PL. Total inspiratory and
expiratory impedance in patients with severe chronic obstructive pulmonary
disease. Clinics. 2011;66(12):2085-91,
10.1590/S1807-59322011001200014.
http://dx.doi.org/10.1590/S1807-59322011...
). However, this preliminary study was
limited to evaluating patients in the severe stages of the disease. To the best of
our knowledge, there are no data in the literature concerning the influence of
airway obstruction on the within-breath respiratory impedance of COPD patients.
In this context, the objectives of the present study were (1) to compare the respiratory mechanics of normal subjects and COPD patients, with an emphasis on the differences between the phases of the respiratory cycle, and (2) to evaluate the contribution of this analysis to COPD diagnosis.
METHODS:
Study design
The present work was a controlled cross-sectional study developed at the State University of Rio de Janeiro. The examinations included spirometry and FOT measurements. The Research Ethics Committee of the State University of Rio de Janeiro approved this study. The work was carried out in accordance with the Declaration of Helsinki and has been registered at ClinicalTrials.gov (ClinicalTrials.gov identifier: NCT01888705). The objectives were explained to all of the participants, and their written consent was obtained before their inclusion in the study.
Subjects
This study involved 114 volunteers, including 20 never-smoking controls with
normal spirometric evaluations and without a previous history of cardiac
disease. Twenty smokers presenting a normal respiratory response to the
spirometric exam constituted the “normal exam” (NE) group. The
study also included 74 patients with stable COPD who were classified according
to the GOLD criteria as having mild (Group I, n=14), moderate (Group II, n=20),
severe (Group III, n=20), or very severe (Group IV, n=20) obstruction (11. GOLD. Global Initiative For Chronic Obstructive Lung Disease -
UPDATE (2013). “Global Strategy for the Diagnosis, Management, and
prevention of Chronic Obstrutive Pulmonary Disease.” http://www.goldcopd.com: NHLBI/WHO; 2013.
http://www.goldcopd.com...
). The eligibility criteria for COPD
included a history of smoking more than ten packs of cigarettes per year; a
ratio of the forced expiratory volume in the first second (FEV1) to
the forced vital capacity (FVC) of less than 0.7; no respiratory infections in
the previous three weeks; an absence of other respiratory diseases; and an
absence of extrathoracic comorbidities, including cardiovascular diseases,
malignant diseases, and chest deformities.
Study protocol
The subjects were informed of the need to suspend the use of bronchodilators during the 12 h that preceded the tests. The examination sequence was carried out as follows: evaluation of clinical history; collection of anthropometric measurements (age, body weight and height) and risk factors associated with the disease; testing of FOT impedance; and finally, gathering of the spirometric measurements.
Spirometry
Flow-volume curves were obtained using a bellows spirometer (Vitatrace VT 130 SL
model; Pro Médico Ind. Ltd., Rio de Janeiro, Brazil) to assess the FEV1,
the FVC, the forced expiratory flow (FEF) between 25% and 75% of the FVC, the
FEF/FVC ratio and the FEV1/FVC ratio. These exams were performed according to
the ATS-ERS guidelines for spirometry (2121. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates
A, et al. Standardisation of spirometry. Eur Respir J. 2005;26(2):319-38,
10.1183/09031936.05.00034805.
http://dx.doi.org/10.1183/09031936.05.00...
). All of the spirometric parameters were assessed as absolute and
percentage values relative to the values predicted for the Brazilian population
(2222. Pereira CA, Sato T, Rodrigues SC. New reference values for
forced spirometry in white adults in Brazil. J Bras Pneumol. 2007;33(4):397-406,
10.1590/S1806-37132007000400008.
http://dx.doi.org/10.1590/S1806-37132007...
).
Within-breath respiratory impedance measurements
Respiratory system impedance (Zrs) was measured at 5 Hz using a device developed
in our laboratory (88. Lemes LN, Melo PL. Forced oscillation technique in the sleep
apnoea/hypopnoea syndrome: identification of respiratory events and nasal
continuous positive airway pressure titration. Physiol Meas. 2003;24(1):11-25,
10.1088/0967-3334/24/1/302.
http://dx.doi.org/10.1088/0967-3334/24/1...
,2323. de Melo PL, Lemes LND. Instrumentation for the analysis of
respiratory system disorders during sleep: Design and application. Review of
Scientific Instruments. 2002;73(11):3926-32, 10.1063/1.1511793.
http://dx.doi.org/10.1063/1.1511793...
). During the measurements, the
instrument applies a low-pressure (2.0 cmH2O peak-to-peak amplitude)
sinusoidal signal to the subject’s respiratory system, which remains
under spontaneous ventilation. The instrument allows the evaluation of the Zrs
from signals coming from a pressure transducer and a pneumotachograph placed
close to the individual’s mouth. The resulting pressure (P) and airflow
(V) signals are used to obtain the within-breath impedance module (Zrs=P/V)
(2323. de Melo PL, Lemes LND. Instrumentation for the analysis of
respiratory system disorders during sleep: Design and application. Review of
Scientific Instruments. 2002;73(11):3926-32, 10.1063/1.1511793.
http://dx.doi.org/10.1063/1.1511793...
). This parameter is traditionally
used in WbFOT measurements (22. Kubota M, Shirai G, Nakamori T, Kokubo K, Masuda N, Kobayashi H.
Low frequency oscillometry parameters in COPD patients are less variable during
inspiration than during expiration. Respir Physiol Neurobiol. 2009;166(2):73-9,
10.1016/j.resp.2009.01.007.
http://dx.doi.org/10.1016/j.resp.2009.01...
,1818. Kanda S, Fujimoto K, Komatsu Y, Yasuo M, Hanaoka M, Kubo K.
Evaluation of Respiratory Impedance in Asthma and COPD by an Impulse Oscillation
System. Internal Med. 2010;49(1):23-30,
10.2169/internalmedicine.49.2191.
http://dx.doi.org/10.2169/internalmedici...
,2020. Silva KK, Lopes AJ, Jansen JM, de Melo PL. Total inspiratory and
expiratory impedance in patients with severe chronic obstructive pulmonary
disease. Clinics. 2011;66(12):2085-91,
10.1590/S1807-59322011001200014.
http://dx.doi.org/10.1590/S1807-59322011...
,2424. van der Putten WJ, MacLeod D, Prichard JS. Within-breath
measurement of respiratory impedance. Physiol Meas. 1993;14(3):393-400,
10.1088/0967-3334/14/3/019.
http://dx.doi.org/10.1088/0967-3334/14/3...
) and is interpreted as
the total mechanical load of the respiratory system (33. Oostveen E, MacLeod D, Lorino H, Farre R, Hantos Z, Desager K, et
al. The forced oscillation technique in clinical practice: methodology,
recommendations and future developments. Europ Respir J. 2003;22(6):1026-41.,
doi: 10.1183/09031936.03.00089403.
10.1183/09031936.03.00089403...
–55. Kaczka DW, Dellaca RL. Oscillation mechanics of the respiratory
system: applications to lung disease. Crit Rev Biomed Eng. 2011;39(4):337-59,
10.1615/CritRevBiomedEng.v39.i4.
http://sx.doi.org/10.1615/CritRevBiomedE...
,),
including the respiratory resistive (Rrs) and reactive (Xrs) effects observed at
5 Hz, as described by Equation 1. Notably, the Xrs reflects the elastic
properties of the respiratory system at 5 Hz.
The within-breath input impedance is usually determined using fast Fourier
transforms (44. Bates JH, Irvin CG, Farre R, Hantos Z. Oscillation mechanics of
the respiratory system. Compr Physiol. 2011;1(3):1233-72.,1818. Kanda S, Fujimoto K, Komatsu Y, Yasuo M, Hanaoka M, Kubo K.
Evaluation of Respiratory Impedance in Asthma and COPD by an Impulse Oscillation
System. Internal Med. 2010;49(1):23-30,
10.2169/internalmedicine.49.2191.
http://dx.doi.org/10.2169/internalmedici...
), cross-correlation or least-squares techniques (55. Kaczka DW, Dellaca RL. Oscillation mechanics of the respiratory
system: applications to lung disease. Crit Rev Biomed Eng. 2011;39(4):337-59,
10.1615/CritRevBiomedEng.v39.i4.
http://sx.doi.org/10.1615/CritRevBiomedE...
). These methods allow measurements with
limited time resolutions, typically of 0.2 s (11) or 0.25 s (15). The present
study used an analog signal-processing circuit that allowed for a continuous
real-time calculation of the WbFOT (2323. de Melo PL, Lemes LND. Instrumentation for the analysis of
respiratory system disorders during sleep: Design and application. Review of
Scientific Instruments. 2002;73(11):3926-32, 10.1063/1.1511793.
http://dx.doi.org/10.1063/1.1511793...
).
This method helps to improve discrimination between the phases of the
respiratory cycle as well as to derive precise measurements at specific points
of interest.
The resulting impedance and flow signals (f ≅ 0.2 Hz) were low-pass filtered at 5 Hz using analog filters (Butterworth, 4th order) to remove the external noise (60 Hz) and were digitized with 12-bit resolution at a sampling rate of 16 Hz. The instrument was calibrated using a reference mechanical load, resulting in measurement errors of <0.5%.
The following secondary parameters were used to characterize the changes in the respiratory mechanics during the different phases of the respiratory cycle:
-
The mean respiratory impedance (Zm), calculated for the complete exam;
-
The mean impedance during the inspiration cycles (Zi);
-
The mean impedance during the expiration cycles (Ze);
-
The mean impedance at the beginning of inspiration (Zbi);
-
The mean impedance at the beginning of expiration (Zbe);
-
The peak-to-peak impedance (Zpp), which is the difference between the Zbe and the Zbi;
-
The mean impedance change (ΔZrs), which is the difference between the Ze and the Zi.
These measurements lasted 120 s and were obtained with the subjects seated and spontaneously breathing while holding their cheeks and the floor of their mouth with their hands to avoid the shunt effect of the upper airways. The data acquisition commenced once the subject was comfortable using the mouthpiece with a good mouth seal. The study subjects were encouraged to breathe in a regular manner, to avoid swallowing and to maintain a tight mouthpiece seal. The recordings were deemed acceptable if the airflow and frequency appeared stable, with no obvious leaks or glottal closures, as determined by visual inspection of the airflow and impedance traces. Measurements with distortions due to artifacts such as coughs or sneezes were also discarded. Whenever the impedance time series was not considered adequate, the maneuver was not considered valid and was repeated. If the correct maneuvers could not be performed, the subjects were excluded from the study. The FOT exams were carried out first, and the delay between the FOT and the spirometric exams was less than 30 min.
Sample size and statistical analysis
To estimate the sample size, a pilot study on a group of 27 subjects (13 subjects with COPD and 14 controls) was conducted using a protocol identical to that described above. Based on these preliminary results, the sample size was calculated based on the difference between the means, assuming type I and type II errors of 1%. The minimum calculated value for this study was 12 individuals for each group.
Initially, the sample characteristics were evaluated using the Shapiro-Wilk test. Depending on these characteristics, we then used the independent t-test or the Mann-Whitney U test to assess between-group differences and a paired-t test and one-way ANOVA to perform intra-group comparisons. Differences were considered statistically significant when p<0.05.
To measure the overall agreement between the variables related to the spirometry
and respiratory impedance, we calculated Spearman’s rank correlation
coefficient for the whole group of studied volunteers. The correlations were
classified as follows (2626. Nair A, Ward J, Lipworth BJ. Comparison of bronchodilator
response in patients with asthma and healthy subjects using spirometry and
oscillometry. Ann Allergy Asthma Immunol. 2011;107(4):317-22,
10.1016/j.anai.2011.07.011.
http://dx.doi.org/10.1016/j.anai.2011.07...
):
-
Small or no correlation: correlation between 0 and 0.25 (or −0.25);
-
Reasonable correlation: between 0.25 and 0.50 (or −0.25 to −0.50);
-
Moderate to good correlation: between 0.50 and 0.75 (or −0.50 to −0.75);
-
Very good to excellent correlation: correlation greater than 0.75 (or −0.75).
We used the area under the receiver operating characteristic curve (AUC) to
evaluate the ability of the within-breath FOT indices to distinguish the
patients from the control subjects. The interpretation of these results followed
previous work, in which an AUC>0.80 was usually considered as adequate for
clinical use (2727. Swets JA. Measuring the accuracy of diagnostic systems. Science.
1988;240(4857):1285-93, 10.1126/science.3287615.
http://dx.doi.org/10.1126/science.328761...
,2828. Golpe R, Jimenez A, Carpizo R, Cifrian JM. Utility of home
oximetry as a screening test for patients with moderate to severe symptoms of
obstructive sleep apnea. Sleep. 1999;22(7):932-7.). More specifically, the curves with AUCs between 0.50
and 0.70 indicate low diagnostic accuracy, AUCs between 0.70 and 0.90 indicate
moderate diagnostic accuracy, and AUCs between 0.90 and 1.00 indicate high
diagnostic accuracy (2727. Swets JA. Measuring the accuracy of diagnostic systems. Science.
1988;240(4857):1285-93, 10.1126/science.3287615.
http://dx.doi.org/10.1126/science.328761...
,2828. Golpe R, Jimenez A, Carpizo R, Cifrian JM. Utility of home
oximetry as a screening test for patients with moderate to severe symptoms of
obstructive sleep apnea. Sleep. 1999;22(7):932-7.). The optimal cut-off point was chosen
to balance the highest values of sensitivity and specificity.
The analyses described in this section were performed using MedCalc¯ 12.3 (MedCalc Software, Mariakerke, Belgium) and STATISTICA¯ 5.0 for Windows (StatSoft Inc., Tulsa, OK, USA).
RESULTS
Anthropometric and spirometric results
The anthropometric and spirometric characteristics of the patients and healthy control subjects are presented in Table 1. The clinical characteristics are also described in this table. There were no significant differences in height among the groups, but there were significant group differences for age, weight and BMI. As observed in Table 1, the patients with COPD had significant reductions in all of the studied spirometric parameters (p<0.001).
Biometric and spirometric characteristics of the studied groups (mean±SD).The right column shows comparisons of the six groups/comparisons between adjacent groups; dashes indicate significant differences.
Whole-breath impedance analysis
Figure 1 depicts the results of the whole-breath analysis for the groups classified according to spirometry. The Zm increased with airway obstruction (ANOVA p<0.0001). The moderate, severe, and very severe groups presented increased Zm values in comparison with the controls (p<0.01).
Respiratory impedance values throughout the respiratory cycle in healthy subjects; in smokers with normal spirometry; and in chronic obstructive pulmonary disease patients with mild (I), moderate (II), severe (III) or very severe (IV) airway obstruction. The top and bottom of the box plots represent the 25th- and 75th-percentile values, respectively. Additionally, the circles represent the mean values, the bars across the boxes represent the median values, and the whiskers outside the boxes represent the 5th- and 95th-percentile values. Differences relative to the controls: *p<0.01; **p<0.0001.
Within-breath respiratory impedance
The respiratory impedance measurements increased with airway obstruction in the COPD patients (Figure 2: Zbi, Zi, Zbe and Ze; ANOVA p<0.0001). Similar comparisons revealed that the Zpp and ΔZrs also increased with airway obstruction (Figure 2E, ANOVA p<0.0001, and Figure 2F, ANOVA p<0.02, respectively).
Comparisons among the mean impedances at the beginning of inspiration (Zbi, A), during the inspiratory phase (Zi, B), at the beginning of expiration (Zbe, C), and during the expiratory phase (Ze, C), in addition to the peak-to-peak impedance (Zpp=Zbe-Zbi; D) and the respiratory cycle dependence (ΔZrs=Ze-Zi; F). The top and bottom of the box plots represent the 25th- and 75th-percentile values, respectively. Additionally, the circles represent the mean values, the bars across the boxes represent the median values, and the whiskers outside the boxes represent the 5th- and 95th-percentile values. Differences relative to the controls: *p<0.05, **p<0.004.
Figure 3 shows the influence of airway obstruction on respiratory impedance along the ventilation cycle in the studied subjects. Respiratory impedance did not change significantly throughout the respiratory cycle in the control and the NE groups (Figure 3A; ANOVA p=ns). In contrast, the impedance in the mild COPD patients showed significant increases from the beginning of inspiration to the expiratory phase (Figure 3A; ANOVA p<0.002). The mild COPD patients presented significantly higher Zbe values compared with the Zbi values (Figure 3B, p<0.002), whereas the Ze was not significantly higher compared with the Zi. Comparisons with the more advanced COPD patients showed more pronounced changes than in the mild COPD patients. Additionally, the Zrs significantly increased from the beginning of the inspiratory phase to the end of the expiratory phase in the moderate, severe and very severe patients (Figures 3A, C, D, and E; ANOVA p<0.0001).
The mean Zrs values during the ventilatory cycle in healthy subjects; in smokers with normal spirometry; and in patients with mild, moderate, severe, or very severe chronic obstructive pulmonary disease. ANOVA: *p<0.002, **p<0.0001.
Correlations between within-breath impedance and spirometry
The associations between these variables are described in Table 2. The Zm, Zi, Ze, Zbi and Zbe showed statistically significant (p<0.0001) moderate to good inverse correlations with all of the spirometric parameters, with the exception of the FVC. Significant moderate to good and reasonable inverse correlations were also observed among the spirometric parameters and the Zpp. Meanwhile, the ΔZrs presented small and reasonable inverse correlations with nearly all of the spirometric parameters and was not correlated with the FVC.
Correlation coefficient for and significance level of the association between respiratory impedance and pulmonary function parameters.
Evaluation of the clinical potential of the within-breath respiratory impedance indices
Table 3 shows the values for the area under the curve (AUC), the sensitivity (Se), and the specificity (Sp) for the optimal cut-off points obtained for the studied FOT parameters. The Zpp performed adequately in the patients with moderate obstruction, whereas five of the six studied parameters showed high performance in those with severe obstruction. In patients with very severe obstruction, all of the studied parameters had a high diagnostic accuracy.
Sensitivity, specificity, and area under the curve values for the optimal cut-off points obtained using receiver operating characteristic curves.
DISCUSSION
Previous studies have compared WbFOT measurements between groups of controls and COPD
patients and have observed clear modifications (22. Kubota M, Shirai G, Nakamori T, Kokubo K, Masuda N, Kobayashi H.
Low frequency oscillometry parameters in COPD patients are less variable during
inspiration than during expiration. Respir Physiol Neurobiol. 2009;166(2):73-9,
10.1016/j.resp.2009.01.007.
http://dx.doi.org/10.1016/j.resp.2009.01...
,1515. Mori K, Shirai T, Mikamo M, Shishido Y, Akita T, Morita S, et
al. Colored 3-dimensional analyses of respiratory resistance and reactance in
COPD and asthma. COPD. 2011;8(6):456-63,
10.3109/15412555.2011.626818.
http://dx.doi.org/10.3109/15412555.2011....
,1818. Kanda S, Fujimoto K, Komatsu Y, Yasuo M, Hanaoka M, Kubo K.
Evaluation of Respiratory Impedance in Asthma and COPD by an Impulse Oscillation
System. Internal Med. 2010;49(1):23-30,
10.2169/internalmedicine.49.2191.
http://dx.doi.org/10.2169/internalmedici...
,2020. Silva KK, Lopes AJ, Jansen JM, de Melo PL. Total inspiratory and
expiratory impedance in patients with severe chronic obstructive pulmonary
disease. Clinics. 2011;66(12):2085-91,
10.1590/S1807-59322011001200014.
http://dx.doi.org/10.1590/S1807-59322011...
,2929. Paredi P, Goldman M, Alamen A, Ausin P, Usmani OS, Pride NB, et
al. Comparison of inspiratory and expiratory resistance and reactance in
patients with asthma and chronic obstructive pulmonary disease. Thorax.
2010;65(3):263-7, 10.1136/thx.2009.120790.
http://dx.doi.org/10.1136/thx.2009.12079...
,3030. Yamauchi Y, Kohyama T, Jo T, Nagase T. Dynamic change in
respiratory resistance during inspiratory and expiratory phases of tidal
breathing in patients with chronic obstructive pulmonary disease. Int J Chron
Obstruct Pulmon Dis. 2012;7:259-69, 10.2147/COPD.
http://dx.doi.org/10.2147/COPD...
).
These findings raised two questions: (1) Is the effect of increasing the degree of
airway obstruction in COPD adequately described by WbFOT measurements? (2) Is
the WbFOT able to contribute to the clinical diagnosis of COPD? Nearly all of
the cited studies used impulse oscillation systems (22. Kubota M, Shirai G, Nakamori T, Kokubo K, Masuda N, Kobayashi H.
Low frequency oscillometry parameters in COPD patients are less variable during
inspiration than during expiration. Respir Physiol Neurobiol. 2009;166(2):73-9,
10.1016/j.resp.2009.01.007.
http://dx.doi.org/10.1016/j.resp.2009.01...
,1515. Mori K, Shirai T, Mikamo M, Shishido Y, Akita T, Morita S, et
al. Colored 3-dimensional analyses of respiratory resistance and reactance in
COPD and asthma. COPD. 2011;8(6):456-63,
10.3109/15412555.2011.626818.
http://dx.doi.org/10.3109/15412555.2011....
,1818. Kanda S, Fujimoto K, Komatsu Y, Yasuo M, Hanaoka M, Kubo K.
Evaluation of Respiratory Impedance in Asthma and COPD by an Impulse Oscillation
System. Internal Med. 2010;49(1):23-30,
10.2169/internalmedicine.49.2191.
http://dx.doi.org/10.2169/internalmedici...
,2929. Paredi P, Goldman M, Alamen A, Ausin P, Usmani OS, Pride NB, et
al. Comparison of inspiratory and expiratory resistance and reactance in
patients with asthma and chronic obstructive pulmonary disease. Thorax.
2010;65(3):263-7, 10.1136/thx.2009.120790.
http://dx.doi.org/10.1136/thx.2009.12079...
,3030. Yamauchi Y, Kohyama T, Jo T, Nagase T. Dynamic change in
respiratory resistance during inspiratory and expiratory phases of tidal
breathing in patients with chronic obstructive pulmonary disease. Int J Chron
Obstruct Pulmon Dis. 2012;7:259-69, 10.2147/COPD.
http://dx.doi.org/10.2147/COPD...
), which differ from the classical FOT,
including in terms of the signal applied at the subject’s mouth and the data
processing (331. Hellinckx J, Cauberghs M, De Boeck K, Demedts M. Evaluation of
impulse oscillation system: comparison with forced oscillation technique and
body plethysmography. Eur Respir J. 2001;18(3):564-70,
10.1183/09031936.01.00046401.
http://dx.doi.org/10.1183/09031936.01.00...
,313. Oostveen E, MacLeod D, Lorino H, Farre R, Hantos Z, Desager K, et
al. The forced oscillation technique in clinical practice: methodology,
recommendations and future developments. Europ Respir J. 2003;22(6):1026-41.,
doi: 10.1183/09031936.03.00089403.
10.1183/09031936.03.00089403...
). An additional limitation is that these studies did not evaluate the
diagnostic use of the WbFOT (22. Kubota M, Shirai G, Nakamori T, Kokubo K, Masuda N, Kobayashi H.
Low frequency oscillometry parameters in COPD patients are less variable during
inspiration than during expiration. Respir Physiol Neurobiol. 2009;166(2):73-9,
10.1016/j.resp.2009.01.007.
http://dx.doi.org/10.1016/j.resp.2009.01...
,1515. Mori K, Shirai T, Mikamo M, Shishido Y, Akita T, Morita S, et
al. Colored 3-dimensional analyses of respiratory resistance and reactance in
COPD and asthma. COPD. 2011;8(6):456-63,
10.3109/15412555.2011.626818.
http://dx.doi.org/10.3109/15412555.2011....
,1818. Kanda S, Fujimoto K, Komatsu Y, Yasuo M, Hanaoka M, Kubo K.
Evaluation of Respiratory Impedance in Asthma and COPD by an Impulse Oscillation
System. Internal Med. 2010;49(1):23-30,
10.2169/internalmedicine.49.2191.
http://dx.doi.org/10.2169/internalmedici...
,2929. Paredi P, Goldman M, Alamen A, Ausin P, Usmani OS, Pride NB, et
al. Comparison of inspiratory and expiratory resistance and reactance in
patients with asthma and chronic obstructive pulmonary disease. Thorax.
2010;65(3):263-7, 10.1136/thx.2009.120790.
http://dx.doi.org/10.1136/thx.2009.12079...
,3030. Yamauchi Y, Kohyama T, Jo T, Nagase T. Dynamic change in
respiratory resistance during inspiratory and expiratory phases of tidal
breathing in patients with chronic obstructive pulmonary disease. Int J Chron
Obstruct Pulmon Dis. 2012;7:259-69, 10.2147/COPD.
http://dx.doi.org/10.2147/COPD...
). Thus, to answer these questions, the present study
investigated the possibility of detecting changes in respiratory mechanics in
progressive airway obstruction in COPD patients using the classical FOT. It was
shown that the WbFOT method reveals changes in the inspiratory and expiratory
impedance that are significantly correlated with the spirometric indices of airway
obstruction. COPD was also found to introduce higher respiratory cycle dependence
that is proportional to the airway obstruction. This study thus confirms the
clinical potential of the within-breath impedance analysis for the diagnosis of
respiratory modifications related to COPD.
The individuals in the group of COPD patients had a lower body mass and BMI than those in the control group (Table 1). This difference may be easily explained considering the clinical condition of these patients, who presented with advanced COPD. As expected, the alterations of routine lung function parameters in the COPD patients were in agreement with the presence of airway obstruction (1), showing significant reductions in the spirometric results.
In agreement with previous studies (1919. Sugiyama A, Hattori N, Haruta Y, Nakamura I, Nakagawa M,
Miyamoto S, et al. Characteristics of inspiratory and expiratory reactance in
interstitial lung disease. Resp Med. 2013 ;107(6):875-82,
10.1016/j.rmed.2013.03.005.
http://dx.doi.org/10.1016/j.rmed.2013.03...
,2929. Paredi P, Goldman M, Alamen A, Ausin P, Usmani OS, Pride NB, et
al. Comparison of inspiratory and expiratory resistance and reactance in
patients with asthma and chronic obstructive pulmonary disease. Thorax.
2010;65(3):263-7, 10.1136/thx.2009.120790.
http://dx.doi.org/10.1136/thx.2009.12079...
,3232. Uchida A, Ito S, Suki B, Matsubara H, Hasegawa Y. Influence of
cheek support on respiratory impedance measured by forced oscillation technique.
SpringerPlus. 2013;2:342, 10.1186/2193-1801-2-342.
10.1186/2193-1801-2-342...
),
we observed small mean respiratory impedance values in normal subjects and
increasing mean respiratory impedance values in COPD patients (Figure 1). COPD is characterized by the presence of airway wall
inflammation and mucus hypersecretion, which result in airway obstruction (11. GOLD. Global Initiative For Chronic Obstructive Lung Disease -
UPDATE (2013). “Global Strategy for the Diagnosis, Management, and
prevention of Chronic Obstrutive Pulmonary Disease.” http://www.goldcopd.com: NHLBI/WHO; 2013.
http://www.goldcopd.com...
,66. Di Mango AM, Lopes AJ, Jansen JM, Melo PL. Changes in respiratory
mechanics with increasing degrees of airway obstruction in COPD: detection by
forced oscillation technique. Resp Med. 2006;100(3):399-410,
10.1016/j.rmed.2005.07.005.
http://dx.doi.org/10.1016/j.rmed.2005.07...
).
These phenomena may explain the increase in the Zm observed in Figure 1. The respiratory system impedance module is associated
with the resistive and reactive properties of the entire respiratory system,
including the lung and chest wall (34. Bates JH, Irvin CG, Farre R, Hantos Z. Oscillation mechanics of
the respiratory system. Compr Physiol. 2011;1(3):1233-72.,43. Oostveen E, MacLeod D, Lorino H, Farre R, Hantos Z, Desager K, et
al. The forced oscillation technique in clinical practice: methodology,
recommendations and future developments. Europ Respir J. 2003;22(6):1026-41.,
doi: 10.1183/09031936.03.00089403.
10.1183/09031936.03.00089403...
). At lower frequencies, such as the frequency
used in this study (5 Hz), the reactive properties are dominated by the elastic
properties of the respiratory system. In the present study, the COPD patients showed
decreased dynamic compliance due to the difficulty encountered by the oscillatory
signals emitted by the FOT when crossing segments of the bronchial tree. This
difficulty is associated with increased small airway resistance in regions usually
denominated as “choke points”, as proposed by Dellacè et al.
(1111. Dellaca RL, Santus P, Aliverti A, Stevenson N, Centanni S,
Macklem PT, et al. Detection of expiratory flow limitation in COPD using the
forced oscillation technique. Eur Respir J. 2004;23(2):232-40.). The formation of choke points
prevents the oscillatory signal from penetrating further into the lung, thus
decreasing the apparent volume and hence the lung compliance. These features result
in more negative reactance values and a consequent increase in the impedance module
(Equation 1). COPD progression is also associated with peribronchial fibrosis and
consequent airway tissue remodeling. This reduced airway compliance may also
introduce a more negative Xrs, contributing to a higher Zrs (Equation 1).
Additionally, the deformation of the thoracic wall associated with lung
hyperinflation in COPD introduces an important restrictive factor into the
interaction between the lung and the thoracic wall. This feature may also help to
explain the increase in the Zm observed in the COPD subjects (Figure 1). Accordingly, the increase in the Zm in the studied
COPD subjects could have been associated with the progressive increase in central
and peripheral airway resistance as well as with a reduction in the compliance of
the respiratory system. Thus, the increase in the Zm (Figure 1) describes the increase in the elastic and resistive
respiratory work associated with the progression of COPD. These results are
consistent with those recently obtained by Paredi et al. (2929. Paredi P, Goldman M, Alamen A, Ausin P, Usmani OS, Pride NB, et
al. Comparison of inspiratory and expiratory resistance and reactance in
patients with asthma and chronic obstructive pulmonary disease. Thorax.
2010;65(3):263-7, 10.1136/thx.2009.120790.
http://dx.doi.org/10.1136/thx.2009.12079...
) and Shinke et al. (1717. Shinke H, Yamamoto M, Hazeki N, Kotani Y, Kobayashi K, Nishimura
Y. Visualized changes in respiratory resistance and reactance along a time axis
in smokers: a cross-sectional study. Respir Investig. 2013;51(3):166-74,
10.1016/j.resinv.2013.02.006.
http://dx.doi.org/10.1016/j.resinv.2013....
) for groups with predominantly moderate obstruction. The findings are
also in line with those reported by Mori et al. (1515. Mori K, Shirai T, Mikamo M, Shishido Y, Akita T, Morita S, et
al. Colored 3-dimensional analyses of respiratory resistance and reactance in
COPD and asthma. COPD. 2011;8(6):456-63,
10.3109/15412555.2011.626818.
http://dx.doi.org/10.3109/15412555.2011....
) and Sugiyama et al. (1919. Sugiyama A, Hattori N, Haruta Y, Nakamura I, Nakagawa M,
Miyamoto S, et al. Characteristics of inspiratory and expiratory reactance in
interstitial lung disease. Resp Med. 2013 ;107(6):875-82,
10.1016/j.rmed.2013.03.005.
http://dx.doi.org/10.1016/j.rmed.2013.03...
) for
groups of COPD patients presenting mainly moderate to severe obstruction and by
Kubota and collaborators (2) for patients presenting severe or very severe
obstruction.
The behavior of the Zrs values throughout the respiratory cycle was different between
the control subjects and the COPD patients (Figures
2 and 3). In particular, in the
control subjects, the Zrs values were approximately constant from the beginning of
inspiration to expiration (Figure 2 and 3A). Recent studies (1919. Sugiyama A, Hattori N, Haruta Y, Nakamura I, Nakagawa M,
Miyamoto S, et al. Characteristics of inspiratory and expiratory reactance in
interstitial lung disease. Resp Med. 2013 ;107(6):875-82,
10.1016/j.rmed.2013.03.005.
http://dx.doi.org/10.1016/j.rmed.2013.03...
,2929. Paredi P, Goldman M, Alamen A, Ausin P, Usmani OS, Pride NB, et
al. Comparison of inspiratory and expiratory resistance and reactance in
patients with asthma and chronic obstructive pulmonary disease. Thorax.
2010;65(3):263-7, 10.1136/thx.2009.120790.
http://dx.doi.org/10.1136/thx.2009.12079...
,3232. Uchida A, Ito S, Suki B, Matsubara H, Hasegawa Y. Influence of
cheek support on respiratory impedance measured by forced oscillation technique.
SpringerPlus. 2013;2:342, 10.1186/2193-1801-2-342.
10.1186/2193-1801-2-342...
) have also reported minimal changes in the
impedance values between inspiration and expiration in normal individuals. In line
with these results, we observed only non-significant changes along the respiratory
cycle in healthy subjects and in smokers (Figure
3A).
In contrast, the COPD patients with mild obstruction presented more pronounced
changes along the respiratory cycle (Figures 3A and
B), showing increased values from the beginning of inspiration to
expiration (p<0.002). Even more pronounced changes were
observed in the patients with moderate, severe or very severe obstruction (Figures 3A, C, D, and E;
p<0.0001). In close agreement with the results described in
Figure 3, Sugiyama et al. (1919. Sugiyama A, Hattori N, Haruta Y, Nakamura I, Nakagawa M,
Miyamoto S, et al. Characteristics of inspiratory and expiratory reactance in
interstitial lung disease. Resp Med. 2013 ;107(6):875-82,
10.1016/j.rmed.2013.03.005.
http://dx.doi.org/10.1016/j.rmed.2013.03...
) and Shinke et al. (1717. Shinke H, Yamamoto M, Hazeki N, Kotani Y, Kobayashi K, Nishimura
Y. Visualized changes in respiratory resistance and reactance along a time axis
in smokers: a cross-sectional study. Respir Investig. 2013;51(3):166-74,
10.1016/j.resinv.2013.02.006.
http://dx.doi.org/10.1016/j.resinv.2013....
) recently observed increased expiratory impedance values in
groups of COPD patients presenting mainly moderate to severe or moderate
obstruction. Yamauchi and collaborators also reported expiratory impedance values
higher than the inspiratory values in patients with mild or moderate obstruction
(3030. Yamauchi Y, Kohyama T, Jo T, Nagase T. Dynamic change in
respiratory resistance during inspiratory and expiratory phases of tidal
breathing in patients with chronic obstructive pulmonary disease. Int J Chron
Obstruct Pulmon Dis. 2012;7:259-69, 10.2147/COPD.
http://dx.doi.org/10.2147/COPD...
). Patients with COPD may exhibit EFL
at rest, and previous studies have shown that the within-breath respiratory
impedance is sensitive to the presence of EFL in COPD (1111. Dellaca RL, Santus P, Aliverti A, Stevenson N, Centanni S,
Macklem PT, et al. Detection of expiratory flow limitation in COPD using the
forced oscillation technique. Eur Respir J. 2004;23(2):232-40.–1313. Dellaca RL, Pompilio PP, Walker PP, Duffy N, Pedotti A,
Calverley PM. Effect of bronchodilation on expiratory flow limitation and
resting lung mechanics in COPD. Eur Respir J. 2009;33(6):1329-37,
10.1183/09031936.00139608.
http://dx.doi.org/10.1183/09031936.00139...
). Under
normal conditions, the low-frequency reactance measurements reflect the elastic
properties of the entire respiratory system. However, if EFL is present, the
oscillatory signal cannot pass through the choke point and reach the alveoli, and
the reactance reflects the mechanical properties of the airways proximal to the
choke point (1111. Dellaca RL, Santus P, Aliverti A, Stevenson N, Centanni S,
Macklem PT, et al. Detection of expiratory flow limitation in COPD using the
forced oscillation technique. Eur Respir J. 2004;23(2):232-40.), which are much stiffer than
those in the periphery. As a result, the reactance increases (becomes more
negative). Because the Zrs increases with the Xrs, as described by Equation 1, the
presence of the EFL may explain the higher Zrs values observed during expiration in
COPD patients (Figures 2 and 3). In this context, the lack of a difference
between Ze and Zi values observed in mild COPD patients (Figure 3B) may be explained by these patients’
negligible flow limitation. Notably, the expiratory measurements were higher than
the inspiratory measurements in the patients with moderate or severe obstruction
(Figures 3C and D). In the very severe
patients (Figure 3E), however, the Ze was not
significantly higher than the Zi.
The Zrs significantly increased with airway obstruction in all phases of the
ventilatory cycle (Figures 2A, B, C, and D).
Previous studies from our group showed higher inspiratory and expiratory impedance
values when comparing asthmatics and healthy subjects using a similar methodology
(1414. Veiga J, Lopes AJ, Jansen JM, Melo PL. Within-breath analysis of
respiratory mechanics in asthmatic patients by forced oscillation. Clinics.
2009;64(7):649-56, 10.1590/S1807-59322009000700008.
http://dx.doi.org/10.1590/S1807-59322009...
). Given that the progression of COPD
is associated with peribronchial fibrosis and consequent airway tissue remodeling,
this reduced airway compliance may introduce a more negative Xrs, thereby
contributing to the increased impedance values (Equation 1). In close agreement with
this theory, the Zbi and Zbe increased significantly with airway obstruction (Figures 2A and C).
In COPD, the change in the tidal volume operating point favors lung hyperinflation,
reducing the efficiency of the diaphragm as a pump and inducing the use of accessory
muscles. In the present study, the recruitment of accessory muscles in the COPD
subjects due to impaired diaphragmatic mechanics may be one possible contributing
factor to the increase in respiratory impedance. Because the respiratory impedance
measurements include the influence of the chest wall, we believe that abnormal
accessory muscle contraction during inspiration may have contributed to the
progressive increase in impedance during inspiration in our patients (Figure 2B). Other aspects may also contribute to
the elevated Zi values, including reduced homogeneity of the time constants in the
lung (66. Di Mango AM, Lopes AJ, Jansen JM, Melo PL. Changes in respiratory
mechanics with increasing degrees of airway obstruction in COPD: detection by
forced oscillation technique. Resp Med. 2006;100(3):399-410,
10.1016/j.rmed.2005.07.005.
http://dx.doi.org/10.1016/j.rmed.2005.07...
,1111. Dellaca RL, Santus P, Aliverti A, Stevenson N, Centanni S,
Macklem PT, et al. Detection of expiratory flow limitation in COPD using the
forced oscillation technique. Eur Respir J. 2004;23(2):232-40.,3333. Johnson MK, Birch M, Carter R, Kinsella J, Stevenson RD. Use of
reactance to estimate transpulmonary resistance. Eur Respir J.
2005;25(6):1061-9, 10.1183/09031936.05.00082504.
http://dx.doi.org/10.1183/09031936.05.00...
). Thus, the increase in the
Zi may have been related to increases in the respiratory resistive and elastic work
presented by these individuals. Moreover, the increase observed during expiration
(Figure 2D) may be explained, at least in
part, by the presence of the EFL and active expiratory efforts.
Figures 2E and F show that the control subjects
exhibited small ΔZrs and Zpp values, which is consistent with physiological
principles and previous studies (22. Kubota M, Shirai G, Nakamori T, Kokubo K, Masuda N, Kobayashi H.
Low frequency oscillometry parameters in COPD patients are less variable during
inspiration than during expiration. Respir Physiol Neurobiol. 2009;166(2):73-9,
10.1016/j.resp.2009.01.007.
http://dx.doi.org/10.1016/j.resp.2009.01...
,1010. Aarli BB, Eagan TM, Ellingsen I, Bakke PS, Hardie JA. Reference
values for within-breath pulmonary impedance parameters in asymptomatic elderly.
Clin Respir J. 2013;7(3):245-52, 10.1111/crj.2013.7.issue-3.
http://dx.doi.org/10.1111/crj.2013.7.iss...
,1919. Sugiyama A, Hattori N, Haruta Y, Nakamura I, Nakagawa M,
Miyamoto S, et al. Characteristics of inspiratory and expiratory reactance in
interstitial lung disease. Resp Med. 2013 ;107(6):875-82,
10.1016/j.rmed.2013.03.005.
http://dx.doi.org/10.1016/j.rmed.2013.03...
).
In contrast, the COPD subjects showed significant increases in respiratory cycle
dependency (ΔZrs and Zpp). This result is in line with previous studies that
also reported increased expiratory-inspiratory differences in patients with COPD
compared with healthy subjects (1818. Kanda S, Fujimoto K, Komatsu Y, Yasuo M, Hanaoka M, Kubo K.
Evaluation of Respiratory Impedance in Asthma and COPD by an Impulse Oscillation
System. Internal Med. 2010;49(1):23-30,
10.2169/internalmedicine.49.2191.
http://dx.doi.org/10.2169/internalmedici...
,1919. Sugiyama A, Hattori N, Haruta Y, Nakamura I, Nakagawa M,
Miyamoto S, et al. Characteristics of inspiratory and expiratory reactance in
interstitial lung disease. Resp Med. 2013 ;107(6):875-82,
10.1016/j.rmed.2013.03.005.
http://dx.doi.org/10.1016/j.rmed.2013.03...
).
The current study shows that all within-breath impedance measurements were associated with airway obstruction (Table 2). The best associations among the impedance and spirometric parameters were obtained with the FEV1 (%), Zm and Ze (R=-0.68, p<0.0001). These moderate to good correlations suggest that these parameters strongly reflect the alterations in the central airways. The association with FEF25-75% (R=-0.67, p<0.0001) also suggests the influence of a smaller peripheral obstruction. The Ze, Zbi and Zbe values follow a similar pattern of moderate to good correlation with the spirometric parameters (Table 2).
Another significant finding in this study was the inverse correlation of the Zpp with the FEV1 (%) and FEV1/FVC (Table 2, R=-0.53 and R=-0.50, respectively), which provides evidence of a relationship between the Zpp and COPD severity. The greatest correlations observed between the ΔZrs and the spirometric parameters were exhibited by the FEF25-75 and FEF/FVC (%) (Table 2, R=-0.33 and R=-0.32, respectively). Although weak, these associations were significant, suggesting that the ΔZrs is related to changes in the peripheral airways.
These findings provide additional evidence of a relationship between the within-breath analysis of respiratory impedance and airway obstruction in COPD. Overall, the results of the present study indicate a moderate to good relationship (Table 2). These findings may be at least partially attributed to the methodological differences between the tests; spontaneous respiration is used in the WbFOT analysis, whereas spirometry employs forced maneuvers. These differences may also be explained by the fact that the WbFOT analysis and spirometry values provide information on different characteristics of the respiratory system. Whereas the impedance module describes its resistive and elastic properties, the spirometric parameters are related to the airflow volumes and flows. Therefore, these methods provide complementary information on different characteristics of the respiratory system.
The WbFOT analysis was not sufficiently sensitive to detect the respiratory system
changes in the smokers and the mild COPD patients (Figure 4). A previous ROC
analysis showed similar AUC values in smokers (1717. Shinke H, Yamamoto M, Hazeki N, Kotani Y, Kobayashi K, Nishimura
Y. Visualized changes in respiratory resistance and reactance along a time axis
in smokers: a cross-sectional study. Respir Investig. 2013;51(3):166-74,
10.1016/j.resinv.2013.02.006.
http://dx.doi.org/10.1016/j.resinv.2013....
). In the present study, the Zpp reached acceptable values for
diagnostic use (AUC>0.80) in the moderate COPD patients. In the severe and very
severe COPD patients, high diagnostic accuracy was observed (AUC>0.90). Under
these conditions, the Zbe was most suitable for correctly identifying the effects of
COPD in the severe patients, with a sensitivity of 100% and a specificity of 95%,
whereas in the very severe patients, the Ze was most suitable, with sensitivity and
specificity values of 95%. These promising results are consistent with physiological
principles (1) and suggest that the Zrs observed in the different phases of the
respiratory cycle may be useful in the diagnosis of COPD.
Our study has certain limitations. First, the presence of a shunt may induce changes
in respiratory impedance that can mask the physiological and pathophysiological
information (33. Oostveen E, MacLeod D, Lorino H, Farre R, Hantos Z, Desager K, et
al. The forced oscillation technique in clinical practice: methodology,
recommendations and future developments. Europ Respir J. 2003;22(6):1026-41.,
doi: 10.1183/09031936.03.00089403.
10.1183/09031936.03.00089403...
). To minimize these errors,
the participants were asked to firmly hold their cheeks during the tests.
Second the relationships between within-breath impedance and dyspnea, exercise capacity, and hyperinflation at the different stages of COPD are also of interest but were not addressed in the present study. This study specifically evaluated the respiratory impedance module. The evaluation of resistive and reactive parameters may complement such measurements, providing additional information associated with respiratory cycle dependence and the EFL, among other phenomena.
We believe that studies focusing on groups of COPD patients with clearly characterized pulmonary emphysema or chronic bronchitis could contribute to a more detailed understanding of the changes in within-breath impedance and should thus be performed in the future.
The correlations between the WbFOT and spirometric parameters were generally moderate to good, indicating that the FOT may provide new and complementary information on respiratory mechanics. Use of the clinical criteria as a gold standard may also demonstrate the added value of the WbFOT over conventional spirometry. We believe that this hypothesis should be evaluated in further studies.
In conclusion, COPD introduces higher respiratory cycle dependence that is
proportional to airway obstruction. WbFOT parameters provide information in addition
to that provided by spirometric measurements and can adequately detect alterations
in the respiratory mechanics in moderate, severe and very severe COPD patients.
These results are in close agreement with physiological principles (011. GOLD. Global Initiative For Chronic Obstructive Lung Disease -
UPDATE (2013). “Global Strategy for the Diagnosis, Management, and
prevention of Chronic Obstrutive Pulmonary Disease.” http://www.goldcopd.com: NHLBI/WHO; 2013.
http://www.goldcopd.com...
–66. Di Mango AM, Lopes AJ, Jansen JM, Melo PL. Changes in respiratory
mechanics with increasing degrees of airway obstruction in COPD: detection by
forced oscillation technique. Resp Med. 2006;100(3):399-410,
10.1016/j.rmed.2005.07.005.
http://dx.doi.org/10.1016/j.rmed.2005.07...
), supporting and adding new information to the results reported
previously (22. Kubota M, Shirai G, Nakamori T, Kokubo K, Masuda N, Kobayashi H.
Low frequency oscillometry parameters in COPD patients are less variable during
inspiration than during expiration. Respir Physiol Neurobiol. 2009;166(2):73-9,
10.1016/j.resp.2009.01.007.
http://dx.doi.org/10.1016/j.resp.2009.01...
,1515. Mori K, Shirai T, Mikamo M, Shishido Y, Akita T, Morita S, et
al. Colored 3-dimensional analyses of respiratory resistance and reactance in
COPD and asthma. COPD. 2011;8(6):456-63,
10.3109/15412555.2011.626818.
http://dx.doi.org/10.3109/15412555.2011....
,1818. Kanda S, Fujimoto K, Komatsu Y, Yasuo M, Hanaoka M, Kubo K.
Evaluation of Respiratory Impedance in Asthma and COPD by an Impulse Oscillation
System. Internal Med. 2010;49(1):23-30,
10.2169/internalmedicine.49.2191.
http://dx.doi.org/10.2169/internalmedici...
,2929. Paredi P, Goldman M, Alamen A, Ausin P, Usmani OS, Pride NB, et
al. Comparison of inspiratory and expiratory resistance and reactance in
patients with asthma and chronic obstructive pulmonary disease. Thorax.
2010;65(3):263-7, 10.1136/thx.2009.120790.
http://dx.doi.org/10.1136/thx.2009.12079...
) and suggesting that WbFOT parameters appear to be good
quantitative indicators of COPD severity. Considering that the WbFOT is easy to
perform, it may be a promising tool to facilitate the diagnosis of respiratory
abnormalities in patients with COPD.
The authors would like to thank JG Noronha Filho, FR Ventromilli, C Lara, and all of the volunteers who participated in the present study. The Brazilian Council for Scientific and Technological Development (CNPq) and the Rio de Janeiro State Research Supporting Foundation (FAPERJ) supported this study.
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Publication Dates
-
Publication in this collection
July 2015
History
-
Received
23 Feb 2015 -
Reviewed
31 Mar 2015 -
Accepted
31 Mar 2015