Lung

, Volume 192, Issue 5, pp 653–659 | Cite as

Correlations Between Small Airway Function, Ventilation Distribution, and Functional Exercise Capacity in COPD Patients

Article

Abstract

Background

Interest in using the nitrogen single-breath washout (N2SBW) test to measure ventilation inhomogeneity and small airway function in COPD patients has grown in recent years. Our aim was to assess the correlation of the measures obtained by the N2SBW test and other pulmonary function parameters with the six-minute walk distance (6MWD), the degree of dyspnea score, and health status in COPD patients.

Methods

In this cross-sectional study, 31 patients with COPD were subjected to the N2SBW test, spirometry, whole-body plethysmography, carbon monoxide diffusing capacity measurement, the six-minute walk test, the modified Medical Research Council (mMRC) scale, and the COPD Assessment Test (CAT).

Results

We found a strong correlation between the 6MWD and the phase III slope of the nitrogen single-breath washout (Phase III slopeN2SBW) (r = −0.796; p = 0.0001). We found moderate correlations between the 6MWD and the residual volume (RV) (r = −0.651; p = 0.0001) and RV/total lung capacity (RV/TLC) (r = −0.600; p = 0.0004). We also found moderate correlations between the CAT score and Phase III slopeN2SBW (r = 0.728; p = 0.0001), RV (r = 0.646; p = 0.0001) and RV/TLC (r = 0.603; p = 0.0003). There was a significant difference between the mMRC grades for the following variables: Phase III slopeN2SBW (p = 0.0001), RV (p = 0.0001), and smoking history (p = 0.008). Multivariate analysis showed that Phase III slopeN2SBW was the only independent predictor of the 6MWD (R2 = 0.703; p = 0.0001), CAT score (R2 = 0.586; p = 0.0001), and mMRC scale (relative risk = 1.14; p = 0.0001).

Conclusions

In patients with COPD, our findings suggest that the ventilation inhomogeneity impacts the functional exercise capacity, the degree of dyspnea, and health status.

Keywords

Chronic obstructive pulmonary disease Respiratory function tests Respiratory mechanics Exercise test 

Introduction

COPD is a serious public health concern of high and still increasing prevalence [1]. Despite the clinical relevance of COPD, many of its characteristics remain poorly understood, such as the contribution of the small airways to the clinical and pathophysiological outcomes [2]. The small airways are thought to be the main site of airflow limitation in individuals with COPD, and damage to these structures is thought to increase with the severity of the disease [3, 4, 5]. Understanding the progression of small airway disease will lead to a better understanding of the pathophysiology of COPD [3, 5].

The lungs are built to allow for perfectly mixing inhaled gas with resident gas. Lung function determines the efficiency of gas mixing [6]. The measurement of lung ventilation inhomogeneity allows for the detection of changes in the peripheral airways, which are known as the lung’s ‘silent zone’ [3, 6, 7]. While the small airways contribute little to airway resistance in healthy lungs, studies have shown that they are the major sites of resistance in COPD [2, 8]. Small airway disease is characterized by the progressive increase of resistance to lung emptying, regional inhomogeneity of the flow and time constants, and premature airway closing [2].

Although the nitrogen single-breath washout (N2SBW) test was first described approximately 60 years ago, interest in its use for assessing small airway function and inhomogeneity in the ventilation distribution in COPD patients has increased in recent years [4, 5]. Timmins et al. [4] showed that in COPD patients, the ratio of the forced expiratory volume in 1 s to the forced vital capacity (FEV1/FVC) was predictive of both emphysema and the closing volume/vital capacity (CV/VC) derived from the washout [4]. Mikamo et al. [5] found significant correlations between the phase III slope of the nitrogen single-breath washout (Phase III slopeN2SBW), lung mechanics measures, and emphysema scores using high-resolution computed tomography (HRCT). It is worth noting that the two studies assessed the N2SBW results as absolute values rather than as percentages of the predicted values. This does not correct the variation that is associated with gender and anthropometric parameters [6, 9].

The N2SBW test is thought to be useful for stratifying patients and assessing the severity of disease [4, 5, 6]. The six-minute walk test (6MWT) is another measure increasingly used to monitor patients with COPD. The 6MWT results have significant correlations with the degree of airway obstruction, the degree of dyspnea, and submaximal physical capacity, and they therefore serve as a prognostic indicator in COPD patients [10]. We hypothesized that the changes in small airways and poor ventilation distribution in COPD patients impact the functional exercise capacity and clinical outcomes. The objective of this study was to assess the correlation of the measures obtained by the N2SBW test and other pulmonary function parameters with the six-minute walk distance (6MWD), the degree of dyspnea, and health status in COPD patients.

Methods

A cross-sectional study was conducted at Newton Bethlem Hospital, Rio de Janeiro, Brazil. All COPD outpatients who attended the clinic between July 2013 and January 2014 were screened for participation in the study. The inclusion criteria were age ≥40 years, smoking history of at least 10 pack-years [4, 9, 11, 12], and a postbronchodilator FEV1/FVC <0.7 [1]. Possible subjects were excluded if they had coexistent asthma or other respiratory disease, α1-antitrypsin deficiency, or an exacerbation of COPD within the past 4 weeks, which was defined as increased dyspnea associated with a change in the quality and quantity of sputum. All the participants were in stable condition at the time of the study. The assessments of each participant were made on the same day. The protocol was approved by the research and ethics committee of our institution, and written informed consent was obtained from all participants.

Clinical Data

The degree of dyspnea was determined using the modified Medical Research Council (mMRC) scale, which has been validated for use in Brazil [13].

The COPD Assessment Test (CAT) questionnaire comprises the following eight items: cough, phlegm, chest tightness, breathlessness, limitation in home activities, confidence to leave the house, sleep, and energy. The responses are scores ranging from zero to five, and patients are required to select a single response for each item. At the end of the test, the scores for all responses are added, allowing for assessment of the clinical impact of COPD. The CAT version validated for use in Brazil was used in this study [14].

Pulmonary Function Tests

The N2SBW test was performed with a HDpft 3000 (nSpire Health, Inc., Longmont, CO, USA), while spirometry, whole-body plethysmography, and carbon monoxide diffusing capacity (DLco) measurement were performed using an HD CPL (nSpire Health, Inc., Longmont, CO, USA). Briefly, in the N2SBW test, the subjects exhale to residual volume (RV), inhale 100 % oxygen to total lung capacity (TLC), and then exhale slowly to RV at a flow rate of approximately 0.5 L/s, during which time the exhaled N2 concentration is recorded at the airway opening.

All lung function parameters were obtained 15 min after the administration of 400 µm of salbutamol per metered-dose inhaler connected to a spacer to minimize the contribution of smooth-muscle contraction [9]. Pulmonary function tests were performed in the following order: N2SBW test, spirometry, DLco, and whole-body plethysmography. All tests followed the standards set by the American Thoracic Society/European Respiratory Society [6, 15]. Buist (N2SBW test), Pereira (spirometry), and Neder (DLco and lung volumes) reference values were used in the interpretation of the lung function parameters [16, 17, 18, 19, 20].

Six-Minute Walk Test

The 6MWT was performed in a 30-meter-long hallway according to the ATS recommendations [21]. A digital oximeter (Onyx 9500, Nonin Medical, Plymouth, MN, USA) was used to measure the heart rate and peripheral saturation. The degree of dyspnea was assessed with the modified Borg scale. All measurements were carried out before the onset of the test, at minute three, and at the end of the test. The tests were repeated twice, and the highest value was recorded [21]. The predicted values for each patient were calculated using Gibbons et al.’s equations [22].

Data Analysis

The sample size was calculated using MedCalc version 8.2 (Medcalc Software, Mariakerke, Belgium). A minimum of 26 cases were required to test for the alternative hypothesis that the correlation coefficient is higher than 0.40 (or less than −0.40), assuming a type I error of 5 % and type II error of 20 % [23].

The distribution of continuous variables was determined using the Shapiro–Wilk test. Normally distributed data were expressed as mean ± SD. Non-normally distributed data were expressed as medians (interquartile ranges). Pearson’s correlation coefficients were calculated to investigate the associations between the lung function parameters and participant characteristics. Correlation coefficients <0.25 (or −0.25) represent a weak correlation; those in the range 0.25–0.50 (or −0.25–−0.50) represent a reasonable correlation; those in the range 0.50–0.75 (or −0.50–−0.75) represent a moderate correlation; and those >0.75 (or −0.75) represent a strong correlation [23]. The characteristics of the COPD patients were compared to the mMRC scale using the independent samples t test or Mann–Whitney test. Multivariate forward stepwise regression analysis was performed to determine the dependent relationship of 6MWD, CAT score, and mMRC scale with the lung function parameters. A logarithmic transformation was applied to the dependent variables to homogenize the variances. The values were adjusted for confounding factors, including gender, age, weight, height, body mass index (BMI), and smoking history. Data analysis was performed using SAS 6.11 software (SAS Institute, Inc., Cary, NC, USA). The statistical significance level was set at p < 0.05.

Results

A total of 42 outpatients were screened for inclusion into the study. Thirty-one patients met the inclusion criteria while eleven patients were excluded for the following reasons: refusal to participate in the study (n = 5), COPD exacerbation (n = 3), coexisting asthma (n = 2), and a history of pulmonary tuberculosis (n = 1).

A total of 26 participants were male, and five were female. All participants were ex-smokers with abstinence for more than 3 years and had a mean smoking history of 50.8 ± 21.5 pack-years. In 45 % of the participants, the mMRC grade was <2, and in 55 %, it was ≥2. In 48 % of the participants, the CAT score was ≤20, and in 52 %, it was >20. In 42 % of the participants, the RV was >150 % of the predicted value, and 52 % exhibited RV/TLC >50 %. In addition, a DLco <80 % of the predicted value was detected in 55 % of the participants. In the N2SBW test, 39 % of the participants exhibited a Phase III slopeN2SBW >350 % of the predicted value, and 45 % of the participants had a CV/VC >150 % of the predicted value. The anthropometric, clinical, and pulmonary function data are presented in Table 1.
Table 1

Characteristics of the COPD patients

Participant characteristics

n = 31

General characteristics

 Age (years)

64.4 ± 7.93

 BMI (kg/m2)

24.1 ± 3.67

 Smoking history (pack-years)

50.8 ± 21.5

 Use of medications

  LAMA

22 (71)

  LABA

16 (51.6)

  ICS

5 (16.1)

 CAT score

20.7 ± 4.75

mMRC scale

 Grade 1

14 (45.1)

 Grade 2

7 (22.6)

 Grade 3

7 (22.6)

 Grade 4

3 (9.68)

GOLD classification

 Mild

3 (9.68)

 Moderate

17 (54.8)

 Severe

9 (29)

 Very severe

2 (6.45)

Lung function

 FVC (% predicted)

76.3 ± 17

 FEV1 (% predicted)

55.9 ± 17.1

 FEV1/FVC (%)

59.1 ± 7.86

 FEF25−75 % (% predicted)

26.2 ± 13.1

 TLC (% predicted)

101 ± 13.1

 RV (% predicted)

155.9 ± 34.3

 RV/TLC (%)

50.8 ± 10.1

 DLco (% predicted)

75 ± 20.4

Nitrogen single-breath washout test

 Phase III slopeN2SBW (% predicted)

347.2 ± 50.5

 CV/VC (% predicted)

167.5 ± 75.9

6MWD (% predicted)

69.6 ± 17.9

Data are mean ± SD or number (%)

BMI body mass index, ICS inhaled corticosteroid, LABA long-acting β2-agonist, LAMA long-acting antimuscarinic agent, CAT COPD assessment test, mMRC scale modified Medical Research Council scale, GOLD Global Initiative for Chronic Obstructive Lung Disease, FVC forced vital capacity, FEV1 forced expiratory volume in one second, FEF2575 % forced expiratory flow during the middle half of the FVC, TLC total lung capacity, RV residual volume, DLco diffusing capacity for carbon monoxide, Phase III slopeN2SBW phase III slope of the nitrogen single-breath washout, CV/VC closing volume/vital capacity, 6MWD six-minute walk distance

The 6MWD exhibited a positive correlation with the FVC, FEV1, FEV1/FVC, and forced expiratory flow during the middle half of the FVC (FEF25−75 %) and a negative correlation with Phase III slopeN2SBW, TLC, RV, and RV/TLC. The CAT score exhibited a positive correlation with smoking history, Phase III slopeN2SBW, TLC, RV, and RV/TLC and a negative correlation with BMI, FVC, and FEV1. Univariate correlations between the lung function parameters, clinical outcomes, and functional exercise capacity are presented in Table 2. There was a significant difference between the mMRC grades for the following variables: smoking history, Phase III slopeN2SBW, FVC, FEV1, FEF25−75 %, TLC, RV, and RV/TLC. The mMRC grades and characteristics of the COPD patients are compared in Table 3.
Table 2

Pearson’s correlation coefficients for lung function parameters and characteristics of the COPD patients

Participant characteristics

6MWD (% predicted)

CAT score

r

p value

r

p value

General characteristics

 Age (years)

−0.082

0.660

−0.003

0.99

 BMI (kg/m2)

0.301

0.099

−0.401a

0.041

 Smoking history (pack-years)

−0.206

0.27

0.405a

0.028

Lung function

 Phase III slopeN2SBW (% predicted)

−0.796c

0.0001

0.728b

0.0001

 CV/VC (% predicted)

−0.180

0.33

0.268

0.14

 FVC (% predicted)

0.409a

0.025

−0.422a

0.019

 FEV1 (% predicted)

0.495a

0.004

−0.411a

0.023

 FEV1/FVC (%)

0.406a

0.026

−0.149

0.42

 FEF25–75 % (% predicted)

0.469a

0.007

−0.347

0.056

 TLC (% predicted)

−0.446a

0.012

0.427a

0.016

 RV (% predicted)

−0.651b

0.0001

0.646b

0.0001

 RV/TLC (%)

−0.600b

0.0004

0.603b

0.0003

 DLco (% predicted)

0.234

0.20

−0.220

0.235

aReasonable correlation

bModerate correlation

cStrong correlation

6MWD six-minute walk distance, CAT COPD assessment test, BMI body mass index, Phase III slopeN2SBW phase III slope of the nitrogen single-breath washout, CV/VC closing volume/vital capacity, FVC forced vital capacity, FEV1 forced expiratory volume in one second, FEF2575 % forced expiratory flow during the middle half of the FVC, TLC total lung capacity, RV residual volume, DLco diffusing capacity for carbon monoxide

Table 3

Comparison between the modified Medical Research Council scale and characteristics of the COPD patients

Participant characteristics

Grade 1–2 (n = 21)

Grade 3–4 (n = 10)

p value

General characteristics

 Age (years)

64.6 ± 8.37

63.9 ± 7.58

0.83

 BMI (kg/m2)

24.9 ± 2.71

22.5 ± 4.83

0.15

 Smoking history (pack-years)

44.9 ± 32.5

63.3 ± 33.8

0.008

Lung function

 Phase III slopeN2SBW (% predicted)

319.2 ± 25.4

406 ± 37.3

0.0001

 CV/VC (% predicted)

169.9 ± 77.2

162.7 ± 76.9

0.83

 FVC (% predicted)

80.6 ± 15.5

67.3 ± 17.3

0.040

 FEV1 (% predicted)

60.7 ± 16

45.7 ± 15.2

0.019

 FEV1/FVC (%)

60.3 ± 7.72

56.6 ± 8

0.19

 FEF25−75 % (% predicted)

29.9 ± 13.3

18.5 ± 9

0.021

 TLC (% predicted)

97.8 ± 11.2

107.9 ± 14.8

0.042

 RV (% predicted)

137 ± 13.3

195.6 ± 30.5

0.0001

 RV/TLC (%)

47.9 ± 9

56.9 ± 10.1

0.018

 DLco (% predicted)

75.9 ± 17.3

72.6 ± 22.1

0.77

BMI body mass index, Phase III slopeN2SBW phase III slope of the nitrogen single-breath washout, CV/VC closing volume/vital capacity, FVC forced vital capacity, FEV1 forced expiratory volume in one second, FEF2575 % forced expiratory flow during the middle half of the FVC, TLC total lung capacity, RV residual volume, DLco diffusing capacity for carbon monoxide

Multivariable analysis was performed to determine whether the lung function parameters can predict the functional exercise capacity and clinical outcomes after considering other factors that may influence the severity of COPD. Phase III slopeN2SBW was the only independent predictor of the 6MWD, CAT score, and mMRC scale. The regression coefficients are shown in Table 4.
Table 4

Regression coefficients to identify determinants of functional exercise capacity, degree of dyspnea, and health status of the studied subjects

Functional exercise capacity and clinical data

Determinant

Regression coefficient

Standard error

p value

R2a

Relative riskb

6MWD (% predicted)

Phase III slopeN2SBW (% predicted)

−0.3180

0.0291

0.0001

0.703

CAT score

Phase III slopeN2SBW (% predicted)

0.0767

0.0096

0.0001

0.586

mMRC scale

Phase III slopeN2SBW (% predicted)

0.1354

0.0687

0.0001

1.14

6MWD six-minute walk distance, CAT COPD assessment test, mMRC scale modified Medical Research Council scale, Phase III slopeN2SBW phase III slope of the nitrogen single-breath washout

aMultivariate linear regression analysis

bMultivariate logistic regression analysis

Discussion

The main findings of this study were that the ventilation inhomogeneity and air trapping in COPD patients are closely associated with lower functional exercise capacity and worse health status. In such patients, the ventilation distribution and air trapping exhibit significant differences according to the degree of dyspnea. In addition, the ventilation inhomogeneity independently contributes to the 6MWD, health status, and degree of dyspnea. Thus far, no other study seems to have investigated the relationships when using the predicted values for the N2SBW test and the 6MWT.

The N2SBW test results should be analyzed as the percentages of the predicted values rather than as the absolute values because, like any other pulmonary function test, the N2SBW test is influenced by demographic data. Teculescu et al. [24] found a marked age dependence of CV, which has been confirmed by numerous studies [6, 9, 19, 20, 25]. Therefore, in contrast to other studies [4, 5], we chose to analyze the N2SBW test parameters based on the predicted values. Elevated Phase III slopeN2SBW values are indicative of elevated ventilation inhomogeneity and reflect differences in the time constants, which depend on both small airway disease and emphysema [9, 26]. In this study, the mean Phase III slopeN2SBW percentage relative to the predicted value was similar to the result reported by Lapperre et al. [9], who also studied COPD patients (314 vs. 347.2 % predicted). Interestingly, HRCT-detected emphysema has also been linked to poor ventilation distribution [4], which suggests that emphysema may be an important cause of ventilation inhomogeneity.

Exercise intolerance is the most distressing and disabling consequence for the majority of COPD patients [27]. Multiple mechanisms contribute to exercise intolerance in these patients, including ventilatory inefficiency, dynamic hyperinflation, gas exchange abnormalities, respiratory muscle dysfunction, peripheral muscle dysfunction, and cardiocirculatory impairment [28, 29, 30, 31]. The 6MWT has been increasingly used to assess the response of COPD patients to exercise, allowing for global analysis of the respiratory, cardiac, and metabolic systems [10, 32]. Due to its simplicity and minimal technological requirements, the test has become a valuable tool for assessing ventilatory limitation in COPD patients [28, 32].

Similar to other studies [33, 34], we also reported significant correlations of the 6MWD with FVC, FEV1, FEV1/FVC, and RV/TLC. However, poor ventilatory distribution is also expected to directly impact patient performance during the 6MWT. Indeed, we observed a clear relationship between Phase III slopeN2SBW and the 6MWD. Curiously, Wakayama et al. [35] observed a significant correlation between the emphysema score and 6MWT (r = -0.74; p < 0.001), but they did not find a correlation between the emphysema score and Phase III slopeN2SBW (r = 0.15). However, these authors did not use the predicted values for the 6MWT and N2SBW test, which may have influenced the results of these correlations. The Phase III slopeN2SBW is a measure of the ventilation distribution, whereas the CV/VC is a measure of closure of the terminal bronchioles [4, 7, 36]. Therefore, we think that the lack of a significant correlation between the CV/VC and 6MWD may indicate that abnormalities in the small airways do not directly impact patient performance during the exercise.

The CAT was designed to provide a simple measure of the impact of COPD symptoms for use in everyday clinical practice in addition to contributing to the assessment of patients’ state of health and to treatment optimization [1, 37]. Similar to our finding, significant correlations of the health status (as assessed by the CAT) with FVC and FEV1 had been observed in previous studies [14, 38]. Additionally, we also found a moderate correlation between the CAT score and Phase III slopeN2SBW, which was not observed by Mikamo et al. [5]. We believe that this discrepancy may be at least partially explained by the fact that one study evaluated the percentages of the predicted values and the other evaluated absolute values. The relationship between the CAT score and Phase III slopeN2SBW indicates that increased ventilation inhomogeneity directly impacts the health status, which raises the possibility of using Phase III slopeN2SBW to monitor patients with COPD in the future. However, future studies that are specifically designed for this purpose are needed to confirm our hypothesis.

Dyspnea is a symptom associated with exercise performance and quality of life, and its reduction is one of the major objectives in the treatment of COPD. In this context, the mMRC scale has been widely used in COPD patients because it is simple and easy to use; it has also been correlated with quality of life, disease severity, and prognosis [39]. In the present study, we observed higher values of Phase III slopeN2SBW, RV, and RV/TLC in patients with greater degrees of dyspnea. Interestingly, Mikamo el al. [5] demonstrated a significant correlation between Phase III slopeN2SBW and MRC scale in these individuals (Rho = 0.49; p = 0.0003). Although evidence has recently emerged to explain dyspnea in mild-to-moderate COPD (the group that is most of our patients), the understanding of its underlying pathophysiology is essential to rationalize treatment strategies [40]. In this context, we believe that ventilation inhomogeneity is an important contributor to dyspnea in COPD patients as well as to other pathophysiological mechanisms, including dynamic hyperinflation, neuromechanical dissociation, gas exchange abnormalities, and inspiratory muscle weakness [40, 41].

The clinical relevance of our results can be found in the N2SBW test, a noninvasive tool that is complementary to spirometry and provides parameters for assessing the ventilation distribution and small airway function. In this investigation, Phase III slopeN2SBW demonstrated an independent role in predicting the 6MWD, CAT score, and mMRC scale. As previously proposed by Mikamo et al. [5], our data support the use of Phase III slopeN2SBW both to stratify patients and to evaluate the treatment response. This proposal is further substantiated by the close relationship of Phase III slopeN2SBW with exercise in the present study. Consequently, monitoring Phase III slopeN2SBW could facilitate the management of COPD patients [9].

The strength of this study is that it is the first to assess the relationship between the N2SBW parameters and functional exercise capacity as measured by the 6MWD in COPD patients. In addition, all values were expressed as the percentages of the predicted values, adjusting the absolute values according to the patients’ gender, age, weight, and height. We consider the small sample size to be the main limitation of our study. We also consider that most of our patients had mild-to-moderate disease and the effects of ventilation inhomogeneity may have been underestimated; however, this subpopulation represents the majority of COPD patients and is still understudied [29, 40]. A more comprehensive health-related questionnaire, such as the Saint George’s Respiratory Questionnaire, could have added more details about the quality of life of our patients [42]. It is also worth mentioning that the forced oscillation technique could have contributed to our study findings by measuring respiratory system resistance, reactance, and expiratory flow limitation. Still, we believe that our results justify further research on the use of the N2SBW test parameters as markers of COPD severity because they may be important for future studies on the treatment for these patients.

In conclusion, this study suggests that ventilation inhomogeneity independently contributes to the functional exercise capacity, degree of dyspnea, and health status in COPD patients. Although our results demand more thorough investigation, our data suggest that monitoring the N2SBW parameters may be added to the management of COPD patients in the future.

Notes

Acknowledgments

The authors wish to thank the Rio de Janeiro State Research Supporting Foundation (FAPERJ).

Conflict of interest

The authors declare no conflict of interest.

Ethical Standards

The experiments are in accordance with the current laws of the Brazil.

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Postgraduate Programme in Medical SciencesState University of Rio de JaneiroRio de JaneiroBrazil
  2. 2.Rehabilitation Sciences Master’s ProgramAugusto Motta University CentreRio de JaneiroBrazil

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