Predictors of dynamic hyperinflation during the 6-minute walk test in stable chronic obstructive pulmonary disease patients

Introduction

Exercise intolerance is a cardinal complaint of patients with chronic obstructive pulmonary disease (COPD) (1). Although the underlying mechanism of exercise intolerance is complex and multifactorial, dynamic hyperinflation (DH) remains a major contributor to exercise limitation in COPD (2). The relationship between DH and exercise capacity has been documented using cardiopulmonary exercise test (CPET) (3-5). In the clinical setting, CPET is often impractical because it requires specialized equipment, trained technicians, and physician supervision. Recent studies demonstrated that the 6-minute walk test (6MWT) provide a simple, safe, and well-tolerated method to detect DH in patients with COPD (6,7). However, the physiological factors responsible for DH development during the 6MWT have not been adequately evaluated. In addition, the effects of DH on ventilatory response to the 6MWT in COPD patients remain largely unknown. Finally, it is unclear whether the contribution to functional exercise capacity from resting lung function, demographic characteristics, exertional dyspnea and DH differs in COPD according to the DH status.

The aims of this study were: (I) to elucidate the physiological factors responsible for DH development during the 6MWT; (II) to compare physiological response to the 6MWT in hyperinflators and non-hyperinflators with COPD; and (III) to delineate the predictors of functional exercise capacity in hyperinflators and non-hyperinflators.

Methods

Participants

This prospective cross-sectional study was conducted between March 2013 and July 2014. Consecutive subjects with mild to very severe COPD from a pulmonary clinic at the Sun Yat-sen Memorial Hospital, Guangzhou, China were eligible for enrollment. COPD was diagnosed based on clinical manifestations, self-reported smoking history, and presence of persistent airflow limitation. Persistent flow limitation was defined as a post-bronchodilator forced expiratory volume in 1 s (FEV₁) to forced vital capacity (FVC) ratio <70% (8). The COPD severity was determined according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines.

The inclusion criteria were: (I) a history of COPD; (II) aged over 40 years; (III) pulse oximetric saturation (S_pO₂) at rest >90% on ambient air; and (IV) no change in medication dosage or symptoms during the preceding 4 weeks.

The exclusion criteria were: (I) serious cardiovascular diseases (including uncontrolled hypertension, unstable angina pectoris, recent myocardial infarction, or congestive heart failure); (II) a diagnosis of obstructive sleep apnea (OSA) by polysomnography (PSG) before enrollment; (III) evidence of malignancy or severe renal or hepatic dysfunction; and (IV) lower limb disability. Figure 1 summarizes the participant eligibility, exclusion, and enrollment process.

Figure 1 The flowchart illustrating participant eligibility, exclusion and enrollment.

The study protocol was approved by the Ethics Committee, Sun Yat-sen Memorial Hospital, Guangzhou, China. All participants gave written informed consent. The study was registered at the Chinese Clinical Trial Registry (Registration Number: ChiCTR-TNRC-15006234, website: http://www.chictr.org/en/).

Group allocation

The study was performed at the Rehabilitation Laboratory of Guangdong Provincial Hospital, Guangzhou, China. Subjects were assigned to two groups based on occurrence of DH, defined as a decline in inspiratory capacity (IC) from baseline greater than zero (ΔIC >0.0 L) after 6MWT (9,10). Patients with a ΔIC >0.0 L in this study were diagnosed with DH (hyperinflators), and those with a ΔIC ≤0.0 L were considered DH negative (non-hyperinflators).

Measurements

Prior to examination, subjects were instructed to avoid strenuous exercise for 24 h. Demographic and clinical data were collected, followed successively by the pulmonary function test, 6MWT, assessment of quality of life and dyspnea. All measurements were obtained by a well-trained technician blinded to the study protocol.

Demographic and clinical data

The age, gender, smoking status, smoking history, body mass index (BMI), comorbidities, medication history, and use of oxygen therapy were recorded in each subject.

Pulmonary function tests

Standard forced expiratory spirometry was performed according to the American Thoracic Society guidelines using an electronic spirometer (CHEST GRAPH HI-101, Tokyo, Japan) before and after administering 400 µg salbutamol sulfate aerosol (Ventolin, GlaxoSmithKline, Shanghai, China) (11). The normal predicted values were determined according to the equations proposed by the European Coal and Steel Community with certain correction coefficients (12). Maximal voluntary ventilation (MVV) was estimated by multiplying FEV₁ by 35.

Inspiratory capacity (IC) maneuvers

The IC was measured with the patient seated after fully explaining the procedure to each subject (13). Satisfactory and consistent technique for the IC maneuvers was established with the subject at rest. After four to six consistent normal breaths, the subject was instructed to inspire the total lung capacity (TLC) and then return to normal breathing. The two largest IC measurements of at least three acceptable trials were required to agree within 5%. The better of two reproducible maneuvers was recorded for analysis.

6-minute walk test (6MWT)

The 6MWT followed the recommendations from American Thoracic Society guidelines (14). Patients were given standardized instructions to walk as fast as possible for 6 min. IC was measured at rest and immediately after walking (within 60 s). The heart rate, breathing pattern, S_pO₂, and the modified Borg dyspnea scale (15) and leg fatigue ratings were recorded before and after walking. We measured lung volume by plethysmography in five subjects before and after the 6MWT. The results showed no significant changes in TLC, which indicated that TLC did not change during walking test. Assuming that TLC does not change during exercise, changes in the IC are used to indirectly reflect the level of DH (16,17).

Dyspnea and quality of life assessment

The degree of dyspnea was assessed using the Modified Medical Research Council (MMRC) dyspnea scale (18). The health-related quality of life (HRQL) was evaluated using the St George’s Respiratory Questionnaire (SGRQ) (19).

Statistical analysis

Data were expressed as the mean ± standard deviation. Statistical analyses were conducted using the Statistical Package for Social Sciences version 18.0. Chi-square analysis was applied to test discrete variables between the both groups. The independent samples t-test or Mann-Whitney U-test was used to compare continuous variables between the two groups. Pearson or spearman correlation coefficients were calculated for relationship between the ΔIC/IC or the 6-minute walk distance (6MWD) and other variables. Stepwise linear regression was performed to identify the factors independently associated with ΔIC/IC or the 6MWD. Variables were selected for use with the stepwise regression model based on the results of univariate analysis (Tables S1,S2 in the supplementary file). A P<0.05 was considered statistically significant.

Table S1 Univariate analysis of ΔIC
Full table

Table S2 Univariate analysis of 6MWD
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Results

Subject characteristics

Table 1 displays the population characteristics. A total of 105 subjects with stable COPD were included in this study. The numbers of patients diagnosed with GOLD stages I, II, III, and IV were 16 (15.2%), 50 (47.6%), 31 (29.5.1%), and 8 (7.6%), respectively. The mean age was 71.34±7.95 years, and men comprised 85.71% of the sample. DH was present in 70 subjects (66.67%), with 10 subjects (10/16) at GOLD stage I, 34 subjects (34/50) at GOLD stage II, 20 subjects (20/31) at GOLD stage III, and 6 subjects (6/8) at GOLD stage IV. Although there were decreasing trends of small airway function and FEV₁/FVC in hyperinflators, no significant differences were observed between the two groups.

Table 1 Clinical and anthropometric characteristics of the subjects
Full table

Multiple regression analysis of DH

The univariate analysis of ΔIC/IC and ΔIC is shown in Table S1. Among the variables, only the maximal mid-expiratory flow (MMF) (% pred) (r=−0.256, P=0.010), the forced expiratory flow after exhaling 50% of the FVC (FEF_50%) (% pred) (r=−0.279, P=0.005) and forced expiratory flow after exhaling 75% of the FVC (FEF_75%) (% pred) (r=−0.212, P=0.033) were negatively correlated with the ΔIC/IC. No significant correlation was observed between FEV₁ and ΔIC/IC (r=0.031, P=0.755). On multivariate regression analysis, the FEF_50% was the only predictor of ΔIC/IC (Table 2). For the ΔIC/IC, the FEF_50% uniquely contributed 27.9% of the variance.

Table 2 Multivariate linear regression for ΔIC and 6MWD
Full table

The effects of DH on response to the 6MWT

The response to the 6WMT in both groups is summarized in Table 3. There were no significant differences in the 6WMD between the two groups. IC decreased by 0.24±0.19 L at the end of walking in hyperinflators. The non-hyperinflators had a higher post-walking V_T (t=2.419, P=0.017) and post-walking V_E (t=2.599, P=0.011) than the hyperinflators did. No obvious difference was observed in the post-walking breathing frequency, Borg dyspnea scale, heart rate, and ΔS_PO₂ between the two groups. After the 6MWT, the decrease of inspiratory reserve volume (IRV) in hyperinflators was significant higher than those of non-hyperinflators (t=-6.226, P<0.001). In addition, the post-walking V_T was significantly and positively correlated with the resting IC (r=0.293, P=0.004) and post-walking IC (r=0.456, P<0.001).

Table 3 The ventilatory response to walking in DH positive and negative group
Full table

Multiple regression analysis of 6MWD

The univariate analysis of the 6MWD is shown in Table S2. In hyperinflators, age and resting IC were independent predictors of the 6MWD. These two factors contributed 60.1% of the variance for the dependent variable. In non-hyperinflators, age and MMRC dyspnea scale were the predictors of the 6MWD. These factors contributed 86.7% of the variance for the dependent variable (Table 2).

Discussion

There were several significant findings in this study. First, DH was common in the subjects with COPD and was easily detected using IC maneuvers during the 6MWT. Second, FEF_50% was the only predictor of DH during the 6MWT in subjects with COPD. Third, the ventilatory response to the 6MWT differed between hyperinflators and non-hyperinflators. Finally, resting hyperinflation was an important predictor of functional exercise capacity in hyperinflators.

We found that 66.67% of subjects with COPD developed DH during the 6MWT. It indicated that DH was considerably common during the 6MWT for subjects with COPD. We did not observe any adverse events related to the IC maneuvers during the 6MWT, which suggests that performing IC maneuvers during the 6MWT is a simple, safe, and well-tolerated method of detecting DH. In this study, there was no significant difference in the airflow obstruction between hyperinflators and non-hyperinflators. In addition, no obvious correlation was observed between airflow obstruction and the severity of DH. These findings imply that airflow obstruction is a poor predictor of the DH, echoing previous findings by Hannink (20).

Many factors are reportedly associated with the occurrence of DH such as age (21), obesity (22), exertional desaturation (23), smoking history (24), and systemic inflammation, etc. However, few studies have focused on the effect of small airway function on DH. Stewart (25) reported that small airway inflammation and structural damage preceded a marked decrease of airflow obstruction, leading to air-trapping even in mild COPD patients. Interestingly, we also observed DH in subjects with mild COPD. Hence, we speculate that small airway obstruction may be related to DH. In the current study, there was a weak but significantly negative relationship between the small airway function and the extent of DH. Moreover, FEF_50% was the only predictor of the DH severity. Our results suggest that small airway function may be partly responsible for the development of DH in patients with COPD. Further studies are warranted to demonstrate whether interventions to improve small airway function can reduce DH in patients with COPD. We did not observe the relationship between DH and age, BMI, exertional desaturation and smoking index. Zafar et al. (23) reported that DH strongly correlated with exertional desaturation during the 6MWT and could be a reason for this desaturation. Our result did not agree with those of Zafar et al. (23).The inconsistency might be underlain by the exclusion of the subjects with resting S_pO₂ less than 90% in our study. The resting S_pO₂ of our subjects was significantly higher than those of Zafar et al.

Patients with COPD experience increased ventilatory demand during exercise. O’Donnell (26) reported that during a high-intensity exercise test, the occurrence of DH constrains increases in tidal volume (V_T). When close to minimal IRV, further increase of ventilatory demands is satiated through an increase in breathing frequency. However, the shortened expiratory time further exacerbates DH, creating a vicious circle. Our results showed that the post-walking V_T was significantly and positively correlated with the resting IC and post-walking IC, which is consistent with previous findings (26). In addition, we observed a remarkable increase in the post-walking V_T in non-hyperinflators instead of hyperinflators. There was an obvious increase in breathing frequency in both two groups. It indicated that the ventilatory response to the walking test differed between the two groups. In hyperinflators, the increased ventilatory demand was met primarily by the increase of breathing frequency. However, in non-hyperinflators, the increased ventilatory demand was satisfied by increasing both the breathing frequency and V_T. Guenette (27) showed that IRV provided a better index of ventilation than hyperinflation during a high-intensity exercise test. However, we did not observe such relationships. Noticeably, we observed an obvious decrease of IRV at the end of walking in hyperinflators. In contrast, there was no obvious change of IRV in non-hyperinflators. This implied that hyperinflators was prone to appear V_T constraint than non-hyperinflators during the 6MWD. O’Donnell (2) demonstrated that the ΔIC was significantly associated with exercise endurance under controlled laboratory conditions in COPD. In this study, although no obvious correlation was observed between the ΔIC and the 6WMD, both the resting IC and post-walking IC were positively correlated with the 6WMD. This suggests an indirect link between DH and exercise performance. We speculate that the inconsistency between our and previous findings is due to the different modes of exercise. The subjects didn’t reach their maximal exercise capacity and ventilatory response during the 6WMT.

The 6MWT is commonly used to assess functional exercise capacity in patients with COPD. In this study, there was no significant difference in the 6MWD between hyperinflators and non-hyperinflators. However, the regression equation for 6MWD is different between the two groups. Age and resting hyperinflation were the predictors of functional exercise capacity in hyperinflators, while age and MMRC dyspnea scale was the predictors of functional exercise capacity in non-hyperinflators. Our results are consistent with the findings of Callens (6). Potentially, interventions improving resting hyperinflation may improve the exercise capacity in hyperinflators, while interventions to alleviate dyspnea may improve exercise capacity in non-hyperinflators. Additional studies are needed to confirm the hypothesis.

This study has some limitations. First, we did not measure the TLC in all patients; therefore, it is unknown whether the TLC was unchanged during the walking test. Despite this, we measured TLC with plethysmography in five subjects before and after the 6MWT. The results showed no significant changes in TLC. Hence, we supposed that TLC did not change after the 6MWT. Second, the decrease in the IC during exercise was quickly resolved (6). Hence, IC maneuvers after the walking test may actually underestimate the true severity of DH, though in our study, post-walking IC was measured within 60 s after completing the walking test. Third, there was only a weak correlation between small airway function and the level of DH. Nevertheless, the relationship was of significantly statistical significance. Additional studies are required to validate our findings, using more accurate methods to detect small airway function, such as late-phase sputum (28), peripheral airway resistance (29), alveolar nitric oxide concentrations (30), and HRCT (31). Finally, other factors known to be associated with impaired exercise capacity in patients with COPD, such as anxiety, depression, skeletal muscle function (32), and cardiovascular abnormalities (33), were not assessed.

In conclusion, DH was common in patients with COPD and easily detected by performing IC maneuvers during the 6MWT. The FEF_50% was the only predictor of DH during the 6MWT, and the ventilatory response to the 6MWT differed between hyperinflators and non-hyperinflators. Resting hyperinflation is an important predictor of functional exercise capacity in hyperinflators.

Acknowledgements

Funding: This study was funded by the Guangdong Provincial Science and Technology Project (2011B080701062 and 2013B022000072) and Guangdong Natural Science Foundation (S2012010008623).

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

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