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Chronic obstructive pulmonary disease
Lung fluid content during 6MWT in patients with COPD with and without comorbid heart failure
  1. Chun-Ta Huang1,
  2. Sheng-Yuan Ruan1,
  3. Yi-Ju Tsai2,
  4. Jung-Yien Chien1 and
  5. Chong-Jen Yu1
  1. 1Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
  2. 2School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei, Taiwan
  1. Correspondence to Dr Jung-Yien Chien; jychien{at}ntu.edu.tw

Abstract

Background Impact of lung fluid content changing during exercise has not been investigated in chronic obstructive pulmonary disease (COPD). Using a novel point-of-care measurement system (remote dielectric sensing (ReDS) system), we aimed to investigate changes in lung fluid content before and after 6-minute walk test (6MWT); especially, differences between patients with and without comorbid heart failure (HF) were evaluated.

Methods From June 2021 to July 2022, patients with COPD referred for 6MWT were prospectively enrolled. Measurements of lung fluid content by ReDS were conducted before and after 6MWT. Data on demographics, exacerbation history, spirometry and 6MWT were collected. Patients were also assessed for comorbid HF by cardiovascular evaluation. The main variables of interest were pre-6MWT ReDS, post-6MWT ReDS and post–pre ∆ReDS.

Results In total, 133 patients with COPD were included. Comparisons between patients with COPD with and without HF indicated similar pre-6MWT ReDS (26.9%±5.9% vs 26.5%±4.7%; p=0.751), but a significant difference in post-6MWT ReDS (29.7%±6.3% vs 25.7%±5.3%; p=0.002). Patients with COPD without HF exhibited a significant decrease in post-6MWT ReDS (from 26.5% to 25.7%; paired t-test p=0.001); conversely, those with HF displayed a remarkable increase in post-6MWT ReDS (from 26.9% to 29.7%; paired t-test p<0.001). Receiver operating characteristic curve analysis showed an area under the curve of 0.82 (95% CI 0.71 to 0.93) for post–pre ∆ReDS in differentiating between patients with COPD with and without HF.

Conclusions Dynamic changes in lung fluid content prior to and following 6MWT significantly differed between patients with COPD with and without HF. Measurements of lung fluid content by ReDS during exercise testing may be of merit to identify patients with COPD with unrecognised HF.

  • Exercise
  • COPD epidemiology

Data availability statement

Data are available upon reasonable request. The data underlying this article will be shared on reasonable request to the corresponding author.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bmjresp-2023-002000

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • The 6-minute walk test (6MWT) is a valuable tool for assessing physical function in patients with chronic obstructive pulmonary disease (COPD) and heart failure (HF); however, the pathophysiological mechanisms impacting exercise capacity vary between these conditions.

    • The remote dielectric sensing (ReDS) system, an Food and Drug Administration-approved device, non-invasively measures lung fluid content and has demonstrated a strong correlation with CT scans.

    • Observing physiological changes during the 6MWT may provide insights into the identification of coexisting HF in patients with COPD.

    WHAT THIS STUDY ADDS

    • A significant disparity in the dynamic changes of ReDS measurements before and after the 6MWT, observed between patients with COPD with and without coexisting HF, demonstrated promising potential in distinguishing HF among patients with COPD.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • Evaluating lung fluid content with the use of ReDS during the 6MWT could potentially assist in identifying patients with COPD with undiagnosed HF.

    Introduction

    The 6-minute walk test (6MWT) is a submaximal exercise test and a good index of physical function in patients with chronic obstructive pulmonary disease (COPD) and heart failure (HF).1 2 Although both patients with COPD and HF may have impaired exercise performance during 6MWT, manifesting as a decline in the distance walked over a period of 6 min (6-minute walk distance (6MWD)), they are associated with different pathophysiological mechanisms. For instance, airflow limitation, degree of emphysema and air trapping are among the determinants of exercise capacity during 6MWT in COPD.3 4 A lower ejection fraction,5 diastolic dysfunction6 and asynchronous left ventricle5 play a contributing role towards compromising physical performance in patients with HF. Moreover, transient pulmonary congestion during exercise is associated with reduced exercise capacity in HF7; however, increased pulmonary arterial pressure associated with COPD at rest or during exercise could theoretically avoid an increase in alveolar capillary pressure and thus pulmonary congestion.8 9

    The remote dielectric sensing (ReDS) system (Sensible Medical Innovations, Netanya, Israel) is a Food and Drug Administration (FDA)-approved device that can measure lung fluid content in absolute values quickly and non-invasively.10–13 The ReDS system is equipped with two sensors, both emitting and receiving low-power electromagnetic signals, to detect the dielectric properties of tissues in between.10 Previous studies have shown a strong correlation of ReDS readings with lung fluid content measured by CT13 and invasively determined pulmonary artery wedge pressure.14 Further, several studies have demonstrated the value of ReDS measurements in guiding clinical management of patients with HF.11 12 A recent proof-of-concept study showed that the ReDS system is a feasible tool to assess the changes in lung fluid content during cardiopulmonary exercise testing in patients with HF with reduced ejection fraction.15

    HF is a common comorbid illness in patients with COPD, with a prevalence ranging from 20% to 70%.16 Given overlapping clinical symptoms and signs and shared pathophysiological processes, diagnosing HF is not always straightforward but challenging in patients with COPD,17 and unrecognised HF is not uncommon.18 Coexistence of COPD and HF is associated with increased morbidity, poorer quality of life and greater use of health resources.19 Additionally, HF increases COPD-related rehospitalisation and all-cause mortality among patients with COPD.20 21 In view of the diagnostic and prognostic significance of HF in COPD, it is of paramount importance for timely diagnosis and management of HF while taking care of patients with COPD. ECG, plasma natriuretic peptides and echocardiogram, among others, provide some useful information in terms of HF diagnosis. Measurements of physiological changes during exercise testing may also shed some light on recognising coexisting HF in patients with COPD.

    In this regard, the present study aimed to evaluate the changes in lung fluid content during 6MWT by using the ReDS system and investigate the differences between patients with COPD with and without comorbid HF.

    Methods

    Design of the study and subjects

    This prospective observational study was conducted at the National Taiwan University Hospital in Taiwan. From June 2021 to July 2022, patients with spirometry-confirmed COPD who were referred for 6MWT were screened for eligibility in this study. Patients were excluded if they had a Body Mass Index (BMI) <22 or >38 kg/m2, experienced acute exacerbation of COPD or acute decompensated HF in past 3 months, had severe pulmonary hypertension, were diagnosed with pulmonary embolism within past 6 months, had comorbid lung cancer, interstitial lung disease or asthma, underwent any kind of lung resection surgery or did not agree to participate in the research.

    ReDS system

    The ReDS Pro System (Sensible Medical Innovations) was used in this study and its technology has been elaborated previously.10 Briefly, the two sensors used in the ReDS system are affixed to the right anterior and posterior thoracic wall without requiring direct skin contact. These sensors, which are small round devices, have the capability to transmit and intercept energy that is either reflected from or transmitted through the pulmonary tissue. By emitting electromagnetic signals through the right mid-thorax and capturing the signals after they pass through the tissues, the sensors provide information about the combined dielectric properties of the pulmonary tissue. The dielectric coefficient of a material is a complex number that describes its interaction with electromagnetic energy, including absorption, reflection and retention. It varies with frequency, and different tissues have distinct dielectric coefficients. The fluid content plays a crucial role in determining the dielectric coefficient of tissues, as water has a high dielectric coefficient. In the case of pulmonary tissue, its dielectric coefficient is determined by the dielectric coefficients of its components (such as blood, lung parenchyma and air) and their concentrations. Since pulmonary tissue consists of contrasting components, namely fluids and air, its dielectric coefficient is highly sensitive to changes in fluid concentration. This sensitivity forms the basis for the device’s proposed accuracy in detecting pulmonary oedema and monitoring its progression over time.10 The ReDS device along with its operating instructions has been described in detail in a recent paper.22 The ReDS measurement takes only 45 s and the overall procedure can be completed within 5 min in experienced hands. The normal range of the ReDS values for lung fluid content is between 20% and 35% as determined previously,13 and the display range for the fluid content parameter is 15%–60% according to the manufacturer’s user manual.

    6-minute walk test

    The 6MWT was performed based on the American Thoracic Society guidelines.23 The test was supervised by a respiratory therapist with specific expertise. Patients were instructed to walk as far as possible for 6 min and standardised verbal encouragement was given every minute during the test.1 Patients were allowed to rest as needed but were encouraged to resume walking as soon as possible. Patients who required long-term oxygen therapy or had hypoxemia at rest can have their usual oxygen flow. Throughout the exertion, oxygen saturation was monitored via a pulse oximeter (SpO2) with a finger probe. The predicted values for the 6MWD were derived from the age, sex, height and weight based on the equation described by Enright and Sherrill.24 The test result was recorded as an absolute value and per cent predicted.

    Study procedures

    All ReDS measurements were performed while the patients were sitting on the chair by a single manufacturer-certified operator. Before the start of the 6MWT, two successive measurements were obtained and their readings were averaged for data analysis. Similarly, another two measurements were made right after the end of the 6MWT. One study has shown almost perfect intrarater reliability of the ReDS system, with an intraclass correlation of 0.966–0.988.25 The operator was blinded to the clinical information of the study participants.

    Following enrolment, the patients underwent a cardiovascular evaluation to confirm or rule out a diagnosis of HF, characterised by either preserved (>40%) or reduced (≤40%) left ventricular ejection fraction (LVEF). The diagnosis of HF was established based on typical symptoms (eg, dyspnoea, orthopnoea, paroxysmal nocturnal dyspnoea, impaired exercise tolerance and/or ankle oedema) and signs (eg, jugular venous distention, hepatojugular reflux, S3 gallop rhythm and/or laterally displaced apical impulse) of HF. This diagnosis was further supported by radiographic (eg, cardiomegaly and/or pulmonary congestion) and sonographic findings (eg, LVEF ≤40% alone or >40% in conjunction with the presence of LV diastolic dysfunction or elevated LV filling pressure) and an N-terminal pro B-type natriuretic peptide level of ≥300 pg/mL. These diagnostic criteria align with published guidelines.26–28

    Data collection

    Patient demographics, smoking status, body habitus and history of exacerbations were collected. The BMI was used as an estimate of body habitus. History of exacerbations in past year was obtained but only moderate to severe exacerbations were recorded.29 Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were retrieved from the spirometry results, and patients were categorised as GOLD 1, 2, 3 and 4 based on the severity of airflow limitation using the per cent predicted FEV1.29 Measurements during the 6MWT included the 6MWD, per cent predicted 6MWD and nadir SpO2. The main variables of interest in this study were the readings of pre- and post-6MWT ReDS and the post–pre differences (∆ReDS).

    Patient and public involvement

    None.

    Statistical analysis

    Numerical variables were reported as means±SDs. Categorical variables were reported as numbers (percentages). Between-group comparisons were conducted by the independent sample t-test, χ2 test or Fisher’s exact test where appropriate. Within-group comparisons were made using the paired t-test. A waterfall plot was used to illustrate the changes in ReDS values prior to and following the 6MWT in patients with COPD with and without HF. The correlation between the 6MWD and post–pre ∆ReDS was assessed using Pearson’s correlation coefficient. Receiver operating characteristic (ROC) curve analysis was applied to evaluate the discriminative value of ReDS measurements, including pre- and post-6MWT ReDS and post–pre ∆ReDS, for differentiating the presence and absence of HF in patients with COPD. The optimal cut-off was defined by the Youden Index,30 and the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were computed accordingly. All analyses were performed in SPSS Statistics V.20.0 software (IBM Corp, Armonk, New York, USA) and two-tailed p values <0.05 were assumed statistically significant.

    Results

    Study population

    The study flow diagram is depicted in figure 1. In total, 133 patients with COPD were included for analysis, with a mean age of 72 years and male predominance (70%). The average FEV1/FVC ratio was 52% and postbronchodilator FEV1 was 62% predicted. The percentage of patients in GOLD 1, 2, 3 and 4 was 23 (N=30), 44 (N=59), 29 (N=38) and 5 (N=6), respectively. The baseline characteristics of patients with COPD with and without HF were similar in our cohort (table 1).

    Figure 1
    Figure 1

    Study flow diagram. 6MWT, 6-minute walk test; COPD, chronic obstructive pulmonary disease; HF, heart failure; ReDS, remote dielectric sensing.

    View this table:
    Table 1

    Characteristics of patients with COPD

    Measurements of 6MWT and ReDS

    The mean distance walked in 6 min was 372 m or 80% predicted among the population with COPD (table 2). The 6MWD was shorter in patients with COPD with HF compared with those without (332 m vs 381 m; p=0.047). The per cent predicted 6MWD was also lower in patients with HF compared with those without HF (73% vs 82%; p=0.049). The nadir SpO2 was similar between the two patient groups.

    View this table:
    Table 2

    6-minute walk test and remote dielectric sensing measurement

    Prior to the 6MWT, the mean value of ReDS measurements was 26.6% in all patients with COPD, without significant difference between those with and without HF (table 2). However, the post-6MWT ReDS value was significantly greater in patients with COPD with HF than those without (29.7% vs 25.7%; p=0.002). The average change in ReDS measurements before and after the 6MWT was also evidently varied between patients with and without HF (2.9% vs −0.8%; p <0.001). Among patients with COPD without HF, the post-6MWT ReDS value significantly decreased from 26.5% to 25.7% (paired t-test p=0.001); conversely, in those with HF, the post-6MWT ReDS value evidently increased from 26.9% to 29.7% (paired t-test p <0.001). A waterfall plot is used to illustrate the changes in ReDS values pre- and post-6MWT (figure 2). In patients with COPD with HF, we observed a moderate negative correlation of post–pre 6MWT ∆ReDS with 6MWD (Pearson r = –0.469; figure 3A) and per cent predicted 6MWD (Pearson r = –0.480; figure 3B). However, the correlations were negligible in those without HF (figure 3C,D).

    Figure 2
    Figure 2

    Waterfall plot of changes in ReDS measurements before and after the 6-minute walk test. ReDS, remote dielectric sensing.

    Figure 3
    Figure 3

    Relationship between dynamic changes in ReDS measurements before and after the 6-minute walk test (6MWT) and 6MWD (A, C) and 6MWD, % predicted (B, D) in patients with chronic obstructive pulmonary disease with (A, B) and without heart failure (C, D). 6MWD, 6-minute walk distance; ReDS, remote dielectric sensing.

    Discriminative value of ReDS in HF

    ROC curve analyses revealed an area under the curve for pre-6MWT ReDS of 0.51, post-6MWT ReDS of 0.69 and post–pre 6MWT ∆ReDS of 0.82 to detect comorbid HF (figure 4). The optimal cut-off by Youden Index for post–pre ∆ReDS was >2%, with sensitivity, specificity, PPV and NPV of 61%, 91%, 58% and 92%, respectively (table 3).

    Figure 4
    Figure 4

    Receiver operating characteristic curves for ReDS measurements prior to and following the 6-minute walk test and their dynamic changes in the detection of heart failure. Area under the curve is 0.51 (95% CI 0.36 to 0.65) for ReDS, pre-6MWT, 0.69 (95% CI 0.57 to 0.80) for ReDS, post-6MWT and 0.82 (95% CI 0.71 to 0.93) for ∆ReDS, post–pre 6MWT. 6MWT, 6-minute walk test; ReDS, remote dielectric sensing.

    View this table:
    Table 3

    Sensitivity, specificity, PPV and NPV by different cut-offs to detect the presence of heart failure

    Discussion

    This is the first study to assess the change in lung fluid content during submaximal exercise in patients with COPD and to evaluate its discriminative value for recognising comorbid HF. The main findings are summarised as follows: (a) patients with COPD with HF performed worse in the 6MWT compared with those without HF; (b) post-6MWT, but not pre-6MWT, ReDS measurements differed between patients with COPD with and without HF; (c) following the 6MWT, the ReDS value significantly decreased in patients without comorbid HF; on the contrary, it evidently increased in those with comorbid HF; (d) the post–pre 6MWT ∆ReDS had a good discriminative power to distinguish between patients with COPD with and without HF. In summary, point-of-care measurements of lung fluid content during the 6MWT using the ReDS system are feasible and useful for detecting comorbid HF in patients with COPD.

    Compared with COPD alone, coexisting COPD and HF are associated with a lower work rate, peak oxygen uptake, circulatory power and ventilatory power during incremental cardiopulmonary exercise testing.31 Comorbid HF introduces amplified negative impact of exercise testing on cerebral blood flow and oxygenation in COPD.32 Moreover, HF exerts adverse respiratory consequences in COPD, which, conversely, induces negative cardiocirculatory effects in HF.33 All these physiological alterations may explain the worse exercise intolerance associated with concomitant COPD and HF. In consistent with aforementioned studies, our findings showed that patients with COPD with HF walked a significantly shorter distance than those without HF during the 6MWT, indicating again the importance of recognising a failing heart in patients with COPD.

    The assessment of lung fluid content during the 6MWT in COPD is a novel application of the ReDS system. The present study showed that this was clinically feasible and ReDS measurements could promptly reflect the short-term physiological response to exercise. A proof-of-concept study by Imamura et al15 also demonstrated the feasibility of the ReDS to assess the change in lung fluid content during cardiopulmonary exercise testing in patients with HF with reduced ejection fraction. In that particular study, the ReDS values showed a numerical increase from 27% to 28% following exercise testing among patients with HF.15 However, it is important to note that this increase was not statistically significant. It is worth mentioning that the study had a relatively small sample size, with only 13 subjects included and analysed.15 In comparison, our patients with COPD with HF showed an increased ReDS value after the 6MWT, suggesting an increase in lung fluid content in response to exercise. Our study results are supported by a recent paper in which exercise elicited an increase in extravascular lung water in patients with HF.34 The exact physiological mechanisms underlying the discrepancy are uncertain but may be partly explained by the differences in patient demographics (41 years vs 74 years), main disabilities (HF vs COPD plus HF) and modalities for exercise testing (cardiopulmonary exercise testing vs 6MWT) in Imamura’s and our studies,15 respectively. Undoubtedly, more comprehensive physiological studies are needed to elucidate the precise mechanisms.

    Interestingly, for the first time, we showed that patients with COPD without HF had significantly decreased lung fluid content following the 6MWT. Patients with COPD frequently develop a high expiratory pressure during exercise,35 which could result in a reduction in venous return and pulmonary capillary blood volume.36 We speculate that these physiological responses to exercise may be associated with diminished lung fluid observed in our study, although more complicated cardiorespiratory regulatory mechanisms are supposed to be involved. Moreover, from a practical point of view, the clinical implication and physiological role of the statistically significant but trivial decrease in lung fluid content are also to be pursued in further studies.

    An important and interesting finding from this study is that the dynamic change in lung fluid content prior to and following 6MWT significantly differed between patients with COPD with and without comorbid HF. In addition, the post–pre 6MWT ∆ReDS displayed a good discriminative value in identifying HF among patients with COPD. In view of the point-of-care, useful information provided non-invasively by the ReDS system and the diagnostic and prognostic implications of HF in COPD,18 37 peri-exercise monitoring of lung fluid content may be a valuable screening tool to detect comorbid HF in patients with COPD. Another well-known cardiac biomarker, B-type natriuretic peptide (BNP), also responds promptly to short-term physical exercise in healthy subjects and patients with HF,38 39 and is of potential value in this regard. However, increased BNP levels immediately after the 6MWT can be observed in diseases other than HF, such as pulmonary arterial hypertension.40 Concomitant measurements of the ReDS and BNP before and after exercise testing in patients with COPD may shed more light on this field.

    One might wonder about the clinical applicability and validity of ∆ReDS >2% before and after the 6MWT in identifying patients with COPD with HF. In this regard, the reproducibility of ReDS measurements becomes a crucial issue. Thankfully, a recent study by Hori et al25 has demonstrated an almost perfect agreement between repeated ReDS measurements. Consequently, a >2% change in ReDS values should be deemed clinically meaningful and applicable in daily practice.

    In our study, the clinical relevance of the ReDS measure suggests its potential for widespread use, for several reasons. First, the ReDS machine’s compact and portable design allows for its operation in various locations.14 41 Second, the cost-effectiveness is evident as, beyond the initial investment in the machine, no additional expenses are incurred during its operation. Furthermore, it requires only a few hours for healthcare providers and even patients to acquire the necessary technical expertise and obtain the manufacturer’s certification required to operate the machine.11 Lastly, each ReDS measurement can be completed within a few minutes, making it a time-efficient tool for clinical practitioners with demanding schedules.14 41

    A few limitations to this study should be mentioned. First, this is a single-centre experience and collaborative multicentre studies are needed to validate our findings and extend the generalisability. Nonetheless, as a pioneer study on this subject, our work will inspire more researchers to dedicate themselves to similar studies. Second, the majority of patients with COPD enrolled in our study were aged population and the results may not be applicable to younger age groups. However, the prevalence of COPD, HF and their coexistence are increasing with age, and the diagnostic challenge is particularly pronounced in an aged society, like Taiwan. Thus, our findings may still deliver the most clinically relevant information for clinicians in an era of global ageing. Third, we applied strict exclusion criteria, as used in previous studies, in order to select appropriate candidates for accurate ReDS measurements. Since the most important feature to differentiate patients with COPD with HF from those without is the within-subject change of peri-exercise ReDS measurements, the application of our study results to those patients with COPD with certain exclusion criteria, such as lung resection surgery or comorbid lung cancer, can be anticipated. Undoubtedly, more works are needed to solve this issue.

    In conclusion, the ReDS system is a feasible, point-of-care technology that can be applied during the 6MWT in patients with COPD. Via measurements of dynamic changes in lung fluid content by the ReDS before and after exercise testing, it can help differentiate between patients with COPD with and without HF. In other words, peri-exercise ReDS measurements may be of merit to identify patients with COPD with unrecognised HF.

    Data availability statement

    Data are available upon reasonable request. The data underlying this article will be shared on reasonable request to the corresponding author.

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study proceeded in accordance with the Declaration of Helsinki and the protocol was approved by the Research Ethics Committee of the National Taiwan University Hospital (202104093DIPA). Participants gave informed consent to participate in the study before taking part.

    Acknowledgments

    We thank the staff of the Eighth Core Lab, Department of Medical Research, National Taiwan University Hospital, for technical support during the study. We also thank Ms Yu-Chen Hsieh for the technical assistance. This study was partially presented at the 2022 Annual Congress of the Taiwan Society of Pulmonary and Critical Care Medicine in

    Kaohsiung, Taiwan.

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    Footnotes

    • Contributors C-TH and J-YC have significantly contributed to the conceptualisation and design of the study, with J-YC acting as the guarantor. S-YR, Y-JT and C-JY have played key roles in the analysis and interpretation of data, as well as revising the manuscript to enhance its intellectual content. C-TH has been responsible for data collection and the initial drafting of the manuscript. J-YC has provided administrative support and supervision throughout the study. All authors have participated in the development of this manuscript and concur with the findings presented. They also confirm that the work is original, has not been previously published and is not currently under consideration for publication elsewhere.

    • Funding This study received partial support from the Ministry of Science and Technology, Taiwan (MOST 111-2314-B-002-201-MY3).

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.