Measurements

Subject characteristics and severity of complaints as age, gender, weight, body mass index (BMI), Charlson Comorbidity Index [21], fat-free mass index, modified Medical Research Council (mMRC) [22], COPD Assessment Test [23], Hospital Anxiety and Depression Scale [24] and Checklist Individual Strength Fatigue [25] were systemically assessed.

Statistical analysis

Statistical analyses were performed using SPSS statistical software program (IBM, New York, USA), version 25.0. Descriptive data were presented as mean ± SD, median (interquartile range 25–75%) or number of patients (percentage), as appropriate. Based on the ESWT Tlim, the subjects were divided into three groups (group 1: <3 minutes, group 2: 3–8 minutes, group 3: >8 minutes). These cut-off points were chosen to reflect the desirable ESWT duration of 3 to 8 minutes [15]. Accordingly, in the results section we focussed on differences in groups 1 and 3 compared to group 2.

Between-groups comparisons for continuous variables were tested by one-way analysis of variance (ANOVA) or Kruskal-Wallis test, as appropriate. Categorical variables were tested with a Chi-square test. When a statistically significant difference was obtained, a pairwise post-hoc test was performed and Bonferroni post-hoc testing was applied to correct for multiple comparisons. A p-value of <0.05 was considered significant.

Univariate and multivariate linear regression models were used to evaluate the association of pulmonary function, physical and ISWT performance variables with the ESWT Tlim. Univariate linear regression models were built using the ENTER method. Explanatory variables with a p-value <0.20 and not strongly correlated (r <0.8) with another variable of interest were used to build a multivariate linear regression model, using the backward method. Variables with a p-value <0.05 in the multivariate linear regression model were considered as independent predictors of ESWT Tlim.

Subgroup characteristics

Gender, BMI, fat free mass index and Charlson Comorbidity Index were similar between groups. Patients in group 3 were younger (59.4±8.6) than patients in group 2 (62.4±7.2, p = 0.021). The severity of dyspnea sensation, as reflected by the mMRC score, was lower in patients from group 3 (median 2(1–3) and mean 1.8±1.2) than group 2 (median 2(1–3) and mean 2.2±1.2, p = 0.006). There were no differences in severity of complaints, COPD Assessment Test, Hospital Anxiety and Depression Scale and Checklist Individual Strength Fatigue scores, between the groups (Table 1).

ISWT performance parameters.

The median ISWT distance of all patients was 280 (200–390) meters. Group 1, 2 and 3 walked 205 (173–328) meters, 285 (200–380) meters and 320 (213–438) meters, respectively. Patients in group 1 desaturated more during the ISWT than group 2 (all p-values <0.001). Furthermore, these patients had a higher rest and maximal dyspnoea Borg score in comparison to group 2 (p<0.001, p = 0.011, respectively). Although the HR before and at the end of the ISWT was comparable between the three groups, the maximal HR during ISWT in ratio to the maximal HR reached during CPET (HRmax_ISWT/HRmax_CPET) was lower in patients from group 3 than in patients from group 2 (p = 0.002). Other ISWT performance parameters were not significantly different for group 1 and 3 in comparison to group 2 (Table 2).

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Table 2. ISWT performance parameters of the whole group and the three subgroups based on tolerated duration during the ESWT.

https://doi.org/10.1371/journal.pone.0249786.t002

ESWT Tlim highly variable

A large interindividual variability in ESWT Tlim was illustrated by the notion that half of the patients with COPD performed the ESWT outside the desired duration of 3–8 minutes. Furthermore, a required termination of the test was needed in 17% of the patients as they reached the maximum test duration of 20 minutes, but probably could have walked even longer. This large interindividual variability is in accordance with a recent study of Maltais et al., who investigated the responsiveness of the ESWT to bronchodilation [13]. In their analysis the authors were urged to exclude patients that had a baseline ESWT Tlim of more than 15 minutes to allow measurable room for improvement on a post-intervention ESWT. So, high interindividual variability in ESWT Tlim requires a larger number of participants in clinical studies to detect an effect of interventions. The interpretation of intervention efficacy is even more complicated as the potential effect size (i.e. post–pre intervention) of ESWT Tlim depends on the pre-intervention ESWT Tlim due to the hyperbolic nature of the load-duration relationship [12]. Therefore, in a population with a high interindividual variability in ESWT Tlim, individual effects of interventions are difficult to compare [12, 14, 15]. The best solution to reduce this variability is to determine the load-duration relationship in every individual. However, this is clinically impractical because it requires the completion of several ESWT tests at various intensities. Another possibility is to perform a second ESWT at an adjusted pace in patients with an ESWT Tlim <3 or >8 minutes. However, the size of the adjustment in pace has not been determined yet and a second ESWT is not always possible due to practical reasons like time constraints. Therefore, it is important to search for other possibilities to reduce the variability in ESWT Tlim. One option would be to better predict the ESWT Tlim prior to its performance in order to individually adjust the ESWT pace with clinical available measures. Therefore, this study further investigated correlates of ESWT Tlim variability.

Pulmonary function and physical performance parameters

Patients performing the ESWT longer than 8 minutes had a higher physical capacity and activity in comparison to group 2. In addition, exercise tolerance obtained by CWRT was also positively related to the ESWT Tlim. On the other hand, patients that could not sustain the ESWT for at least 3 minutes, were characterized by a lower FEV₁ (L) than patients in group 2 and several pulmonary function measures were negatively associated with ESWT Tlim. Pulmonary dysfunction is a well-known contributor to exercise intolerance in patients with COPD [10, 11]. In short, ventilatory capacity is limited by airflow obstruction and hyperinflation, which may even exacerbate during exercise. On the other hand, ventilatory demand in patients with COPD may be increased as a result of abnormal pulmonary gas exchange, increased work of the respiratory muscles and early lactate production in the peripheral muscles [16, 37–40]. This leads to increased sensations of dyspnoea during exercise and explains why the severity of pulmonary dysfunction is related to the ability to sustain a certain exercise load [37, 38]. However, it should be stressed that the load of the ESWT is normalized for maximal exercise capacity, as ESWT pace is individually set at 85% of maximal ISWT pace. Despite this normalization, pulmonary function, physical capacity and physical activity are still related to the time patients can sustain this individually assessed pace. This suggests that the load-duration relationship is affected by these measures. The load-duration relation is described by two parameters; the critical load and the curvature constant [10–12]. Neder et al. previously reported that both parameters are reduced in patients with COPD in comparison to healthy controls [11]. The results of the current study suggest that even within the COPD population, critical load and the curvature constant might be influenced by pulmonary function, physical capacity and physical activity.

Thus, the current findings suggest that, in addition to maximal ISWT pace, measures of pulmonary function, physical capacity and physical activity, if clinically available, might be helpful to more adequately set ESWT pace. It appears that patients with more severe airway obstruction should be set at paces slower than 85% of maximal pace and patients with higher physical capacity and activity levels at paces faster than 85% of maximal pace. However, exact cut-off values and sizes of adjustment should be explored in future studies.

ISWT performance parameters

Because ESWT pace is based on maximal ISWT speed, it is essential that the ISWT is performed with maximal effort and using a standardized operating procedure. Therefore, we investigated performance measures obtained during ISWT. In contrast to healthy individuals, the exercise capacity of most patients with COPD is not limited by cardiac output [37]. So maximum HR during ISWT cannot be used to establish maximal effort in patient with COPD. Accordingly, we examined ISWT HR in ratio to the maximum HR obtained during CPET, i.e. HRmax_ISWT/HRmax_CPET. We found that this ratio was significantly lower in patients that displayed an ESWT Tlim >8 minutes (group 3). Furthermore, the ratio was negatively associated with ESWT Tlim. This indicates that some patients with an ESWT time >8 minutes might have performed sub-maximally on their ISWT. A longer ESWT Tlim was also associated with a reduced increase of perceived leg fatigue during ISWT. Although this is a subjective measure, it is in line with a sub-maximal effort during the ISWT. A more objective indication of maximal effort can be provided by additional physiological measures like minute ventilation, oxygen consumption and/or blood lactate values [31], but these would make the ISWT less accessible and more expensive. Our data suggest that if maximal attained HR during CPET is available it can be used together with simple non-invasive measurement of HR during ISWT to provide an estimation of ISWT effort.

Additionally, patients with a shorter ESWT Tlim desaturated more during the ISWT than patients with a longer ESWT Tlim, which was also reported during the ESWT. This might suggest that patients who desaturate more during the ISWT should perform the ESWT at a lower relative load than 85%.

Predicting ESWT

Because our data showed that several clinically obtained measures significantly correlated with ESWT Tlim, we further investigated if a model could be built to predict ESWT Tlim. Based on a multivariate linear regression model, BMI, VO₂max, CWRT time, physical activity, ISWT speed, dyspnoea Borg score at rest and delta leg fatigue Borg score during ISWT were identified as independent predictors of ESWT Tlim. Although each of these parameters significantly contributes to ESWT Tlim variability, the total explained variance is only ~30%. Therefore, it is important to evaluate additional factors that might be associated with ESWT Tlim. For example, dynamic hyperinflation and reduced leg muscle endurance are known to frequently occur in patients with COPD and affect exercise tolerance independent of the severity of pulmonary dysfunction [2, 39, 41–43]. Further research is necessary to assess if these or other factors could improve the accuracy of predicting ESWT Tlim. Eventually, a proper prediction model with clinical available measures might help clinicians to identify patients that are expected to reach an ESWT Tlim outside the desired timeframe of 3–8 minutes [44] and to decide if ESWT pace should be set a different level than 85% of maximal ISWT pace.

Study limitations

In our design ESWT pace was based on patients’ maximal pace obtained from one ISWT. Because Dyer et al. reported a learning effect in a second ISWT [45], two ISWT tests are recommended when the ISWT is used to measure change over time or interventions [19]. However, when ISWT is only used to set ESWT pace, one test has been postulated to be sufficient [46]. Although we expect that performing two ISWT’s prior to ESWT might reduce the interindividual variability, it does not necessarily eliminate the need of a second ESWT in all patients. Furthermore, two ISWT’s would increase the amount of tests in all patients, while our data show that with one ISWT half of the patients perform their ESWT within the desired duration of 3–8 minutes.