Dynamic hyperinflation induced by the 6-minute pegboard and ring test in hospitalized patients with exacerbated COPD.

BACKGROUND: The six-minute pegboard and ring test (6-PBRT) has been used to evaluate functional capacity of the upper limbs in stable chronic obstructive pulmonary disease (COPD) patients. To the best of our knowledge, no studies have evaluated dynamic hyperinflation (DH) during exercise with upper limbs in the hospital setting. The aim of this study was to evaluate physiological responses and DH induced by 6-PBRT in hospitalized patients with acute exacerbation of COPD (AECOPD).
METHODS: A cross-sectional study was conducted in a tertiary hospital enrolling patients who were hospitalized due to AECOPD. All included participants underwent an evaluation of lung function and 6-PBRT when they reached minimum clinical criteria. Ventilatory and hemodynamics parameters were monitored during 6-PBRT and until 6 minutes of rest after the test. Symptoms of dyspnea and upper limb fatigue were also measured.
RESULTS: Eighteen patients (71.3±5.1 years) with a mean FEV1 of 43.2±18.3% were included in the study (11 females). Prevalence of DH after 6-PBRT was 50% (considering the drop of 150 ml or 10% of inspiratory capacity, immediately after the end of the test). There was a significant increase in respiratory rate, minute volume, dyspnea, and upper limb fatigue after the end of 6-PBRT (p<0.05). Dyspnea recovered more precociously than the perception of fatigue, being reestablished within four minutes of rest. An increase in heart rate, systolic and diastolic blood pressures was also induced by 6-PBRT (p<0.05), requiring 6 minutes of recovery to return to baseline. No adverse events were observed during 6-PBRT. We concluded that 6-PBRT induces physiological changes during its execution, at safe levels, requiring a maximum of 6 minutes for recovery. Finally, the test proved to be safe and applicable for patients hospitalized due to AECOPD.

Introduction

Chronic obstructive pulmonary disease (COPD) is an important cause of morbidity and mortality in the world and represents a large proportion of users of the health system [1]. The natural course of the disease is punctuated by aggravation episodes, known as exacerbations, leading to deterioration and mortality associated with the disease [2, 3]. Acute exacerbation of COPD (AECOPD) contributes to worsening lung function and symptoms [3], reduced activities of daily living (ADL) [4], altered muscle function [5], a substantial decline in functional status [4, 6] and quality of life [1], and increased morbidity and mortality [1, 5].

Ventilatory impairment continues to be the main factor limiting exercise capacity for most patients. Increased ventilator demand during physical activity may hyperinflate patients with COPD due increased functional residual capacity (FRC) and decreased inspiratory capacity (IC) [7]. Exercise intolerance involving upper limbs is due to increased ventilator and metabolic demand, development of dynamic hyperinflation, and thoracoabdominal asynchrony during these activities [8-10]. It is assumed that such changes are responsible for the greater sensation of fatigue and dyspnea leading to early interruption during activities, simple ADLs of self-care, such as eating, personal hygiene, bathing, washing hair, and getting dressed [11], especially those performed without support [12].

Some tests have been described in the literature and are recognized as simple, valid and reproducible for assessing the functional capacity of upper limbs in stable COPD, such as the Unsupported Upper Limb Exercise Test (UULET) [13], Grocery Shelving Task (GST) [14] and 6-minute pegboard and ring test (6-PBRT) [15]. The 6-PBRT is the most commonly used and was first described by Celli et al. [16]. The relationship between 6-PBRT and parameters of pulmonary function [15, 17], strength and endurance of upper limbs [18, 19], incremental upper limb test [18], and upper-extremity physical ADLs [17] has been demonstrated in patients with stable COPD. In addition, 6-PBRT has also been used to show the efficacy of upper limb exercise training programs [20] since its responsiveness has already been documented [18, 21].

However, these authors did not assess inspiratory capacity reduction and the development of dynamic hyperinflation following 6-PBRT. Recent studies have observed the development of dynamic hyperinflation (DH) after an increase in load during exercise with cycle ergometer for upper limbs in patients with COPD [22] and the direct influence of exercise modality with upper limbs on the occurrence of dynamic hyperinflation [8]. Despite this safety and applicability, to date, there are no studies that have evaluated DH during 6-PBRT in hospitalized patients with AECOPD.

Considering that ventilatory limitation, characterized by dynamic hyperinflation, is an important cause for the interruption of physical activity, it is necessary to know the tests to evaluate the functional capacity at the time of AECOPD, as well as their applicability and safety in the hospital setting, and thus in the future guide pulmonary rehabilitation programs focusing on upper limb training in the hospital phase. Therefore, this study aims to evaluate ventilatory and hemodynamic responses; to verify the prevalence of dynamic hyperinflation during the 6-minute pegboard and ring test (6-PBRT); and also to evaluate the safety and applicability for hospitalized patients for an acute exacerbation of COPD.

Materials and methods

Ethics and participants

We conducted a cross-section study on hospitalized patients with exacerbated COPD at Hospital Sírio-Libanês from July 1, 2015 to July 30, 2016. The sample was obtained consecutively, and patients of both genders were recruited, admitted at the hospital for treatment of AECOPD. Inclusion criteria were as follows: 1) patients with previous diagnosis of COPD before hospitalization [1]; 2) patients with exacerbated COPD classified as level II according to the American Thoracic Society (ATS) and the European Respiratory Society (ERS) [23]; 3) without cognitive or motor deficit observed from the initial evaluation which limited the performance of the tests; 4) absence of heart or other pulmonary disease previously diagnosed by the patient’s physician; 5) patients who had not undergone recent thoracoabdominal surgery within one month; 6) body mass index <35 kg/ m2; 7) age <85 years; and 8) without use of vasoactive drugs. The following exclusion criteria were considered: 1) inability to perform the evaluations within the criteria of technical acceptability according to methodological description and 2) cardiorespiratory instability during the tests (intense dyspnea, arrhythmias, angina, elevated heart rate above 80% of maximal heart rate predicted by age and peripheral oxygen saturation below 88% refractory to oxygen supplementation). All participants included in the study signed the Informed Consent Term, previously approved by the Ethics Committee of the Hospital Sírio-Libanês (number HSL2014-66).

Study design and experimental procedures

Patients in the present study underwent to an evaluation protocol performed on a single day. The protocol was applied as soon as the patients presented the following minimum clinical criteria: use of noninvasive mechanical ventilation for less than 2 hours per period of 6 hours, resting dyspnea less than 7 (very intense) on the modified Borg scale, respiratory rate less than 25 incursions per minute, SpO2 greater than 88% (considering the use of oxygen supplementation) and absence of a paradoxical respiratory pattern. All the patients performed the pulmonary function test and 6-PBRT. Two specific questionnaires related to lung disease were applied to the patients: one of the influence of dyspnea and fatigue in the ADL—the Pulmonary Functional Status Dyspnea Questionnaire (PFSDQ-M). This questionnaire is composed of three domains: dyspnea influence on ADLs, influence of fatigue on ADLs, and change in ADLs in comparison to the period before the disease onset [24]. Upper-extremity ADLs were assessed using PFSDQ-M specific to patients with COPD and validated for the Brazilian population [25]; and another on the impact of COPD symptoms—the COPD Assessment Test (CAT), using a validated version for the Brazilian population [26]. Anthropometric data, personal antecedents and life habits of each participant were also collected. Medical treatment was carried out according to local guidelines and included steroids, antibiotics, oxygen, and bronchodilators. Individual doses of each were titrated, and the decisions about admittance and discharge were made by the physician, who was not involved with the study protocol.

We requested that the short-term bronchodilator should not be performed 2 hours before the tests ensuring that similar conditions were established for all patients during the tests. Pulmonary function test was performed according to international guidelines using a portable spirometer (Koko pulmonary function testing model; nSpire Health Company, Longmont, CO, USA) previously calibrated. At least three acceptable maneuvers and two repeatable maneuvers were performed. The highest values obtained for each of the spirometric variables were considered, which were expressed in absolute and in percentage of the expected values of normality according to the methods and criteria recommended by the ATS and ERS. [27]. The 6-PBRT was used for assessment of functional capacity of upper limbs. The test consisted of moving the rings from the on one level to the other two pins fixed on a higher level on a vertical support. Two pins were positioned at shoulder height and the other two 20 cm above the shoulder level. A total of 10 rings (weighing 50 g each) were placed on each lower pin. Participants were instructed to use both hands simultaneously and move the rings from the lower level to the upper level. After placing all the rings on the upper level, participants were asked to move the rings to the lower level and so on. This cycle should be repeated as often as possible in 6 minutes. The final score was the total number of rings moved. The test could be stopped if there was intense dyspnea, fatigue or any other serious discomfort, and participants were encouraged to retake the test as soon as possible, without the timer being stopped. The evaluator encouraged participants to use standardized phrases every minute during the test, following the ATS recommendations [28, 29]. Briefly, individuals were instructed to use both hands simultaneously and move the rings from the lower level to the upper one on a vertical support. After positioning all the rings on the upper level, the subjects repositioned the rings on the lower level and so on. The individual was instructed to repeat the cycle as many times as possible in 6 minutes, the final score being the total number of rings displaced. Ventilatory and hemodynamics parameters were monitored during 6-PBRT and until six minutes of rest after the test. Dyspnea and fatigue of upper limbs were also measured using the Modified Borg Scale.

Dynamic hyperinflation assessment

Dynamic Hyperinflation (DH) was evaluated by means of serial inspiratory capacity (IC) measurements by the slow vital capacity maneuver. The maneuvers were performed at rest, immediately after the test and every two minutes after the end of the 6-PBRT, up to a total time of six minutes. Minute volume was evaluated before and after the 6-PBRT. Assessments were performed using a hand-held portable spirometer (Spiropalm 6MWT; Cosmed, Rome, AL, Italy), with a silicon face mask coupled to the patient by means of a headcap and an elastic belt. DH was defined as a decrease in IC at the end of the 6-PBRT, of at least 150 ml or a decrease of 10%, compared to the IC obtained at rest () [22, 30].

Symptoms, ventilator and hemodynamics measurements during and after 6-PBRT.

Abbreviations: 6-PBRT, six-minute pegboard and ring test; DH, dynamic hyperinflation.

Feasibility and safety

In order to evaluate the feasibility of the test, we verified the time of assembly and displacement of the device to the destination unit where the patient was hospitalized and the frequency of patients who were able to perform the test according to their standardization.

Regarding safety, the following adverse events were considered: desaturation during exercise (SpO2 <85), loss of access (central or peripheral), loss of nasoenteral tube, dizziness, headache, hypotension (MAP <65 mmHG), angina, tachycardia (HR >80% of maximal HR), bradycardia (HR <50 bpm), muscular or limiting joint pain, severe dyspnea (modified Borg scale > 8), hypertension (MAP >120 mmHg) and intense sweating.

Statistical analyses

A statistical package (SigmaPlot 11.0; Systat Software Inc.) was used for the statistical analysis of the data. Data distribution was analyzed by the Shapiro-Wilk test. According to normality in data distribution, data were described as mean and standard deviation or median and interquartile range. Comparison of IC, modified Borg scale, respiratory rate, SpO2, HR, systolic blood pressure and diastolic blood pressure measured before, immediately after, and every two minutes after the 6-PBRT was performed by the simple variance analysis (repeated measures ANOVA) test. The comparison of variables between the group of patients who presented DH and did not present DH during 6-PBRT was performed using Student's t test (parametric data) and Wilcoxon (non-parametric data). For all tests, p <0.05 was considered statistically significant. Based on the results of the study by Colucci et al. (2010), who found a difference in inspiratory capacity values obtained before and after exercise of upper limbs of 290 ± 220 ml and estimating to observe a similar effect, using a 5% error (test power = 80%), it was necessary to include 17 patients in the study.

Results

A total of 73 hospitalized patients with exacerbated COPD were screened: 41 patients did not meet the inclusion criteria, 12 patients refused, and 2 patients dropped out of the study. The final sample consisted of 18 individuals ().

Screening flow chart.

Abbreviations: AECOPD, acute exacerbation of chronic obstructive pulmonary disease.

The performance in 6-PBRT was worse in patients with AECOPD (244.88 ± 63.20 number of rings moved) when compared to the average of expected reference values for normal population (375.44 ± 21.63 predicted number of rings moved) (p < 0.001) [31]. Patients who hyperinflated in the test performed worse when compared to those who did not hyperinflate (230.22 ± 68.56; 259.55 ± 57.49 respectively), however this result was not significant (P = 0.34).

The demographic and spirometric characteristics of the 18 patients are shown in

Ventilatory responses during and after 6-PBRT

There was a reduction in IC in the post-test evaluation but with no significant difference (p>0.05). However, when we analyzed the patients individually, we observed that nine patients (50%) presented DH during 6-PBRT (reduction of 150ml or 10% in the inspiratory capacity). We also observed that after six minutes at the recovery phase, only three patients (16.6%) still fulfilled the criteria for DH ().

Serial IC measurements during and after 6-PBRT (repeated measures ANOVA).

Abbreviations: NS, not significant; IC, inspiratory capacity; L, liters; 6-PBRT, six-minute pegboard and ring test; min, minutes.

Patients presented an increase in respiratory rate after the test (p = 0.04), recovering completely with/within 2 minutes of rest. Regarding the minute volume, we observed a statistically significant change (p = 0.02) when comparing basal values and the values immediately after the end of the test (). There was no difference in peripheral oxygen saturation during and after 6-PBRT (p>0.05).

Respiratory rate and minute volume responses.

Abbreviations: cpm, cycles per minute; 6-PBRT, six-minute pegboard and ring test; NS, not significant; L, liters; min, minutes; * significant difference when compared to basal values.

Hemodynamic responses during and after 6-PBRT

We observed a significant increase in HR immediately after the test (p<0.0001). For systolic blood pressure (SBP), we observed statistically significant differences immediately after the end of 6-PBRT (p<0.0001) and in the second minute of recovery after the test (p = 0.02). Finally, for diastolic blood pressure (DBP), we observed a statistically significant difference only immediately after the test (p = 0.04) ().

Heart Rate, systolic and diastolic blood pressure responses.

Abbreviations: bpm, beats per minute; NS, not significant; 6-PBRT, six-minute pegboard and ring test; SBP, systolic blood pressure; DBP, diastolic blood pressure; min, minutes; * significant difference when compared to basal values.

Symptom responses during and after 6-PBRT

We can observe a significant increase in the modified Borg scale for dyspnea and upper limbs fatigue assessment, immediately after the end of 6-PBRT, with dyspnea recovery in 2 minutes of rest and fatigue in 6 minutes of rest ().

Upper limbs fatigue and dyspnea responses during and after 6-PBRT.

Abbreviations: 6-PBRT, six-minute pegboard and ring test; min, minutes; NS, not significant; * significant difference when compared to basal values.

Feasibility and safety of 6-PBRT in hospitalized patients with AECOPD

All participants (100%) completed the 6-PBRT, which was interrupted by 10 patients (55.5%), but this interruption happened for a few seconds and after the recovery of the symptom that led to the interruption, the patient ran the test again until its conclusion. Dyspnea was the cause of interruption observed in one patient and upper limbs fatigue was the cause of interruption for two patients. Both symptoms were observed as main cause of interruption for the others 7 patients. We observed a maximum interruption time of 20 seconds.

There was no record of adverse events during the 6-PBRT. We evaluated the time of assembly and transportation of the equipment, and it proved to be a device of simple handling, with a mean of 11 ± 6.72 minutes between transport and assembly.

Discussion

The current study allows us to observe the main results: 1) the prevalence of dynamic hyperinflation induced by the 6-minute pegboard and ring test was 50% in hospitalized patients for acute exacerbation of chronic obstruction pulmonary disease (AECOPD); 2) The 6-PBRT induced hemodynamic and ventilatory responses with complete recovery within 6 minutes at the end of the test; and 3) 6-PBRT is safe and feasible to this population.

There are few studies that evidenced dynamic hyperinflation after upper limb exercise and no study has evaluated it after 6-PBRT. In our study the prevalence of DH was 50%, higher than that observed in the first study that described DH during exercises with upper limbs [32]. We believe that this result was observed due to the different modalities of exercise and the fact that 6-PBRT was applied during the exacerbation phase. In a previous study, DH developed during the exercise with cycle ergometer for upper limb was correlated directly to the exercise load. The prevalence of DH in exercise with 50% of the maximum load was 41.1%, while for the loads of 65% and 80%, the prevalence was 66.6% and 79.1%, respectively [22]. In our study, the prevalence was equivalent to that observed by Colluci et al. (2005) during exercise with load between 50–65% of the maximum determined in incremental test [22]. This result suggests that 6-PBRT in patients with AECOPD may correspond to a moderate intensity exercise test.

Our results also demonstrated an increase in respiratory rate after the end of the 6-PBRT, with recovery of baseline values occurring within 2 minutes of rest. Since the increased respiratory rate is one of the main factors for the occurrence of dynamic hyperinflation, we understand that 6-PBRT promotes ventilatory responses in the studied population, but not enough to generate hyperinflation of large magnitude. Our results also agree with previous findings that demonstrated DH and thoracoabdominal asynchrony developed during two techniques (diagonal exercise and cycle ergometer) in patients with stable COPD, and which observed that there was an increase in respiratory rate in both exercise modalities, but which had a statistically greater variation during the exercise with an upper limb cycle ergometer, in which the patients presented DH and more asynchrony [8].

As expected, the minute volume (MV) showed significant increase immediately after the end of the test. It is already known that the mechanisms which promote DH are increased MV, reduced expiratory time, increased elastic work and, finally, decreased respiratory work efficiency. Colluci et al (2010) showed that, regardless of the load stipulated to the exercise, there was an interruption of the exercise when reaching an MV of approximately 39L/min [22]. Castro et al. (2013) found values of 27.9 L/min and 36.7 L/min in two different exercises performed for upper limbs [8]. In another study, Satake et al. (2015) demonstrated a mean MV of 28.24 ± 9.21 L/min at the peak of exercise, as a possible mechanism causing dyspnea [33]. The mean number found in our study for MV at the end of 6-PBRT was 19.5 ± 3.31 L/min, suggesting that ventilatory mechanisms probably had little impact on the development of dynamic hyperinflation. Despite of this, the intolerance to the test could be confirmed since the patients with AECOPD presented worse performance when compared to the reference values for the normal Brazilian population [31].

Few studies have evaluated the hemodynamic responses during the 6-PBRT. We observed that the heart rate and diastolic blood pressure at the end of the test returned rapidly to their baseline values, requiring only 2 minutes of rest for this recovery. While to reestablish the systolic blood pressure, it took 4 minutes of rest. Only one study evaluated the same parameters immediately after the end of 6-PBRT, finding values similar to ours [15]. However, this study was conducted in an outpatient setting. These results suggest that 6-PBRT does not cause hemodynamic changes outside a safety margin that may limit their execution.

Another important finding of the current study was that the dyspnea was restored faster than fatigue, evaluated by the modified Borg scale. It is already well established in the literature that the sensation of dyspnea and fatigue may be one of the main limiters of unsupported upper limb exercise tolerance in patients with COPD [34, 35] and dyspnea is related to the stimulus levels at the respiratory center and to the magnitude of dynamic hyperinflation [36]. Similar results were demonstrated by Zhan et al. (2006), who observed lower values for a modified BORG scale for the evaluation of dyspnea compared to fatigue in stable patients with COPD [15]. Previous studies have found similar values for fatigue and dyspnea for incremental activity with upper limbs [22] and a linear increase in dyspnea, as well as the decrease in inspiratory capacity during the 6-minute walk test, suggesting that the cause of increased dyspnea assessed by the BORG scale occurred as a consequence of dynamic hyperinflation [33].

Some studies have already shown that the improvement of dyspnea after AECOPD is associated with a reduction in pulmonary dynamic hyperinflation (increase in IC) [37, 38]. Static hyperinflation, which increases even more during exacerbations, is very relevant for understanding the cause of increased dyspnea [39]. In a later study, an assessment of static and dynamic hyperinflation was performed during AECOPD and after a period of stabilization. Patients were evaluated in this trial with a metronome rhythm test aimed to change the IC during tachypnea. This mechanism was sensitive to induce dynamic hyperinflation, but did not find an additional increase beyond the change in static hyperinflation already induced by exacerbation [40].

Regarding the applicability of the test, we observed that the equipment is simple, of fast assembly, and the demand of execution of the 6-PBRT requires only one evaluator. All patients completed the test, with interruption occurring in with 10 patients (55.5% of the sample). All the patients returned and completed the total time of 6 minutes of evaluation, as described in the test methodology. The main reason for interrupting was the fatigue of upper limbs. Felisberto at al. (2018) showed a strong correlation of the performance in 6-PBRT with the increase in fatigue of upper limbs (r = -0.76) [29].

To the best of our knowledge, there are no other studies published in the literature that have evaluated the ventilatory and hemodynamic responses, nor the applicability and safety of 6-PBRT in hospitalized patients with AECOPD. The test demonstrated hemodynamic and ventilatory changes at levels considered safe and with a return to baseline values in a maximum of 6 minutes of rest. The presence of any adverse events that discontinue 6-PBRT definitively has not been demonstrated, showing that 6-PBRT can be considered applicable and safe for this population.

In this context, we reinforce that 6-PBRT is an excellent tool to evaluate the functional capacity of upper limbs and may be included within pulmonary rehabilitation programs during the acute exacerbation phase of COPD in the hospital setting. In addition, the results of the current study suggest continuing studying the responsiveness to a pulmonary rehabilitation program in the hospital phase, as we know of its ability to evaluate the response to upper limb training in an outpatient setting. However, new studies are necessary to evaluate predictive factors to develop DH.

The main limitations of our study were the number of patients who refused to participate, even though they had similar characteristics to the study population; and the impossibility of evaluating the tidal volume during the test, which would give us more accurate information about the ventilation and mechanisms that cause dynamic hyperinflation. Another important limitation of the study was that we did not evaluated the static hyperinflation. This could have provided ventilatory demand regarding pulmonary function in AECOPD patients and how this phenomenon could influence the magnitude of DH and the frequency of symptoms such as dyspnea during the execution of 6-PBRT.

Conclusion

The 6-PBRT promotes ventilatory and hemodynamic changes during its execution, requiring a maximum of 6 minutes for its recovery. This test proved to be safe and applicable for hospitalized patients with COPD for acute exacerbation.

11 Aug 2020

PONE-D-20-20208

Dynamic hyperinflation induced by the 6-minute pegboard and ring test in hospitalized patients with exacerbated COPD

PLOS ONE

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Reviewer #1: The manuscript entitled “Dynamic hyperinflation induced by the 6PBRT in hospitalized patients with exacerbated COPD” the authors present the findings that the 6PBRT is safe and applicable for patients hospitalized due to AECOPD.

The data collected in this study contribute to our understanding of this phenomenon and the manuscript could be considered for publication following revisions.

There is a limitation. To overcome this limitation, the authors could do 6PBRT in patients with not only AECOPD and patients with recovered AECOPD. To overcome this limitation, it is necessary that to compare patients with AECOPD and who have recovered from AECOPD.

Please check line 95 and 319, bibliography marks are wrong style.

Reviewer #2: The authors wrote an interesting manuscript regarding dynamic hyperinflation during COPD exacerbations. Very strong is that they used actual physical maneuvers to assess this. The used actual changes from base line to assess the changes which is strong to. Unfortunately the was no information regarding the DH in stable state for the included patients

I do have some comments

Mayor:

Was the trial registered in a public database? What was the predefined primary endpoint for the test? The manuscripts suggests that at first the overall occurrence of DH was the endpoint, which when proved non significant was switched towards cross sectional analysis.

There is no information about the presence of static hyperinflation in the reported patients during the exacerbation, please discuss how this might influence the interpretation of the now presented results

Please report data about the treatment patients were receiving during the exacerbations and the policy regarding the last dose of bronchodilators prior to the measurements.

The PFSDQ-M and CAT were applied to the patients but not reported

Minor

Why was the cutoff of 150 ml chosen rather 100 ml for IC? Please discuss

Please discuss the relation between the presence of static hyperinflation during exacerbation with DH. (For inspiration see e.g DOI: 10.1183/09031936.05.00136304 , DOI: 10.2147/COPD.S154878, DOI: 10.1164/rccm.200504-595OC DOI: 10.1016/S2213-2600(15)00459-2 )

Please discuss the known information and previous trials assessing DH during exacerbations e.g. with other test such as metronome and relate your outcomes to those

Please discuss the lack of data regarding stable state for the interpretation of the results. E.g. what if DH was present in stable state and actually got better or vice versa, and what about static hyperinflation during stable state and the influence on the now presented results

Please extend the baseline data of the patients with more clinical parameters

Please explain the high number of interruptions during the tests

Please explain the high number of dropouts

Reviewer #3: Reason for Reject: A small study and of low impact with a specific task that says something on disease and upper extremity fitness and general fitness therefore, but i do not think that this belongs to a journal with such high impact factor due to rather low priority.

Reviewer #4: Thank you for the opportunity to review this manuscript. I send some suggestions to improve the quality of the study.

The aim of this study was to evaluate physiological responses and Dynamic Hyperinflation induced by the 6-minute pegboard and ring test in hospitalized patients with acute exacerbation of COPD. There is this gap in the literature on the study of the occurrence of dynamic hyperinflation during activities of unsupported upper limbs such as 6PBRT.

The proposal of the study aims to answer this question and its basis is structured by the scientific literature, however I felt a lack of greater theoretical basis justifying its realization. Only 21 studies were used as references for the construction of the text and there are more papers available in the literature that support the ideas pointed out and of great scientific relevance that can contribute.

- Were the values obtained in the pulmonary function test compared to specific reference values for the population?

- The original description of the test should be reported/referenced on line 162.

- Two specific questionnaires related to lung disease were applied (PFSDQ-M and CAT), but the results were not presented.

- 10 patients interrupted the test for the reasons indicated in lines 297-299, however the time of this interruption was not presented, and we know that this time can influence the values obtained. In addition, the information that all patients completed the 6 minutes of the test was only informed in the discussion section. Did any patient complete the 6 minutes of the test at rest?

- The statistical tests that were performed and which variables and moments were considered to calculate must be presented and signaled in the figure 3.

- The number of rings moved during the test was not shown. I believe that this value should be informed to the reader.

- Also, inform the number of rings for patients who presented HD and those who did not. Did patients present HD move a lower number of rings?

Was the number of rings obtained by patients lower than the normal value already established for the population?

- The aim of this study was to evaluate physiological responses and DH induced by 6PBRT in hospitalized patients with acute exacerbation of COPD, however I consider it important to point out if the occurrence of HD was able to provide worse performance in the test and not only if it occurs or not.

- Line 331: “dynamic hyperinflation” = DH.

- Lines 337-339: "The mean number found in our study for MV at the end of 6PBRT was 19.5 ± 3.31 L / min, suggesting that ventilatory mechanisms probably had little impact on the development of dynamic hyperinflation and intolerance to the test". How can the test intolerance be pointed out if we do not know if the patients had lower than expected ring number values?

- Lines 373-376: "The main limitations of our study were the number of patients who refused to participate, even though they had similar characteristics to the study population; and the impossibility of evaluating the tidal volume during the test, which would give us more accurate information about the ventilation and mechanisms that cause dynamic hyperinflation ". There are recent studies that can support the occurrence of greater ventilatory demand impacting patients' performance in tests to evaluate the functional capacity of upper limbs such as 6PBRT.

- The aims must be answered at the conclusion of the study; however, evaluating the safety and applicability of 6PBRT for hospitalized patients with COPD for acute exacerbation was not pointed out as an initial aim of the study.

**********

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Reviewer #1: Yes: Takeda Kenichi

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

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10 Sep 2020

Ms. Ref. No.: PONE-D-20-20208

Title: Dynamic hyperinflation induced by the 6-minute pegboard and ring test in hospitalized patients with exacerbated COPD

Dear Dr. Stelios Loukides,

We really appreciated the contributions made by the review team. We sought to achieve the best possible revision of each of the reviewers’ concerns. We understand that in fact the suggestions were relevant to the improvement of the manuscript and we are available to elucidate further clarification if necessary.

REVIEWERS’ COMMENTS:

Reviewer #1:

1. The manuscript entitled “Dynamic hyperinflation induced by the 6PBRT in hospitalized patients with exacerbated COPD” the authors present the findings that the 6PBRT is safe and applicable for patients hospitalized due to AECOPD.

The data collected in this study contribute to our understanding of this phenomenon and the manuscript could be considered for publication following revisions.

There is a limitation. To overcome this limitation, the authors could do 6PBRT in patients with not only AECOPD and patients with recovered AECOPD. To overcome this limitation, it is necessary that to compare patients with AECOPD and who have recovered from AECOPD.

Authors: We appreciate this observation. Our study was one of the pioneers investigating the use of 6PBRT as a tool for assessing exercise tolerance in a hospital setting. In this study, we would like to investigate the limitations imposed by the exacerbation in the applicability an

d safety of the test, as well, to understand the prevalence of hyperinflation during the teste. We did not aim to evaluate the patient in the stable or recovered phases.

2. Please check line 95 and 319, bibliography marks are wrong style.

Authors: We appreciate the reviewer's observation. The change was made in the text.

Reviewer #2:

3. Was the trial registered in a public database? What was the predefined primary endpoint for the test? The manuscripts suggest that at first the overall occurrence of DH was the endpoint, which when proved non significant was switched towards cross sectional analysis.

Authors: We thank the reviewer for the question. Our study had the transversal design aimed to evaluate dynamic hyperinflation with 6-minute pegboard and ring in patients with exacerbated COPD. Primary endpoint was occurrence of DH and the secondary endpoints was hemodynamic and respiratory changes induced by 6PBRT. We emphasize that the functional test chosen in this study was previously described in the literature. This is not a randomized clinical trial. Therefore, the rules of mandatory registration in a public Clinical Trials database are not applicable to our study design.

4. There is no information about the presence of static hyperinflation in the reported patients during the exacerbation, please discuss how this might influence the interpretation of the now presented results.

Authors: We appreciate the reviewer's observation. Static lung volumes such as residual volume and total lung capacity were not measured. This could have provided ventilatory demand regarding pulmonary function in exacerbated COPD patients. We authors discuss and agree that this is a limitation. We added this information in the “limitation” paragraph of the “Discussion” section.

5. Please report data about the treatment patients were receiving during the exacerbations and the policy regarding the last dose of bronchodilators prior to the measurements.

Authors: We appreciate the reviewer's observation. The authors agree that these notes are relevant and the treatment patients was added and described in the “Materials and methods” section. As a policy regarding the last dose of bronchodilators before measurements, we requested that the short-term bronchodilator should not be performed 2 hours before the tests, ensuring that similar conditions were established for all patients during all tests.

6. The PFSDQ-M and CAT were applied to the patients but not reported.

Authors: We appreciate the reviewer's observation and sorry for this mistake. We added theses complementary information in Table 1 with demographic and spirometric characteristics of the study participants.

7. Why was the cutoff of 150 ml chosen rather 100 ml for IC? Please discuss.

Authors: We appreciate the reviewer's observation. This cutoff value was used according to the previous study by O’Donnell (2001) and Colucci (2010)

8. Please discuss the relation between the presence of static hyperinflation during exacerbation with DH. (For inspiration see e.g DOI: 10.1183/09031936.05.00136304 , DOI: 10.2147/COPD.S154878, DOI: 10.1164/rccm.200504-595OC DOI: 10.1016/S2213-2600(15)00459-2)

Please discuss the known information and previous trials assessing DH during exacerbations e.g. with other test such as metronome and relate your outcomes to those.

Authors: We thank the reviewer for this important observation. The primary objective of our study was to verify the occurrence of dynamic hyperinflation during 6PBRT and possible limitations for the execution of the test, such as ventilatory and hemodynamic responses in order to develop a clinical tool for assessing functional capacity during exacerbation. Until data collection there were a few studies carried out with this population at the time of exacerbation during hospitalization. In order, to clarify this relevant point, we added the reference and discussion in the seventh paragraph of the “Discussion” section. We also added this information in the “limitation” paragraph.

9. Please discuss the lack of data regarding stable state for the interpretation of the results. E.g. what if DH was present in stable state and actually got better or vice versa, and what about static hyperinflation during stable state and the influence on the now presented results.

Authors: We appreciate this observation. To ensure the safety of the test we aimed to evaluate the patient during the exacerbation in order to verify the applicability and safety of the test in the hospital setting. In this study, unfortunately, we didn’t evaluate static hyperinflation and we added this information in the “limitation” paragraph.

10. Please extend the baseline data of the patients with more clinical parameters

Authors: We appreciate the reviewer's suggestion. Table 1 with demographic and spirometric characteristics of the study participants has been updated.

11. Please explain the high number of interruptions during the tests.

Authors: We thank the reviewer for the question. All participants (100%) concluded the 6-PBRT, being the same interrupted by 10 patients, but this interruption happened for a few seconds. After the recovery of the symptoms that led to the interruption, the patients ran the test again until its conclusion. Dyspnea was the cause of interruption observed in one patient and upper limbs fatigue was the cause of interruption for two patients. Both symptoms were observed as main cause of interruption for the others 7 patients. We observed a maximum interruption time of 20 seconds. We added these informations in the “Results” section.

12. Please explain the high number of dropouts.

Authors: We are grateful for the question. The explanation of droputs are described in figure 2.

Reviewer #3

13. Reason for Reject: A small study and of low impact with a specific task that says something on disease and upper extremity fitness and general fitness therefore, but I do not think that this belongs to a journal with such high impact factor due to rather low priority.

Authors: The authors would like to request a reconsideration of our manuscript after the comments of reviewers 1, 2 and 4 and the opportunity to respond offered by the editor. All comments have been taken into consideration and we understand that the study has some limitations. We have included all additional data in the objectives, methods and discussion sessions, including the limitations. Thus, we believe we have improved our manuscript. Regarding the sample size we calculated the number of patients that should be included considering the primary objective, according the previous published data of Collucci and O’donell. In addition, we would like to point out that there are no studies evaluating the safety of using 6-PBRT in patients with exacerbated COPD, making it an extremely relevant study for hospital clinical practice.

Reviewer #4

14. Thank you for the opportunity to review this manuscript. I send some suggestions to improve the quality of the study.

Authors: We are grateful for this feedback and suggestions.

15. The aim of this study was to evaluate physiological responses and Dynamic Hyperinflation induced by the 6-minute pegboard and ring test in hospitalized patients with acute exacerbation of COPD. There is this gap in the literature on the study of the occurrence of dynamic hyperinflation during activities of unsupported upper limbs such as 6PBRT.

The proposal of the study aims to answer this question and its basis is structured by the scientific literature; however I felt a lack of greater theoretical basis justifying its realization. Only 21 studies were used as references for the construction of the text and there are more papers available in the literature that support the ideas pointed out and of great scientific relevance that can contribute.

Authors: We thank the reviewer for this important observation. For better understanding, we rewrote the third and fourth paragraph of the section "Introduction" and we complement it with references from important studies on the subject.

16. Were the values obtained in the pulmonary function test compared to specific reference values for the population?

Authors: We thank the reviewer for the question. In the present study we follow the reference according to American Thoracic Society (ATS)/ European Respiratory Society to perform spirometry. For better understanding, we rewrote the sentence about assessment in the “Materials and methods” section.

17. The original description of the test should be reported/referenced on line 162.

Authors: We appreciate the reviewer's suggestion. This information was included in the “Materials and methods” section.

18. Two specific questionnaires related to lung disease were applied (PFSDQ-M and CAT), but the results were not presented.

Authors: We appreciate the reviewer's observation. Table 1 with demographic and spirometric characteristics of the study participants has been updated with this information.

19. 10 patients interrupted the test for the reasons indicated in lines 297-299, however the time of this interruption was not presented, and we know that this time can influence the values obtained. In addition, the information that all patients completed the 6 minutes of the test was only informed in the discussion section. Did any patient complete the 6 minutes of the test at rest?

Authors: We thank the reviewer for the question. All participants (100%) concluded the 6-PBRT and no patient completed the test at rest. We observed interruptions during the test by 10 patients, and these interruptions happened for a few seconds. The maximum interruption time observed in a test was 20 seconds. For better understanding, we rewrote this sentence in the “Results” section.

20. The statistical tests that were performed and which variables and moments were considered to calculate must be presented and signaled in the figure 3.

Authors: We appreciate this observation. We added this information in the legend in Figure 3.

21. The number of rings moved during the test was not shown. I believe that this value should be informed to the reader.

Authors: We appreciate the reviewer's observation. We added the data in the “Results” section.

22. Also, inform the number of rings for patients who presented HD and those who did not. Did patients present HD move a lower number of rings?

Authors: We thank the reviewer for the question. Patients who hyperinflated in the test presented worse performance when compared to those who did not hyperinflate (230.22 ± 68.56 vs 259.55 ± 57.49, respectively). However, this result was not significant (P = 0,34). We added this information in the “Results” section.

23. Was the number of rings obtained by patients lower than the normal value already established for the population?

Authors: We thank the reviewer for the question. The performance in 6-PBRT was worse in patients with exacerbated COPD when compared to the predicted values for normal population. We added this information in the “Results” section.

24. The aim of this study was to evaluate physiological responses and DH induced by 6PBRT in hospitalized patients with acute exacerbation of COPD, however I consider it important to point out if the occurrence of HD was able to provide worse performance in the test and not only if it occurs or not.

Authors: We really appreciate the reviewer's suggestion. These results were added to the manuscript.

25. Line 331: “dynamic hyperinflation” = DH

Authors: We appreciate the reviewer's observation. The change was made in the manuscript.

26. Lines 337-339: "The mean number found in our study for MV at the end of 6PBRT was 19.5 ± 3.31 L / min, suggesting that ventilatory mechanisms probably had little impact on the development of dynamic hyperinflation and intolerance to the test". How can the test intolerance be pointed out if we do not know if the patients had lower than expected ring number values?

Authors: We really appreciate the reviewer's observation. We added this information in the “Results” and “Discussion” sections.

27. Lines 373-376: "The main limitations of our study were the number of patients who refused to participate, even though they had similar characteristics to the study population; and the impossibility of evaluating the tidal volume during the test, which would give us more accurate information about the ventilation and mechanisms that cause dynamic hyperinflation ". There are recent studies that can support the occurrence of greater ventilatory demand impacting patients' performance in tests to evaluate the functional capacity of upper limbs such as 6PBRT.

Authors: We appreciate this observation. We observed and described studies that showed this increase in ventilatory demand, but so far there are no studies that demonstrate this phenomenon with the patient in hospital for AECOPD.

28. The aims must be answered at the conclusion of the study; however, evaluating the safety and applicability of 6PBRT for hospitalized patients with COPD for acute exacerbation was not pointed out as an initial aim of the study.

Authors: We appreciate the reviewer's observation. We note that this objective was not reported in the summary and introduction section. This information was added in the manuscript.

Submitted filename: RESPONSE TO REVIEWERS Cassia 03.09_reviao 08_09_20.docx

Click here for additional data file.

19 Oct 2020

Dynamic hyperinflation induced by the 6-minute pegboard and ring test in hospitalized patients with exacerbated COPD

PONE-D-20-20208R1

Dear Dr. Yamaguti,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

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Kind regards,

Stelios Loukides

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

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The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

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PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

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Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The manuscript entitled “Dynamic hyperinflation induced by the 6PBRT in hospitalized patients with exacerbated COPD” the authors present the findings that the 6PBRT is safe and applicable for patients hospitalized due to AECOPD.

The data collected in this study contribute to our understanding of this phenomenon and the manuscript could be considered for publication following revisions.

The authors report 6PBRT in patients with only on AECOPD. Please report data about the recovered pulmonary function test after hospitalization patients with AECOPD. And It is necessary that 6PBRT data in patients with recovered AECOPD. It will help us to understand how severe those patients with AECOPD and COPD.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Kenichi Takeda

23 Oct 2020

PONE-D-20-20208R1

Dynamic hyperinflation induced by the 6-minute pegboard and ring test in hospitalized patients with exacerbated COPD

Dear Dr. Yamaguti:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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Thank you for submitting your work to PLOS ONE and supporting open access.

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on behalf of

Dr Stelios Loukides

Academic Editor

PLOS ONE

Table 1

Demographic and spirometric characteristics of the study participants.

Data are presented by mean ± standard deviation.

Variables	Patients with AECOPD (n = 18)
Age (years)	71.28 ± 5.14
Gender (F/M)	11/7
Body Mass (Kg)	70.05 ± 13.40
Height (m)	1.65 ± 0.09
BMI (Kg/m2)	25.90 ± 5.07
CAT	26.38 ± 9.34
PFSDQ-M fatigue	44.88 ± 25.74
PFSDQ-M dyspnea	43.16 ± 27.45
PFSDQ-M change in ADLs	49.38 ± 28.44
Oxygen supplementation at rest	5
Oxygen supplementation during test	9
GOLD classification (II / III / IV)	7/5/6
Lung funtion post-bronchodilator
FEV1 (% predicted)	43.22 ± 18.33
FVC (% predicted)	62.61 ± 19.91
FEV1/FVC	0.50 ± 0.12
VC (% predicted)	61.22 ± 19.53
IC (L)	1.51 ± 0.45

Abbreviations: AECOPD, acute exacerbation of chronic obstructive pulmonary disease; n, number of individuals; F, female; M, male; kg, kilograms; m, meters; BMI, body mass index; m2, square meters; CAT, COPD Assessment Test; PFSDQ-M, Pulmonary Functional Status Dyspnea Questionnaire; ADLs, activities of daily living; GOLD, Global Initiative for Chronic Obstructive Lung Disease; FEV1, forced expiratory volume in the first second; FVC, forced vital capacity; VC, vital capacity; IC, inspiratory capacity; L, liters.