Interstitial lung diseases (ILD) include various pathologies characterised by alveolar and interstitial space damage, pulmonary inflammation usually coupled with fibrosis, decreased pulmonary capacity, and impaired gas exchange (28). Patients generally present with reduced exercise tolerance, as well as exercise-induced arterial hypoxemia (EIAH), dyspnoea, and leg discomfort that occur early during exercise (30). A 6-min walk test (6MWT) and/or cardiopulmonary exercise testing are routinely used to measure the functional exercise capacity of patients with ILD, and 6MWT may provide an idea of prognosis and functional status (14,30,31,33). The 6MWT is a validated and standardized test (3) that is easy to administer, well tolerated, reflective of daily life activities, which measures endurance of patients. The distance walked and arterial O2 desaturation during the 6MWT have been shown to be good indicators of disease severity and mortality in patients with idiopathic pulmonary fibrosis (IPF) and nonspecific interstitial pneumonia (7,30).
Another challenge, the 6-min stepper test (6MST), has been recently proposed as a convenient method to evaluate exercise tolerance and the effects of home-based respiratory rehabilitation in patients with ILD (20,39). The reproducibility and sensitivity of the 6MST have been previously demonstrated in patients suffering from chronic obstructive pulmonary disease (COPD) (5). The space needs of the 6MST are modest, and to the contrary to the 6MWT, the test is easily implemented. Delourme et al. (12) recently reported a positive correlation between performance in the 6MST and 6MWT in patients with various ILD. However, the patients had significantly lower arterial O2 desaturation during the 6MST compared with the 6MWT. Because the rate of desaturation is an important criterion for the prescription of O2 therapy to patients, further investigation of the tests is needed (12). Additionally, a heart rate (HR) plateau is generally observed in patients performing the 6MWT, whereas the 6MST is more commonly associated with HR drift and greater leg discomfort (12). These observations suggest that the muscular, physiologic, and cardiorespiratory responses occurring during the tests may differ and possibly contribute to the difference in arterial O2 desaturation. Moderno et al. (34) suggests an increase tidal volume (V T) may minimize EIAH in patients with interstitial pulmonary fibrosis. We thus hypothesized that an increase of ventilatory equivalent ratio for O2 (V˙E/V˙O2), and minute ventilation (VE) and V T at a same oxygen uptake (V˙O2), may contribute to the lesser O2 desaturation occurring during the 6MST compared with 6MWT. Thus, our aim in this study was to better characterize the tests by comparing the cardiorespiratory responses of ILD patients during the 6MWT and the 6MST.
The study was conformed to the Declaration of Helsinki. Approval for the use of the data was provided by the institutional review board of the French Learned Society for Pulmonology (CEPRO 2011-039), and written informed consent was obtained from all patients.
The study was performed between March 2013 and March 2015, and the recruitment stopped when the required number of subjects was reached. Patients followed up at the Center for Rare Pulmonary Diseases of the Lille University Hospital (Lille, France) were recruited by pulmonologists, during a routine monitoring. Inclusion criteria were as follows: diagnosis of ILD according to established criteria by high-resolution CT and lung biopsy if necessary (2,4), resting pulse O2 saturation (SpO2) ≥88%, no use of continuous O2 therapy, ability to perform exercises without help. The details of inclusions are presented in Figure 1.
On the morning of the study day, patients underwent plethysmography and then performed the 6MWT followed by the 6MST or vice versa. The order of the tests was determined by a randomization list manually built by the main author. A rest period of at least 30 min was allowed between tests to ensure complete recovery.
The 6-min exercise tests
The 6MWT was performed according to the American Thoracic Society (2002) recommendations using a 30-m corridor (3). Patients were instructed to walk at their own pace for 6 min while attempting to cover as much distance as possible (23). The distance walked was noted every minute. No familiarization to the walk test has been conducted the during the study day.
The 6MST was performed as previously described, using a stepper (5). The stepper (Stepper réglable athlitech, Groupe Go Sport, Sassenage, France) consisted of two foot-plates which move up and down alternately. The height from the floor to the higher position of the step was of 21 cm. The starting position of the stepper was as follows: left or right step in the upper position, according to the patient preferred position, the other step down, and the arms along the body. An entire cycle or a (stroke) was defined by return to the initial position. The stepper was placed near the wall so that patients could place a hand on the wall for support in case of exhaustion or imbalance. The object of this test is to make the highest number of strokes as possible during a 6-min duration. The number of strokes was noted every minute. A 15-s familiarization period was allowed 15 min before the start of the 6MST. The remaining time was announced at each minute, and no encouragement was given to the subjects during either test.
On both tests, the instructions were similar and based on the ATS guidelines (3): The object of this test is to walk as far as possible/to make the highest number of strokes you can for 6 min. Six minutes is a long time, so you will be exerting yourself. You will probably get out of breath or become exhausted. You are permitted to slow down or accelerate, stop and rest as necessary, but it is preferable not to stop. However, if you feel the need to take a break due to intolerable dyspnoea, muscle gene, or for another reason, you can stop. […].
Forced vital capacity, forced expiratory volume in 1 s, total lung capacity, and diffusing capacity of the lung for carbon monoxide were measured by body plethysmography and spirometry (BodyBox 5500 Medisoft Sorinnes, Belgium). Predicted normal values were derived from standard equations recommended by the European Respiratory Society (38).
Measurements during 6MWT and 6MST
Gas exchange was measured continuously during the rest and exercise using a portable device (MetaMax 3B, Cortex, Germany). V˙O2, carbon dioxide output (V˙CO2), V˙E, breathing frequency (Bf), V T, respiratory exchange ratio (RER), V˙E/V˙O2 and respiratory equivalent ratio carbon dioxide (V˙E/V˙CO2) were obtained for each breath. Data were recorded every 5 s, and the average value per minute was used for statistical analysis. HR was monitored simultaneously using a belt compatible with the gas exchange analyzer (Polar FS3C, Oy, Finland).
SpO2 was recorded every minute using a pulse oximeter (Novametrix 513 Pulse Oximeter, Wellingford, CT). Resting (SpO2rest) and minimum SpO2 during exercise (SpO2nadir) were recorded, and ΔSpO2 (SpO2rest − SpO2nadir) was calculated.
Dyspnoea and leg discomfort were assessed on a 10-point Borg Scale at rest and after each test (6).
Blood samples were drawn before and immediately after each test by finger-prick capillary using a lancet and capillary tube. Blood lactate was analyzed by photometry (Miniphotometer Plus LP 20, Dr. Lange, Germany).
The primary outcome was the intertest comparison of cardiorespiratory responses during the 6MWT and 6MST. The sample size was calculated according to the V˙E/V˙O2 data, used as an indicator of hyperventilation, from the first 10 subjects, with an alpha of 5% and 80% power to detect. Eleven subjects were required to detect a difference using ANOVA. Values are expressed as the mean ± SD. Data were analyzed using SigmaStat (Software version 3.5). The univariate normality assumptions were verified with the Kolmogorov–Smirnov test, and the Brown–Forsythe variation of Levene test was used to verify the homogeneity of variances. Paired t-test and a nonparametric Wilcoxon test were used to compare resting values and lactate, leg discomfort, dyspnoea, and SpO2. ANOVA on rank for repeated measures (time and test) were used to compare the evolution of cardiorespiratory parameters at rest and at each minute of both tests. When the ANOVA test was significant at P < 0.05, Tukey’s post hoc test for multiple comparisons was applied. A P value less than 0.05 was considered statistically significant.
A total of 31 patients with ILD completed the tests; 14 patients with IPF, 10 with chronic sarcoidosis, six with idiopathic nonspecific interstitial pneumonia, and 1 with unclassifiable fibrotic ILD (Table 1). Although no subject received oxygen therapy during both tests, nine patients used oxygen therapy during the daily life activities. No significant difference in the performance to 6MWT was observed between patients who performed it first versus last (462 ± 86 m and 470 ± 83 m, respectively, P = 0.79) nor to 6MST (272 ± 89 and 314 ± 92 steps, respectively, P = 0.21).
Cardiorespiratory values were not significantly different at rest before the 6MWT and 6MST. During exercise, V˙O2 was significantly lower and RER and V˙E/V˙O2 significantly higher between the second and sixth minutes of the 6MST compared with the 6MWT (V˙O2, P = 0.002; RER, P < 0.001; and V˙E/V˙O2, P < 0.001; Fig. 2). HR was significantly higher at the end of the 6MST compared with the 6MWT (P < 0.05; Fig. 2). The V˙E/V˙CO2 ratio decreased significantly from rest to the end of exercise (P < 0.001) and was not different between both tests at any time. The ANOVA F-statistic showed a significant intertest difference in the evolution of V˙E and V T (P < 0.001) but differences at the individual timepoints were not significant (Fig. 2). During the last 3 min of exercise, V˙O2 and V˙E increased more during the 6MST than the 6MWT (V˙O2, 99 ± 123 vs 44 ± 85 mL·min−1, P = 0.02 and V˙E 6.2 ± 6.6, vs 2.7 ± 3.5 L·min−1, P = 0.005, respectively). The V˙CO2 slope was not different between both tests.
Dyspnoea and leg discomfort scores and blood lactate concentrations are reported in Table 2. Blood lactate concentrations and leg discomfort scores were significantly higher at the end of the 6MST than at the end of the 6MWT (Table 2).
SpO2 was the same before the 6MST and 6MWT, but decreased to a significantly greater extent during the 6MWT than the 6MST (Fig. 2). The SpO2nadir and ΔSpO2 were higher and lower, respectively, during the 6MST compared with the 6MWT (Table 2).
To compare the impact of the 6MWT and 6MST on HR, V˙E, and V˙CO2 at the same V˙O2, we analyzed data from two groups of patients separately. One group consisted of 13 patients for whom the mean V˙O2 at the end of the 6MWT differed by less than 10% from that at the end of the 6MST (“similar” V˙O2 group). The second group consisted of 18 patients for whom the equivalent difference in mean V˙O2 was ≥10% (“dissimilar” V˙O2 group). No significant difference in baseline pulmonary function testing of the patients with “similar” or “dissimilar” V˙O2 was observed. In similar V˙O2 group, V˙E, V T, HR, and V˙CO2 were higher during the 6MST compared with the 6MWT (P < 0.001; Fig. 3), but this difference was not apparent in the dissimilar V˙O2 group, as was observed for the entire study group (Fig. 2). For both the similar V˙O2 group and the whole study cohort, SpO2 was reduced to a greater extent by the 6MWT than by the 6MST (Figs. 2 and 3).
Our results demonstrate that the 6MST and the 6MWT induce different physiologic responses, raising interesting questions about the effect of different exercise types on hypoxemia in ILD patients and the mechanisms underlying the effect. The main observations from this study were that the 6MST induced i) a greater ventilatory response, as reflected by the higher V˙E/V˙O2; ii) a smaller decrease in SpO2; iii) a greater increase in blood lactate concentration; and iv) more perceived leg discomfort than did the 6MWT.
As previously reported in COPD patients (5), despite a different physiopathology compared with ILD, subjects had a larger increase in V˙O2 during the 6MWT than the 6MST. Additionally, after an initial increase during the third first minutes of exercise tests, during the 6MST, V˙O2 continues to rise from the third to the sixth minute, whereas a plateau was observed during the same period of the 6MWT, as previously reported for ILD patients (22). It seems likely that the recruitment of additional muscle fibers and the contraction regimen during intense constant work exercise are major contributors to the V˙O2 slow component that may be observed (25,26,42). This last also implies that both V˙E and the mechanical power of breathing increase, as previously demonstrated (10,25). We may thus hypothesize that the 6MST requires more localized muscle effort, as reflected by the higher leg discomfort, and involves a higher percentage of muscle fibers (mainly recruited in the vastus muscle) compared with the 6MWT. The relatively smaller effects of the 6MST on V˙O2 and SpO2 may also reflect the more peripheral physical effort compared with the greater whole-body effort required by the 6MWT.
In agreement with a previous study (12), our results showed that the 6MST induced less severe EIAH in ILD patients than did the 6MWT. Previously, several studies have also reported higher arterial O2 desaturation during walking or running compared with cycling in both endurance-trained athletes with EIAH (17,40) and patients with respiratory diseases (9,21,22,24,32,35,37). This phenomenon was mostly attributed to differences in ventilatory responses, especially the ventilatory pattern dependent on exercise modality (9,21,24,32,37). According to Galy et al. (17), hypoventilation characterized by smaller V T would explain the greater EIAH during running compared with cycling. In the case of IPF patients, it may be the increase in V T and not the Bf that minimizes EIAH. In our study, the 13 subjects in the “similar” V˙O2 group had greater V˙E and V T during the 6MST than the 6MWT, but they had similar Bf in both tests. As previously suggested, the larger V T may thus have contributed to the smaller EIAH during the 6MST. Mahler et al. (32) hypothesized that better ventilation during cycling than walking induces a greater alveolar partial pressure of O2 (PAO2), thereby minimizing the reduction in SpO2 by optimising the ventilation–perfusion ratio.
Cockcroft et al. (9) reported that COPD patients had a higher ventilatory response during a cycling test than during a 6MWT which they attributed to more severe metabolic acidosis, as reflected by lower pH, higher arterial partial pressure of carbon dioxide (PaCO2), and higher lactate production after the cycling test. However, at the present time, there is no comprehensive explanation for the control of ventilation in response to exercise below or above ventilator threshold and the role of lactate, V˙CO2, and metabolic acidosis on hyperventilation has been re-assessed (36). In addition, Mahler et al. (32) reported that COPD patients ventilate more during an incremental cycling test than during an incremental walking test, even before the ventilatory threshold was reached, suggesting another explanation than the role of metabolic acidosis. However, Mahler et al. (32) reported that COPD patients ventilate more during an incremental cycling test than during an incremental walking test, even before the anaerobic threshold was reached, suggesting another explanation than the role of metabolic acidosis. Studies lead in healthy subjects, comparing different muscle mass implication at similar metabolic workload or not, strongly suggest that the muscle contraction regimen between different exercise modes may influence the V˙O2 slow component (8,26), ventilation (1), and leg peripheral fatigue (41). According to the authors, the mechanisms implicate the recruitment of Type II motor units in the case of greater localized muscle mass use (8,26,41). Therefore, in our study, a plausible explanation for the higher ventilator response during the 6MST is the recruitment of more muscle fibers with a glycolytic profile, which are more O2 costly than oxidative profile muscle fibers (11,29). It is likely that in ILD patients, the energy metabolism of Type I fibers is shifted toward glycolysis, and Type II fibers, especially hybrid IIA/IIX and IIX fibers, are atrophied as observed in COPD (18,19). Therefore, a simple increase in activation and recruitment of Type I fibers may account for the observed changes in ILD patients. The exercise-induced hyperpnoea observed in this study may be triggered by increased blood flow to the muscle and subsequent changes in vascular resistance that stimulate groups III and IV afferent muscle fibers (13). In COPD patients, during a constant cycling test, Gagnon et al. (15) observed a decrease in Bf, V˙E and V˙E/V˙CO2 ratio when blocking III and IV afferent signal from the lower limbs, but a similar PaCO2 compared with the placebo condition. The leg discomfort and blood lactate concentration were also decreased under the Fentanyl condition (15). These findings suggest that the metabolic acidosis is not the primary stimulus of hyperventilation in some patients with respiratory diseases and highlight the importance of the neural and muscular components (15,32). Our study does not allow us to identify mechanistic differences in ventilation between the 6MST and 6MWT, and further work will be necessary to answer this question.
Finally, alveolar hypoxia and EIAH may be at least due to their pathology characteristics. A decrease in pulmonary compliance, dynamic hyperinflation, and/or destruction of alveolocapillary bed may preclude the renewing of alveolar air, leading to a heterogeneous alveolar hypoventilation or a hypoperfusion (16,27). However, it is unlikely that the sole pathology explains the difference of O2 desaturation between both tests.
The major limitation of this study is the lack of arterial blood gas measurement and muscle activity analysis. However, our study offers the first information about cardiorespiratory responses during the 6MST and 6MWT. A minor limitation is also the lack of individualization of the resistance level during stepper. Depending on patients’ weight, it probably had an impact on the muscular work of the legs, despite the fact that patients may have adapted their strokes speed to the perceived difficulty. Finally, very severe subjects requiring oxygen at rest were excluded, because it would have been inconsistent and technically difficult to measure cardioventilatory responses to exercise in those patients. This exclusion criterion could partly explain the good 6 MW distance measured in our study, compared with the literature (23).
ILD patients displayed different cardiorespiratory responses during both tests, mainly characterized by a lower pulsed oxygen desaturation and a higher ventilatory response during the 6MST. The more localized muscle mass during the 6MST probably play a major role in these responses, and further studies should be conducted on the relationship between the lower limb muscles activity, ventilator pattern and oxygen arterial desaturation in ILD patients.
The results of the present study do not constitute endorsement by ACSM. The study was funded by the URePSSS, Unité de Recherche Pluridisciplinaire Sport, Santé, Société, University of Lille (Lille, France) and no external financial was provided for this study.
Conflict of interest: Each author, BC, VB, AG and BW, declares having no conflicts of interest relevant to this study.
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