Clinical Investigations

Respiration 2009;78:154160 DOI: 10.1159/000187717

Received: August 18, 2008 Accepted after revision: September 24, 2008 Published online: December 18, 2008

Preserving Oxygenation during Walking in Severe Chronic Obstructive Pulmonary Disease: Noninvasive Ventilation versus Oxygen Therapy
M. Dreher E. Doncheva A. Schwoerer S. Walterspacher F. Sonntag H.J. Kabitz W. Windisch
Department of Pneumology, University Hospital Freiburg, Freiburg, Germany

Key Words Noninvasive ventilation Mechanical ventilation Respiratory insufficiency Chronic obstructive pulmonary disease Exercise

Abstract Background: Physical activity is known to cause significant deoxygenation in patients with severe chronic obstructive pulmonary disease (COPD). Although noninvasive positive pressure ventilation (NPPV) has been shown to improve oxygenation and physical activity in these patients, no practical approach for the application of NPPV during walking has yet been established. Objective: To elucidate the most effective approach to preserving oxygenation during walking in patients with severe COPD receiving long-term NPPV. Methods: Three 12-min walking tests were performed in a randomized cross-over design on 3 consecutive days, comparing the usual and double dosages of oxygen versus NPPV plus the usual dosage of oxygen. The ventilator and oxygen tank were placed in a backpack. Results: Eleven patients (FEV1 26 8 9% predicted) completed the study, while 8 patients refused to walk with NPPV, due to the weight of the ventilatory device (7.3 kg with NPPV vs. 3.1 kg without). PaO2 changes during walking differed [p = 0.01, repeated-measures (RM)-ANOVA], whereas dyspnea was unchanged. The difference in PaO2 change was 14.0 8 16.6 mm Hg (unadjusted p = 0.0036, critical level = 0.017, RM-ANOVA) in favor

of NPPV compared to the usual dosage of oxygen. Changes in FEV1, tidal volume and inspiratory impedance were in favor of NPPV-aided exercise (all p ! 0.05, RM-ANOVA). Walking distance was reduced under NPPV (555 8 227 m) compared to the usual (619 8 210 m) and double (622 8 215 m) dosages of oxygen (p = 0.024, RM-ANOVA). Conclusions: NPPV plus supplemental oxygen, but not oxygen alone, preserves oxygenation during walking in patients with severe COPD. However, dyspnea and walking distance were not improved due to the burden of carrying the heavy ventilatory equipment in a backpack. Copyright 2008 S. Karger AG, Basel

Introduction

Patients with severe chronic obstructive pulmonary disease (COPD) suffer from dyspnea, even during mild exertion, and, as a consequence, exercise capacity is severely reduced in these patients [1]. Thus, several studies have shown that simple, routine activities of daily life such as walking or stair-climbing result in exercise-induced hypoxemia in patients with severe COPD [24]. Therefore, the prevention of dyspnea and oxygen decline during exercise is of clinical importance, particularly in
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2008 S. Karger AG, Basel 00257931/09/07820154$26.00/0 Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Accessible online at: www.karger.com/res

Michael Dreher, MD Department of Pneumology, University Hospital Freiburg Killianstrasse 5, DE79106 Freiburg (Germany) Tel. +49 761 270 3706, Fax +49 761 270 3704 E-Mail michael.dreher@uniklinik-freiburg.de

view of the fact that patients with severe COPD are at high risk of dying from cardiovascular complications following exercise-induced hypoxemia [57]. The application of noninvasive positive pressure ventilation (NPPV) during exercise has the potential to alleviate this problem, since NPPV has been shown to (1) increase minute ventilation, despite reduced inspiratory effort [8], (2) unload inspiratory muscles [9, 10] and (3) prolong the duration of exercise-induced lactatemia [11], thus reducing dyspnea on exertion and improving exercise tolerance [8, 1218]. However, in the majority of these physiological studies, NPPV was assessed during exercise programs with the ventilator placed beside the treadmill or bike, or with a rollator. Therefore, the feasibility of long-term NPPV-aided exercise in the home environment remains unclear. Interestingly, a recent randomized cross-over trial indicated that patients with very severe COPD receiving long-term NPPV to treat chronic hypercapnic respiratory failure show improvements in oxygenation, dyspnea and walking distance when walking is aided by both NPPV and supplemental oxygen, compared to walking with supplemental oxygen alone [3]. In this study, both the ventilator and the oxygen tank were placed on a rollator, precluding the need for patients to carry the heavy devices. However, this would seem impractical for application at home, and higher dosages of supplemental oxygen were not comparably tested in this study. For this reason, NPPV cannot yet be recommended for aiding physical activity at home, even though it might preserve physical activity in certain situations, such as in hospitalized patients awaiting lung transplantation [3]. Therefore, the present study aimed to test the feasibility of NPPV-aided walking whilst carrying the ventilatory devices in a backpack. This would allow the patient to easily use NPPV during exercise at home. In addition, the present randomized cross-over trial tested the physiological and clinical effects of NPPV used during walking when compared to the use of supplemental oxygen at either the usual resting dosage or at a double dosage. It was hypothesized that NPPV coupled with supplemental oxygen is practical when carried in a backpack and superior to different dosages of supplemental oxygen alone in the prevention of exercise-induced oxygen desaturation.
Methods
The study protocol was approved by the Institutional Review Board for Human Studies at the Albert Ludwig University, Freiburg, Germany, and was performed in accordance with the

ethical standards laid down in the Declaration of Helsinki. Written informed consent was obtained from all patients. Patients Patients were recruited if they (1) exhibited stable COPD with chronic hypercapnic respiratory failure [Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage IV], (2) reported dyspnea even during mild exertion and (3) were already undergoing optimal treatment with antiobstructive and anti-inflammatory medication, in addition to long-term oxygen therapy according to GOLD criteria [19]. All patients clearly stated that their exercise capacity was limited by dyspnea rather than by skeletal muscle weakness. All patients were on long-term NPPV for at least two months prior to the study and were therefore already familiarized with NPPV. All patients were studied during a routine control visit for NPPV. Patients were excluded if they presented with an acute exacerbation of COPD. Acute exacerbation was defined as an increase for at least two consecutive days in any two major symptoms (dyspnea, sputum purulence and sputum amount) or in one major and one minor symptom (wheeze, sore throat, cough and symptoms of a common cold). Further exclusion criteria were: severe obesity (BMI 135 kg/m2), post-tuberculosis syndrome, rib cage deformities, neuromuscular disorders and bronchial carcinoma. Study Design Lung function parameters (Masterlab-Compact Labor; Jaeger, Hochberg, Germany), blood count and values of N-terminal pro-B-type natriuretic peptide were assessed at baseline. A 12min walking test (12MWT) was performed with the same flow of supplemental oxygen as that used at home (normal dosage of supplemental oxygen, Study Arm A). Subsequently, two further 12MWTs were performed in a randomized cross-over design, one with a double dose of supplemental oxygen (Study Arm B) and one with internal battery-powered NPPV, in addition to the normal dosage of supplemental oxygen (Study Arm C). Thus, three 12MWTs were performed on three consecutive days with standardized instructions given during each test. For walking, the oxygen tank and the ventilator were placed in a backpack (fig. 1). Walking with supplemental oxygen alone was performed without carrying the ventilator, but using the same backpack (fig. 2). The following data were recorded before and after the 12MWT: perceived exertion ratings for dyspnea (BDS) and limb discomfort (BSlimb) using the modified Borg Scale [20]; blood gases taken from the arterialized earlobe (cobas b221; Roche, Stuttgart, Germany); blood pressure; heart rate; tests of inspiratory muscle function [mouth occlusion pressure 0.1 s after the onset of inspiration during normal breathing (P0.1), specific inspiratory impedance (P0.1 ! ti/Vt), max imal static inspiratory mouth occlusion pressure sustained for 1.0 s and measured at residual volume [21] and sniff nasal pressure recorded at functional residual capacity [22]]; lung function parameters, and the 12-min walking distance (12MWD). Measurements were performed in the following standardized order: blood pressure, heart rate, blood gases, spirometric data, sniff nasal pressure and mouth occlusion pressures. Blood gases were taken immediately before and after the 12MWT while the patient breathed spontaneously with supplemental oxygen. During Study Arm C, patients were immediately switched from NPPV to supplemental oxygen alone after walking, with subsequent measurements of blood gases. Resting during the 12MWT was allowed if

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1
Color version available online

2
Color version available online

Fig. 1. COPD patient during the 12MWT

with NPPV in addition to supplemental oxygen (Study Arm C). Fig. 2. COPD patient during the 12MWT with supplemental oxygen alone (Study Arms A and B).

needed. The number and duration of resting periods were recorded. In addition, oxygen saturation (SpO2), BDS, BSlimb and walking distance were recorded after the 6-min time point of the 12MWT. NPPV and Oxygen Supply Due to chronic hypercapnic respiratory failure, all patients had been carefully established on NPPV prior to the study. Long-term NPPV was applied in a pressure-limited assist/control mode except for one patient, who was ventilated in a volume-controlled mode. Ventilator settings were chosen in order to maximally decrease elevated PaCO2 levels, as has been previously described in more detail by our group [2325]. NPPV was performed at home with the following different ventilators: PV 401, VIVO 30 and VIVO 40 (Breas Medical AB, Mlnlycke, Sweden); Legendair (Airox, Pau, France), and PLV 100 (Respironics Inc., Murrysville, Pa., USA). For walking with NPPV, all patients used the Breas VIVO 40 (Breas Medical) with a Silentflow exhalation valve (Weinmann, Hamburg, Germany). For walking, the ventilator mode was changed to bilevel positive pressure ventilation, allowing the patient to trigger inspiration and expiration. Inspiratory positive airway pressure, expiratory positive airway pressure and breathing frequency each corresponded to the values used at home. Supplemental oxygen during walking was applied using the Helios Marathon Portable Oxygen Unit H850 (Puritan Bennett, Galway, Ireland). Predetermination of Study End Points The primary end point of the current study was defined as the difference in the change in PaO2 during walking with different dosages of supplemental oxygen (Study Arms A and B) and NPPV (Study Arm C). Secondary end points were defined as the differ-

ences in the 12MWD, ratings of perceived exertion assessed by the modified Borg Scale, blood gases, lung function parameters and measures of inspiratory muscle function. Statistical Analysis Statistical analysis was performed using Sigma-Stat (version 3.1; Systat Software Inc., Point Richmond, Calif., USA). Unless otherwise stated, all data are presented as means 8 standard deviation (SD) after testing for normal distribution (KolmogorovSmirnov Test). The null hypothesis was defined as there being no difference in the change in PaO2 during walking with different dosages of supplemental oxygen (Study Arms A and B) compared to walking with NPPV plus supplemental oxygen (Study Arm C). A sample size determination (ANOVA, power 0.8, 2-sided type I error 0.05, three groups) was performed according to previous findings, with an estimated SD of 7.5 mm Hg for the mean difference in PaO2 change during walking and a difference of at least 10.4 mm Hg between walking with different types of assistance [3]. At least eleven subjects were needed for rejection of the null hypothesis. Comparisons between the different study arms (A, B and C) were performed using a one-way repeated-measures (RM)ANOVA, including an all-pairwise comparison (normally/nonnormally distributed data, Holm-Sidak/Tukey test). Differences are given with unadjusted p values and critical levels in the case of normally distributed data. In the case of non-normally distributed data, statistical significance was assumed with a p value of !0.05. When comparing patients who completed the study protocol to dropout patients, the unpaired t test for normally distributed data was used. The 95% confidence interval of the mean (95% CI) is given where appropriate.

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Table 1. Demographic data, lung function parameters and mea-

Table 2. Differences in PaO2 changes during walking when com-

sures of inspiratory muscle function (n = 11; 1 female) Age, years BMI, kg/m2 Smoking, pack years Hb, g/dl Hct, % proBNP, pg/ml FVC, % predicted FEV1, % predicted FEV1/FVC, % TLC, % predicted RV, % predicted PImax1.0, kPa P0.1, kPa P0.1 ! ti/VT, kPa ! s/ml SnPa, kPa 63810 28.685.0 40831 15.181.5 46.183.8 1378165 51816 2689 38.587.4 115821 263880 5.081.7 0.780.2 0.8480.27 4.181.6

paring Study Arms A (normal dosage of supplemental oxygen), B (double dosage of supplemental oxygen) and C (noninvasive ventilation in addition to normal dosage of supplemental oxygen) B vs. A PaO2 change, mm Hg Unadjusted p value Critical level 4.1812.8 0.35 0.05 C vs. A 14.0816.6 0.0036 0.017 C vs. B 9.9812.3 0.03 0.025

BMI = Body mass index; FEV1 = forced expiratory volume in 1 s; FVC = forced vital capacity; Hb = hemoglobin; Hct = hematocrit; P0.1 = mouth occlusion pressure 0.1 s after the onset of inspiration during normal breathing; PImax1.0 = maximal inspiratory mouth pressure sustained for 1.0 s; proBNP = N-terminal pro-B-type natriuretic peptide; RV = residual volume; SnPa = sniff nasal pressure; ti = inspiratory time; TLC = total lung capacity; VT = tidal volume.

Results

Nineteen patients were included in the present study. Eight patients refused to perform the 12MWT with NPPV (Study Arm C). All of these patients stated that the backpack was too heavy with the ventilator included (7.3 kg with NPPV plus the oxygen tank vs. 3.1 kg with the oxygen tank alone). Results are therefore restricted to the eleven patients who completed the entire study protocol. Patient characteristics are given in table 1. Significant comorbidity was evident in these patients: seven suffered from arterial hypertension under optimal medication, five from stable coronary heart disease without relevant cardiac function impairment, two from mild pulmonary hypertension, three from diabetes mellitus type II under oral medication and one from moderate osteoporosis. Patients who completed the entire study protocol had significantly higher values for hemoglobin (15.1 8 1.5 vs. 12.9 8 1.7 g/dl, 95% CI 4.1 to 0.9; p = 0.005) and hematocrit (46.1 8 3.8 vs. 40.4 8 4.3%, 95% CI 9.8 to 1.6; p = 0.01) compared to patients who declined to walk with the ventilator. However, when patients who completed the study were compared to those who dropped out, no differences were found in demographic data, lung funcPreserving Oxygenation during Walking in Severe COPD

tion parameters, N-terminal pro-B-type natriuretic peptide and ventilation parameters (all p 6 0.05). The mean duration of long-term NPPV was 27 8 33 months (range 281). Mean inspiratory positive airway pressure was 29 8 4 mbar; mean expiratory positive airway pressure was 4 8 1 mbar, and mean respiratory rate was 19 8 2/min. The mean inspiratory trigger was set at 4 8 1 and the mean expiratory trigger was set at 2 8 0. The mean flow rate of supplemental oxygen during walking was 2 8 1 l/min for Study Arm A and Study Arm C and 4 8 1 l/min for Study Arm B. Interfaces were not changed during walking compared to those used at home; full face masks were used in ten patients and nasal masks were used in nine patients. There was a significant difference in the change in PaO2 during walking with different dosages of supplemental oxygen supply and walking with NPPV (p = 0.011, RM-ANOVA). PaO2 decreased during walking with different dosages of oxygen (Study Arms A and B) by 8.2 8 10.9 and 4.2 8 10.9 mm Hg, respectively, but increased by 5.8 8 10.0 mm Hg when walking was performed with NPPV (Study Arm C). The differences in PaO2 changes during the three study arms served as the primary outcome parameter and are shown in table 2 and figure 3. PaCO2 increased comparably during all study arms (table 3). Differences in changes in blood pressure, heart rate, lung function parameters, measures of inspiratory muscle function and BSlimb during the 12MWT are shown in table 3. The median increases in BDS during the 12MWT were 4 (interquartile range 2.3 6.4), 3 (interquartile range 2.05.9) and 4 (interquartile range 2.45.8) for Study Arms A, B and C, respectively, and were devoid of any differences (all p 6 0.05; table 3). However, when comparing NPPV (Study Arm C) to different dosages of oxygen (Study Arms A and B), the 12MWD revealed a difference of 64.1 8 70.6 m (unadjusted p = 0.015, critical level = 0.017, RM-ANOVA) in favor of Study Arm A and 66.4 8 86.6 m (unadjusted p = 0.019, critical level = 0.025) in favor of Study Arm B (table 3).
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Table 3. Changes ( ) in parameters during the 12MWT with different dosages of oxygen (Study Arms A and B) and NPPV (Study

Arm C) Variables PaO2, mm Hg PaCO2, mm Hg pH HR, /min Mean BP, mm Hg FVC, % predicted FEV1, % predicted P0.1, kPa VT, ml P0.1 ! ti/VT, kPa ! s/ml PImax1.0, kPa SnPa, kPa BDSa BSlimba 12MWD, m Study Arm A (single dosage of oxygen) 8.2810.9b 5.284.3 0.0380.03 28.6817.9 6.887.1b 4812 1.482.5b 0.0780.10 498343 0.0780.16b 0.581.88 0.380.8 4 (2.256.375) 0 (03) 6198210b Study Arm B (double dosage of oxygen) 4.2810.9 3.382.2 0.0380.02 14.3819.7 9.287.1 5813 0.183.2 0.0280.17 1688346 0.0180.17 0.481.1 0.180.9 3 (25.875) 0.5 (03) 6228215b Study Arm C (NPPV) 5.8810.0b 7.087.9 0.0580.04 24.4816.0 15.487.8b 2822 2.484.0b 0.0180.19 1108393 0.1980.27b 0.181.7 0.281.2 4 (2.3755.75) 0 (02.75) 5558227b RM-ANOVA p value 0.011 0.256 0.126 0.114 0.013 0.90 0.043 0.257 0.047 0.007 0.357 0.146 0.266 0.196 0.024

BP = Blood pressure; HR = heart rate; FVC = forced vital capacity; FEV1 = forced expiratory volume in 1 s; P0.1 = mouth occlusion pressure 0.1 s after the onset of inspiration during normal breathing; PaCO2 = arterial partial pressure of carbon dioxide; PaO2 = arterial partial pressure of oxygen; PImax1.0 = maximal inspiratory mouth pressure sustained for 1.0 s; SnPa = sniff nasal pressure; ti = inspiratory time; VT = tidal volume. a Median values are given with interquartile ranges. b Unadjusted p value less than the critical level following one-way RM-ANOVA (overall significance level = 0.05, including an allpairwise comparison using the Holm-Sidak method).

Change in PaO2 during walking (mm Hg)

15 10 5 0 5 10 15 Study Arm A

Study Arm B

Study Arm C

There was no significant difference in the number of rests (A: 2 8 2, B: 2 8 2, C: 2 8 3) or the duration of resting periods (A: 45 8 64, B: 63 8 97, C: 84 8 110 s) during the three study arms (all p 6 0.05, RM-ANOVA). After 6 min of walking, there was no significant difference in BDS and BSlimb between the study arms. However, SpO2 after 6 min was different across the three study arms (A: 86 8 8, B: 89 8 5, C: 92 8 4%; p = 0.04, RMANOVA). Here, the difference in SpO2 between Study Arms A and C was 6.3 8 7.8% (unadjusted p = 0.012, critical level = 0.017). Furthermore, the walking distance after 6 min was different between the three study arms (A: 311 8 105, B: 322 8 105, C: 284 8 110 m; p = 0.01, RM-ANOVA).

Fig. 3. Changes in PaO2 during the 12MWT with single (Study Arm A) and double (Study Arm B) dosages of supplemental oxygen and with NPPV in addition to the single dosage of supplemental oxygen (Study Arm C). * Unadjusted p = 0.0036 (critical level = 0.017) following one-way RM-ANOVA (overall significance level = 0.05, including an all-pairwise comparison using the Holm-Sidak method). T bars represent the 95% CI.

Discussion

The main finding of the present study revealed that the addition of NPPV to supplemental oxygen during walking in patients with very severe COPD produced superior values for PaO2 compared to walking with supplemental
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oxygen alone. Despite the double dose of supplemental oxygen in the absence of NPPV, the decline in PaO2 could not be prevented. This is suggested to be of clinical importance, since the risk for significant cardiac comorbidities [5, 26, 27], as well as for frequent or complex ventricular arrhythmias, is highest in patients with the most impaired lung function, like those included in the present study [7]. Therefore, the addition of NPPV to supplemental oxygen is theoretically associated with the lowest risk of complications due to exercise-related oxygen desaturation. In addition, changes in FEV1 and tidal volume were in favor of NPPV, thus accentuating the physiological benefits of NPPV-aided walking. Furthermore, specific inspiratory impedance, a marker of the load imposed on the inspiratory muscles, decreased when using NPPV, but remained unchanged when oxygen was given alone. Although global inspiratory muscle strength did not differ among the three study arms, the aforementioned findings indicate that a reduced load is imposed on the inspiratory muscles in the presence of NPPV. This is in line with previous findings that reported unloading of inspiratory muscles in COPD patients during NPPV-aided exercise [9, 10]. Further important observations in the present study were that dyspnea during walking was unrelated to the setting and, in particular, that dyspnea was not reduced despite the substantial improvement in oxygenation when walking with NPPV. This confirms that dyspnea during exercise is not exclusively related to oxygenation in patients with severe COPD. In contrast, several previous studies demonstrated that NPPV is capable of reducing exercise-induced dyspnea in COPD patients [8, 9, 12, 16, 28]. Patients in these studies had a milder form of the disease without the presence of chronic hypercapnic respiratory failure, thus distinguishing them from the patients who participated in the present study. However, the finding that dyspnea was not reduced, despite improved oxygenation with NPPV-aided walking, is in contrast to our previous study, where the documented improvement in oxygenation that was associated with NPPV-aided walking was coexistent with reduced dyspnea [3]. In this earlier study, patients performed a 6-min walking test, whereas in the present study, patients walked for 12 min in order to both increase the exercise load and detect more pronounced differences in any changes in physiological parameters. However, after 6 min of the 12MWT, there was no improvement in dyspnea when walking was aided by NPPV. The most likely explanation for this discrepancy is the fact that patients in our previous study used a rollator to carry the ventilator and the oxygen tank, while a backpack was used in the current study.
Preserving Oxygenation during Walking in Severe COPD

Here, the rollator is suggested to not only prevent the need for the patient to carry the heavy devices, but also to guarantee maximum efficacy of the respiratory auxiliary muscles. This hypothesis is further supported by a previous study showing that the use of a rollator improves walking distance and increases ventilatory capacity in COPD patients [29]. In contrast, the load of the backpack in the present study might also have negatively influenced respiratory auxiliary muscle function. Walking distance was reduced during NPPV-aided walking in the present study, both at 6 and 12 min, despite improved oxygenation. This is in contrast to our previous study, where improvements in oxygenation gained by NPPV during walking were coexistent with prolonged walking distances [3]. Again, the burden of carrying the devices in a backpack is the most likely reason for the reduced walking distance compared to the prolonged walking distance when using a rollator. This is further supported by the observations that a large proportion of the current patients (42%) refused to carry the backpack containing the ventilator and that the mean blood pressure was increased during NPPV-aided walking. For this reason the present study emphasizes that while the effects of NPPV on oxygen preservation during exercise in patients with severe COPD are clearly beneficial, the burden caused by the weight of the devices used to supply NPPV must be taken into account. Therefore, for patients with severe COPD, the best approach to assist walking, which is perhaps the most significant daily activity that causes dyspnea and oxygen desaturation, is yet to be established. Although there was no need to carry the ventilator when walking with a double dose of oxygen, this approach did not decrease dyspnea, nor did it prolong walking distance or prevent exercise-induced oxygen decline. Therefore, doubling the oxygen dosage does not appear to be the best approach to aid exercise in stable hypercapnic COPD patients. In conclusion, patients with very severe COPD have optimal PaO2 values following walking when NPPV is added to supplemental oxygen, but not when supplemental oxygen, even at a double dose, is used without NPPV. However, dyspnea and walking distance were not improved when carrying the heavy devices (ventilator and oxygen tank) in a backpack, despite improved oxygenation. This is in contrast to previous reports, where the use of a rollator for transporting the ventilator resulted in improvements in oxygenation, dyspnea and walking distance [3]; however, this method is suggested to be less practical in the home environment. Therefore, more practical and acceptable forms of ventilatory support for walking need to be established.
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Acknowledgements
All patients are gratefully acknowledged for their participation in this study. We thank Christine Gall (Center for Clinical Studies, Freiburg, Germany) for statistical consulting and Dr. Sandra Dieni for proofreading the manuscript prior to submission.

Conflict of Interest
The study group received an open research grant from Breas Medical AB, Mlnlycke, Sweden. The authors state that neither the study design, the results, the interpretation of the findings nor any other subject discussed in this paper were dependent on support.

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