Respiratory muscle function during a six-week period of normocapnic hyperpnoea training

Respiratory Physiology & Neurobiology 188 (2013) 208–213

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Respiratory muscle function during a six-week period of normocapnic hyperpnoea training David Johannes Walker a , Thomas Ertl a , Stephan Walterspacher a , Daniel Schlager a , Kai Roecker b , Wolfram Windisch c , Hans-Joachim Kabitz a,∗ a

Department of Pneumology, University Hospital Freiburg, Killianstrasse 5, D-79106, Freiburg, Germany Department of Sports-Medicine, University Hospital Freiburg, Germany c Lung Center Cologne-Merheim, Kliniken der Stadt Köln GmbH, University of Witten/Herdecke, Germany b

a r t i c l e

i n f o

Article history: Accepted 7 May 2013 Keywords: Diaphragm Ergospirometry Twitch transdiaphragmatic pressure Spirotiger Respiratory muscle endurance training

a b s t r a c t Respiratory muscle endurance training (normocapnic hyperpnoea, RMET) improves maximal volitional ventilation (MVV) and respiratory muscle endurance while volitionally-assessed respiratory muscle strength remains unchanged (prior-to-post comparison). What remains unclear is how respiratory muscle function changes/adapts during a defined period of RMET in highly-trained subjects. This study assessed respiratory muscle function during a six-week period of RMET in 13 highly-trained, healthy subjects. Weekly-assessed twitch mouth pressure (prior/post 2.20 ± 0.41 kPa vs. 2.43 ± 0.61 kPa; p = 0.14); twitch transdiaphragmatic pressure (prior/post 3.04 ± 0.58 kPa vs. 3.13 ± 0.48 kPa; p = 0.58) and maximal inspiratory pressure (prior/post 12.6 ± 3.6 kPa vs. 13.9 ± 3.8 kPa; p = 0.06) did not increase. MVV (prior/post 175 ± 18l/min vs. 207 ± 30l/min; p = 0.001), sniff nasal pressure (prior/post 11.8 ± 2.8 kPa vs. 14.0 ± 2.9 kPa; p = 0.003) and maximal expiratory pressure (prior/post 16.9 ± 5.8 kPa vs. 20.9 ± 4.9 kPa; p = 0.006) each increased. In conclusion, non-volitionally assessed diaphragmatic strength does not increase during six weeks of RMET in highly-trained subjects, while expiratory muscle strength and MVV rose. Future studies should clarify if these findings apply when assessed during respiratory muscle strength rather than endurance training. © 2013 Elsevier B.V. All rights reserved.

1. Introduction Respiratory muscle training (RMT) has been shown to improve exercise performance in healthy subjects (McConnell and Romer, 2004; Illi et al., 2012). Basically, there are three different methods of RMT: (i) pressure threshold loading, (ii) flow resistive loading, and (iii) voluntary normocapnic hyperpnoea (McConnell and Romer, 2004). While the former two techniques predominantly comprise strength RMT, the latter is considered to most closely resemble respiratory muscle endurance training (RMET) (Illi et al., 2012; McConnell and Romer, 2004). Given that respiratory muscle function is of high-speed and low-resistance during (intensive) whole-body exercise, RMET has been proposed to most accurately mimic these physiological demands (Verges et al., 2010). RMET prolongs the time to exhaustion during sustained normocapnic hyperpnoea and increases maximum sustainable ventilatory capacity, vital capacity and maximal voluntary ventilation (MVV)

∗ Corresponding author. Tel.: +49 761 270 37060; fax: +49 761 270 37040. E-mail address: [email protected] (H.-J. Kabitz). 1569-9048/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.resp.2013.05.005

(Leith and Bradley, 1976; Markov et al., 2001; McConnell and Romer, 2004; Verges et al., 2009). Furthermore, RMET is capable of prolonging exercise time to exhaustion during constant load cycling (Verges et al., 2009). In contrast, it has been repeatedly shown that strength RMT and RMET fail to promote improvements in maximal oxygen uptake (V˙ O2 max ), maximal workload and gas exchange in healthy subjects (Hanel and Secher, 1991; Illi et al., 2012). While data exist which compared respiratory muscle function prior and post RMET it still remains unclear how non-volitionally assessed respiratory muscle function changes or adapts during the training period. Therefore, this study aimed to prospectively investigate respiratory muscle function by the use of volitional and – for the first time – non-volitional tests during a six-week RMET period in highly-trained subjects. 2. Materials and methods The study received approval from the Institutional Review Board for Human Studies at the University Hospital Freiburg, Germany, and written informed consent was given by each subject before

D.J. Walker et al. / Respiratory Physiology & Neurobiology 188 (2013) 208–213

participation. All procedures conformed to the standards described in the latest version of the Declaration of Helsinki. 2.1. Subjects Thirteen healthy, highly-trained male cyclists who were not under any medication participated in the study. All subjects were advised to avoid stressful physical activity for 24 h, food for 2 h and caffeine-intake for 6 h prior to measurements. Every single participant was instructed and agreed to keep the personal training type and duration constant throughout the entire course of the study. 2.2. Lung function tests, exercise testing and pressure recordings Pulmonary function tests were assessed by bodyplethysmography (ZAN 500® , nSpire Health GmbH, Oberthulba, Germany) according to international guidelines (Miller et al., 2005a,b; Wanger et al., 2005) and reference values according to Matthys et al., 1995. Exercise testing was performed on a computer-controlled, eddy-current-braked cycle ergometer (Ergoselect 100® , Ergoline, Bitz, Germany). An ergospirometric device (ZAN-600® , nSpire Health GmbH, Oberthulba, Germany) registered heart rate, gas-exchange (breath-by-breath method) and ventilation. Blood lactate (Super GL® , Hitado Diagnostic Systems, Moehnensee, Germany) was measured from the arterialized ear lobe (Finalgon® , Boehringer Ingelheim Pharma, Ingelheim, Germany). All pressure signals were recorded by a multiple pressure transducer (ZAN-400® , nSpire Health GmbH, Oberthulba, Germany). The pneumotachograph ZAN-100-Flowhandy-II® (nSpire Health GmbH, Oberthulba, Germany) was used for airflow recordings. While participants had their mouth closed, twitch esophageal (TwPes) and gastric (TwPga) pressures were assessed during bilateral anterior magnetic phrenic nerve stimulation (BAMPS) at 100% power output (Magstim 2002® , Magstim, Wales, United Kingdom) (Mills et al., 1996; Polkey and Moxham, 2001). Gastric and esophageal pressures were measured by a thin conventional double-balloon catheter (nSpire Health GmbH, Oberthulba, Germany) inserted trans-nasally into the distal esophagus (balloon volume 1.5 ml of air) and stomach (balloon volume 3.0 ml of air). Calculation of twitch transdiaphragmatic pressure (TwPdi) was performed by subtracting TwPes from TwPga. Controlled twitch mouth pressure (TwPmo) during BAMPS was assessed using a computer-controlled inspiratory pressure trigger to avoid glottic closure as described in detail elsewhere (Kabitz et al., 2007). Supramaximality was not re-tested in this study, since it has already been shown that BAMPS reliably achieves supramaximal phrenic nerve stimulation (Mador et al., 1994; Mills et al., 1996). BAMPS was performed while subjects sat on a standardized chair with back rest after exact localization of coil position (Mills et al., 1996; Polkey and Moxham, 2001). In order to minimize the confounding effects of enhanced contractile response due to twitch potentiation (Mador et al., 1994; Vandervoort et al., 1983; Wragg et al., 1994), standardized maximal static inspiratory efforts lasting 5 s each were performed prior to all twitch pressure assessments. TwPdi measurements were accepted if (i) gastric and esophageal pressure signals remained within baseline pressure at least 50 ms before magnetic stimulation, and (ii) all twitch pressure curves displayed a characteristic twitch response (Kabitz et al., 2007; Windisch et al., 2005). If these criteria were not fulfilled, supplemental twitch impulses were performed until 5 valid twitch pressures were recorded. Ventilatory drive was estimated by mouth occlusion pressure after 0.1 s of inspiration (P0.1 ). Maximal static inspiratory/expiratory mouth occlusion pressure measured from residual volume/total lung capacity (PImax /PEmax ), and maximal voluntary

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ventilation in 15 s (MVV) were obtained based on previous recommendations (American Thoracic Society, 2002). Sniff nasal pressure (SnPna) was assessed at functional residual capacity, as described previously (Héritier et al., 1994). All volitional tests on respiratory muscle function were performed at least seven times if the top two values differed <10%. If this was not the case, the series was extended until this criterion was met (American Thoracic Society, 2002). 2.3. Respiratory muscle endurance training Subjects undertook 30 min of RMET for 6 days a week, plus one day of rest, for a total training period of 6 weeks. RMET was performed using a commercially available normocapnic hyperpnoea device (Spirotiger® , Idiag AG, Fehraltorf, Switzerland). In brief, this device ensures normocapnia by partial carbon dioxide rebreathing into a bag, with subjects breathing at a given tidal volume (VT ) and breathing frequency (fb ). VT was set at 50–60% of each subject’s vital capacity, while minute ventilation was set at 60% of the subject’s initial MVV, as described previously (Renggli et al., 2008; Verges et al., 2007). Participants were thoroughly familiarized with the device prior to the training period. Thereafter, participants performed RMET at home. The correct use of the training device was additionally ensured at each ensuing visit after the initiation of RMET. Each participant was instructed to document their training settings on a daily basis. According to the improvements achieved during RMET, participants were also told to adjust the initial training settings of the device on a daily basis, as outlined previously (Verges et al., 2007). In brief, the following three scenarios occurred: (i) If subjects did not feel exhausted after 25 min of training, they had to increase fb by 5 breaths/min for the final 5 min. For the next training session, fb had to be increased by 2 breaths/min. (ii) If subjects felt exhausted after 25 min of training, they were told to decrease fb by 5 breaths/min for the final 5 min. For the next training session, fb remained unchanged compared to the previous settings. (iii) If case (i) and (ii) did not apply, subjects were told to increase fb by 1 breath/min for the next training session. 2.4. Experimental protocol A synopsis of the entire experimental protocol is given in Fig. 1. 2.4.1. Pre-training (A–B) and post-training (A–B) visits At pre- and post-training visit A, V˙ O2 max was measured during a standardized incremental workload test (90 s rest; 90 s unloaded pedaling; 50 W steps lasting 180 s each until exhaustion) (American Thoracic Society, 2002). Throughout the entire exercise protocol pedaling frequency had to be maintained between 90–95 revolutions per minute. A drop below 90 revolutions/min for three consecutive seconds, despite verbal encouragement, was defined as the stop criterion. At pre- and post-training visit B, respiratory muscle function tests (P0.1 , PImax , PEmax , SnPna, TwPmo, TwPdi, MVV) and bodyplethysmography were consecutively performed. 2.4.2. Weekly assessment visits During the weekly assessment visits (week I–VI) the following procedures were performed: (i), respiratory muscle function tests (P0.1 , PImax , PEmax , SnPna, TwPmo, MVV); (ii), spirometry; (iii), verification of the daily RMET settings and documentation records.

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Additional Assessment to TwPdi I LFT

Assessment

A B

B A

Incremental Workload Test

#

[time]

#

*

* RMET Period

Assessment PImax I PEmax I SnPna I TwPmo I MVV

Fig. 1. Experimental study design. Prior to the 6-week respiratory muscle endurance training (RMET), subjects performed an incremental workload test (#, pre-training visit A), and underwent lung function testing (LFT) and assessment of twitch transdiaphragmatic pressure (TwPdi) (*), twitch mouth pressure (TwPmo), maximal static inspiratory pressure (PImax ), maximal static expiratory pressure (PEmax ), sniff nasal pressure (SnPna) and maximal volitional ventilation (MVV) (pre-training visit B). At the end of each week of RMET measurements of TwPmo, PImax , PEmax , SnPna, MVV were performed (end of week I–VI, ). At the end of the RMET period, all measurements conducted at visits A and B were repeated (# post-training visit A and *B).

Table 1 Demographic data, lung function and incremental workload test parameters from the initializing study phase (n = 13).

Mean SD±

Age (years)

BMI (kg/m2 )

VC (%pred)

FEV1 (%pred)

V˙ O2 max (ml/min/kg)

HRmax (min−1 )

BLmax (mmol/l)

WLmax (W)

26.8 3.7

22.8 2.3

104 8

102 8

60.9 6.6

190 8

11.0 2.4

371 36

BLmax = blood lactate values at exercise termination; BMI = body-mass index; FEV1 = forced expiratory volume in 1 s; VC = vital capacity; HRmax = heart rate at exercise termination; V˙ O2 max = maximal oxygen uptake; WLmax = maximal workload.

2.5. Statistical analysis Statistical calculations were performed with Sigma-Plot 11.2® software (Systat Software, Point Richmond, USA). Data are presented as mean ± standard deviation (SD), unless otherwise stated. The 95% confidence interval of the mean (C.I.) is given where appropriate. A two-group comparison was performed using the paired Student’s t-test for normally distributed data. Statistical significance was assumed with an ␣-level of <0.05. According to the sample size determination 13 subjects had to be included in the study. This was based on an expected mean difference of 0.35 kPa between TwPmo prior to and post RMET (paired Student’s t-test; power, 0.8; two-sided type I error, 0.05) with an estimated SD of 0.40 kPa. The mean TwPmo difference value of 0.35 kPa would reflect an increase of about 15%.

3. Results 3.1. Pre-training (A–B) and post-training (A–B) visits Demographic data, results from the lung function and exercise tests are presented in Table 1. Lung function was normal in all subjects and physical training status was deemed as excellent, as can be seen from the results for V˙ O2 max . There was no significant change when comparing mean values for forced expiratory volume in 1 s (4.70 ± 0.49 l vs. 4.67 ± 0.52 l, p = 0.70) and vital capacity (5.97 ± 0.57 vs. 6.03 ± 0.57, p = 0.70) prior and following the entire RMET period.

3.2. Weekly assessment visits Fig. 2 illustrates the results from weekly assessment of MVV (2A), SnPna (2-B), PImax (2-C), and PEmax (2-D) over the entire training period. MVV, SnPna, and PEmax showed an increase when pre- vs. post training conditions were compared (all p < 0.01), while PImax revealed a strong tendency toward higher values (p = 0.055). MVV showed an initial increase during the first two weeks of training and plateaued thereafter. In contrast, SnPna and PEmax increased steadily over the entire training period. The progression of TwPmo over the six-week training period is presented in Fig. 3. There was

no significant increase in TwPmo values when pre- and post training values were compared (p = 0.135). Table 2 presents a detailed comparison of the key-variables for respiratory muscle function and exercise performance in pre- vs. post training. V˙ O2 max , maximal heart rate, blood lactate and maximal workload did not change (all p > 0.05). The mean and individual values for pre- vs. post training assessment of the key-variables are further illustrated in Fig. 4.

4. Discussion This is – to the best of our knowledge – the first study to investigate diaphragmatic force generation during a 6-week period of respiratory muscle endurance training (normocapnic hyperpnoea) by the use of non-volitionally-assessed twitch pressures. The main finding is that volitionally-assessed inspiratory (SnPna) and expiratory muscle strength (PEmax ) increased following the training period while TwPmo does not increase over the entire period.

Table 2 Pre- vs. post-training assessments of key-variables for respiratory muscle function and exercise performance.

MVV (l/min) TwPmo (kPa) TwPdi (kPa) SnPna (kPa) PImax (kPa) PEmax (kPa) WLmax (W) V˙ O2 max (ml/min/kg) Blood lactate (mmol/l) HRmax (min−1 )

Pre training

Post training

175 ± 18 2.20 ± 0.41 3.04 ± 0.58 11.8 ± 2.8 12.6 ± 3.6 16.9 ± 5.8 371 ± 36* 60.7 ± 6.6* 11.0 ± 2.4* 190 ± 8*

207 2.43 3.13 14.0 13.9 20.9 379 63.0 10.4 190

± ± ± ± ± ± ± ± ± ±

30 0.61 0.48 2.9 3.8 4.9 35* 8.1* 2.4* 8*

p = 0.001 p = 0.135 p = 0.577 p = 0.003 p = 0.055 p = 0.006 p = 0.386 p = 0.147 p = 0.678 p = 0.093

MVV = maximal volitional ventilation; TwPmo = twitch mouth pressure; TwPdi = twitch transdiaphragmatic pressure; SnPna = sniff nasal pressure; PImax = maximal static inspiratory pressure; PEmax = maximal static expiratory pressure; WLmax = maximal workload; V˙ 2 max = maximal oxygen uptake; HRmax = maximal heart rate. * n = 11.

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B 18

220

16

200

14

SnPna [kPa]

MVV [l/min]

A

180

12

160

10

140

8

0

211

0

baseline

I

II

III

IV

V

Baseline

post training

C

I

II

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post training

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PEmax [kPa]

PImax [kPa]

14

12

20

15

10

10 0

0

baseline

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post training

baseline

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Fig. 2. (A)–(D) Progression of maximal volitional ventilation (MVV; A), sniff nasal pressure (SnPna; B), maximal static inspiratory pressure (PImax ; C) and maximal static expiratory pressure (PEmax ; D) before, during and after the 6 week RMET period. Values for baseline vs. post training reflect measurements taken at the end of the corresponding week (I–V).

4.1. 1. Critique of methods The sample size (n = 13) of this study may appear rather small. This is particularly relevant in terms of a potential type II error at the primary endpoint, i.e. there might have been a difference in TwPmo before and after the training period which was not detected due to the small sample size. However, the sample size in the present study is comparable to previous studies in the field (Sonetti et al., 2001; Verges et al., 2007). Another potential point of criticism is that the overall effects of training were not compared to a control group performing “sham”

3.0 2.8 2.6

TwPmo [kPa]

2.4 2.2 2.0 1.8

training. This might lead to confounding effects on volitionallyassessed respiratory muscle function assessment, whereby an increase could be attributed to learning effects. This holds true with regard to results on SnPna and PEmax which increased following the training period. However, the primary endpoint is a non-volitionally-assessed marker of respiratory muscle strength and, therefore, learning effects do not confound these results. In addition, this test (i.e. TwPmo) revealed that there was no increase when values before and after the training period were compared. Furthermore, it has been shown that the performance outcome of respiratory muscle training is not affected by the presence or absence of a control group (Illi et al., 2012). Finally, it might be argued that there is a discrepancy between the fact that the training method is based on endurance training (high-speed, low-resistance) rather than strength training (highresistance, low-speed, Verges et al., 2009), whereas the assessment of respiratory muscle function is based on strength parameters. The primary justification for this disparity is the fact that, in contrast to gold standard twitch pressures, there are currently no conclusivelyestablished, non-volitional methods available for the assessment of respiratory muscle endurance. Furthermore, training that primarily focuses on respiratory endurance is also suggested to impact – at least in part – on respiratory muscle contractility.

1.6

4.2. Current findings in the light of the available body of literature

1.4 0 baseline

I

II

III

IV

V

post training

Fig. 3. Development of twitch mouth pressure (TwPmo) before, during and after the 6-week RMET period. Values for baseline vs. post training reflect measurements taken at the end of the corresponding week (I–V).

PImax values only showed a tendency toward increasing over the entire training period, but this increase was not significant. This is in line with previous reports in which PImax remained relatively unchanged (Verges et al., 2009; Wylegala et al., 2007). SnPna was not investigated in earlier studies. Noteworthy, SnPna increased

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25

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n.s.

n.s.

4.0

4.0

20

3.5

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PImax [kPa]

TwPmo [kPa]

TwPdi [kPa]

3.5

2.5

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2.5 2.0

2.0

10

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p = 0.001

D 280

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p= 0.003

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p = 0.006

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SnPna [kPa]

MVV [l/min]

25

15

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20

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post training

Baseline

post training

Fig. 4. (A)–(F) Mean and individual values for prior vs. post training assessment including the 95% C.I. for twitch transdiaphragmatic pressure (TwPdi; A), twitch mouth pressure (TwPmo; B); maximal static inspiratory pressure (PImax ; C); maximal volitional ventilation (MVV; D); sniff nasal pressure (SnPna; E) and maximal static expiratory pressure (PEmax ; F). n.s. = not significant.

while PImax only tended to do so and TwPmo and TwPdi did not. This might be explained by the fact that SnPna is the only dynamically assessed marker on inspiratory muscle function compared to the static maneuvers and RMET might beneficially impact on this. Interestingly, peak inspiratory flow, however, has been shown not to increase following RMET (Verges et al., 2009). The only pre-existing studies which used non-volitional tests on respiratory muscle function revealed that TwPdi did not increase when baseline values were compared to values obtained after 4–6 week periods of training (Hart et al., 2001; Verges et al., 2007, 2009). Importantly, the current study is first to provide a weekly assessment of twitch pressures throughout an entire training period, and to demonstrate that there is no increase in TwPmo during this time. Regarding PEmax , the observed linear increase demonstrates that normocapnic hyperpnoea is capable of improving expiratory muscle strength. This is in contrast to previous results, where no increase in PEmax was observed after four weeks of normocapnic hyperpnoea (Verges et al., 2009). It should be, however, considered that changes in lung volumes over the training period might have an influence on assessment of respiratory muscle function. Finally, MVV increased with an early improvement, followed by no further increase toward the end of the study protocol. Notably, an increase in MVV was achieved despite the fact that MVV baseline values in this highly-trained cohort were rather high compared to the predicted normal values (Verges et al., 2009). Similar improvements

have also been reported in studies that compared MVV values prior to and following the training period (Verges et al., 2009). When comparing the present study to previous investigations (Verges et al., 2009) it needs to be considered that the current training protocol included notably more training sessions and this is suggested to impact on the current results. 4.3. Absence of increased diaphragmatic force generation Interestingly, there was no increase in TwPmo over the entire training period. This is surprising, given that normocapnic hyperpnoea is known to improve MVV and respiratory muscle endurance (Illi et al., 2012; Verges et al., 2009). To this end, it is important to note that this study recruited highly-trained competitive cyclists. For this particular cohort it was previously shown that the margin for improvement in respiratory muscle function is narrow compared to subjects with a low physical training status and therefore in whom a major improvement can be expected (Illi et al., 2012). However, the potential benefits of improved MVV and respiratory muscle endurance in highly-trained competitive sportsmen are extremely relevant to high-end performance, since even a minor enhancement could result in an overall improvement in physical output (Illi et al., 2012). Of note, the observed increase in MVV in the present (and several previous) cohort(s) occurred in the absence of an increase in

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diaphragmatic force generation as assessed by twitch pressures. This demonstrates that the increase in ventilation and respiratory endurance (as shown previously) are unlikely to be explained by an increase in diaphragmatic strength. 5. Conclusion Non-volitionally assessed diaphragmatic force generation in highly-trained subjects did not change during six weeks of normocapnic hyperpnoea. Expiratory and volitionally-assessed inspiratory (i.e. SnPna) muscle strength, however, increased over the training period, whereas respiratory endurance (i.e. MVV) rose in the early phases but did not elevate further over the remaining time. Future studies need to verify whether these observations also hold true for respiratory muscle strength rather than endurance training. Acknowledgements The present study was supported by a research grant from the German Research Society DFG (Deutsche Forschungsgemeinschaft, KA 2992/2-1), Bonn, Germany. We would like to acknowledge all subjects for the effort they devoted to this study. We would also like to thank Idiag AG (Fehraltorf, Switzerland) for their technical support. We are grateful to Dr. Claudia Schmoor (Biometry and Data Management, Center of Clinical Trials, University Medical Center Freiburg, Germany) for statistical advice and Dr. Sandra Dieni and Franziska Farquharson for valuable assistance with the manuscript prior to submission. References American Thoracic Society, 2002. ATS/ERS statement on respiratory muscle testing. American Journal of Respiratory and Critical Care Medicine 166, 518–624. Hanel, B., Secher, N.H., 1991. Maximal oxygen uptake and work capacity after inspiratory muscle training: a controlled study. Journal of Sports Sciences 9, 43–52. Hart, N., Sylvester, K., Ward, S., Cramer, D., Moxham, J., Polkey, M.I., 2001. Evaluation of an inspiratory muscle trainer in healthy humans. Respiratory Medicine 95, 526–531. Héritier, F., Rahm, F., Pasche, P., Fitting, J.W., 1994. Sniff nasal inspiratory pressure A noninvasive assessment of inspiratory muscle strength. American Journal of Respiratory and Critical Care Medicine 150, 1678–1683. Illi, S.K., Held, U., Frank, I., Spengler, C.M., 2012. Effect of respiratory muscle training on exercise performance in healthy individuals: a systematic review and metaanalysis. Sports Medicine 42, 707–724. Kabitz, H.-J., Walker, D., Walterspacher, S., Windisch, W., 2007. Controlled twitch mouth pressure reliably predicts twitch esophageal pressure. Respiratory physiology & neurobiology 156, 276–282. Leith, D.E., Bradley, M., 1976. Ventilatory muscle strength and endurance training. Journal of Applied Physiology 41, 508–516.

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