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ORIGINAL ARTICLE

Rationale of the Combined Use of Inspiratory and Expiratory Devices in Improving Maximal Inspiratory Pressure and Maximal Expiratory Pressure of Patients With Chronic Obstructive Pulmonary Disease Elvia Battaglia, MD, Alessandro Fulgenzi, BSci, Maria Elena Ferrero, MD ABSTRACT. Battaglia E, Fulgenzi A, Ferrero ME. Rationale of the combined use of inspiratory and expiratory devices in improving maximal inspiratory pressure and maximal expiratory pressure of patients with chronic obstructive pulmonary disease. Arch Phys Med Rehabil 2009;90:913-8. Objective: To examine the rationale of the combined use of a new expiratory device in association with a previously assessed inspiratory device in improving 3 indicators of the respiratory muscle strength, for example, maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), and dyspnea grade. Design: Randomized trial. Setting: Home-based pulmonary rehabilitation. Participants: Adults (N⫽32; mean age, 68y). Main Outcome Measure: We instructed 32 patients with mild to very severe COPD to use the devices, and randomized them in a 1:1 ratio: they were assigned to the sham training control group (16 patients who trained at a load not able to improve MIP and MEP) or to the training group (16 patients). The patients trained at home twice daily for 15 minutes, 7 days a week, for 12 months. MIP and MEP as well as dyspnea perception were evaluated at 1, 6, and 12 months from the beginning of the training. The impact of additional work of breathing was measured at baseline and after the use of the expiratory device. Results: The patients who performed the respiratory training showed significant and progressive improvements of MIP (81⫾4 at 12 months vs 57⫾7 as basal values expressed in cm H2O; P⬍.05) and MEP (97⫾2 at 12 months vs 62⫾4 as basal values; P⬍.05) at the end of the training. In addition, they showed a significant reduction of dyspnea perception (1.18⫾ 0.29 vs 2.93⫾0.32 as basal values; P⬍.05) at the end of the training. Conclusions: This study suggests that home exercise with the combined use of our expiratory and inspiratory devices leads to a significant improvement of respiratory muscle function in patients with mild to very severe COPD. Key Words: Pulmonary disease, chronic obstructive; Rehabilitation. © 2009 by the American Congress of Rehabilitation Medicine

From the Pulmonary Department, San Carlo Borromeo Hospital (Battaglia); Institute of General Pathology, University of the Study (Fulgenzi, Ferrero), Milan, Italy. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit on the authors or on any organization with which the authors are associated. Reprint requests to Maria Elena Ferrero, MD, Istituto di Patologia Generale, Università degli Studi di Milano, Via Luigi Mangiagalli, 31, 20133 Milano, Italy, e-mail: [email protected] 0003-9993/09/9006-00498$36.00/0 doi:10.1016/j.apmr.2008.12.019

ESPIRATORY MUSCLE FUNCTION is severely comR promised in patients with COPD. Several new studies indicate the advantages provided by the use of devices able to improve the inspiratory muscle activity in subjects with COPD. In fact, a recent systematic review, aimed to determine the effects of IMT in adults with COPD, has shown that targeted resistive or threshold IMT was associated with significant improvements in some outcomes of inspiratory muscle strength and endurance, exercise capacity, work rate maximum, and dyspnea.1 Moreover, when in adults with COPD the effect of IMT was compared with other rehabilitation interventions, such as education, significant improvements in inspiratory muscle strength and endurance and in the dyspnea scale on a QOL measure were shown in participants in the IMT versus education group.2 In addition, an interval-based high-intensity IMT (3 times a week for 8 weeks), performed at the highest tolerable inspiratory threshold load, has been demonstrated to be useful in improving inspiratory muscle function in subjects with moderate to severe COPD, yielding meaningful reductions in dyspnea and fatigue.3 We also previously showed that the use of a new flow-volumetric inspiratory exerciser was efficient in reducing symptoms and improving QOL in patients with COPD.4 The daily home IMP, performed by using an inspiratory device at intensive level for 6 months, was able to improve the respiratory parameters significantly in each patient. The use of IMT has been shown to provide clinical benefits in patients with COPD; on the contrary, the effects of specific expiratory muscle training previously have been difficult to evaluate. However, recent results show that a 5-week program of expiratory training improved symptoms and QOL in patients with severe COPD.5 Some data suggest that there is probably no additional benefit in combining expiratory and inspiratory muscle training.6 Moreover, it seems that IMT is slightly superior to expiratory muscle training in providing further benefits over the improvement of respiratory muscle functions, such as the reduction in dyspnea.7 In the present study, we assessed the usefulness of a new respiratory device that is a positive expiratory pressure resistive trainer. This device is

ANOVA COPD FEV1 GOLD IMT MEP MIP QOL WBimp

List of Abbreviations analysis of variance chronic obstructive pulmonary disease forced expiratory volume in 1 second Global Initiative for Chronic Obstructive Lung Disease inspiratory muscle training maximal expiratory pressure maximal inspiratory pressure quality of life work of breathing

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endowed with some peculiar details different from those in the other commonly used devices. In fact, an expiratory device can be used alone by the patient to perform expiratory muscle training. Alternatively, it can be connected to an inspiratory exerciser to perform both inspiratory and expiratory muscle training. We tested the latter properties of the device by studying its efficacy in pulmonary rehabilitation of patients with mild to very severe COPD, when used for 1 year, and paired with the use of the inspiratory muscle trainer we assessed previously. We employed the inspiratory and expiratory devices to verify whether their contemporary use was able to improve the functional parameters MIP and MEP, which indicate the inspiratory and expiratory muscle strength, respectively. In addition, we tested the exercise capacity and dyspnea grade by means of the Borg scale. We tested the possibility to improve the respiratory functions of patients with COPD by using the combined inspiratory and expiratory muscle training for a long time, because previously it has been shown that the benefits of 12 weeks of IMT declined gradually over 1 year of follow-up if maintenance training was not performed.8 METHODS Characteristics of the Device Respilifta is a disposable (single-patient rather than singleuse) device specifically designed for expiratory exercise when used alone, and for both inspiratory and expiratory exercise when associated with Respivol or other similar inspiratory muscle trainer devices (fig 1). It allows the real-time evaluation of inspiratory and expiratory flow of the patient. It consists of a chamber supporting a column containing a mobile indicator (float) useful for the evaluation of the total expiratory volume. A mouthpiece tube endowed of a filter is connected to one side of the chamber. On the other side of the chamber is inserted a slim washable silicon valve, which is able to close the air flow during the expiration and to open the air flow when inspiration occurs, after the association with an inspiratory device such as Respivol.4 Obviously, this side of the chamber is closed by a plug when the Respilift is used alone. All the components of the device can be easily assembled and are washable. Participants The investigations were performed after approval of the institutional ethics committee on human research, and all patients signed the informed consent. Thirty-two stable subjects with COPD (mean age, 68y) were enrolled in the study. In all the subjects, the diagnosis of COPD was made as previously reported4 on the basis of the functional obstruction criteria as described in the GOLD guidelines on spirometry.9 All the subjects also performed a test of bronchodilation with the inhalation of 400␮g salbutamol and repeated spirometry 20 minutes after the inhalation. None of the subjects tested revealed a significant bronchodilation (minor of 12% of the basal values, according to GOLD guidelines). GOLD criteria were also followed for staging COPD severity into mild (FEV1⬎80%, stage I), moderate (FEV1 between 50% and 80%, stage II), severe (FEV1 between 50% and 30%, stage III), and very severe (FEV1⬍30%, stage IV). The subjects were randomized in a 1:1 ratio by using sealed envelopes to undergo either the respiratory muscle training (training group) or training at a load known not to yield improvements in inspiratory and expiratory muscle function (airflow resistance was set at ⫾5% MIP: sham training control group). Ten patients from the Arch Phys Med Rehabil Vol 90, June 2009

Fig 1. Respivol and Respilift are depicted. Upper panel, Respilift alone. Lower panel, 2 combined devices.

training group were affected by cardiac diseases (hypertension, ischemic heart disease, valvulopathy); 9 patients were affected by 2 different associated heart disorders. All the training patients were given medical therapy for COPD: 11 patients received fluticasone propionate (250␮g twice daily) and salmeterol xinafoate (50␮g twice daily); 5 patients received fluticasone propionate (250␮g twice daily) plus salmeterol xinafoate (50␮g twice daily) plus oxitropium bromide (200␮g twice daily). In the sham training control group, 10 patients of 16 were affected by cardiac diseases. Control patients were given medical therapy for COPD: 8 received fluticasone propionate (250␮g twice daily) plus salmeterol xinafoate (50␮g twice daily) plus tiotropium bromide (18␮g/die); 6 patients received fluticasone propionate (250␮g twice daily plus salmeterol xinafoate 50␮g twice daily); 2 patients received salmeterol xinafoate (50␮g twice daily). The differences in medications were not significant. In all the patients of the 2 groups (training and sham training controls), COPD was associated with a very mild asthmatic component (all were ex-smokers), and inhaled steroid was used. No patient used oral steroids, and no exacerbation occurred during the follow-up period and the 2 months before enrollment. All the patients completed the study. Procedure First, all patients were instructed to use the inspiratory exerciser Respivol, as previously reported.4

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After a sufficient training time with Respivol alone at home (about 10 days for each patient), the patients received ambulatorial training to use both Respivol and Respilift (aimed to employ the mouth both in inspiration and in expiration) until achieving at least 30 minutes of exercise a day (15 minutes in the morning and 15 minutes in the evening). Successively, each patient trained at home twice daily for 15 minutes, 7 days a week, for 12 months. The patients gradually progressed in the time until reaching 15 minutes twice a day with an increase of 5 minutes of the exercise every 2 days. The impact of additional work of breathing was also measured at baseline and after the use of Respilift. Each patient was evaluated in the first visit, before the use of the exercisers, after 1 month, after 6 months, and after 12 months from the beginning of the training. The ventilatory variables, tidal volume and breathing frequency, were recorded for each patient by spirometry before the use of the exercisers and at each programmed visit. The evaluation of heart rate and of dyspnea was performed before, during, and at the end of training by using the Borg scale. The compliance with the use of both the Respivol and the Respilift was verified by a telephone interview of a hospital nurse at least once a week. All the patients performed the respiratory training at home, and the visits were performed at the hospital. MIP and MEP Measure MIP and MEP were measured together (Sensor Medics; Vmax 22b) in each patient at each programmed visit and expressed in cmH2O. MIP static at resting ventilation and MEP at total lung capacity against an obstructed mouthpiece with a small leak to minimize oral pressure artefacts were measured, using a differential pressure transducer (Statham SC 1001c). The subjects, comfortably seated and wearing a noseclip, performed maximal inspiratory and expiratory efforts and were instructed to maintain maximal pressure for at least 3 seconds. The maneuvers were repeated until 3 measurements with less than 5% variability were recorded, and the measures of MIP and MEP were conducted together 24 hours after the intervention. The highest value obtained was used for analysis. Pressure transducers were calibrated with a water manometer before studying each patient. Dyspnea Measurement The Borg scale in rating of perceived exertion to measure breathlessness was used for each subject at baseline and at 1 month, 6 months, and 12 months of training. Dyspnea values were tested at rest at the end of the six-minute walk test and during pneumologic visits as scheduled. Statistical Analysis All of the results are expressed as mean ⫾ standard error of the mean. To determine whether there were differences between groups at different times, and between the various times of treatment, the MIP and MEP data were analyzed with repeated-measures ANOVA using a mixed model (between groups, within times, split-plot design) after Geisser-Greenhouse adjustments, with NCSS statistical software.d For post hoc multiple comparison, the Tukey-Kramer test was used. Values of P less than .05 were considered statistically significant. The data regarding WBimp and the comparison between the subgroups of patients with COPD varying in severity have been analyzed by 1-way ANOVA.

RESULTS Patients Enrolled Thirty-two patients, 16 in the rehabilitation group and 16 in the sham training control group, were included in the present study. The characteristics of the patients enrolled for the study are summarized in table 1. As reported in the table, 7 patients of the training group and 8 of the sham training group were affected by severe or very severe COPD. The other patients presented mild or moderate COPD. No hospitalizations or major illness occurred in the patients during the trial. Four patients in the training group and 2 patients in the sham training group presented a transient exacerbation that did not require steroid or antibiotic therapy, but just a mucolytic treatment. Additional Work of Breathing The impact of additional WBimp values, measured at baseline (without the spirometer), were lowest (0.31⫾0.07J/L) and significantly increased using the Respilift (0.50⫾0.15; P⬍.05 by ANOVA), but such increase was significantly lower than that induced by other incentivators (data not shown).10-12 Effects of Respiratory Training on MIP and MEP The values of MIP and MEP measured at different months after the beginning of the use of Respilift associated with Respivol are reported in figure 2. Repeated-measures ANOVA showed significant F values for time (5.02; P⬍.001; df⫽3; power⫽.85) and time ⫻ group (21.3; P⬍.001; df⫽3; power⫽ .99) factors in the case of MIP data, whereas for MEP data, F values were significant for group (5.27; P⬍.02; df⫽1; power⫽ .63), time (8.59; P⬍.001; df⫽3; power⫽.94), and time ⫻ group (39.97; P⬍.001; df⫽3; power⫽1). MIP values after 12 months were significantly different from basal and from controls (P⬍.01), whereas MEP values after 6 months were significantly different from basal and 1 month and from controls at any time (P⬍.05); after 12 months, values were similarly different, but at a higher level of significance (P⬍.01). Notably, the improvement of MEP values of the 7 patients with more severe COPD was significantly less evident Table 1: Characteristics of the Enrolled Patients Parameters

Control Group

Training Group

Subjects (n°) Mean age (y) Sex (M/F) FEV1 (L)* FEV1 (%)* FVC (L)* FEV1/FVC (%)* Duration of COPD (y)* Stage of COPD Stage I (mild) Stage II (moderate) Stage III (severe) Stage IV (very severe) Comorbidity Hypertension Ischemic cardiopathy Valvulopathy

16 69 9/7 1.39⫾0.12 59.90⫾3.72 2.42⫾0.14 61.42⫾1.94 16.5⫾1.2

16 66 10/6 1.38⫾0.14 55.65⫾4.12 2.33⫾0.16 57.77⫾2.82 15.4⫾0.8

3 5 6 2 10 6 3 1

2 7 5 2 9 4 4 2

Abbreviation: FVC, forced vital capacity; F, female; M, male. *Values are mean ⫾ SD.

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Fig 2. (A) MIP and (B) MEP values, expressed in cmH2O, measured in patients with COPD (sham training control and training group) at different times from the beginning of the training with Respilift associated with Respivol. *P<.05 vs basal, 1 month and 6 months of sham training control group and vs basal and 1 month of training group; **P<.01 vs basal, 1 month, 6 months, and 12 months of sham training control group and vs basal, 1 month, and 6 months of training group.

(MEP⫽68.17⫾4.31) with respect to that of the other patients (MEP⫽83.11⫾4.32). Dyspnea Levels Dyspnea values, as assessed by Borg scale, were significantly improved in training patients, as reported in figure 3. DISCUSSION The rehabilitation of subjects with COPD is an important clinical problem. In the recent past, the implementation of the self-management programs aimed to facilitate behavior and lifestyle modifications by patients with COPD has improved health status and reduced hospital admissions.13 Moreover, a physiologic approach to the most common techniques to reduce dyspnea (pursed lip breathing and diaphragmatic breathing) have been proposed to patients with COPD subjected to a pulmonary rehabilitation program.14,15 The relief of dyspnea was reached by (1) increasing strength and endurance of the respiratory muscles, (2) optimizing the pattern of thoracoabdominal motion, (3) reducing dynamic hyperinflation of the rib cage and improving gas exchange,16 and (4) reducing the ventilatory demands during exercise by conditioning limb muscles. The effectiveness of different combinations of pulmonary rehabilitation program components (exercise training alone, exercise training plus activity training, exercise training plus a lecture series) has been successively examined. Evidence for Arch Phys Med Rehabil Vol 90, June 2009

additional benefits of activity-specific training combined with exercise was found. A behavioral method emphasizing structured controlled breathing and supervising physical activity was significantly more effective than didactic instruction in facilitating additional gains and meeting participants’ learning needs.17 Notably, pulmonary rehabilitation programs using multidisciplinary teams to optimize physical and social functioning of patients with chronic respiratory impairment have been shown particularly useful for patients with severe COPD.18 Many studies have applied different respiratory training programs to patients with COPD with the aim to obtain improvement of their pulmonary functions. More frequently, IMTs have been suggested and used in patients with COPD.3,19-22 However, the expiratory muscle training has also been proposed recently for subjects with COPD, taking into account that such patients present an impairment of expiratory muscle strength and endurance.23 A comparison of specific expiratory, inspiratory, and combined muscle training programs has been previously performed in patients with COPD. The specific training of the inspiratory and expiratory muscles improved both muscle strength and endurance.22 Moreover, the increase in the distance walked in 6 minutes was greater in patients who received specific inspiratory muscle training or combined inspiratory and expiratory muscle training than in those who received expiratory muscle training alone.24 Patients affected by COPD have been demonstrated to display inspiratory muscle weakness and especially diaphragm muscle fiber dysfunction.25 We have studied the benefits of IMT in patients with COPD with the use of a new flow-volumetric inspiratory exerciser Respivol and have shown the efficacy of such device in improving respiratory functional parameters.4 In the present study, we have tested the efficacy of the combined use of (1) a new expiratory exerciser named Respilift and (2) the inspiratory exerciser Respivol that we previously tested. The aim was to increase inspiratory and expiratory muscle function together in patients with COPD and to assess such improvement by assaying their MIP and MEP for a long time (until 1 year). We have decided to test, among the lung functional parameters, the MIP and MEP values, because they are important indicators for assessing the strength of inspiratory and, respectively, expiratory muscles, and are used as diagnostic parameters in patients with pulmonary diseases.

Fig 3. Dyspnea grade values expressed by Borg scale, in basal condition and at different times of training. *P<.05 vs basal, 1 month, and 6 months of sham training control group and vs basal and 1 month of training group; **P<.01 vs basal, 1 month, 6 months, and 12 months of sham training control group and vs basal, 1 month, and 6 months of training group.

COMBINED INSPIRATORY AND EXPIRATORY TRAINING, Battaglia

Great care has been taken to ensure familiarization with assessments of training by each studied patient. Our results demonstrate that the constant exercise with Respilift associated with Respivol, performed for 6 and 12 months, significantly improved the MIP and MEP values measured in basal conditions in patients with COPD. The differences in the obtained results by the different patients are evident, possibly depending on the severity of COPD. In fact, the 7 studied training patients with COPD at stage III or IV revealed reduced improvements in MIP and MEP after 6 or 12 months of training compared with patients with COPD at stage I and II. Because the efficacy of training is shown by comparison with the results obtained in sham training control group, we found that the increase in patient observations to validate our results further could be unnecessary. The measures of MIP and MEP have been accurately performed, even if in a few cases the value determination presented some difficulties. The delayed improvement (6 months) in MIP and MEP of our patients is not a result of the fact that they were working against low pressure, under the limit needed to induce training effects (eg, 20%–30% of MIP), but probably is a result of the fact that the grade of COPD was severe. In fact, the improvement of MEP values of the patients with more severe COPD was significantly less evident than that of the other patients, as reported in the Results section. In addition, the delayed improvement could be a result of the fact that some patients were under oxygen therapy and others were emphysematous. Our hypothesis is confirmed by the delayed improvement of the dyspnea perception in the same patients. Some of the Respilift characteristics should be described. The device is an expiratory exerciser. However, it can be used in association with an inspiratory exerciser, such as the Respivol, with the aim to increase the performance of both the expiratory and inspiratory muscles. Moreover, the additional WBimp of the Respilift is low compared with that of other incentivators.10,11 Incentive spirometers with low additional imposed WBimp permit increase of the maximal sustained inspiration and, thus, enhance incentive spirometry performance.11 The exerciser Respilift can be suggested to patients at high and moderate risk of postoperative pulmonary complications.11 The Respilift is light, easy to handle and to dismount, and washable. The correct use of such device permits to the diaphragm to have a progressive and slow lowering. Because of all these characteristics, we can also suggest Respilift use in diseases different from COPD in which the respiratory muscle function is impaired—for example, Parkinson disease, tumors of the respiratory airways, chronic cardiac failure, and chest surgery. The Respilift can be used alone or in association with inspiratory incentivators such as Respivol. Our data show that both Respivol and Respilift are suitable for use in patients with COPD and that their combined use improves MIP and MEP of such patients. CONCLUSIONS Patients with mild to severe COPD could consider the advantages of the combined use of inspiratory and expiratory devices to improve respiratory function and dyspnea perception. Acknowledgments. We acknowledge Matteo Maria Pecchiari, MD, for his support in performing pressure studies of the Respilift; and Silvio Riccardo Bareggi, MD, and Martino Recchia, BSci, for support in performing statistical analysis.

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References 1. Geddes EL, Reid WD, Crowe J, O’Brien K, Brooks D. Inspiratory muscle training in adults with chronic obstructive pulmonary disease: a systematic review. Respir Med 2005;99:1440-58. 2. Crowe J, Reid WD, Geddes EL, O’Brien K, Brooks D. Inspiratory muscle training compared with other rehabilitation interventions in adults with chronic obstructive pulmonary disease: a systematic literature review and meta-analysis. COPD 2005;2:319-29. 3. Hill K, Jenkins SC, Philippe DL, Shepherd KL, Hillman DR, Eastwood PR. High-intensity inspiratory muscle training in COPD. Eur Respir J 2006;27:1119-28. 4. Battaglia E, Fulgenzi A, Bernucci S, Giardini ME, Ferrero ME. Home respiratory muscle training in patients with chronic obstructive pulmonary disease. Respirology 2006;11:799-804. 5. Mota S, Güell R, Barreiro E, et al. Clinical outcomes of expiratory muscle training in severe COPD patients. Respir Med 2007;101: 516-52. 6. Weiner P, McConnell A. Respiratory muscle training in chronic obstructive pulmonary disease: inspiratory, expiratory, or both? Curr Opin Pulm Med 2005;11:140-4. 7. Crisafulli E, Costi S, Fabbri LM, Clini EM. Respiratory muscles training in COPD patients. Int J Chron Obstruct Pulmon Dis 2007;2:19-25. 8. Weiner P, Magadle R, Beckerman M, Weiner M, Berar-Yanay N. Maintenance of inspiratory muscle training in COPD patients: one year follow-up. Eur Respir J 2004;23:61-5. 9. National Institutes of Health. National Heart, Lung and Blood Institute. WHO Workshop, 1988. Global Initiative for Chronic Obstructive Lung Disease. Review 2004. 10. Mang H, Obermayer T, Weindler J. Comparison of inspiratory work of breathing through six different spirometers. Respir Care 1988;33:955-64. 11. Weindler J, Kiefer RT. The efficacy of postoperative incentive spirometry is influenced by the device-specific imposed work of breathing. Chest 2001;119:1858-64. 12. Raven PB, Jackson AW, Page K, Moss RF, Bradley O, Skaggs B. The physiological responses of mild pulmonary impaired subjects while using a “demand” respirator during rest and work. Am Ind Hyg Assoc J 1981;42:247-57. 13. Bourbeau J, Nault D, Dang-Tan T. Self-management and behaviour modification in COPD. Patient Educ Couns 2004;52:271-7. 14. Gigliotti F, Romagnoli I, Scano G. Breathing retraining and exercise conditioning in patients with chronic obstructive pulmonary disease (COPD): a physiological approach. Respir Med 2003;97: 197-204. 15. Gosselink R. Controlled breathing and dyspnea in patients with chronic obstructive pulmonary disease (COPD). J Rehabil Res Dev 2003;40:25-33. 16. Gosselink R. Breathing techniques in patients with chronic obstructive pulmonary disease (COPD). Chron Respir Dis 2004;1: 163-172. 17. Norweg AM, Whiteson J, Malgady R, Mola A, Rey M. The effectiveness of different combinations of pulmonary rehabilitation program components: a randomized controlled trial. Chest 2005;128:663-72. 18. Hill NS. Pulmonary rehabilitation. Proc Am Thorac Soc 2006;3: 66-74. 19. Kim MJ, Larson JL, Covey MK, Vitalo CA, Alex CG, Patel M. Inspiratory muscle training in patients with chronic obstructive pulmonary disease. Nurs Res 1993;42:356-62. 20. Preusser BA, Winningham ML, Clanton TL. High- vs lowintensity inspiratory muscle interval training in patients with COPD. Chest 1994;106:110-7. 21. Villafranca C, Borzone G, Leiva A, Lisboa C. Effect of inspiratory muscle training with an intermediate load on inspiratory power output in COPD. Eur Respir J 1998;11:28-33. Arch Phys Med Rehabil Vol 90, June 2009

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22. Lotters F, van Tol B, Kwakkel G, Gosselink R. Effects of controlled inspiratory muscle training in patients with COPD: a metaanalysis. Eur Respir J 2002;20:570-6. 23. Weiner P, Magadle R, Beckerman M, Weiner M, Berar-Yanay N. Specific expiratory muscle training in COPD. Chest 2003;124:468-73. 24. Weiner P, Magadle R, Beckerman M, Weiner M, Berar-Yanay N. Comparison of specific expiratory, inspiratory, and combined muscle training programs in COPD. Chest 2003;124:1357-64. 25. Ottenheijm CA, Heunks LM, Dekhuijzen PN. Diaphragm muscle fiber dysfunction in chronic obstructive pulmonary disease: to-

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ward a pathophysiological concept. Am J Respir Crit Care Med 2007;175:1233-40. Suppliers a. Medinet Spa, Via Londonio 12, 20154 Milano, Italy. b. Macron Technologies Inc, 7902 W Waters Ave, Ste J, Tampa, FL 33615. c. Statham Institute Inc, 254 Carpenter Rd, Hato, Rey, Puerto Rico. d. NCSS, 329 N 1000 East, Kaysville, UT 84037.

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