Med. J. Cairo Univ., Vol. 82, No. 1, June: 411-418, 2014 www.medicaljournalofcairouniversity.net Aerobic Exercise Plus Insiratory Muscle Training Efficacy on BODE Index in Chronic Obstructive Pulmonary Disease (COPD) Patients MAGDy M. AhMED, Ph.D.*; ABlA M. hamed, Ph.D.** and heba helmy, M.D.*** The Deartments of P.T. for Internal Diseases*,**, Faculty of Physical Theray, October 6 University*, Misr University for Science & Technology** and Chest***, Faculty of Medicine, October 6 University Abstract Background: Insiratory muscle training (IMT) has been alied during ulmonary rehabilitation in atients with chronic obstructive ulmonary disease (COPD). However, it remains unclear if the addition of IMT to a general exercise training rogram leads to additional clinically relevant imrovements in atients with COPD. Aim of the Study: The aim of this study was to investigate whether the addition of insiratory muscle trainer (IMT) to a general exercise training rogram for 2 months imroved 6 min walking distance, ulmonary functions, health-related quality of life, in atients with COPD or not. Design: This study was conducted from January 2013 to November 2013 in Giza chesthosital. Patients: This study conducted on forty atients with moderate COPD men aged 45 to 55 years for 2 months. Intervention: The 40 men were randomly assigned to two grous; Grou (1) (n=20) and Grou (2) (n=20). Both grous followed an exercise training rogram for 2 months. Grou (1) received an additional insiratory muscle training (IMT) rogram for the same eriod. Main Outcomes Measures: Weight, body mass index (BMI), ulmonary function tests including, FVC, and /FVC, and Six minutes walk test, mmrc and BODE index. Results: After 2 months, men in Grou (1) (IMT and exercise training) showed a highly significant imrovement in ulmonaryfunctions ( with <0.0001, FVC with <0.001), 6MWD with <0.001, and BODE indexwith <0.0001). In Grou (2) (exercise training) also demonstrated significant statistically differences in the mean s in ulmonary functions (FEV1 with <0.001, FVC with <0.0001), 6MWD with <0.001, and BODE indexwith <0.000 1). The imrovement in Grou (1) was more than in Grou (2) in all variables. Conclusions: The resent study found that short-term aerobic training rogram lus IMT had the caacity to break out the Corresondence to: Dr. Magdy M. Ahmed, E-mail: Dr_Magdy_Mostafa@yahoo.com vicious circle of dysnea, hysical inactivity and exercise intolerance-the hallmark features of COPD atients and imrove some comonents of BODE index. Key Words: COPD Insiratory muscle training Aerobic exercise. Introduction CHRONIC obstructive ulmonary disease (COPD) is a major cause of chronic morbidity and mortality worldwide [1]. COPD is characterized by ersistent exiratory flow limitation which is usually rogressive [2]. Dysnea is the most rominent exerciselimiting symtom of the disease, which leads to chronic avoidance of hysical activities [3]. COPD affects 4% to 6% of the oulation. It is a major cause of morbidity throughout the world, and the fourth leading cause of death within the United States [4]. Chronic bronchitis and emhysema are the disease entities that may be resent in varying combinations in individuals with COPD, with dysnea and exercise intolerance being the most revalent resenting comlaints [5]. The mechanisms for dysnea and exercise intolerance are multifactorial and include increased resistance to airflow (esecially during exiration), imaired gas exchange resulting in hyoxemia and hyercania [6], dynamic hyerinflation [7], and skeletal muscle dysfunction [8]. While each of these contributing factors interacts with each other, individuals with COPD demonstrate an early onset of lactic acidosis during exercise and an inability to meet the associated ventilatorydemand. Therefore, interventions that imrove ventilation, such as insiratory muscle training (IMT), may have the otential to reduce dysnea and imrove exercise tolerance [9]. Consequently, low-hysical activity levels contribute to 411
412 Aerobic Exercise Plus Insiratory Muscle Training Efficacy skeletal muscle deconditioning and exercise caacity reduction, which imact negatively on healthrelated quality of life [10]. Insiratory muscle dysfunction is another extra ulmonary manifestation, which is often resent in atients with COPD [11]. It contributes to hyoxemia, hyercania, dysnea and decreased exercise tolerance [12]. A multidimensional rognostic index that takes into account several indicators of COPD rognosis is the BODE index (body mass index [BMI], obstructive ventilatory defect severity, dysnea severity, and exercise caacity). The comonents are derived from measures of the body mass index (weight in kg/height in m 2 ), ercent redicted, and the modified Medical Research Council dysnea score. A BODE score greater than 7 is associated with a 30 ercent 2-year mortality; whereas a score of 5 to 6 is associated with 15 ercent 2-year mortality. If the BODE score is less than 5, the 2-year mortality is less than 10 ercent [13]. The diagnosis of COPD should be susected in all atients who reort any combination of the following: Chronic cough, chronic sutum roduction, dysnea at rest or with exertion, or a history of inhalational exosure to tobacco smoke, occuational dust, or occuational chemicals. Dysnea with exertion may be underareciated by individuals who unknowingly restrict their activity level. COPD is tyically slowly rogressive, ersistent, and exacerbated by resiratory infection [14]. Chronic obstructive ulmonary diseases is confirmed when a atient, who has symtoms that are comatible with COPD, is found to have airflow obstruction (/FVC ratio less than 0.70 and an less than 80 ercent of redicted) and there is no alternative exlanation for the symtoms and airflow obstruction (e.g., bronchiectasis, vocal cord aralysis, tracheal stenosis) [15]. Pulmonary rehabilitation including exercise training, education, nutritional intervention and sychosocial suort is a standard care for atients with COPD to counteract extra ulmonary disease manifestations [16]. Insiratory muscle training (IMT) has also been alied frequently and is extensively studied in recent years in atients with COPD. From meta-analyses of randomized controlled trials (RCTs) in atients with COPD, it can be concluded that IMT as a stand-alone theray imroves insiratory muscle function (strength and endurance), decreases symtoms of dysnea and imroves exercise caacity [17]. The of IMT as an add-on to a general exercise training rogram is, however, still under debate. While IMT always results in significant imrovements in insiratory muscle function, its additional effects on more clinically relevant outcomes (e.g., functional exercise caacity and quality of life) are insufficiently suorted by scientific evidence so far [18]. From subgrou analyses in the most recent meta-analysis, it was concluded that significant additional effects of IMT on more clinically relevant outcomes are more likely to be found in atients with insiratory muscle weakness [19]. It was recently shown that adjunctive IMT led to significantly greater functional imrovements in a well-designed RCT in atients with chronic heart failure selected for insiratory muscle weakness [20]. The outcome of this study will therefore have a direct imact on clinical ractice, as the results will clarify whether adjunctive IMT leads to suerior clinically relevant imrovements for atients with COPD. Functional outcomes of relevance to atients (exercise caacity, quality of life, articiation in daily hysical activity and symtoms) were therefore chosen as the main outcomes. The aim of this study was to evaluate the beneficial effects of generalized aerobic exercise in addition to insiratory muscle training for treatment of COPD using several validated methods to measure outcomes as BODE index and ulmonary function tests, 6MWT, and MRC dysnea score. Subjects and Methods This study was erformed in Giza chest hosital, from January 2013 to November 2013. In this study, forty COPD male atients were included, and randomly divided into 2 grous; Grou (1) (n=20) and Grou (2) (n=20). Both grous followedan exercise training rogram on walking treadmill. Grou (1) received an additional insiratory muscle training (IMT) rogram. Inclusion criteria: - Male aged 40-60 years. - Current or ex-smokers with a smoking history of 10 ack years. - An established history and clinically stablemoderate COPD and receive their routine drugs. Exclusion criteria: - Any subject with heatic or renal imairment was excluded. - Current diagnosis of asthma or resiratory disorders other than COPD. - Chest radiograh indicating diagnosis other than COPD.
Magdy M. Ahmed, et al. 413 - had a lung-volume reduction surgery and/or a lung translant. - Receiving long-term oral corticosteroid theray. - Severe uncontrolled diseases likely to interfere with the study. - Diagnosed sychiatric or cognitive disorders. - Orthoedic roblems having an imact on our study. - Previous inclusion in rehabilitation rogram (<1 year). Patients were informed about the study rotocol rior to the start of the rehabilitation rogram. Informed consent would be obtained at that time. Both grous followed an exercise training rogram for 2 months. Grou (1) received an additional IMT rogram described to the atients as resistance training at high intensity. for ulmonary function testing (VmaxAutobox, Sensor Medics, Bilthoven, The Netherlands) [2]. 4- Assessment of COPD: 2 methods to evaluate the severity of COPD were used; first there is the GOlD classification and the BODE INDEX (which comose of four items B for body mass index, O for level of obstruction using, D for dysnea score, and E for exercise tolerance). A- GOLD Classification of COPD: Table (2): Classification of severity of COPD according to GOlD classification (GOlD, 2011) [2]. GOlD 1 Mild 80% redicted GOlD 2 Moderate 50% <80% redicted GOlD 3 Severe 30% <50% redicted GOlD 4 Very severe < 30% redicted 1- Comlete medical history taking: Each subject in the study was submitted to the following: A- history taking included dysnea scoring according to mmrc (modified medicalresearch council) for assessing the severity of breathlessness [2]. Table (1): MMRC dysnea questionnaire for assessing the severity of breathlessness. Questions Score I get breathless only with strenuous exercise 0 I get short of breath when hurrying on the level or 1 walking u a slight hill. I walk slower than eole of same age do on the level because of breathlessness or I have to sto for breath when walking on my own ace on the level I sto for breath after walking about 100 m or after a 3 few minutes on the level. I am too breathless to leave the house, or I am 4 breathless when dressing or undressing. MMRC = Modified Medical Research Council [2]. B- Comlete clinical examination including (weight, height, and BMI). - The body mass index (BMI): It is defined as the individual body mass divided by the square of his height-with the universally being given in units of kg/m 2 [21]. 2- Chest X-ray (osterior-anterior view). 3- Pulmonary function study: Including, FVC, and /FVC ost bronchodilator according to the Euroean Resiratory Society guidelines B- BODE index: For assessment of COPD severity. Table (3): Variables and oint s used in BODE index. Variable (ercent of redicted) Distance walked in 6 minutes (m) Points on BODE index 0 1 2 3 65 50-64 36-49 35 350 250-349 150-249 149 MMRC dysnea scale Δ 0-1 2 3 4 Body-mass index >21 21 N.B.: All the revious measurements were done for all atients 2 before and at the end of the study. 5- Treadmill six minutes walk test: Use of a treadmill to determine the 6 MWD allow constant monitoring during the exercise. Standardized instructions and encouragement similar to those for the corridor walk were given, according to ATS guidelines [22]. Patients were instructed to walk as far as ossible during the time-that is, as fast as ossible. They were told that they could slow down or even sto if necessary. There was no warming u before test. The initial treadmill seed was zero, and the test began when treadmill activated and the atient started walking. The atient controlled the treadmill seed during the test and could sto to rest at any time, as in the hallway test. Before, during, or after treadmill walk test, the walk testing was discontinued if the atient had thoracic ain, intolerable dysnea, crams, dizziness, staggering, diahoresis, allor, or an SO 2 <90% [22].
414 Aerobic Exercise Plus Insiratory Muscle Training Efficacy Training instrument: - Insiratory muscle trainer: The threshold trainer is a small lastic handheld device sulied by Resironics. It includes a mouthiece and a calibrated sring loaded valve. The valve controls a constant insiratory ressure training load and the atient must generate the insiratory ressure in order for the insiratory valve to be oened and allow inhalation of air. The amount of resistance can be adjusted by varying the comression of the sring-loaded valve. Adjustment from 7cm h 2 O to 41cm h 2 O is ossible. Threshold insiratory muscle trainer; Resironics, Cedar Grove, NJ 07009-1201 USA [23]. Intervention: 1- Aerobic exercise training: Patients in both grous followed a 2-month exercise training rogram. An Outatient hosital Based-Exercise rogram for a eriod of 8 weeks of aerobic training as graduated treadmill exercises was initiated uon the results of the exercise testing, so the exercise rescrition was individually designed. Training frequency was three sessions er week, resulting in a total of 24 training sessions. Duration of the training session increased from 20-30min at the start of the rogram to 30-40min after 2 months. The overall training intensity was increased gradually during the course of the rogram. An adequate training intensity for endurance conditioning usually targeted 70-85% of the individually determined maximal heart rate. The maximal heart rate can be estimated from the formula (220 minutes age) [24]. The exercise session was subdivided into: Warm u: 5-10 minutes of both light muscular stretching and insiratory muscle training to avoid muscle strains and injuries. Stimulus hase: 10-30min. Of treadmill exercise using Electrical treadmill with different seeds and inclination grades. Cool down hase: This relaxation eriod after the stimulus hase ensures the body not exeriences any muscular roblems. It includes 5-10min. Of continued exercise with a seed 1km/h with zero inclination. Progression of exercise includes: First week of training should be at 60-70% of the individually determined maximum heart rate to allow for the develoment of motor skills and musculoskeletal conditioning. As atient tolerance for exercise imroved, the duration of walking increase gradually and the target is increased by 5-10% of the maximum heart rate. After 4 weeks of training, exercise intensity achieves a level of 80% of maximum heart rate, as it was increased gradually every 2 weeks. 2- Insiratory muscle training rogram: Patients in Grou (1) received high-intensity IMT. The training load in this study was adjusted according to data from a reviously erformed ilot study about a home-based, high-intensity IMT rogram in atients with COPD. Total daily training time was 21min, consisting of 6 cycles of 30 breaths (2 cycles, 3 times daily). There was aroximately 3.5min of resistive breathing during every cycle, each followed by 1min of resting. Patients were trained 7 days/week, for 8 weeks using the Power breathe Kh1 device (POWERbreatheKh1, hab International ltd, Southam, UK). Statistical analysis: All statistical calculations were done using comuter rogram SPSS (Statistical Package for the Social Science; SPSS Inc., Chicago, Il, USA) version 15 for Microsoft Windows. Data were statistically described in terms of means±standard deviation (±SD), median, and range. Comarison between the both grous was done using Student t-test for indeendent samles. Within grou comarison was done using aired t-test. -s less than 0,05 was considered statistically significant. Results There was no significant difference between both grous before the start of the rogram (Table 4) regarding the demograhic data (age and body mass index). There was a highly statistically significant difference in Siro metric measurements in grou 1 (aerobic ex. lus IMT) before and after the intervention (Table 5). Also, there was a significant difference in Siro metric measurements in grou (aerobic ex. only) before and after the intervention (Table 6). There was a statisticallysignificant imrovement in 6MWD with an increase of 72 meters in grou1 (aerobic ex. lus IMT) and an increase of 54 meters in Grou (2) (aerobic ex. only) as shown in (Tables 5,6) resectively. Table (4): Demograhic data of Grou (1) before and after the study. Characteristics Age (year) BMI (kg/m 2 ) Grou (1) Before 52.32± 8.09 27.54± 4.23 Significance at 0.05. BMI : Body mass index. Grou (1) After 26.4± 3.6 0.74 Grou (2) Before 51.2± 8.17 26.95± 5.08 Grou (2) After 26.4± 3.6 0.88 0.23
Magdy M. Ahmed, et al. 415 Table (5): Siro metric measurementsin Grou (1) (aerobic ex. lus IMT) before and after the intervention. Table (9): Comarison of Sirometric measurements and BODE indexin both grous after the end of the rogram. Characteristics Before After within grou 1 (Mean±SD) (Mean±SD) Characteristics Grou 1 Grou 2 54.96±18.3 73.25±14.38 0.0001 * (% of redicted) FVC 69.22±22.81 83.6±18.32 0.001 * /FVC 51.42±10.99 48.15±17.14 0.022* 6 MWD (in meters) 93.42±11.32 165.54±11.32 0.0001 * (% of redicted) 73.25±14.38 66.65±17.4 0.002 FVC 83.6±18.32 79.2±11.8 0.03 /FVC 48.15±17.14 46.34 ±15.4 0.01 6 MWD (in meters) 165.54±11.32 133.4±9.6 0.001 BODE index 4.9±1.33 5.35±1.05 0.64 * - <0.05 statistically significant. * : Significance at 0.05. FEV 1 : Forced exiratory volume in 1 st second. FVC : Forced vital caacity. 6MWD : 6 minute walking distance. Table (6): Siro metric measurementsin Grou (2) (aerobic ex. only) before and after the intervention. Characteristics Before After within grou 2 (Mean±SD) (Mean±SD) 60 50 40 30 20 Grou 1 Grou 2 56.7 ± 20.3 66.65±17.4 0.001 * (% of redicted) FVC 71.56±19.75 79.2±11.8 0.0001 * /FVC 49.5±11.2 46.34±15.4 0.003 * 6 MWD (in meters) * : Significance at 0.05. 79.35±13.18 133.4±9.6 0.0001 * Table (7): BODE index in bothgrous, before and after the end of the rogram (aerobic ex. lus IMT). BODE index in grou 1 BODE index in grou 2 Before Mean±SD 7.2± 1.4 6.9±1.6 * - <0.05 statistically significant. After Mean±SD 4.9±1.33 5.35±1.05 0.0001 * 0.0001 * BODE: The body mass index (B), degree of airflow obstruction (O), functional dysnea (D), and exercise caacity (E). Table (8): Change in BODE indexin both grous after the end of the rogram. 10 0 Age BMI Fig. (1): Age and BMI in both grous before the study. 180 160 140 120 100 80 60 40 20 0 140 120 100 Before After Grou 1 FVC 6MWD Fig. (2):, FVC and 6 MWD grou1 before and after the study. Before After Grou 2 BODE index in grou 1; n (% within the grou) Imroved* 19 (95%) Not imroved 1 (5%) 0.0001 80 60 40 BODE index in grou 2; n (% within the grou) 16 (80%) 4 (20%) * Imrovement: At least one unit change in the BODE index. 0.001 BODE: The body mass index (B), degree of airflow obstruction (O), functional dysnea (D), and exercise caacity (E). 20 0 FVC 6MWD Fig. (3):, FVC and 6 MWD grou 2 before and after the end the study.
416 Aerobic Exercise Plus Insiratory Muscle Training Efficacy 5.4 5.3 5.2 5.1 5 4.9 4.8 4.7 4.6 Grou 1 Grou 2 BODE index Fig. (4): BODE index of both grous after the end of the study. Discussion The quality of life for a erson suffering from COPD diminishes as the disease rogress. Worldwide, the revalence of moderate ( <80% redicted) to very severe ( <30% redicted) COPD is 10%. COPD also is associated with substantial societal burden and mortality. Using disability-adjusted life years (DAlys) as a measure of burden of disease, COPD is rojected to increase from the 11 th leading cause of DAlys in 2002 to the seventh leading cause in 2030. Similarly, in 2002 COPD was the fifth leading cause of death and is rojected to be the fourth leading cause of death in 2030 [24]. The aim of our study was to investigate the effects of insiratory muscle training (IMT) as an adjunct to an exercise training rogram for atients with COPD using several validated measures in assessment and treatment of COPD. After the ulmonary rehabilitation rogram, several outcomes measures such as 6MWD, MRC dysnea score, BODE index, and ulmonary muscle function tests were evaluated. The resent study showed many beneficial effects of adding IMT as an adjunct method to the ulmonary rehabilitation in COPD atients. This agree with Padula and yeaw [25] showed that insiratory muscle training (IMT) is a technique that is designed to imrove the erformance of the resiratory muscles (RMs) that may be imaired in a variety of conditions. Interest in IM training has exanded over the ast two decades, and IM training has been used in an increasingly wide range of clinical conditions. Desite the lack of a clear exlanation for how insiratory muscle dysfunction contributes to the dysnea and exercise intolerance exerienced by those with COPD, there is a considerable amount of research that has investigated the efficacy of IMT for imroving insiratory muscle strength, insiratory muscle endurance, dysnea, and exercise tolerance. To date, 6 systematic reviews [26-31] have been comleted. The first review with meta-analysis by Smith et al., [26] in 1991 concluded that no beneficial effects of IMT were seen in insiratory muscle function or exercise tolerance, but this review was limited by the inclusion of studies that did not control for training intensity. A 2002 udate by lotters et al., [27] reviewed articles investigating IMT alone or in combination with exercise, and demonstrated imrovements in insiratory muscle strength, insiratory muscle endurance, and dysnea. In 2005 a third grou of investigators erformed further meta-analysis and review of IMT alone [29] and IMT in combination with aerobic exercise [31]. They examined outcomes for insiratory muscle strength, endurance, dysnea, exercise tolerance, and health-related quality of life (hrql). This grou then further udated these reviews in 2008 [29,30]. These udates affirmed revious results that IMT alone significantly imroves insiratory muscle strength, insiratory muscle endurance, and dysnea. They also concluded that IMT alone also imroves hrql and exercise tolerance [28]. Further, they demonstrated that IMT in combination with exercise comared to exercise alone may only have additional benefit with resect to imrovements in maximal insiratory ressure. The above studies were in agreement with our results. Pulmonary rehabilitation is an imortant comonent in the management of COPD. It has been shown to imrove exercise caacity and health related quality of life, and to reduce breathlessness, anxiety or deression, and the frequency and length of hositalizations related to COPD [2]. Exercise training, a key comonent of a ulmonary rehabilitation rogram, may include aerobic exercise such as cycling or walking as well as uer and lower extremity strength training [31]. Exercise training is the cornerstone of comrehensive rehabilitation rograms in atients with COPD [32]. Although secific exercise modalities can be alied to reverse muscle dysfunction, exercise intolerance, and reduced health-related quality of lifethere is a substantial heterogeneity in the resonse to exercise training among atients with clinically stable COPD [33]. The resent study imlemented moderate to high intensity training rogram with gradually increasing of the intensity to maximize the training effects. As atient tolerance for exercise imroved, the duration of walking on 6MWD was imroved in both grous from (93.4m to 165m) in Grou (1) and from (79.35m to 133.4m) in Grou (2). This in con-
Magdy M. Ahmed, et al. 417 sistent with Clark et al., [34] who demonstrated dramatic imrovement in treadmill walking time and suggested that their rogram would be alicable in atients with COPD with a wide range of functional defects. The imrovement in exercise caacity after aerobic training rogram may be due to: 1) reconditioning, this reinforces the articiation of chronic reduction in conditioning as the main mechanism of the eriheral skeletal muscle dysfunction & exercise intolerance in COPD atients [35]. This finding correlated with a meta-analysis done by Clark et al., [34], in a controlled 12-wk study of outatient ulmonary rehabilitation, the 6-min walk distance increased by 80m at 6wk (half-way in the rogram), 113m at the end of the rogram, and 96m 12 week after the rogram ended. The resent study used BODE index to evaluate the effect of IMT lus aerobic exercise on COPD. It demonstrated that 19 atients or (95%) in grou1 (IMT lus ex.) showed a statistically significant imroved in BODE index after 8 weeks. On the other hand, 16 atients or 80% in Grou (2) (aerobic ex.only) showed a statistically significant imroved in BODE index after 8 weeks. This finding suorted by Cote and Celli [36], who showed that the BODE index could be used to evaluate the effect of ulmonary rehabilitation and defined one unit change in BODE index as being clinically significant because it imlies a change in any of its comonent of a magnitude large enough to influence clinical outcomes. likewise, one unit change in the 6MWD in the BODE score far exceeds than 50m. Considered to be clinically significant changes for this test [37]. Similarly, one unit change in the comonent of the BODE index reflects the thresholds that have been acceted by the Euroean Resiratory Society and Global Initiative for Chronic Obstructive lung Disease (GOlD) as the basis for the hysiological staging of COPD [2]. The resent study also showed, that there was a statistically significant imrovement of both & FVC hysiological arameters of both grous (IMT and aerobic traininggrou) and (aerobic training grou) (Table 9), after the end of the rogram. This findingsuorts the concet that COPD is associated with local & systemic manifestations) andthat aerobic training rogram may roduce great imrovements in skeletal muscle function (both resiratory & eriheral muscles). Gohar, [38] was fully consistent with this, he found that there was a significant imrovement of both FVC and arameters in COPD atients undergo lower limb exercise for 6 weeks. Conclusions: The clinical benefits of imroved dysnea, walking test distance and quality of life aeared to be due to clinical benefits of adding IMT to aerobic exercise. - The resent study found that short-term aerobic training rogram lus IMT had the caacity to break out the vicious circle of dysnea,hysical inactivity and exercise intolerance-the hallmark features of COPD atients and imrove some comonents of BODE index. - The resent study indicated that IMT can be a useful art of ulmonary rehabilitation for COPD atients. Further studies are required to determine which atients are most likely to benefit from this training modality. - We anticiate that the outcomes of this study will be of direct relevance to clinical ractice. The results of this study should therefore be incororated immediately into evidence-based treatment recommendations for clinical ractice. References 1- MANNINO D.M. and BUIST A.S.: Global burden of COPD: Risk factors, revalence, and future trends. lancet, 370: 765-73, 2007. 2- Global Initiative for Chronic Obstructive lung Disease (GOlD): Global Strategy for the Diagnosis, Management and Prevention of COPD htt://www.goldcod.org/.ref Tye: Internet Communication, 2011. 3- O DONNEll D.E., TRAVERS J., WEBB K.A., et al.: Reliability of ventilatory arameters during cycle ergometer in multicenter trials in COPD. Eur. Resir. J., 34: 866-74, 2009. 4- MANNINO D.M.: COPD: Eidemiology, revalence, morbidity, and mortality, and disease heterogeneity. Chest, 121: 121-126, 2002. 5- PAUWElS R.A., BUIST A.S., CAlVERlEy P.M., JEN- KINS C.R. and hurd S.S.: Global strategy for the diagnosis, management, and revention of chronic obstructive ulmonary disease. Am. J. Resir. Crit. Care Med., 163: 1256-1276, 2001. 6- CASABURI R.: Exercise training in chronic obstructive lung disease. In Casaburi R., Petty T.l., editors. Princiles and Practice of PulmonaryRehabilitation. Philadelhia, PA: Saunders,. 204-224, 1993. 7- lacasse y., MARTIN S., lasserson T.J., et al.: Meta-analysis of resiratory rehabilitation in chronic obstructive ulmonary disease. A Cochrane systematic review. Eura. Medicohys, 43: 475-85, 2007. 8- DECRAMER M., DEMEDTS M., ROChETTE F., et al.: Maximal transresiratory ressures in obstructive lung disease. Bull. Eur. Physioathology Resir., 16: 479-90, 2008. 9- POlKEy M.I., KyROUSSIS D., hamnegard C.h., et al.: Diahragm strength in chronic obstructive ulmo-
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