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00005768-201107000-0000100005768_2011_43_1135_correa_inspiratory_7article< 115_0_22_5 >Medicine & Science in Sports & Exercise© 2011 American College of Sports MedicineVolume 43(7)July 2011pp 1135-1141Inspiratory Muscle Training in Type 2 Diabetes with Inspiratory Muscle Weakness[CLINICAL SCIENCES]CORRÊA, ANA PAULA S.1; RIBEIRO, JORGE P.1,2; BALZAN, FERNANDA MACHADO1; MUNDSTOCK, LORENA1; FERLIN, ELTON LUIZ1; MORAES, RUY SILVEIRA1,21Exercise Pathophysiology Research Laboratory and Cardiovascular Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, BRAZIL; and 2Department of Medicine, Faculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, BRAZILAddress for correspondence: Ruy Silveira Moraes, M.D., Sc.D., Cardiology Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, 90035-007, Porto Alegre, Rio Grande do Sul, Brazil; E-mail: .Submitted for publication August 2010.Accepted for publication December 2010.ABSTRACTPurpose: Patients with type 2 diabetes mellitus may present weakness of the inspiratory muscles. We tested the hypothesis that inspiratory muscle training (IMT) could improve inspiratory muscle strength, pulmonary function, functional capacity, and autonomic modulation in patients with type 2 diabetes and weakness of the inspiratory muscles.Methods: Maximal inspiratory muscle pressure (PImax) was evaluated in a sample of 148 patients with type 2 diabetes. Of these, 25 patients with PImax <70% of predicted were randomized to an 8-wk program of IMT (n = 12) or placebo-IMT (n = 13). PImax, inspiratory muscle endurance time, pulmonary function, peak oxygen uptake, and HR variability were evaluated before and after intervention.Results: The prevalence of inspiratory muscle weakness was 29%. IMT significantly increased the PImax (118%) and the inspiratory muscle endurance time (495%), with no changes in pulmonary function, functional capacity, or autonomic modulation. There were no significant changes with placebo-IMT.Conclusions: Patients with type 2 diabetes may frequently present inspiratory muscle weakness. In these patients, IMT improves inspiratory muscle function with no consequences in functional capacity or autonomic modulation.Patients with diabetes mellitus may present pulmonary functional abnormalities, which are associated with chronic hyperglycemia (28). These abnormalities may include reduction in lung volumes (8) and carbon monoxide diffusion (12), as well as decreased pulmonary compliance, lung elastic recoil (38), and inspiratory muscle strength (4,19). The performance of the inspiratory muscles is of particular interest because it may influence exercise tolerance in some clinical conditions in which inspiratory muscle weakness (IMW) is present (15,31,32). Indeed, hyperglycemic patients with insulin-dependent diabetes mellitus may present increased ventilatory response to exercise, with possible consequences to exercise tolerance (28). Moreover, despite some conflicting results, inspiratory muscle training (IMT) has been shown to improve exercise tolerance in healthy individuals (3,13,18,21) as well as in patients with chronic heart failure (32), chronic obstructive pulmonary disease (15), cerebrovascular disease (36), or neuromuscular disorders (5).Recently, Kaminski et al. (20) have shown that patients with type 2 diabetes mellitus (DM) with autonomic neuropathy had reduced inspiratory muscle strength, suggesting that IMW might be associated with autonomic dysfunction in these patients. However, the prevalence of IMW in DM is unknown, neither is the response to IMT. As a corollary to what happens in other clinical conditions, we raised the hypothesis that DM with autonomic neuropathy could have a high prevalence of IMW and that IMT could improve inspiratory muscle strength with consequences to functional capacity and autonomic modulation. The present randomized clinical trial was conducted to test these hypotheses.METHODSStudy design and participants.A prospective, randomized, controlled trial was conducted in patients with DM, according to the National Diabetes Data Group criteria (1), recruited from the Endocrinology Outpatient Clinic of the Hospital de Clínicas de Porto Alegre, who presented maximal inspiratory pressure (PImax) <70% of predicted (27). This cutoff value has been arbitrarily chosen to define patients with inspiratory muscle weakness (32). Exclusion criteria were body mass index > 33 kg·m−2, history of exercise-induced asthma, infectious disease, osteoarticular disease, cardiac and pulmonary diseases, as well as regular alcohol or tobacco consumption in the past 6 months. Because regular aerobic exercise may improve inspiratory muscle strength in patients with IMW (42), only sedentary patients were recruited. The protocol was approved by the Committee for Ethics in Research of the Hospital de Clínicas de Porto Alegre, and all subjects signed a written informed consent form.Patients were initially evaluated by medical history, physical examination, and the determination of PImax. Eligible patients were randomly assigned to IMT or to placebo IMT (P-IMT) for 8 wk. Before and after the intervention, pulmonary function tests, inspiratory muscle function tests, cardiopulmonary exercise testing, cardiovascular autonomic function tests, and 24-h analysis of HR variability were obtained. All evaluations were performed by investigators who were unaware of the allocation of patients to different interventions.Inspiratory muscle training.Patients received either IMT or P-IMT for 30 min seven times per week for 8 wk using the Threshold Inspiratory Muscle Trainer device (Health Scan Products, Inc., Cedar Grove, NJ) according to a protocol previously described (7). In short, for the IMT group, inspiratory load was set at 30% of maximal static inspiratory pressure, and weekly measures of PImax were obtained to maintain training loads at 30% of the PImax. The P-IMT followed the same schedule, using the lowest pressure offered by the device (7 cm H2O). Each week, six training sessions were performed at home and one training session was supervised at the hospital.Pulmonary function.Measurements of forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and maximal voluntary ventilation (MVV) were obtained with a computerized spirometer (Eric Jaeger, GmbH, Würzburg, Germany), as recommended by the American Thoracic Society (2), and results were expressed as a percentage of predicted (30).Inspiratory muscle function.Inspiratory muscle function testing was performed using a pressure transducer (MVD-500 V.1.1 Microhard System; Globalmed, Porto Alegre, Brazil), connected to a system with two unidirectional valves (DHD Inspiratory Muscle Trainer, Chicago, IL) as previously described (7). In short, PImax was determined in deep inspiration from residual volume against an occluded airway with a minor air leak. The test was repeated at least 12 times to find si measurements with <10% variation. Predicted values were corrected for age and gender (27). Inspiratory muscle endurance (Pthmax) was determined by an incremental test and expressed as a percentage of PImax (Pthmax/PImax). Finally, subjects breathed against a constant inspiratory submaximal load equivalent to 80% Pthmax, and the time elapsed to task failure was defined as the inspiratory endurance time (7). For the endurance tests, a target inspiratory-expiratory time ratio of 0.75 was recommended.Cardiopulmonary exercise testing.Maximal functional capacity was assessed with an incremental exercise test, on a treadmill (Inbramed 10200, Porto Alegre, Brazil), using a ramp protocol, as previously described (7). Twelve-lead ECG tracings were obtained every minute (Nihon Khoden Corp., Tokyo, Japan), and blood pressure was measured every 2 min with a standard cuff sphygmomanometer. During the test, gas exchange variables were measured breath-by-breath by a previously validated system (Metalyzer 3B, CPX System; Cortex, Leipzig, Germany).Cardiac autonomic function testing.Autonomic neuropathy was determined by the presence of more than one abnormal autonomic cardiovascular function test (11), as previously standardized in our institution (43). The tests used were the following: HR response during deep breathing (normal values >6), HR response during the Valsalva maneuver (normal values >1.2), HR and blood pressure responses to orthostatic position (normal values >1.06 and <25 mm Hg, respectively), and blood pressure response to handgrip (normal values >10 mm Hg).Heart rate variability.Twenty-four-hour ECG recordings were obtained with a SEER Light digital recorder (GE Medical Systems Information Technologies, Milwaukee, WI). The recorded data were analyzed using a MARS 8000 analyzer (Marquete Medical Systems, Milwaukee, WI) as previously described (29). In short, time domain and frequency domain analyses of HR variability (HRV) were performed according to recommendations from the European Society of Cardiology and North American Society of Pacing and Electrophysiology (37). For the time domain analysis, the following 24-h indices were calculated: mean of all normal RR intervals, SD of all normal RR intervals, root mean square of successive differences of adjacent RR intervals, and percentage of successive differences between normal adjacent RR intervals above 50 ms. For the frequency-domain analysis, the following components of the spectral analysis of HR were assessed: total power spectrum (0.003-1 Hz), low frequency (0.04-0.15 Hz), high frequency (0.15-0.5 Hz), and low-frequency/high-frequency ratio. The spectral analysis of HR was calculated at 5-min intervals, during rest, and after a 5-min sympathetic stimulation by passive orthostatism with a 70% tilt.Statistical analysis.Data were analyzed on the Statistical Package for Social Sciences (version 14.0 for Windows; SPSS, Inc., Chicago, IL). On the basis of the results of previous studies with IMT performed in our laboratory (6,7,42), we estimated that a sample size of 12 individuals in each group would have a power of 80% to detect a 20% difference in PImax, for an α of 0.05. Descriptive data are presented as mean ± SD. Baseline data for the two intervention groups and the group of patients who were not included in the study were compared by ANOVA, and post hoc comparisons were performed with the Tukey test. Categorical variables were compared with the Fisher exact test. The effects of interventions were compared by two-way ANOVA for repeated measures (RM-ANOVA), and post hoc analysis was conducted by the Tukey test to compare weekly values of PImax.RESULTSPatients.Figure 1 presents the flow of patients in the study. Of the 148 patients with DM evaluated for inspiratory muscle strength, 43 (29%) had PImax < 70% of predicted. Of these patients, two were excluded for obesity, four were excluded for presence of heart failure, and four were excluded for regular practice of physical exercise. Of the 33 patients randomized to the IMT and P-IMT groups, two were excluded from the IMT group because of ischemia on the cardiopulmonary test, and one patient in the P-IMT group died in a car accident. Three patients from the IMT group and two from the P-IMT group later refused to continue in the protocol. Therefore, after 8 wk, 13 patients in the P-IMT group and 12 patients in the IMT group were analyzed.FIGURE 1-Flow diagram of the study.Table 1 presents the baseline characteristics of patients randomized to IMT and P-IMT, as well as the 123 patients screened who did not participate in the protocol. The three groups presented similar characteristics except for less utilization of angiotensin-converting enzyme inhibitors in patients of the screening group and more frequent utilization of diuretics in the P-IMT group. As by protocol, the screening group had higher PImax when compared with the randomized patients. There were no differences in PImax, Pthmax/PImax, and endurance time between the IMT and P-IMT groups.TABLE 1. Baseline characteristics of randomized and screened patients.Pulmonary function.Table 2 shows the results of pulmonary function tests. After 8 wk of intervention, there were no changes in FVC, FEV1, and MVV in the IMT and P-IMT groups.TABLE 2. Pulmonary function, inspiratory muscle function, and cardiopulmonary exercise testing before and after intervention.Inspiratory muscle function.Figure 2 shows the weekly values of PImax, demonstrating that IMT induced marked improvement in PImax, which was apparent after the second week of training and reached an increment of 108% after 8 wk, whereas in the P-IMT group, there was no significant change. Likewise, inspiratory muscle endurance, evaluated by the Pthmax/PImax, and endurance time increased only after IMT (Table 2).FIGURE 2-Mean ± SD weekly PImax during the training period. *RM-ANOVA: P < 0.001 time effect; P < 0.001 training effect; P < 0.001 interaction.Cardiopulmonary exercise testing.Table 2 shows that there were no significant changes in any of the cardiopulmonary exercise testing-derived variables after IMT or P-IMT.Cardiac autonomic function testing.At baseline, all randomized patients presented more than one abnormal cardiovascular autonomic test. In the IMT group, 10 patients presented two abnormal test results and 2 patients presented three abnormal test results. In the P-IMT group, seven patients presented two abnormal tests and six presented three abnormal tests.HR variability.Table 3 shows time- and frequency-domain indices of HRV before and after intervention. Twenty-four-hour indices of HRV as well as power spectral components of HRV at rest and after sympathetic stimulation by passive orthostatism were unaffected by IMT or P-IMT.TABLE 3. Twenty-four-hour indices of HR variability and spectral analysis of HR at rest and during passive orthostatism before and after intervention.DISCUSSIONThe major findings of the present study were that IMW is frequent in DM, occurring in 29% of screened individuals, and that IMT is able to reverse the loss of inspiratory muscle strength in these patients. However, the improvement in inspiratory muscle strength after training was not accompanied by changes in functional capacity or autonomic modulation. These findings were obtained in a placebo-controlled randomized trial, with blind evaluation of outcomes, conducted in DM with autonomic neuropathy and IMW.The mechanisms responsible for the development of IMW in DM are still poorly understood. Experiments have identified respiratory muscle weakness in rats with streptozotocin-induced diabetes, with evidence of phrenic nerve neuropathy, characterized by axonal atrophy and significant reduction in myelin (33). Wanke et al. (41) assessed respiratory muscle strength in DM patients and healthy controls by measuring transdiaphragmatic pressures and PImax during bilateral stimulation of the phrenic nerve and from voluntary muscle contraction. Although only patients with more accentuated polyneuropathy presented reduced respiratory muscle strength, phrenic nerve latencies were normal, suggesting that impaired diaphragm function was not caused by phrenic neuropathy (40). In contrast, Kabitz et al. (19) demonstrated an association between diabetic polyneuropathy and impaired respiratory neuromuscular function assessed by phrenic nerve stimulation in DM. In the present study, diabetic polyneuropathy was not evaluated; therefore, more studies should be conducted to elucidate its role on the development of IMW in DM.We have consistently shown that the same IMT program used in the present study improves inspiratory muscle strength, induces diaphragm hypertrophy, and increases functional capacity in patients with chronic heart failure and IMW (6,7,42). Therefore, contrary to what has been proposed by others (32), the training stimulus of this protocol results in clear functional and structural adaptations. Our patients had preserved peak exercise capacity at baseline, and IMT resulted in no significant change in V˙O2peak. However, similar to the present findings, even in chronic obstructive pulmonary disease patients, IMT may not be associated with a significant improvement in peak exercise capacity (24). Likewise, IMT has no significant effect on peak exercise capacity in healthy individuals, but it may improve performance during high-intensity constant workload exercise (3). Another possible explanation for our findings may be the activation of the inspiratory muscle metaboreflex, which controls the competition for blood flow between inspiratory muscles and skeletal muscles in healthy individuals (9) as well as in patients with chronic obstructive pulmonary disease (39) and in chronic heart failure (6). Therefore, it is conceivable that DM might not improve functional capacity after IMT because they have an attenuated inspiratory muscle metaboreflex. However, this hypothesis deserves to be formally tested by controlled experiments.Patients with DM and autonomic neuropathy may present abnormal HRV (26) and increased risk of mortality (25). Whole-body aerobic exercise improves HRV in DM without autonomic dysfunction or with mild autonomic neuropathy (16,23). Despite its beneficial effects on functional capacity in chronic heart failure, Laoutaris et al. (22) found no significant effect of IMT on HRV of these patients. Likewise, in our study, the increase in inspiratory muscle strength with IMT did not lead to any change in HRV in time and frequency domains, and there was no correlation between PImax and autonomic modulation. All of our patients showed reduced PImax and evidence of pronounced autonomic impairment, as indicated by the presence of abnormal autonomic tests, absence of change in the spectral components of HR during sympathetic stimulation (Table 3), and reduced indices of 24-h HRV considering expected values for age (38).This study has several limitations. Inspiratory muscle function was evaluated with volitional noninvasive tests and, therefore, part of the improvement in these measures could have been related to a learning effect. Hart et al. (14) evaluated the effects of IMT using the Powerbreathe® device in healthy individuals, showing that improvement in PImax after intervention could be due to a learning effect because it had no influence on diaphragm strength assessed by magnetic stimulation of the phrenic nerve. However, we took care to control the breathing strategy in the inspiratory muscle endurance tests, probably reducing this confounding factor. Moreover, both the IMT group and the P-IMT had their PImax measured every week, and despite these repeated measures, the P-IMT showed no significant learning effect in the measurement of PImax (Fig. 1). Finally, we cannot exclude the possibility that higher-intensity IMT could have resulted in improvement in functional capacity in our patients, as has been suggested by a meta-analysis in chronic obstructive pulmonary disease (34) as well as studies in cystic fibrosis (10) and chronic heart failure (22). However, the size of the mean increment in PImax in the present study is remarkably similar to that obtained with the same protocol in patients with chronic heart failure (7), suggesting that a training effect on the inspiratory muscles was obtained and that further increments in training intensity would unlikely change the outcome.In conclusion, IMW occurs frequently in DM and can be reversed by IMT. In these patients, IMT does not improve pulmonary function, functional capacity, and autonomic modulation. These findings may have clinical implications during situations where pulmonary functional reserve may be of clinical relevance. One such a situation is in the preoperative evaluation for major surgery. For instance, PImax is associated with functional capacity after coronary artery bypass surgery (35) and preoperative IMT has been shown to reduce pulmonary complications after this surgical intervention (17). Therefore, the measurement of PImax may be particularly important in the preoperative evaluation of patients with DM, and this should be addressed in future studies.A. P. S. Corrêa was supported by grant from the Coordination for the Improvement of Higher Education Personnel (CAPES), Brazil. This study was supported by Fundo de Incentivo à Pesquisa do Hospital de Clínicas de Porto Alegre (FIPE - HCPA). 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[CrossRef] [Medline Link] [Context Link] HEART RATE VARIABILITY; PULMONARY FUNCTION; EXERCISE CAPACITY; CARDIOPULMONARY|00005768-201107000-00001#xpointer(id(R3-1))|11065213||ovftdb|SL00004560201010945711065213P67[CrossRef]|00005768-201107000-00001#xpointer(id(R3-1))|11065405||ovftdb|SL00004560201010945711065405P67[Medline Link]|00005768-201107000-00001#xpointer(id(R4-1))|11065213||ovftdb|00005069-199910000-00029SL0000506919996753911065213P68[CrossRef]|00005768-201107000-00001#xpointer(id(R4-1))|11065404||ovftdb|00005069-199910000-00029SL0000506919996753911065404P68[Full Text]|00005768-201107000-00001#xpointer(id(R4-1))|11065405||ovftdb|00005069-199910000-00029SL0000506919996753911065405P68[Medline Link]|00005768-201107000-00001#xpointer(id(R5-1))|11065405||ovftdb|SL0103689820091038411065405P69[Medline 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