Inspiratory muscle dysfunction in patients with severe obstructive sleep apnoea M-Y. Chien*
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Inspiratory muscle dysfunction in patients with severe obstructive sleep apnoea M-Y. Chien*
Eur Respir J 2010; 35: 373–380 DOI: 10.1183/09031936.00190208 CopyrightßERS Journals Ltd 2010 Inspiratory muscle dysfunction in patients with severe obstructive sleep apnoea M-Y. Chien*,#, Y-T. Wu*,#, P-L. Lee",+, Y-J. Chang1 and P-C. Yang+ ABSTRACT: Repetitive inspiratory effort against an obstructed airway and intermittent hypoxia may be deleterious to the inspiratory muscles in patients with obstructive sleep apnoea (OSA). We investigated muscular dysfunction by comparing the strength, endurance and fatigability of inspiratory muscles and knee extensors in patients with newly diagnosed severe OSA compared with matched controls. The measurements included strength and endurance tests of both muscles, and a fatigue trial with simultaneous surface electromyography of the diaphragm and the vastus lateralis during voluntary contractions and in response to magnetic stimulation. To our knowledge, this is the first investigation to assess peripheral muscle performance in severe OSA patients versus controls. Patients in the OSA group exhibited significantly lower strength and endurance in both muscles than the control group. The fatigue index decreased significantly exclusively in the inspiratory muscles of OSA patients. Magnetic stimulation-evoked compound muscle action potential latencies increased and the amplitudes decreased significantly in the diaphragm, but not in the vastus lateralis after a fatigue test in the OSA group. In conclusion, a significantly lower functional performance was shown for both inspiratory muscles and knee extensors in the OSA group. However, higher fatigability was only seen in the inspiratory muscles of patients with severe OSA. KEYWORDS: Inspiratory, knee extensors, magnetic stimulation, nerve conduction delay, obstructive sleep apnoea, surface electromyography epetitive obstruction of the upper airway and apnoea/hypopnoea during sleep is a feature of obstructive sleep apnoea (OSA) syndrome [1]. An obstructed airway and the subsequent asphyxia may lead to increased inspiratory efforts and, hence, the chronic overload of inspiratory muscles [2]. The chronic overuse of the diaphragm was reported to put OSA subjects at risk of inspiratory muscles fatigue [3]. However, whether diaphragm fatigue actually occurs in OSA patients is still controversial [4–6]. GRIGGS et al. [4] have shown that pleural pressure relaxation rates during voluntary sniff maneuvers were prolonged in the morning compared with the preceding night prior to sleep in OSA patients. However, MONTSERRANT et al. [5] reported lack of evidence for diaphragmatic fatigue during the night in these patients. They explained that the fatiguing levels of inspiratory effort generated throughout the night did not continue for sufficiently long periods to develop impaired contractility. R causes muscle damage [7]. OSA has been considered a systemic oxidative disorder [8]. Therefore, it is logical to hypothesise that systemic skeletal muscle dysfunction may develop in patients with OSA, in addition to disorders of the upper airway muscles. However, studies addressing this issue were conducted in animal models and have shown conflicting results [9, 10]. AFFILIATIONS *School and Graduate Institute of Physical Therapy, College of Medicine, # Physical Therapy Center, " Center of Sleep Disorder, + Division of Pulmonary and Critical Care Medicine, Dept of Internal Medicine, National Taiwan University Hospital, Taipei, and 1 Dept of Physical Therapy, Chang Gung University, Tao-Yuan, Taiwan. CORRESPONDENCE P-C. Yang Dept of Internal Medicine National Taiwan University Hospital No 1 Jen-Ai Road Section 1 Taipei 10051 Taiwan E-mail: [email protected] Received: Dec 16 2008 Accepted after revision: July 16 2009 First published online: July 30 2009 The purpose of this study was to investigate the effect of OSA on muscular strength, endurance, and the fatigability of inspiratory muscles and peripheral knee extensors in patients with severe OSA compared with those in the control group. Comparisons made between these two types of muscle were aimed to determine whether the effects of OSA were generalised or specific to the muscles subjected to increased use. The unique repetitive deoxygenation–reoxygenation pattern in OSA patients may induce free radical production and oxidative stress, which METHODS 15 males aged 40–65 yrs with newly diagnosed severe OSA who had an apnoea/hypopnoea index (AHI) of o30 events?h-1 and an Epworth sleepiness scale (ESS) score of o10 were recruited at the Sleep Research Centre (National EUROPEAN RESPIRATORY JOURNAL VOLUME 35 NUMBER 2 European Respiratory Journal Print ISSN 0903-1936 Online ISSN 1399-3003 c 373 SLEEP-RELATED DISORDERS M-Y. CHIEN ET AL. Taiwan University Hospital, Taipei, Taiwan). The control group consisted of 15 age-, height- and weight-matched subjects (AHI ,5 events?h-1) not diagnosed with OSA from the Sleep Research Centre. Subjects were excluded if they presented with any active medical diseases, nervous system diseases, major pulmonary dysfunction, morbid obesity, diabetes under the control of oral hypoglycemic agents, alcoholism (o50 g per day) or recent infection. All the participants at the time of the study were not receiving pharmacological or mechanical treatment. The study was approved by the Institutional Ethics Committee (National Taiwan University Hospital, Taipei, Taiwan), and all subjects were informed of the procedures in detail and gave their written informed consent prior to enrolment. This study is a registered clinical trial at ClinicalTrials.gov (NCT00813852). Diagnosis of OSA The definitive diagnosis of OSA depended on an in-laboratory overnight polysomnography recording system (Embla, Medcare, Iceland) demonstrating an elevated AHI, which was calculated as the total episodes of hypopnoeas and apnoeas per hour of sleep according to the criteria of the American Academy of Sleep Medicine [1]. The level of daytime sleepiness was assessed using the ESS score in the morning after nocturnal polysomnography. Normal values ranged from 2 to 10, with scores o10 indicating daytime sleepiness [11]. Anthropometrics, pulmonary function tests and physical activity evaluation Body weight and height, and circumferences of the neck, waist, and hip were measured. Body mass index (BMI) and waist-tohip ratio were also calculated. Pulmonary function tests were performed by using a computerised spirometer (Chestgraph HI-701; Chest MI Inc., Tokyo, Japan) with the subjects in a sitting position, according to the standardised procedure [12]. The forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio were recorded. pressure gauge (Model 4103; Boehringer Ingelheim, Norristown, PA, USA) using standard procedures [12]. Maximal voluntary ventilation (MVV) manoeuvres were used as the index of inspiratory muscle endurance and for the fatigue-induced protocol according to the diagnostic recommendations by the Chestgraph HI-701 spirometer [12]. Ventilation time was calculated by the computer automatically. A previous study by our group reported that diaphragmatic fatigue could be induced by the two-set MVV manoeuvres with a 5-min rest in between [14]. The fatigue index was defined as the post-MVV manoeuvres PI,max divided by the pre-MVV manoeuvres PI,max, which represents how much the muscle tension declined upon repetitive contraction. For routine muscle fatigue measurements, the decrease in force generated from a maximal volitional contraction is often used as a fatigue index. Functional performance and fatigue index of knee extensors The Cybex 6000 (Lumex Inc., Ronkonkoma, NY, USA) was used to measure the strength and endurance of the right knee extensors. Each subject was instructed to perform five maximal isometric knee extension contractions at a 60u knee flexion angle. Each contraction lasted for 5 s, with a resting period of at least 15 s between trials [15]. The means of five maximal isometric contraction peak torques (Newton-metre; N-m) were calculated for data analysis. The endurance test consisted of 30 cycles of alternative knee extension/flexion isokinetic contractions at the speed of 180u?s-1. Before each test, subjects performed three submaximal trials to become familiarised with the test. The muscular endurance was evaluated by the total work (N-m) generated during 30 cycles of contractions as the total area under the torque curve for knee extension movement, which would be automatically provided by the Cybex system [15]. Physical activity was evaluated with a 7-day recall questionnaire, which was designed to determine calories expended on all activities during the previous 7-day period [13]. The total energy expenditure was the sum of energy consumed by all activities. After 30 cycles of isokinetic contractions, each participant performed three maximal isometric knee extension contractions at 60u knee flexion angle again. The fatigue index was defined as the mean of the peak torques of isometric contractions at post-endurance test divided by the preendurance value. Functional performance and fatigue index of inspiratory muscles The maximal inspiratory pressure (PI,max) indicative of muscle strength was measured from residual volume with an aneroid Magnetic stimulation Cervical magnetic stimulation (CMS) was performed by a Magstim 220 stimulator (Magstim, Whitland, Wales, UK) equipped with a circular doughnut-shaped 90-mm coil Protocol: Maximal voluntary contractions Magnetic stimulation Parameters: Root mean square Median frequency CMAP amplitude CMAP latency FIGURE 1. 374 Fatigue test Magnetic stimulation Maximal voluntary contractions CMAP amplitude CMAP latency Root mean square Median frequency Schematic diagram demonstrating the protocol for the fatigue test. CMAP: compound muscle action potential. VOLUME 35 NUMBER 2 EUROPEAN RESPIRATORY JOURNAL M-Y. CHIEN ET AL. SLEEP-RELATED DISORDERS a) 400 b) µV 200 0 -200 -400 90 80 70 µV 60 50 40 30 20 10 0 0 5 10 15 20 25 30 c) 0 5 10 15 20 25 30 35 0 10 20 30 40 Time s 50 60 70 d) 4 µV 2 0 -2 -4 2.5 2.0 µV 1.5 1.0 0.5 0 0 FIGURE 2. 10 20 30 40 Time s 50 60 70 Examples of a, b) raw electromyopgraphy recordings and c, d) root mean square during maximal voluntary contractions in one patient with severe obstructive sleep apnoea. Diaphragm a) before and b) after fatigue test. Vastus lateralis c) before and d) after fatigue test. EUROPEAN RESPIRATORY JOURNAL VOLUME 35 NUMBER 2 375 c SLEEP-RELATED DISORDERS M-Y. CHIEN ET AL. producing a maximum output of 2.5 Tesla (Magstim) using standard techniques as described previously [16]. Stimulations were delivered with the maximal output of the stimulator. Subjects were asked to keep their neck slightly bent forward for stimulating the phrenic nerve [16], while lying on the Cybex table with the coil placed below the inguinal ligament and 2 cm laterally from the femoral artery for stimulating the femoral nerve [17]. Surface electromyopgraphy recordings for the diaphragm and vastus lateralis The surface electromyopgraphy (EMG) signals were simultaneously and continuously acquired by means of bipolar electrodes from the right diaphragm and the right vastus lateralis (VL). For the diaphragm, the electrodes were placed in the seventh or eighth intercostal space on the right side of the body at the midclavicular line [18, 19]. The electrodes were also placed on the skin overlying the lower third of the VL muscle (10–12 cm above the knee joint) and the electrodes were aligned longitudinally to the direction of the muscle fibres. The distance between the two electrodes was kept below 2 cm and the reference electrodes were placed on the sternum and patella. The skin surface was well prepared and cleaned with alcohol to obtain a low inter-electrode resistance prior to positioning the electrodes. Experimental protocol All the subjects performed five maximal voluntary contractions (MVCs), followed by five magnetic stimulations. Subsequently, inspiratory muscle fatigue was induced by two MVV manoeuvres with a 5-min rest between each trial, while knee extensor fatigue was induced by 30 repetitions of isokinetic contractions. Immediately after the fatigue protocols, another five magnetic stimulations were performed as described previously and were followed by five MVCs (,1 min after the fatigue test). The testing protocol is illustrated in figure 1. EMG data analysis All EMG signals were amplified (EMG100A; Biopac Systems Co., Goleta, CA, USA), band-pass filtered between 10 Hz to 1,000 Hz, and digitised at a sampling rate of 2 kHz. Subsequently, the final signal was acquired and analysed off-line later using commercially available software (AcqKnowledge 3.9.1 software for Windows; Microsoft Office). The parameters of the surface EMG (sEMG) signals during MVCs included root mean square (RMS) values of the amplitude and median power frequency (MPF). The means of the first three voluntary sEMG signals (pre- and post-MVV PI,max, pre- and post-test maximal isometric knee contractions) (fig. 2), and the first three and the last three breaths during MVV manoeuvres and during 30-cycle isokinetic endurance test were calculated. RMS was used to quantify the diaphragm activation, i.e. combined processes of diaphragm motor unit recruitment and motor firing rate [20]. The influence of the electrocardiogram on sEMG signals was minimised by recording from the right side of the body. To further minimise any signal contamination by electrocardiogram on the diaphragmatic sEMG signals during PI,max effort, RMS was measured from the segments between QRS complexes. 376 VOLUME 35 NUMBER 2 The conduction time of the phrenic nerve and femoral nerve were measured as the time elapsed between the stimuli delivered by CMS and the onset of the compound muscle action potential (CMAP), which was specifically marked by the first deviation of the signal from baseline (CMAP latencies) (fig. 3). CMAP latencies and amplitudes provided thereafter corresponded to the average of five stimulations. The voluntary EMG and the diaphragm CMAPs are myoelectric signals that represent different meanings: the voluntary signal represents the summated electrical activity generated by asynchronously firing motor units, whereas the diaphragm CMAPs represents the summated synchronised electrical activity generated by all motor units after a supramaximal stimulus of the phrenic nerve [21]. Statistical analysis Statistical analyses were performed using SPSS version 11.5 for Windows (SPSS Inc., Chicago, IL, USA). Data were expressed as mean¡SD. Comparisons of basic characteristics between the two groups were made by independent unpaired t-tests. The MVC force and sEMG parameters were analysed using a repeated measured ANOVA to assess the difference between the baseline and the post-fatigue test in each group. An a-value was set at 0.05. RESULTS Baseline characteristics of the study group There was no significant difference in the basic demographic characteristics, current smokers, and energy expenditure of daily activities between the two groups except that the OSA group had significantly higher values of AHI and ESS (table 1). All the participants had normal FVC, FEV1 and FEV1/FVC ratio. However, the patients with severe OSA had significantly lower values of both FVC and FEV1 than the controls. Functional performance and sEMG parameters at baseline Patients with severe OSA had significantly lower baseline strength (PI,max and peak torque values for the knee extensors) and endurance than the controls at baseline (p,0.05; table 2). Diaphragmatic sEMG revealed significantly lower MPF in patients with severe OSA than those in the control group (p,0.05). sEMG recordings for VL revealed significantly lower RMS in patients with severe OSA than those in the control group (p,0.05).The evoked sEMG for the diaphragm response to CMS showed a significantly longer CMAP latency (7.28¡0.66 ms) and lower CMAP amplitude (1.4¡0.5 mV) in patients with severe OSA than those in the control group (p,0.05). It also showed a significantly longer CMAP latency (5.41¡0.74 ms) of evoked sEMG for the VL response to magnetic stimulation in patients with severe OSA than those in the control group (p,0.05). Functional performance and sEMG parameters after the fatigue test A similar trend was found for the strength decline and voluntary sEMG parameters of inspiratory muscles and knee extensors in the two groups (table 2). As the muscles of OSA patients were weaker than those of the controls, the level of fatiguing tasks might be relatively higher for the OSA group. The fatigue index derived during maximal voluntary efforts was significantly different between the two groups in the EUROPEAN RESPIRATORY JOURNAL M-Y. CHIEN ET AL. SLEEP-RELATED DISORDERS a) 1.0 TABLE 1 Baseline characteristics of the subjects 0.8 OSA group mV 0.6 p-value 0.4 Subjects 15 15 0.2 Age yrs 51.3¡6.5 51.2¡7.0 0.979 8 5 0.462 Current smoker# 0 Anthropometrics -0.2 -0.4 -0.6 -0.8 0 20 40 60 Time ms 80 100 120 Body weight kg 75.0¡8.1 73.6¡7.8 0.625 Body height cm 168.1¡5.8 167.4¡3.7 0.698 BMI kg?m-2 26.6¡3.1 26.3¡3.0 0.786 Neck circumference cm 38.3¡3.2 37.9¡2.1 0.463 Waist circumference cm 90.6¡10.4 89.2¡10.6 0.724 Hip circumference cm 99.8¡6.9 99.1¡7.2 0.656 Waist-hip ratio % 90.8¡8.2 90.0¡8.3 0.829 AHI events?h-1 54.0¡21.7 2.3¡1.0 ,0.001 Epworth sleepiness scale 11.1¡3.1 8.3¡3.6 0.033 Sleep efficiency % 83.2¡8.7 92.0¡4.1 0.002 Average Sa,O2 % 92.3¡4.5 96.2¡7.8 0.005 Lowest Sa,O2 % 71.0¡9.0 88.9¡2.7 ,0.001 Sleep examination b) 0.8 0.6 0.4 0.2 mV Control group Pulmonary function test 0 FVC L FVC % pred -0.2 FEV1 L FEV1 % pred -0.4 FEV1/FVC % Physical activity kcal?kg-1?day-1 -0.6 -0.8 0 20 40 60 80 100 120 Time ms 140 160 180 200 3.8¡0.7 4.3¡0.6 0.040 102.3¡9.4 111.7¡11.4 0.020 3.1¡0.6 3.5¡0.5 0.064 100.8¡11.1 108.2¡8.2 0.047 81.6¡3.7 80.8¡6.6 0.926 35.1¡2.9 38.6¡6.3 0.059 Data are presented as n or means¡ SD, unless otherwise stated. OSA: obstructive sleep apnoea; BMI: body mass index; AHI: apnoea/hypopnoea index; Sa,O2; arterial oxygen saturation; FVC: forced vital capacity; % pred: % FIGURE 3. Example of electromyopgraphy recordings of a) the right predicted; FEV1: forced expiratory volume in 1 s. #: Chi-squared test. diaphragm and b) vastus lateralis for motor responses (compound muscle action potential) with magnetic stimulation in a patient with severe obstructive sleep apnoea. inspiratory muscles (0.86 versus 0.92; p,0.05), but not in the knee extensors (0.94 versus 0.95; p.0.05). The diaphragmatic voluntary sEMG MPF declined significantly from baseline to the end of the second MVV manoeuvre and returned slightly at post-MVV manoeuvres PI,max (p,0.05; fig. 4). A similar trend was shown in VL; however, no statistical significance was detected. The diaphragmatic CMAP latency and amplitude showed significant changes after the MVV manoeuvres in the severe OSA group (latency: 7.28¡0.66 versus 7.48¡0.65 ms; amplitude: 1.4¡0.5 versus 1.2¡0.5 mV; p,0.05). However, there were no significant changes in CMAP latency and amplitude of the VL after the endurance test. DISCUSSION This study demonstrated that severe OSA patients have significantly lower functional performance in strength and endurance, and a prolonged CMAP latency in response to magnetic stimulation of both the inspiratory muscles and knee extensors, but only the inspiratory muscles showed significantly increased fatigability in performance and sEMG assessments. This is the first investigation that we know of in EUROPEAN RESPIRATORY JOURNAL assessing peripheral muscle performance in severe OSA patients versus controls. Methodological considerations Diaphragm muscle activity can be assessed either as a pressure or an EMG response which was recorded with surface, intramuscular needle or oesophageal electrodes. However, transdiaphragmatic pressure method and oesophageal EMG have the disadvantage of their invasiveness and discomfort. Use of intramuscular needle electrodes avoids cross-talk but contains disadvantages of invasiveness and sampling bias. sEMG recordings provide a popular, routine tool to investigate chest wall muscle function but can be confounded by noise and cross-talk [22]. This is a potential limitation of sEMG. Thus, electrodes were placed in the way that minimises cross-talk, as suggested by previous researches [18, 19]. Subjects were well supported during testing to minimise the activities of the adjacent trunk muscles. It was well established that force production by the diaphragm could be significantly reduced by fatigue induced by periods of high-intensity voluntary isocapnic ventilation [23]. During a 2min MVV manoeuvre there was a progressive reduction in ventilation and transdiaphragmatic pressure generation associated with the development of fatigue of the diaphragm [23]. Isocapnic maximal sustained ventilation for 8 min has also VOLUME 35 NUMBER 2 377 c SLEEP-RELATED DISORDERS TABLE 2 M-Y. CHIEN ET AL. Strength, endurance, and surface electromyographic parameters of inspiratory muscles and knee extensors before and after the fatigue protocol OSA group# Control group# Pre-test Post-test Pre-test Post-test PI,max cmH2O 73.3¡22.3 63.1¡20.3" 100.3¡19.2* 92.7¡19.7" MVV L 130.4¡29.2 Inspiratory muscles Fatigue index % 85.9¡6.2 Root mean square mV 73.0¡23.2 Median frequency Hz CMAP latency ms 149.3¡33.0* 92.3¡6.4* 62.2¡20.7" 87.9¡20.4* 74.5¡19.1" 103.6¡14.6 100.3¡13.4 116.5¡17.4* 113.2¡14.5* 7.28¡0.66 7.48¡0.65",+ 6.56¡0.76* 6.60¡0.72 1.4¡0.5 1.2¡0.5" 1.7¡0.4* 1.6¡0.4 Peak torque N-m 140.9¡21.3 133.1¡20.0" 167.7¡26.9* 158.9¡20.0" CMAP amplitude mV Knee extensors Endurance N-m 1424.3¡247.1 Fatigue index % 94.6¡5.8 Root mean square mV 1.8¡0.6 1.7¡0.6 2.3¡0.6* 2.1¡0.5 Median frequency Hz 93.7¡11.3 88.6¡13.2+ 100.7¡12.1 94.3¡11.2" CMAP latency ms 5.41¡0.74 5.44¡0.82 5.01¡0.74* 5.00¡0.74 8.8¡3.1 8.5¡2.4 9.7¡2.2 9.6¡2.1 CMAP amplitude mV 1821.3¡277.7* 95.3¡7.4 Data are presented as mean¡SD. OSA: obstructive sleep apnoea; PI,max: maximal inspiratory pressure; MVV: maximal voluntary ventilation; CMAP: compound muscle action potential; N-m: Newton-metre. #: n515; ": p,0.05, pre-test and post-test comparisons within the group; +: p,0.05, significant group effect by using repeated measures ANOVA. *: p,0.05, pre-test variable comparisons between groups. been suggested as fatiguing procedures [12]. Our preliminary study has also demonstrated that two-set 15-s MVV manoeuvres could induce diaphragmatic fatigue in young healthy participants [14]. Our study employed MVV manoeuvres and 30 cycles of isokinetic knee contractions for determining the endurance of inspiratory muscles and knee extensors, respectively, which, strictly speaking, were not standardised endurance tests by the definition. However, they are widely utilised for clinically evaluating functional muscle endurance [12, 15]. Functional performance of inspiratory muscles and knee extensors In this study, inspiratory muscles (diaphragm) and knee extensors (VL) were selected to explore the effect of the functional changes observed in OSA patients. The chronic overloading of inspiratory muscles against an obstructed upper airway could lead to structural and metabolic adaptations. Peripheral muscle was chosen as a control because it was considered not to be overloaded during sleep. Several studies have compared the inspiratory muscles and peripheral muscles in patients with OSA. MEZZANOTTE et al. [24] reported a significantly lower PI,max in severe OSA subjects, but SHEPHERD et al. [25] reported that the PI,max was not different between the subjects whose AHI was ,20 events?h-1 and .20 events?h-1. In this study, we found significantly lowered values of PI,max in patients with severe OSA compared to those without OSA. The weakened diaphragm would reduce the collapsing force during apnoeas thereby offsetting the large negative pressure generated by the 378 VOLUME 35 NUMBER 2 diaphragm. However, the cause–effect relationship could not be determined in the present study. With regard to the performance of the lower extremity muscles among OSA patients, little investigation has been performed in humans. SAULEDA et al. [26] obtained a needle biopsy of quadriceps femoris in severe OSA patients and found structural and bioenergetic changes in the skeletal muscles. Nevertheless, some studies have shown conflicting results regarding limb muscle performance in OSA animals [9, 10]. Our study is the first investigation that we know of in showing lower strength and endurance of knee extensors in the OSA group, but not fatigability. Future studies are needed to confirm this observation. It is noteworthy that factors such as nutrition, obesity state and physical activity have profound effects on muscle performance [27]. In our study, the groups were matched for the anthropometric parameters; therefore, the difference in muscular strength could not be attributed to them. However, the relatively lower physical activity levels might be related to the lower baseline muscular strength of both examined muscles in the severe OSA group. In addition, the possibility that lower values of PI,max and peak torques represent difference in effort and cooperation between two groups could not be excluded, even though we gave maximal encouragement to each participant during all the tests. Fatigability of the inspiratory muscles Previous studies have shown conflicting results regarding whether inspiratory muscles fatigue during OSA [4–6]. One possible reason is the fatigue index may not distinguish EUROPEAN RESPIRATORY JOURNAL M-Y. CHIEN ET AL. a) SLEEP-RELATED DISORDERS nervous system to prevent further inspiratory muscle fatigue; thus acting as a protective mechanism. Median power frequency Hz 140 120 100 However, significant decreases in CMAP latencies and amplitudes after MVV manoeuvres developed in patients in the severe OSA group, thereby suggesting the diaphragm muscle was responsible for inspiratory muscle fatigue in these patients. Because peripheral muscle fatigue can result in persistent muscle fatigue and longer recovery periods, it is likely that this peripheral neuromuscular fatigue was responsible for the decline in function of inspiratory muscles, i.e. decreased PI,max and endurance. * 80 60 40 20 0 Pre PI,max b) MVV early MVV end Post PI,max Median power frequency Hz 120 100 Study limitations This study had several limitations. First, as we did not measure twitch pressure in response to the stimulation of phrenic nerves and femoral nerve, this study could not answer whether the decreased strength of the inspiratory muscle and knee extensors was due to decreased recruitment and/or decreased contractility per se. Nevertheless, the study demonstrated decreased CMAP amplitude that could represent the delayed neurotransmitter in OSA patients compared with the controls. 80 60 40 20 0 Prevoluntary FIGURE 4. The decrease of sEMG amplitudes and power spectra of the inspiratory muscles found in this study may reflect decreased motor unit recruitment from a decreased activation [29], or hypoxia induced decreases in muscle pH that promote fatigue [30]. Further studies are needed to explore the associated mechanisms. Isokinetic early Isokinetic end Postvoluntary Group mean values of median power frequency of the a) right diaphragm and b) vastus lateralis for voluntary contractions before, during and after fatigue test by maximal voluntary ventilation (MVV) manoeuvres for inspiratory muscles and isokinetic test for knee extensors. PI,max: maximal inspiratory pressure. &: obstructive sleep apnoea; h: control. *: p,0.05, significant group effect by using repeated measures ANOVA. between different types of fatigue, i.e. central fatigue and peripheral neuromuscular fatigue. In contrast to the conventional fatigue test induced by MVCs, externally applied electrical or magnetic stimulations for peripheral nerve roots that measure the CMAP after stimulation have long been known to evaluate peripheral neuromuscular function [16, 17]. CMAP measures the peripheral neuromuscular fatigue (especially neurotransmitters) in the muscles bypassing the central nervous system. EL-KABIR et al. [28] have shown that in patients with OSA treatment with nasal continuous positive airway pressure, the twitch transdiaphragmatic pressure did not improve in response to bilateral CMS. However, the study included lack of repeated polysomnography and compliance data of continuous positive airway pressure treatment, and no control group. Our results revealed a significant decrease in the sEMG RMS amplitude after MVV manoeuvres but not CMAP amplitudes in control subjects. These findings indicate that MVV manoeuvres might induce central fatigue, which was considered as a pre-emptive fatigue induced by the central EUROPEAN RESPIRATORY JOURNAL Secondly, we did not measure lung volume changes before and immediately after MVV manoeuvres. Thus it may be difficult to thoroughly interpret the changes in CMAP characteristics. Previous studies had reported that CMAP amplitude and latency would be affected by different lung volumes [21, 22]. We assumed both groups in our study were influenced to the same extent; however, the result showing significant difference of CMAP amplitude and latency could provide important information regarding the neuromuscular characteristics of inspiratory muscles in OSA patients. Future studies should examine the effect of OSA on inspiratory muscles fatigue by using comprehensive measurement tools. Thirdly, the unequal fatiguing tasks produced by OSA and control participants might complicate the comparison of fatigue indices. The lower baseline PI,max and peak torques of knee extensors in the OSA group would bring about the different fatigue tasks for the OSA and the control group. According to that, future study should strive to employ a more standardised fatigue tests for further refinement of this study. Implications A significantly lower strength and endurance for inspiratory muscles and knee extensors of severe OSA patients were found in comparison with their age and BMI-matched controls. Therefore, systemic effects of chronic intermittent hypoxia and reoxygenation on skeletal muscles in OSA populations could not be completely ruled out. However, higher fatigability either during voluntary contractions or in response to magnetic stimulations was only exhibited in the inspiratory muscles of patients with severe OSA. Peripheral neuromuscular fatigue of the diaphragm might contribute to this increased fatigability; therefore, we speculated that the VOLUME 35 NUMBER 2 379 c SLEEP-RELATED DISORDERS M-Y. CHIEN ET AL. underlying mechanisms of muscular adaptation to chronic increase use played a critical role in this pathological state when compared with the systemic effects on skeletal muscles occurring in OSA patients. CLINICAL TRIALS This study is registered at ClinicalTrial.gov (NCT00813852). SUPPORT STATEMENT The authors received financial support from the National Science Council (Taiwan) (96-2314-B-002-022-MY3). STATEMENT OF INTEREST None declared. REFERENCES 1 Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine Task Force. Sleep 1999; 22: 667–689. 2 Wilcox PG, Paré PD, Road JD, et al. Respiratory muscle function during obstructive sleep apnea. Am Rev Respir Dis 1990; 142: 533–539. 3 MacIntyre NR. Muscle dysfunction associated with obstructive pulmonary disease. Respir Care 2006; 51: 840–848. 4 Griggs GA, Findley LJ, Suratt PM, et al. Prolonged relaxation rate of inspiratory muscles in patients with sleep apnea. Am Rev Respir Dis 1989; 140: 706–710. 5 Montserrat JM, Kosmas EN, Cosio MG, et al. 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