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1 From the Department of Pulmonology, University Hospital Maastricht and the Asthma Centre Hornerheide, Horn, Netherlands.
2 Supported by a research grant from the University Hospital Maastricht, Netherlands. 3 Reprints not available. Address correspondence to MPKJ Engelen, Department of Pulmonology, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, Netherlands. E-mail: m.engelen{at}pul.unimaas.nl.
ABSTRACT
Background: Skeletal muscle weakness is a prominent problem in many patients with chronic obstructive pulmonary disease (COPD).
Objective: The aim of the study was to determine the relation between skeletal muscle function, body composition, and lung function in COPD (emphysema and chronic bronchitis) patients and healthy volunteers.
Design: In 50 patients with chronic bronchitis, 49 patients with emphysema, and 28 healthy volunteers, skeletal muscle function was assessed by handgrip and linear isokinetic dynamometry. Whole-body and subregional fat-free mass (FFM) were assessed by dual-energy X-ray absorptiometry.
Results: Whole-body and extremity FFM were significantly lower in patients with emphysema (P < 0.001) and chronic bronchitis (P < 0.05) than in healthy volunteers, but trunk FFM was significantly lower only in patients with emphysema (P < 0.001). Extremity FFM was not significantly different between the COPD subtype groups, despite significantly lower values for whole-body and trunk FFM (P < 0.05) in patients with emphysema. Absolute skeletal muscle function (P < 0.001) and muscle function per kilogram of whole-body FFM were significantly lower in both COPD subtype groups than in healthy volunteers (P < 0.05), but no significant difference was found between patients with chronic bronchitis and those with emphysema. Muscle function per kilogram of extremity FFM was not significantly different between the 3 groups and was not associated with forced expiratory volume in 1 s.
Conclusion: Skeletal muscle weakness is associated with wasting of extremity FFM in COPD patients, independent of airflow obstruction and COPD subtype.
Key Words: Skeletal muscle weakness • extremity fat-free mass • chronic bronchitis • emphysema • chronic obstructive pulmonary disease • COPD • dual-energy X-ray absorptiometry • humans
INTRODUCTION
Skeletal muscle weakness is observed in many patients with chronic obstructive pulmonary disease (COPD) (1, 2). This muscle weakness is recognized as an important factor in COPD patients because it affects their physical capacity by reducing peak exercise performance and enhancing symptom intensity (1, 3). Furthermore, muscle weakness and a reduced exercise capacity in COPD patients have been shown to increase the utilization of health care resources (4).
Muscle wasting is one of the factors that can be considered in the pathogenesis of skeletal muscle weakness in COPD. In earlier studies, depletion of whole-body fat-free mass (FFM), mainly consisting of muscle mass, has been observed in both COPD inpatients (5) and outpatients (6). No data are available on whether depletion of whole-body FFM in COPD patients is the result of a general process affecting multiple body compartments or whether it preferentially influences specific body subregions (ie, extremities). This information seems important because in a recent study by Bernard et al (7), skeletal muscle weakness in COPD patients was related to peripheral muscle atrophy, as assessed by thigh muscle cross-sectional area (CSA). Absolute quadriceps strength was significantly lower in these COPD patients than in a healthy control group, whereas the ratio of quadriceps strength to muscle CSA was not significantly different between the 2 groups. Furthermore, quadriceps strength and muscle CSA were positively correlated with the severity of airflow obstruction.
However, assessment of muscle CSA is not easily applicable in clinical practice. Recently, we showed that dual-energy X-ray absorptiometry (DXA) is a clinically valid method for the assessment of whole-body composition and bone mineral loss in COPD patients (8). Moreover, DXA makes it possible to assess FFM and lean mass (ie, bone-free FFM) in several body subregions. This information might be important in the diagnosis of skeletal muscle weakness because extremity FFM gives a more detailed reflection of physically active muscle mass during daily life activities.
Two previous studies reported FFM depletion in the COPD subtypes chronic bronchitis and emphysema (6, 9), but FFM depletion was present to a greater extent in emphysema patients. In addition, the emphysema patients had lower values for forced expiratory volume in 1 s (FEV1) than the chronic bronchitis patients. These 2 findings suggest that emphysema patients are more prone to peripheral skeletal muscle wasting and weakness than are patients with chronic bronchitis.
The purpose of the present study was to examine whether assessment of whole-body FFM gives a reflection of extremity FFM in patients with chronic bronchitis and emphysema and in healthy volunteers, as assessed by DXA. The second aim was to compare skeletal muscle function between the 3 study groups and to find out whether possible differences are related to differences in whole-body and subregional FFM, the severity of airflow obstruction, or both.
SUBJECTS AND METHODS
Study population
All studied COPD patients were consecutively admitted to a pulmonary rehabilitation center for inpatient rehabilitation. Patients were selected on the basis of the presence of chronic airflow limitation (10) (FEV1 <70% of the predicted value) and irreversible obstructive airway disease (<10% improvement of FEV1 after inhalation of a bronchodilating agonist). All patients were clinically stable and without a respiratory tract infection. Patients with malignancies, gastrointestinal disorders, or severe endocrine disorders or who had undergone surgery recently were excluded from the study. As a result, a group of 99 patients (77 men, 22 women) (Table 1) remained for further analysis. This group was further stratified into those with chronic bronchitis (n = 50) and those with emphysema (n = 49) by high-resolution computed tomography (HRCT). Twenty-eight healthy, age-matched volunteers free of disease participated as the control group. The study was approved by the Medical Ethical Committee of the University Hospital Maastricht.
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TABLE 1.. Whole-body and subregional fat-free mass (FFM) and lean mass and skeletal muscle function of patients with emphysema or chronic bronchitis and of healthy volunteers1
Assessment of skeletal muscle function of the upper and lower extremities
Isometric handgrip strength was assessed in all subjects by using a Harpenden handgrip dynamometer (Yamar; Preston, Jackson, MI). The isometric grasp of the right hand was determined by measuring the maximally developed strength of the flexors of the fingers. The highest value of 3 maneuvers was used for statistical analysis.
Linear isokinetic muscle function of the lower limbs was assessed by a multijoint dynamometer device (Aristokin; LODE, Groningen, Netherlands). While seated with knees bent at a 90° angle, the subjects' feet were attached to a fixed support, leaving the ankles free to rotate. The subjects performed maximal isokinetic extension of the legs against an applied resistance of 250 N. The rate at which the seat shifted backward was set at 20 cm/s (preload: 150 N; duration preload: 0.3 s). Thus, the force generated by the subject increased with increasing voluntary effort, but the velocity of the contraction remained constant at 20 cm/s. At this isokinetic rate, the maximal energy generated by the legs mainly determined the outcome of performance. The highest power value (in W) from 5 technically well-performed repetitions was used in the statistical analysis. Before testing, each subject was familiarized in a standardized way with the equipment and the requested movement.
Assessment of whole-body and subregional fat-free mass and lean mass
Whole-body FFM, which consists of lean mass and bone mineral mass, was determined by scanning each subject on a DPX bone densitometer (Lunar Radiation Corporation, Madison, WI). For more technical details, see reference 8. FFM and lean mass were assessed in the whole body and in several body subregions (eg, trunk, arms, and legs); the latter were obtained by positioning cuts with Lunar software. Extremity FFM was obtained by summing the FFM of the arms and legs. Precision of subregional measurements is known to be poorer than that of the whole body (11, 12). The same operator performed the positioning of the cuts for all images scanned to avoid interoperator variability. Quality-assurance tests were run daily.
Assessment of emphysema
In the COPD group, evaluation of the presence and severity of parenchymal destruction, which is a hallmark of emphysema (13), was performed by HRCT with use of a commercial scanner (Somatom Plus; Siemens, Erlangen, Germany) at a voltage of 137 kVp, a current of 220 mA, a collimation of 1.0 mm, and a scanning time of 1 s. Five HRCT scans were obtained while the patients were in a supine position and held their breath at end expiration: 2 scans of the upper and 2 scans of the lower lung zones at 3 and 6 cm above and below the carina and 1 scan at the carina. Images were made at a level of -800 Hounsfield units (HU) and a window width of 1600 HU, appropriate for lung detail. The severity and extent of emphysema in each scan were visually scored on a 4-point scale by 2 independent observers according to the direct observational method developed by Sakai et al (14). For each of the 10 lung sections, the score for the severity of emphysema was multiplied by the extent; the resulting scores were subsequently summed to give a total HRCT score. Visual HRCT scores ranged from 0 (no emphysema) to 120 (severe emphysema). Stratification of the patients by HRCT score resulted in 2 groups: those with an HRCT score <30 (no or trivial emphysema) and those with an HRCT score 30 (mild-to-severe emphysema). The group with no or trivial emphysema was defined as the chronic bronchitis group.
Pulmonary function tests
All subjects underwent spirometry. The highest value from 3 technically acceptable assessments was used. The FEV1 value obtained was related to a reference value and expressed as a percentage of the predicted value (15).
Statistical analysis
Results are expressed as means ± SDs. The SPSS 7.5 for WINDOWS (SPSS Inc, Chicago) computer software program was used for statistical analysis. Analysis of covariance (ANCOVA), with sex as covariate, followed by Tukey's pairwise multiple comparison procedure were used to determine possible differences in skeletal muscle function and subregional FFM and lean mass between the patients with chronic bronchitis and emphysema and the healthy volunteers. In all groups, linear regression analysis was used to calculate the slope and the intercept coefficients from the relation between whole-body FFM (dependent variable) and extremity or trunk FFM (independent variable). Furthermore, in each group, the slope and intercept coefficients of the 2 lines were statistically compared by using a t test as described by Kleinbaum et al (16). ANOVA with Bonferroni correction was used to compare the slopes and intercept coefficients among the groups. Linear regression analysis was also performed to determine the relation between muscle function per kilogram of extremity FFM (dependent variable) and FEV1 (independent variable) for the entire study population. The significance level was set at P < 0.05.
RESULTS
Ninety-nine patients with moderate-to-severe airflow obstruction (FEV1: 38.5 ± 13.3% of predicted) and 28 healthy volunteers were studied. Forty-nine COPD patients were defined as having emphysema and 50 as having chronic bronchitis. Airflow obstruction was significantly (P < 0.001) more severe in the emphysema patients (FEV1: 33.4 ± 10.8% of predicted) than in the chronic bronchitis patients (43.6 ± 13.7% of predicted). The use of maintenance corticosteroid medication, which is suggested to influence muscle performance, was not significantly different between the chronic bronchitis and emphysema patients (oral corticosteroid use: 54% compared with 50%, respectively; prednisone dose <10 mg/d).
Whole-body FFM was significantly lower in the emphysema patients than in the chronic bronchitis patients (P < 0.05) and the healthy volunteers (P < 0.001), partly because the emphysema patients had a significantly lower trunk FFM than the other 2 groups (P < 0.01) (Table 1). Whole-body FFM was significantly lower in the chronic bronchitis patients than in the healthy volunteers, whereas no significant difference was found in trunk FFM between these 2 groups. Extremity FFM was significantly lower in the 2 COPD subtype groups than in the healthy volunteers (P < 0.001), but no significant difference was found in extremity FFM between the 2 COPD subtype groups. In all comparisons, the findings for lean mass were the same as those for FFM.
Extremity FFM expressed as a percentage of whole-body FFM was significantly lower (P < 0.001) in both the chronic bronchitis (39.7 ± 2.9%) and the emphysema (40.9 ± 2.7%) patients than in the healthy volunteers (46.2 ± 1.6%) and tended to be lower in the chronic bronchitis group than in the emphysema group (P = 0.054).
In Figure 1, whole-body FFM is plotted against subregional FFM (extremity compared with trunk) for the patients with chronic bronchitis or emphysema and the healthy volunteers. In all groups, whole-body FFM was highly significantly correlated with extremity FFM as well as with trunk FFM (r > 0.94; data not shown). To assess whether there was a significant difference in the relation between whole-body FFM and extremity FFM compared with trunk FFM for each group, the slopes and intercept coefficients of the 2 regression lines were compared. The slopes of the 2 lines were not significantly different between the 3 groups. However, the intercept of the regression line for extremity FFM was lower than that for trunk FFM in the chronic bronchitis group (estimated vertical distance: 4.9 kg; 95% CI: 4.3, 5.5 kg) and the emphysema group (estimated vertical distance: 3.2 kg; 95% CI: 2.7, 3.7 kg) than in the healthy volunteers. Values for the intercept of trunk FFM and extremity FFM were not significantly different from those of the healthy volunteers.
FIGURE 1. . Scatter plot of whole-body fat-free mass (FFM) against subregional trunk FFM () and extremity FFM (•) in 50 chronic bronchitis (CB) patients, 49 emphysema patients, and 28 healthy volunteers (HV). The regression lines are as follows: CB:FFMextremity = (0.47 x FFMwhole body) - 3.85; FFMtrunk = (0.49 x FFMwhole body) + 0.16; emphysema:FFMextremity = (0.45 x FFMwhole body) – 2.12; FFMtrunk = (0.48 x FFMwhole body) - 0.19; HV:FFMextremity = (0.71 x FFMwhole body) – 2.03; FFMtrunk = (0.45 x FFMwhole body) + 0.50.
Isometric skeletal muscle strength of the upper extremities as well as isokinetic skeletal muscle function of the lower extremities (Table 1) were significantly lower in the 2 COPD subtype groups than in the healthy volunteers (P < 0.001), but were not significantly different between the 2 COPD subtype groups. Expressed as a percentage of the mean value for healthy volunteers, handgrip strength was 82 ± 24% in the chronic bronchitis group and 79 ± 23% in the emphysema group; the power of the lower extremities was 80 ± 23% in the chronic bronchitis group and 80 ± 24% in the emphysema group. Additionally, muscle function expressed per kilogram of whole-body FFM (Table 1) was significantly lower in the 2 COPD subtype groups than in the healthy volunteers. However, when handgrip strength and the power of the lower extremities were expressed per kilogram of extremity FFM, no significant differences were found between the 3 groups. Moreover, the ratio of handgrip strength to extremity FFM as well as the ratio of the power of the lower extremities to extremity FFM were not associated with FEV1 (r = -0.03 and r = 0.04, respectively) (Figure 2).
FIGURE 2. . Scatter plot of the ratio of handgrip strength to extremity FFM against forced expiratory volume in 1 s (FEV1) and the ratio of power to extremity FFM against FEV1 in 50 chronic bronchitis patients (), 49 emphysema patients (•), and 28 healthy volunteers (+). Regression lines for the whole study population are as follows: handgrip strength:extremity FFM = (-0.0004 x FEV1) + 1.20; power:extremity FFM = (0.002 x FEV1) + 9.19.
DISCUSSION
The present study showed that skeletal muscle function in absolute terms and per kilogram of whole-body FFM was significantly lower in the 2 COPD subtype groups than in the healthy volunteers, but was not significantly different between the 2 COPD subtype groups. Muscle function expressed per kilogram of extremity FFM was not significantly different among the 3 groups and was not associated with airflow obstruction.
Skeletal muscle weakness has been reported to be a serious problem in many patients with COPD (1, 3). However, these studies were limited by the absence of a healthy control group, by the fact that body weight but not body composition was assessed, or by both. Until recently, it was unclear whether skeletal muscle weakness in COPD patients is actually related to a disturbed body composition or to alterations in the contractile properties of the peripheral skeletal muscles. Bernard et al (7) showed that absolute quadriceps strength was lower in COPD patients than in healthy subjects, but the ratio of quadriceps strength to muscle CSA was not significantly different between the 2 groups. Our results agree with their findings that muscle function of the upper and lower extremities was lower in COPD patients than in a healthy control group, but that the ratio of muscle function to extremity FFM was comparable in the 2 groups. The findings were independent of the underlying disease (chronic bronchitis or emphysema), suggesting that the contractile properties of the peripheral skeletal muscles are preserved in both COPD subtype groups. Despite the fact that the emphysema group had more severe airflow obstruction (as reflected by lower FEV1 values) than the bronchitis group, no association was found between muscle function expressed per kilogram extremity FFM and FEV1. This observation is in contrast with the finding of Bernard et al (7), who found that quadriceps strength and muscle CSA were positively correlated with FEV1 in COPD patients. On the basis of the findings of their study, muscle function is lower in patients with chronic bronchitis and emphysema than in healthy subjects, being lowest in those with emphysema. The present study showed that skeletal muscle weakness in chronic bronchitis patients as well as in emphysema patients was due to loss of extremity FFM, but was not related to airflow obstruction.
In the present study, muscle function per kilogram of whole-body FFM was significantly lower in the 2 COPD subtype groups than in the healthy volunteers, whereas no significant difference was found in muscle function per kilogram of extremity FFM between the 3 groups. This suggests that whole-body FFM is not a good reflection of extremity FFM in the COPD groups. Both COPD subtype groups had significantly lower whole-body and extremity FFM values than the healthy volunteers. A strong relation was found between the 2 measures in all groups, suggesting that whole-body FFM is a good reflection of extremity FFM, independent of the underlying lung disease. Assessment of lean mass (ie, bone-free FFM) did not further improve this relation. However, extremity FFM expressed as a percentage of whole-body FFM was significantly lower in the 2 COPD subtype groups than in the healthy volunteers and tended to be even lower in the chronic bronchitis group. The lower extremity FFM values in both COPD subtype groups was not reflected in whole-body FFM. This dissociation needs to be considered when peripheral skeletal muscle function is evaluated in these patient populations. This is also particularly important when traditionally and more commonly applied body-composition techniques are used, which can only assess whole-body FFM. When this dissociation is not taken into account, normal whole-body FFM values may partly mask the loss of extremity FFM in emphysema patients and particularly in chronic bronchitis patients.
Deconditioning because of chronic inactivity may be an important factor contributing to the loss of extremity FFM in COPD patients. In healthy subjects, muscle disuse results in muscle fiber atrophy (17) and when the duration of disuse increases, there is progressive loss of peripheral muscle mass (18). In the studied COPD groups, handgrip strength was 81% of the control value and the power of the lower extremities was 80% of the control value. This suggests that skeletal muscle weakness in COPD affects the upper and lower extremities to the same extent. This is in contrast with the findings of earlier studies (3, 19) that reported a more pronounced decrease in muscle strength of the lower extremities. Our finding is quite remarkable because, on the basis of the results of these other studies, one would expect the physical activity level of the lower extremities of COPD patients to be lower than that of the upper extremities.
However, our finding also implies that besides muscle disuse, other factors likely negatively influence muscle strength in COPD patients. Prolonged administration of oral corticosteroids (particularly high doses of fluorinated steroids) is known to cause muscle weakness and myopathic changes (20, 21). In patients with severe COPD (22), steroid-induced myopathy (after prolonged prednisone use at a dose >10 mg/d) was characterized by fiber atrophy. In the present study, half of the COPD patients were using oral corticosteroids (prednisone dose: <10 mg/d) as maintenance medication. The percentage of patients using oral corticosteroids was not significantly different between the COPD subtype groups.
FFM has been shown to be lower in COPD patients exhibiting an acute phase response (23) than in patients without an acute phase response. Furthermore, an elevated concentration of lipopolysaccharide binding protein, which is a positive acute phase protein, has been related to decreased plasma amino acid concentrations in patients with severe COPD (24). We hypothesized that to enhance acute phase protein synthesis, a redistribution of amino acids from the skeletal muscle to the liver takes place. Enhanced amino acid fluxes in the skeletal muscle will increase local protein degradation. When this situation is not balanced by adequate protein synthesis, a catabolic state may induce extremity muscle loss in COPD patients. If this hypothesis is correct, it may also explain the comparable values for extremity FFM found in the emphysema and chronic bronchitis groups because no significant differences in systemic inflammatory mediators were found (25).
In the present study, we showed that DXA effectively determined skeletal muscle weakness in COPD patients via regional (extremity) FFM assessment. To further expand the value of DXA in the clinical evaluation of body composition in COPD patients, it is necessary to evaluate the effects of intervention strategies on subregional body composition. In FFM-depleted COPD patients, FFM can be increased by nutritional supplementation, which enhances protein synthesis. Furthermore, physical training benefits this group because it can act as an important anabolic stimulus. In non-FFM–depleted COPD patients, strength training of the peripheral skeletal muscles alone may be sufficient to increase skeletal muscle mass and function. In these ways, enhanced limb skeletal muscle mass and function may increase exercise capacity and eventually result in an improved quality of life in COPD patients.
REFERENCES