Abstract
Peripheral muscle weakness is commonly found in patients with chronic obstructive pulmonary disease (COPD) and may play a role in reducing exercise capacity. The purposes of this study were to evaluate, in patients with COPD: (1) the relationship between muscle strength and cross-sectional area (CSA), (2) the distribution of peripheral muscle weakness, and (3) the relationship between muscle strength and the severity of lung disease. Thirty-four patients with COPD and 16 normal subjects of similar age and body mass index were evaluated. Compared with normal subjects, the strength of three muscle groups (p < 0.05) and the right thigh muscle CSA, evaluated by computed tomography (83.4 ± 16.4 versus 109.6 ± 15.6 cm2, p < 0.0001), were reduced in COPD. The quadriceps strength/thigh muscle CSA ratio was similar for the two groups. The reduction in quadriceps strength was proportionally greater than that of the shoulder girdle muscles (p < 0.05). Similar observations were made whether or not patients had been exposed to systemic corticosteroids in the 6-mo period preceding the study, although there was a tendency for the quadriceps strength/thigh muscle CSA ratio to be lower in patients who had received corticosteroids. In COPD, quadriceps strength and muscle CSA correlated positively with the FEV1 expressed in percentage of predicted value (r = 0.55 and r = 0.66, respectively, p < 0.0005). In summary, the strength/muscle cross-sectional area ratio was not different between the two groups, suggesting that weakness in COPD is due to muscle atrophy. In COPD, the distribution of peripheral muscle weakness and the correlation between quadriceps strength and the degree of airflow obstruction suggests that chronic inactivity and muscle deconditioning are important factors in the loss in muscle mass and strength.
Peripheral muscle weakness is commonly observed in patients with chronic obstructive pulmonary disease (COPD), and its possible contribution to exercise intolerance has been recently recognized (1, 2). In stepwise multiple regression analysis, quadriceps strength was a significant correlate of exercise capacity and 6-min walking distance, independent of the impairment in respiratory function (1, 2). As suggested by the positive relationship between muscle strength and exercise tolerance and by the improvement in quality of life occurring after strength training in patients with COPD (3), muscle weakness may contribute to the altered quality of life of these patients.
Better understanding of the distribution and the cause of muscle weakness in patients with COPD would help develop new therapeutic approaches in the rehabilitation of these patients. For instance, it would be useful to know if muscle weakness is simply due to a loss in muscle mass or if dysfunction at the level of the neuromuscular activation, and/or muscle contractile apparatus is present. Although previous studies suggest that muscle mass is commonly decreased in patients with COPD (4), it is still unclear if muscle weakness can be attributed entirely to muscle atrophy. A proportional decline in strength and in muscle mass would suggest that muscle atrophy is the sole cause of weakness whereas a disproportionate reduction in muscle strength compared with muscle mass would support that the muscle contractile apparatus and/or the neuromuscular activation are altered. In this regard, Decramer and coworkers found no correlation between total muscle mass, estimated from the creatinine–height index, and quadriceps strength in patients with COPD and suggested that the decrease in muscle strength was primarily caused by a myopathy (5). However, the presence of myopathy in their patients may well have been explained by the use of systemic corticosteroid which was an inclusion criterion of the study.
It is also unclear whether muscle weakness is a generalized problem or if some muscle groups are preferentially affected. This information could be useful in designing strength training programs targeted to the more affected muscle groups. In addition, the distribution of muscle weakness may help identify the underlying pathologic process. In states associated with simple muscle atrophy, such as nutritional depletion, the loss of upper limb muscle function is equal to or greater than that of the lower limbs (6), whereas with chronic inactivity and disuse atrophy, preferential involvement of the muscles with the greatest decrease in utilization is likely to occur.
In patients with COPD, there is a relationship between FEV1 and the functional status (7). Accordingly, a relationship between peripheral muscle strength and the severity of airflow obstruction, if present, would support the idea that chronic inactivity and muscle deconditioning are important in explaining muscle weakness in patients with COPD.
The objectives of this study were to evaluate in patients with COPD (1) the relationship between peripheral muscle strength and surface area, (2) the distribution of peripheral muscle weakness, and (3) the relationship between muscle strength and the severity of lung disease. For these purposes, maximal strength of three muscle groups was measured in 34 patients with COPD and 16 age-matched normal subjects while their thigh muscle cross-sectional area was directly assessed by computed tomography.
Thirty-four males with COPD were recruited for this study. The diagnosis of COPD was based on the smoking history and on pulmonary function tests showing irreversible bronchial obstruction (8-11). Sixteen healthy sedentary and nonsmoking males of similar age were recruited by means of newspaper advertisement and served as control subjects. The research protocol was approved by the institutional ethics committee.
Computed tomography. A computed tomography (CT) of the right thigh halfway between the pubic symphisis and the inferior condyle of the femur was performed using a fourth-generation Toshiba Scanner 900S (Toshiba). Each image was 10-mm thick and was taken at 120 kV and 200 mA with a scanning time of 1 s while the subject was lying in the supine position. The thigh muscle cross-sectional area (CSA) was obtained by measuring the surface area of the tissue with a density of 40 to 100 Hounsfield units (HU). This range of density was chosen because it corresponds to the density of muscle tissue (12). All CT images were analyzed blindly by one investigator (G.C.). Computed tomography was used to estimate muscle mass because it is more specific than anthropometric measurements (13). For instance, the age-related fat infiltration of the muscles, which cannot be detected with anthropometric measurements, can be identified by computed tomography because of the fat specific density.
Anthropometric measurements. Before exercise testing, height and weight were measured according to standardized methods (6).
Strength measurements. Measurement of maximal voluntary strength was done during dynamic contractions against an hydraulic resistance (HF STAR, Hydrafitness Total Power; Henley Health Care, Belton, TX). This apparatus consists of a chair equipped with three levers (one for the lower limbs, two for the upper limbs) that can be pulled or pushed against a piston which has six levels of hydraulic resistance. With this system, the force generated increases with the effort while the velocity of contraction remains almost constant (14). The strength of three muscle groups was measured with the subject seated comfortable and performing a rapid and powerful movement of the chosen segment. The strength of the lower limbs was measured during bilateral knee extension (mostly quadriceps), and that of the shoulder girdle during (1) a seated press (mostly the pectoralis major muscles), and (2) a bilateral movement combining elbow flexion and shoulder adduction (mostly latissimus dorsi muscles). To ensure that the best possible efforts were obtained, subjects were carefully instructed to perform maximal effort at high velocity for each of the six resistance levels and closely supervised during the procedure. The three lowest hydraulic levels were used to familiarize the subjects with the technique. The same movements were repeated at the higher levels until the generated strength reached a plateau. Two sets of measurements separated by 30 min were obtained for each muscle group and the higher values obtained are reported.
Exercise testing. Subjects were seated on an electrically braked ergocycle (Quinton Corival 400; A-H Robins, Seattle, WA) and connected to the gas analysis system through a mouthpiece. Five-breath averages of minute ventilation (V˙e), oxygen uptake (V˙o 2), and CO2 output (V˙co 2) were measured by an automated system equipped with a pneumotachograph, O2 and CO2 analyzers, and a mixing chamber (Quinton Qplex; A-H Robins, Bothel, WA). After 5 min of rest, a progressive stepwise exercise test was performed up to the individual maximal capacity. Each exercise step lasted 1 min and increments of 10 and 20 W were used in COPD and normal subjects, respectively.
Statistical analysis. Values are reported as mean ± SD. The average daily dose of corticosteroid taken during the 6-mo period preceding the study was calculated by taking into account all oral and parenteral doses of corticosteroid prescribed to the patients and converting them into prednisone equivalent (5). The coefficient of variation for the strength measurements obtained for each muscle group was calculated by dividing the mean of the within-patient standard deviations by the overall mean score. For the analysis, the measured parameters were grouped into three categories: (1) subject characteristics and pulmonary function tests, (2) muscle strength and CSA, and (3) parameters at maximal effort. For each category, a one-way analysis of variance (ANOVA) was used to compare normal subjects with COPD patients. A similar approach was used to compare muscle strength and CSA between patients exposed and unexposed to systemic corticosteroids in the 6-mo period preceding the study. In COPD, the relative strength (expressed in percent mean normal subjects value) of the quadriceps was compared with that of the two other muscle groups using the paired t test. Regression analyses were performed using the least-squares method. A value of p < 0.05 was considered statistically significant.
Characteristics of the normal subjects and patients with COPD are presented in Table 1. Age, height, weight, and body mass index were comparable in both groups. Albumin levels were within normal values in patients and none of them reported weight loss in the preceding year. Patients had, on average, moderate to severe airflow obstruction with an FEV1 of 42 ± 14% predicted, normal resting PaO2 and PaCO2 . Thirteen patients had received systemic corticosteroids in the 6-mo period preceding the study; the average daily dose of prednisone amounted to 5 ± 5 mg in these individuals.
| Normals (n = 16 ) | COPD (n = 34) | |||
|---|---|---|---|---|
| Age, yr | 64 ± 5 | 66 ± 7 | ||
| Height, m | 1.71 ± 0.05 | 1.68 ± 0.07 | ||
| Weight, kg | 76 ± 15 | 74 ± 15 | ||
| BMI, kg m−2 | 26 ± 4 | 26 ± 5 | ||
| Albumin, g L−1† | — | 43 ± 3 | ||
| FEV1, L | 3.1 ± 0.4 | 1.1 ± 0.4‡ | ||
| FEV1, % pred | 107 ± 12 | 42 ± 14‡ | ||
| FVC, % pred | 94 ± 9 | 66 ± 17‡ | ||
| TLC,% pred | 98 ± 11 | 116 ± 17‡ | ||
| Dl CO, % pred | 107 ± 14 | 69 ± 26‡ | ||
| PaO2 | 100 ± 14 | 80 ± 10‡ | ||
| PaCO2 | 38 ± 4 | 41 ± 6 | ||
| pH | 7.44 ± 0.03 | 7.42 ± 0.03§ |
All subjects competed the incremental exercise test to their maximal subjective capacity. The peak power output achieved in the COPD group was 59 ± 26 watts with a peak V˙o 2 of 1.1 ± 0.3 L/min. The peak power output of the control group was significantly greater at 159 ± 32 W with a peak V˙o 2 of 2.3 ± 0.5 L/min (p < 0.005). As expected, peak heart rate (130 ± 21 and 159 ± 9) and minute ventilation (42 ± 14 and 97 ± 26) were also lower in COPD (p < 0.005).
The strength of the three different muscle groups was significantly lower in COPD compared with control subjects (Figure 1). Group mean value for the strength of the quadriceps, pectoralis major, and latissimus dorsi muscles was 80 ± 16 versus 58 ± 15 kg, 76 ± 17 versus 64 ± 13 kg, 62 ± 11 versus 52 ± 11 kg, for normal subjects and COPD patients, respectively (all p < 0.005). The coefficient of variation of the two sets of strength measurements obtained averaged 6, 8, and 7% for the quadriceps, pectoralis major muscles, and latissimus dorsi muscles, respectively.
Fig. 1. Group mean values (± SD) for the strength of the quadriceps, pectoralis major, and latissimus dorsi muscles obtained in normal subjects and in COPD. There was a significant reduction in strength of three muscle groups in patients with COPD compared with normal subjects. *p < 0.005.
[More] [Minimize]CT images of one representative subject of each group are provided in Figure 2. The considerably smaller thigh muscle area in the patient with COPD compared with the normal subject can be appreciated. Individual and group mean values for thigh muscle CSA obtained in both groups are shown in Figure 3. Thigh muscle CSA was markedly decreased in COPD patients averaging 83.4 ± 16.4 versus 109.6 ± 15.6 cm2 in normal subjects (p < 0.0001).
Fig. 2. Computed tomography of one representative subject of each group. The thigh muscle cross-sectional area (CSA) was considerably reduced in the COPD patient (right panel ) compared with that of the normal subject (left panel ) amounting to 79.6 cm2 to 118.5 cm2, respectively.
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Fig. 3. Individual values for the thigh muscle CSA obtained in both groups. The horizontal lines represent group mean value. The thigh muscle CSA was significantly decreased in patients with COPD compared with normal subjects. *p < 0.0001.
[More] [Minimize]The strength of the pectoralis major (64 ± 11 versus 63 ± 14 kg) and latissimus dorsi muscles (51 ± 11 versus 52 ± 11 kg), and the thigh muscle cross-sectional area (78 ± 17 versus 87 ± 16 cm2) were not significantly different between patients who did and those who did not receive systemic corticosteroids (p > 0.05). In contrast, the strength of the quadriceps was significantly smaller in those who received corticosteroids compared with those unexposed to this medication (50 ± 16 versus 63 ± 13 kg, p < 0.05). When taking into account only the 21 COPD patients who had not received systemic corticosteroids, significant reductions in the strength of the three muscle groups and the thigh muscle CSA were still found compared with normal subjects (p < 0.005).
The relationship between thigh muscle CSA and quadriceps strength is shown in Figure 4. As expected, a significant positive correlation was found between both variables for the group as a whole (r = 0.73, p < 0.0001) and when taking into account only the patients with COPD (r = 0.65, p < 0.0001). Using the different isopleths for strength/CSA ratio, it can be appreciated that the mean values (0.7 ± 0.2 versus 0.7 ± 0.1 kg/cm2 in COPD and normal subjects, respectively), and the range of this ratio were similar for both groups. The quadriceps strength/thigh muscle CSA ratio was not significantly different between the patients exposed or not to systemic corticosteroids (0.6 ± 0.2 versus 0.7 ± 0.1 kg/cm2, respectively, p = 0.15). However, in five patients exposed to corticosteroids, the strength/thigh muscle CSA was below the lower value obtained in the normal group (Figure 4).
Fig. 4. The relationship between the quadriceps strength and the thigh muscle CSA. Small squares and circles represent individual values and the large square and circle the mean values (± SD) for the normal subjects and COPD patients, respectively. Open and closed circles represent COPD patients unexposed (steroids −) or exposed (steroids +) to corticosteroids, respectively. Using the isopleths for strength/thigh muscle CSA ratio represented by the solid lines, it can be appreciated that the range and the mean values of this ratio were comparable for both groups. In five patients exposed to corticosteroids, the strength/thigh muscle CSA ratio was below the lower value obtained in the normal group.
[More] [Minimize]In COPD, the strengths of the three muscle groups expressed in percent mean normal subjects value were compared in order to evaluate the distribution of muscle weakness. Identity plots depicting the individual values of the relative strength of the quadriceps, pectoralis major, and latissimus dorsi muscles are provided in Figure 5. In patients, the relative strength of the quadriceps (60 ± 15% mean normal subjects value) was significantly smaller than that of the other two muscle groups (72 ± 15, and 76 ± 15% for the pectoralis major and latissimus dorsi muscles, respectively, p < 0.05). This was true whether or not COPD patients were exposed to systemic corticosteroids (Figure 5).
Fig. 5. Identity plots depicting the relative strength of the quadriceps, and that of the pectoralis major (left panel ), and latissimus dorsi muscles (right panel ). All strength measurements are expressed in percent mean normal subjects values. Open and closed circles represent COPD patients unexposed or exposed to corticosteroids, respectively. In the majority of patients, the relative strength of the quadriceps was significantly smaller than that of the other two muscle groups (p < 0.05). This was true whether or not patients were exposed to corticosteroids.
[More] [Minimize]A significant relationship was found between quadriceps strength and FEV1 percentage of predicted value (Figure 6, r = 0.55, p < 0.0005). Not shown in the figure, a similar relationship was found between the thigh muscle CSA and FEV1 percentage of predicted value (r = 0.66, p < 0.0001). In COPD, a significant positive relationship was found between quadriceps strength and thigh muscle area, and peak V˙o 2 (r = 0.50 and 0.63, respectively, p < 0.005).
Fig. 6. Relationship between FEV1 percentage of predicted and the quadriceps strength. A significant positive relationship was found (r = 0.55, p < 0.0005).
[More] [Minimize]Our results extend those of previous studies on peripheral muscle function in patients with COPD by showing that their quadriceps strength/thigh muscle CSA ratio is similar to that of normal subjects. This study also indicates that the quadriceps are proportionally weaker than the shoulder girdle muscles and that quadriceps strength and thigh muscle CSA correlate with the degree of airflow obstruction. Similar observations were made whether or not patients had been exposed to systemic corticosteroids in the 6-mo period preceding the study, although there was a tendency for the quadriceps strength/ thigh muscle CSA ratio to be lower in patients who had received systemic corticosteroids. Like others (1, 2), we found peripheral muscle weakness and a significant relationship between quadriceps strength and peak V˙o 2 in patients with COPD. The significance of these findings is discussed subsequently.
Before interpreting the results, some methodological considerations should be discussed. Although it would have been interesting to report the CSA of each individual muscle group of the thigh, we elected to measure only the entire thigh muscle CSA. This was done to avoid significant measurement errors because the respective borders of each individual muscle group were often difficult to discern. Could the conclusion that muscle strength/CSA ratio is preserved in COPD be modified if the quadriceps CSA, as opposed to the thigh muscle CSA, was used in the calculation? There is evidence that limb immobilization produces a greater amount of atrophy in the quadriceps than in other thigh muscles (15), indicating that the quadriceps CSA should be proportionally smaller than that of the entire thigh. Because of this, the method that we used should have underestimated the actual muscle strength/CSA ratio. Accordingly, it can be concluded that the muscle strength/ CSA ratio is not reduced in COPD.
The preserved quadriceps strength/thigh muscle CSA ratio in COPD implies that the muscle contractile apparatus is preserved. This observation is important because it suggests that restoring muscle mass should normalize muscle strength. Given the positive relationship between quadriceps strength and exercise tolerance in patients with COPD (1, 2), the possibility to increase muscle mass appears as a promising therapeutic strategy. In patients with COPD, exercise training alone or combined with nutritional intervention or anabolic drugs results in a modest increase in muscle mass and strength with equivocal effect on exercise tolerance (3, 16, 17). Whether it will be possible to achieve greater improvement in these parameters that could translate into clinically significant gain in exercise tolerance is presently unclear.
The preferential distribution of muscle weakness to the lower limb was clear in the present study and confirms previous results of Gosselink and coworkers who found lower values for quadriceps strength compared with hand grip strength in patients with moderate to severe COPD (1) and those of Newell and coworkers who reported that the elbow flexors' strength was preserved in patients with moderate COPD (18). This uneven muscle weakness distribution and the positive correlation between muscle strength and CSA and the FEV1 percentage of predicted value are consistent with the concept that muscle deconditioning and disuse atrophy explain, at least in part, muscle weakness in these individuals. Although the level of daily activities was not measured in our patients, their severe reduction in FEV1 and poor exercise capacity suggest that it was reduced, resulting in less intense recruitment of their lower limb muscles. By contrast, their shoulder girdle muscles were probably more involved in activities of daily living, explaining why their strength was relatively maintained. Furthermore, in COPD, the pectoralis major and the latissimus dorsi muscles may also act as accessory inspiratory muscle, another potential source of stimulation (19, 20).
Some results of the present study are at variance with the findings of Hamilton and coworkers who reported modest reduction in peripheral muscle strength that was comparable between upper and lower limbs in a large group of patients with obstructive or restrictive pulmonary diseases with, on average, moderate degree of airflow impairment (2). Discrepancies regarding the degree and distribution of muscle weakness found between our and their study can possibly be explained by differences in patients' characteristics such as the severity of airflow obstruction.
Decramer and coworkers evaluated the effects of corticosteroid on peripheral muscles in 21 patients with COPD and reported a loss in strength that was out of proportion to the loss in total body muscle mass (5). This is in keeping with previous animal studies showing that corticosteroids may alter muscle function without causing muscle atrophy (21). We found the similar results in five patients exposed to systemic corticosteroid in the 6-mo period preceding the study (Figure 4), although no statistically significant difference in the quadriceps strength/thigh muscle CSA ratio could be found between patients exposed or unexposed to systemic corticosteroids. A likely explanation for this is that only prednisone was used in our patients, whereas most patients studied by Decramer and coworkers received methylprednisolone. This corticosteroid may have a greater potential to alter muscle function than prednisone (5, 21).
Nutritional depletion and chronic hypoxia may contribute to muscle weakness in patients with COPD (22). The distribution of muscle atrophy found in our patients is not consistent with atrophy induced by malnutrition since in this condition the loss of upper limb muscle mass should be equal or greater than that of the lower limbs (6). It should be noted however that a normal body mass index does not entirely exclude malnutrition as a cause of muscle atrophy and weakness because the rate of muscle loss with malnutrition may be faster than the rate of body weight (6). Chronic resting hypoxia was not found in our patients and is therefore not an issue in these individuals.
In summary, in patients with stable COPD, the loss of muscle mass is in proportion to the reduction in strength suggesting that the muscle contractile apparatus is preserved. The preferential loss in lower limb muscle mass and strength and their relationship with FEV1 percentage of predicted suggest that muscle deconditioning and the related disuse atrophy are important factors in explaining peripheral skeletal muscle dysfunction in COPD.
The authors thank Marthe Bélanger, Anne-Marie Bezeau, Marie-Josée Breton, Gisèle Deshaies, Alexandra Lauzier, Anita LeBlanc, Jacqueline Lepage, Jacynthe Rondeau, and Ginette Turbide for their assistance, Serge Simard for his statistical assistance, and Drs. Yvon Cormier and Claude H. Coté for helpful suggestions regarding the manuscript. The authors are also grateful to the respirologists of the Centre de Pneumoligie de l'Hôpital Laval for supporting Dr. Maltais in his research.
Supported in part by the Fonds de la recherche en santé du Québec and by la fondation JD Bégin, Université Laval.
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Dr. Maltais is a clinician–scientist of the Fonds de la recherche en santé du Québec.
