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Published ahead of print on June 26, 2003, doi:10.1164/rccm.200303-398OC
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American Journal of Respiratory and Critical Care Medicine Vol 168. pp. 989-994, (2003)
© 2003 American Thoracic Society

Function and Bulk of Respiratory and Limb Muscles in Patients with Cystic Fibrosis

Christophe Pinet, Marie Cassart, Pietro Scillia, Michel Lamotte, Christiane Knoop, Georges Casimir, Christian Mélot and Marc Estenne

Departments of Chest Medicine, Radiology, Physiotherapy, and Intensive Care Medicine, Erasme University Hospital, Brussels, Belgium

Correspondence and requests for reprints should be addressed to Marc Estenne, M.D., Chest Service, Erasme University Hospital, 808, Route de Lennik, B-1070 Brussels, Belgium. E-mail: mestenne{at}ulb.ac.be


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Inspiratory muscle weakness due to lung hyperinflation and muscle wasting may occur in cystic fibrosis. We therefore measured diaphragm function and bulk in 18 stable patients with cystic fibrosis and 15 matched control subjects; the abdominal and quadriceps muscles were studied for comparison. We assessed diaphragm mass, abdominal muscle thickness, twitch transdiaphragmatic and gastric pressures, quadriceps cross-section and isokinetic strength, and lean body mass. Lean body mass, quadriceps strength, and quadriceps cross-section were lower in patients with cystic fibrosis. Twitch transdiaphragmatic pressure was 23% lower and twitch gastric pressure was 22% greater in patients with cystic fibrosis than in control subjects, but diaphragm mass and abdominal muscle thickness were similar in the two groups. For any given lean body mass and quadriceps cross-section, patients with cystic fibrosis had greater diaphragm mass and abdominal muscle thickness. Diaphragm mass had greater intersubject variability in patients with cystic fibrosis than in control subjects. We conclude that diaphragm strength is decreased but abdominal muscle strength is increased in patients with cystic fibrosis. Diaphragm and abdominal muscle bulk are not affected by the general muscle wasting, which suggests that there may be a training effect of cystic fibrosis on respiratory muscles. However, the variability of diaphragm mass indicates that this beneficial response does not occur in all patients with cystic fibrosis.

Key Words: cystic fibrosis • diaphragm • inflammation • respiratory muscles • training

Cystic fibrosis is the most common life-threatening autosomal recessive disorder in the white population, with the main cause of death being respiratory failure (1). The gradual deterioration in pulmonary function is the consequence of airflow obstruction due to inflammatory processes involving the bronchial wall and producing disseminated bronchiectasis. The high airway resistance plays a key role in the development of ventilatory failure, but weakness of the inspiratory muscles may also be involved (2–7). By producing pulmonary hyperinflation, airflow obstruction makes these muscles work at shorter than optimal lengths, and the loss of body weight occurring in a high proportion of patients (8)—owing to a combination of pancreatic insufficiency, poor energy intake, and catabolic state associated with chronic infection—may produce respiratory muscle wasting. So, ventilatory failure in patients with cystic fibrosis may result from an imbalance between the load on, and the capacity of, the inspiratory muscle pump, as previously suggested in patients with severe chronic obstructive pulmonary disease (COPD) (9).

Available studies of inspiratory muscle strength in cystic fibrosis, however, have provided conflicting results, showing either decreased (2–7), normal (10–14), or supranormal values (15–17); the latter were attributed to a training effect of the respiratory disease. The different clinical profiles of the patients in terms of age, respiratory compromise, and nutritional status, and the different methodologies used to assess inspiratory muscle strength, make it difficult to interpret these studies. In addition, because inspiratory muscle bulk was not assessed, the complex interplay between hyperinflation, malnutrition, and training could not be analyzed appropriately.

In view of the importance of a better understanding of inspiratory muscle function in designing therapeutic strategies such as dietary supplementation or muscle training in patients with cystic fibrosis, we undertook the present study to assess the mass and strength of the diaphragm in a group of patients with variable degrees of respiratory and nutritional impairment. The function and bulk of the abdominal and quadriceps femoris muscles were studied for comparison. Some of the results of these studies have been previously reported in the form of an abstract (18).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
We studied 18 patients with cystic fibrosis and 15 normal subjects matched for age, height, and sex (Table 1) . Patients had a stable clinical state and an FEV1 of less than 60% of predicted (19). All subjects were informed of the nature and extent of the study and gave written informed consent, as approved by the Human Studies Committee of Erasme University Hospital (Brussels, Belgium).


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  		TABLE 1. Details of study population

 
Pulmonary Function
Standard pulmonary function was measured by body plethysmography. Blood samples were obtained from the radial artery for measurements of PaO2 and PaCO2, with the patient resting and breathing room air.

Diaphragm Mass
Diaphragm mass was computed from values of diaphragm surface area and thickness. Diaphragm surface area was measured by a technique based on spiral computerized tomography (20, 21). The computerized tomography scanner (Somatom Volume Zoom; Siemens, Erlangen, Germany) was also used to measure supine functional residual capacity (FRC) (21). Diaphragm thickness was measured in the zone of apposition by B-mode ultrasound, using an 8- to 12-MHz linear probe (Power Vision 8000; Toshiba, Tokyo, Japan) (22). In all subjects, measurements of diaphragm surface area and thickness were obtained at supine FRC; in the control subjects, these measurements were also made during voluntary relaxation at a volume corresponding to the mean supine FRC of the patients to enable comparison of diaphragm mass in the two groups at a similar absolute lung volume.

Diaphragm Strength
Maximal twitch stimulation of the phrenic nerves was performed at supine FRC, and the resulting transdiaphragmatic pressure was measured with conventional balloon-tipped catheters (23). Two or three runs of five or six twitches separated by 2–3 minutes of quiet breathing were obtained.

Abdominal Muscle Thickness
The thickness of the four abdominal muscle layers was measured on the right side at supine FRC with a high-resolution 8- to 12-MHz ultrasound linear probe (24). Abdominal muscle thickness was computed as the cumulative thickness of all muscle layers.

Abdominal Muscle Strength
With the subject seated, paired bilateral stimulations of the lower thoracic nerve roots (frequency, 33 Hz; 100% maximal stimulator output) were delivered at FRC with a magnetic coil applied over the T10 spinal level (24); the resulting changes in gastric pressure were measured.

Quadriceps Cross-sectional Area
The cross-sectional area of the quadriceps of the dominant leg was measured on a computerized tomography scan obtained midway between the femoral head and the medial femoral condyle (25).

Quadriceps Strength
The maximum isokinetic (60°/second) strength of the quadriceps of the dominant leg was measured with a Cybex dynamometer.

Nutritional Status
Nutritional status was assessed by computing body mass index, and by measuring lean and fat body mass by electrical bioimpedance (BIA, 101/S bioelectrical analyzer; Akem, Florence, Italy) (26).

Data Analysis
The muscular surface area of the diaphragm (Amu) was calculated as Adi x 0.84, where Adi is the total surface area of the muscle (27). Diaphragm mass was computed as Amu x Tdi x 1.04, where Tdi is diaphragm thickness and 1.04 is the density of the muscle (27). Data are expressed as means ± SD throughout the text, tables, and figures. Statistical analyses were made using paired and unpaired t-tests, single and multiple linear regression analyses, and covariance analysis, when appropriate.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Average values for anthropometric characteristics and lung volumes in the patients with cystic fibrosis and the control subjects are summarized in Tables 1 and 2 . The two groups were matched for age, sex and height, but body mass index, lean body mass, and fat body mass were significantly lower in the patients. Two patients had insulin-dependent diabetes mellitus. No patient was treated with oral corticosteroids. Pulmonary function tests revealed a severe obstructive ventilatory defect in the patients with pulmonary hyperinflation, and moderate hypoxemia.


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  		TABLE 2. Lung function and blood gas data in study population

 
Average values for diaphragm, abdominal, and quadriceps muscles bulk and strength are displayed in Figures 1–3 . Because of intolerance to esophageal and gastric balloons, values of gastric pressure were not available for two patients and values of transdiaphragmatic pressure were not available for one patient. Compared with normal subjects, patients had a 23% reduction in twitch transdiaphragmatic pressure, which was associated with a 17% decrease in the surface of diaphragm apposed to the rib cage (p < 0.02). Diaphragm mass was similar in the two groups; as a result, transdiaphragmatic pressure per unit diaphragm mass was significantly reduced in the patients (0.12 ± 0.06 versus 0.19 ± 0.07 cm H2O/g, p = 0.013). In contrast, because patients had a decreased lean body mass, diaphragm mass normalized by lean body mass was 37% greater in patients than in normal subjects (p < 0.01). The lower right panel in Figure 1 shows that diaphragm mass was positively correlated with lean body mass in the two groups (r2 = 0.77 and 0.34 in control subjects and patients, respectively), but that the regression line in the patients was displaced toward higher values of mass (p < 0.01 by covariance analysis). Multiple regression analysis indicated that the best equation predicting diaphragm mass included lean body mass (LBM) in the control subjects (diaphragm mass = –87.2 + 5.14 x LBM [adjusted r2 = 0.78; p = 0.0001]), and LBM and airway resistance (Raw) in the patients (diaphragm mass = –119.5 + 6.01 x LBM + 0.217 x Raw [adjusted r2 = 0.51; p < 0.002]).



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  		Figure 1. Average values of transdiaphragmatic pressure (Pdi) elicited by twitch stimulation of the phrenic nerves in 17 patients with cystic fibrosis and 15 control subjects, and of diaphragm mass (Mdi) in 18 patients with cystic fibrosis and 15 control subjects. LBM = lean body mass.

 


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  		Figure 3. Average values of quadriceps peak torque (PT) and cross-sectional area (quad CSA) in 18 patients with cystic fibrosis and 15 control subjects.

 


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  		Figure 2. Average changes in gastric pressure (Pga) elicited by stimulation of the abdominal muscles of 16 patients with cystic fibrosis and 15 control subjects, and average values of cumulated thickness of the abdominal muscles (Tab) in 18 patients with cystic fibrosis and 15 control subjects.

 
Figure 2 shows that changes in gastric pressure elicited by abdominal muscle contraction were 22% greater in patients than in control subjects. The thickness of the transversus abdominis was also 27% greater in patients (p < 0.04), but differences between groups for the three other abdominal muscle layers and for cumulative abdominal muscle thickness did not reach statistical significance. Average values of gastric pressure per unit abdominal muscle thickness or per unit transversus abdominis thickness were not significantly different in the two groups. In contrast, the ratio of abdominal muscle thickness over lean body mass was 29% greater in patients; plots of abdominal muscle thickness versus lean body mass showed significant correlations in the two groups (r2 = 0.66 and 0.5 in control subjects and patients, respectively), but here also, the regression line computed for the patients was displaced toward higher values of muscle thickness (p < 0.01).

Figure 3 illustrates that quadriceps peak torque and cross-sectional area were 36 and 35% lower in patients than in control subjects. On average, values of peak torque per unit cross-sectional area were similar in the two groups. The plot of quadriceps cross-sectional area versus lean body mass shows that the regression lines (r2 = 0.84 and 0.72 in control subjects and patients, respectively) obtained for the two groups were superimposed.

Diaphragm mass and abdominal muscle thickness showed a positive linear correlation in both patients (r2 = 0.47) and control subjects (r2 = 0.5). Diaphragm mass and abdominal muscle thickness were also positively correlated with quadriceps cross-sectional area in the control subjects (r2 = 0.77 and 0.63, respectively), but no correlation was found in the patients; in most patients, values of diaphragm mass (Figure 4) and abdominal muscle thickness were displaced above the regression line found for the control subjects.



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  		Figure 4. Relationship between Mdi and quad CSA in 18 patients with cystic fibrosis and 15 control subjects.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The present studies have shown that (1) cystic fibrosis patients with severe respiratory compromise and denutrition have a weak diaphragm; (2) this alteration is not due to muscle atrophy; (3) for any given lean body mass and quadriceps cross-sectional area, patients with cystic fibrosis have heavier diaphragms and thicker abdominal muscles than control subjects, consistent with respiratory muscle training; and (4) diaphragm mass in patients with cystic fibrosis shows substantial intersubject variability, which is only partially explained by differences in nutritional status and respiratory impairment.

Critique of Methods
Ultrasound measurements of diaphragm thickness in the zone of apposition have previously demonstrated that the relationship between diaphragm thickness and lung volume is characterized by an increased rate of muscle thickening as lung volume increases (22, 28). This observation was attributed to regional differences in diaphragm shortening with lung volume, that is, changes in thickness in the zone of apposition may not be representative of overall changes in muscle thickness (22). To evaluate the potential impact of this limitation on the assessment of diaphragm mass, values of mass were compared at two different volumes in the normal subjects, that is, their actual FRC and a volume corresponding to the mean FRC of the patients. On average, diaphragm mass increased by 8% with this increase in volume (p < 0.001). However, comparing values of muscle mass obtained in the patients with those obtained in the control subjects either at their actual FRC (as done in Figure 1) or at the patients' FRC did not significantly alter the results. In both comparisons, the ratio of diaphragm mass over lean body mass was significantly greater in the patients, and the regression line between diaphragm mass and lean body mass obtained in the patients was displaced toward higher values of mass compared with that in the control subjects.

Function and Bulk of Diaphragm
Previous studies have reported a 15–40% reduction in maximum static inspiratory mouth pressure in cystic fibrosis patients with moderate airflow obstruction (2–7). In the single study (2) that specifically investigated diaphragm function in a group of 15 patients with cystic fibrosis, lower values of transdiaphragmatic pressure (obtained during maximum voluntary efforts) were associated with lower values of FEV1 and body mass index and higher values of RV/TLC, but no comparison was made with a control group. The present results demonstrate that diaphragm strength assessed by phrenic stimulation is reduced by about 20% at FRC. However, the normal value of diaphragm mass indicates that, in the malnourished patients of this study, the reduction in twitch transdiaphragmatic pressure was not accounted for by muscle atrophy.

The etiology of reduced diaphragm strength is potentially multifactorial. Muscle shortening secondary to hyperinflation is a likely mechanism. The decrease in twitch transdiaphragmatic pressure found in the patients of this study was similar to the reduction previously reported in patients with COPD (4.2 cm H2O/L increase in FRC in the present study compared with 3.5 cm H2O/L in the study by Polkey and coworkers [29] and 4.2 cm H2O/L in the study by Similowski and coworkers [30]). However, because we did not compare values of Pdi at a similar absolute lung volume in patients and control subjects, we cannot assert that muscle shortening was the sole mechanism involved. Another potential factor is the presence of increased blood levels of proinflammatory cytokines. In vitro, tumor necrosis factor-{alpha} compromises the contractile function of murine diaphragm and limb muscle fibers (31), and it has been suggested that such inflammatory mediators may account for the reduced quadriceps contractility (i.e., force per unit muscle bulk) found in patients with chronic heart failure (32). A systemic inflammatory response may also be elicited in the context of cystic fibrosis (33) and impair skeletal muscle function.

Furthermore, there might be a deleterious effect of malnutrition on diaphragm function, independent of its effect on muscle bulk. Studies performed in undernourished patients without respiratory disease have suggested that malnutrition may impair skeletal muscle contractility. For example, in a study of 16 undernourished patients (mean body weight, 71% of ideal body weight), Arora and Rochester (34) reported that respiratory muscle strength was reduced out of proportion (that is, by 63%) to the expected loss of muscle mass. Murciano and colleagues (35) reported that 45 days of refeeding in 15 patients with anorexia nervosa increased the ratio of twitch transdiaphragmatic pressure over body weight from 0.43 to 0.58. In another study of six patients with anorexia nervosa (36), 4–8 weeks of refeeding with parenteral nutrition increased the maximal strength of the adductor pollicis before any increase in muscle mass could be detected. Altogether these observations are consistent with an altered contractile function of the diaphragm and limb muscles in malnourished patients. However, results of studies in patients with anorexia nervosa may not apply to patients with malnutrition caused by other diseases (37), and these results are at variance with experimental data obtained in rodents. Several studies of rats or hamsters have clearly demonstrated that a period of 4 weeks of food deprivation does not alter diaphragm or peripheral muscle contractility, that is, when normalized by muscle mass or fiber cross-sectional area, peak twitch and tetanic tensions were similar to those found in control animals (38, 39). Similarly, in the patients studied here, abdominal and quadriceps muscle strength normalized by muscle bulk were not decreased, which would argue against a deleterious effect of circulating inflammatory mediators or denutrition on skeletal muscle contractility.

Function and Bulk of Abdominal Muscles
The change in gastric pressure elicited by stimulation of the abdominal muscles was increased in patients compared with healthy control subjects, which likely reflects the increase in thickness of the transversus abdominis. This finding is particularly meaningful as hyperinflation was expected to lengthen the muscle (40) and reduce its thickness; in fact, such a combined effect of fiber hypertrophy and lengthening might explain why the thickness of the rectus abdominis, external oblique, and internal oblique muscles was not increased. Because the abdominal muscles were stimulated at a higher lung volume in the patients, muscle lengthening may have contributed to the increase in strength. We do not think, however, that this factor played a significant role. In our previous study using the same technique of abdominal muscle stimulation (24), we found that lung volume had only a modest effect on changes in gastric pressure, that is, gastric pressure increased by 5.4 cm H2O for each 1-L increase in volume; in the present study, gastric pressure was 17.7 cm H2O greater in the patients than in the control subjects, although the difference in FRC averaged only 1 L. Therefore, the increase in abdominal muscle strength found in the patients should be considered as being primarily related to muscle hypertrophy.

Different Response of Respiratory and Limb Muscle Bulk
For any given lean body mass and quadriceps cross-sectional area, patients with cystic fibrosis had increased diaphragm mass and abdominal muscle thickness; this indicates that the general muscle wasting that affected the quadriceps did not involve the respiratory muscles. No study in humans has compared the effect of malnutrition on the bulk of respiratory versus limb muscles, but data in patients with anorexia nervosa indicate a substantial weakness of both respiratory (34, 35) and peripheral (36, 37) muscles. In rodents, chronic undernutrition produces either a similar decrease in diaphragm and limb muscle fiber cross-sectional area (41) or a greater decrease in diaphragm than in limb muscle mass (39). So, there is no reason to believe that the preservation of a normal diaphragm and abdominal muscle bulk in the patients of this study could be explained by a preferential effect of denutrition on quadriceps lean tissue. Rather, we suggest that this difference reflects a specific training effect of the respiratory disease on the diaphragm and abdominal muscles. The observation that diaphragm mass in the patients tended to increase with airway resistance provides indirect support to this interpretation.

Variability of Diaphragm Mass in Patients with Cystic Fibrosis
Diaphragm mass was much more variable in patients than in control subjects. Multiple linear regression analysis showed that patients with greater lean body mass and airway resistance tended to have heavier diaphragms, but these factors accounted for only about 50% of the interpatient variability in muscle mass. The present study was not designed to identify other potential factors, but the role of systemic inflammation should be considered. There is convincing evidence that muscle wasting in chronic disease states, including COPD, is promoted by proinflammatory cytokines such as tumor necrosis factor-{alpha} (42), which increase muscle protein breakdown and decrease muscle anabolism. This deleterious effect may involve both limb and respiratory muscles, in particular the diaphragm (42). So we hypothesize that different degrees of systemic inflammation may explain, at least in part, between-patient differences in diaphragm mass, that is, patients with more inflammation would have a reduced increase in mass in response to training, and vice versa (43).

Clinical Implications
A previous report (8) has shown that wasting is an independent predictor of mortality in cystic fibrosis. The present study indicates, however, that wasting does not involve the diaphragm to a similar extent in all patients. Assessing diaphragm muscularity may help identify those patients who fail to increase muscle bulk in response to increased respiratory loading, and hence may be at increased risk of respiratory failure and death. Therapeutic interventions aimed at increasing diaphragm muscularity and strength (including nutritional supplementation [5, 10], respiratory muscle training [15], and possibly administration of antagonists of proinflammatory cytokines, alone or in combination) might be particularly relevant in these patients.


   Acknowledgments
 
C.P. has no declared conflict of interest; M.C. has no declared conflict of interest; P.S. has no declared conflict of interest; M.L. has no declared conflict of interest; C.K. has no declared conflict of interest; G.C. has no declared conflict of interest; C.M. has no declared conflict of interest; M.E. has no declared conflict of interest.

The authors are indebted to B. Morlion, R. C. Sà, and M. Paiva (Biomedical Physics Laboratory, Free University of Brussels, Brussels, Belgium) for support in the data analysis.


   FOOTNOTES
 
Supported by fellowships from the European Respiratory Society (ERS), the Association Régionale d'Assistance Respiratoire à Domicile (ARARD), and the Association pour le Développement des Recherches Biomédicales au Centre Hospitalier de Marseille (ADEREM) (C.P.). This study was supported by the Association Belge de Lutte contre la Mucoviscidose (ABLM).

This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Received in original form March 19, 2003; accepted in final form June 17, 2003


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 METHODS
 RESULTS
 DISCUSSION
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V. Dufresne, C. Knoop, A. Van Muylem, A. Malfroot, M. Lamotte, C. Opdekamp, G. Deboeck, M. Cassart, B. Stallenberg, G. Casimir, et al.
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Skeletal muscle weakness, exercise tolerance and physical activity in adults with cystic fibrosis
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P. J. Barry, D. F. Waterhouse, C. M. Reilly, T. J. McKenna, E. F. McKone, and C. G. Gallagher
Androgens, Exercise Capacity, and Muscle Function in Cystic Fibrosis
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 Clin RehabilHome page
W. D. Reid, E. L. Geddes, K. O'Brien, D. Brooks, and J. Crowe
Effects of inspiratory muscle training in cystic fibrosis: a systematic review
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F. Bellemare and A. Jeanneret
Sex differences in thoracic adaptation to pulmonary hyperinflation in cystic fibrosis
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M. E. Sahlberg, U. Svantesson, E. M. L. M. Thomas, and B. Strandvik
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 ThoraxHome page
C Pinet, P Scillia, M Cassart, M Lamotte, C Knoop, C Melot, and M Estenne
Preferential reduction of quadriceps over respiratory muscle strength and bulk after lung transplantation for cystic fibrosis
Thorax, September 1, 2004; 59(9): 783 - 789.
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M. J. Tobin
Sleep-Disordered Breathing, Control of Breathing, Respiratory Muscles, Pulmonary Function Testing in AJRCCM 2003
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M. J. Tobin
Pediatrics, Surfactant, and Cystic Fibrosis in AJRCCM 2003
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F. Maltais
Skeletal Muscles in Chronic Airflow Obstruction: Why Bother?
Am. J. Respir. Crit. Care Med., October 15, 2003; 168(8): 916 - 917.
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