INTRODUCTION

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Proximal myopathies may affect respiratory muscles and result in ventilatory failure (1). Secondary lung and chest-wall mechanical alterations combine with the primary muscle abnormality to impair the conversion of respiratory center activity into tidal volume (VT) (2). Myopathies provide a unique opportunity to study ventilatory failure and the adaptation of the respiratory system to inspiratory muscle weakness, without the large confounding effects of increased CO₂ production, airway obstruction, and dead space ventilation found in chronic obstructive pulmonary disease (COPD) (3).

Myotonic dystrophy (MD, Steinert's disease), an autosomal dominant multisystem disease, is the most frequent adult form of muscular dystrophy. A number of reports have emphasized the occurrence of chronic hypercapnia in myotonic dystrophy (4, 5). In an analysis linking hypercapnia to respiratory mechanics, pattern of breathing, and response to carbon dioxide rebreathing, Gibson and colleagues (6) concluded that lung and thoracic mechanical alterations were likely to explain the apparent abnormalities of ventilatory control in this disorder. They argued, quite correctly, that an impaired response to CO₂ rebreathing does not allow the inference of an impaired central ventilatory output in weak subjects. They also suggested that excessive daytime somnolence might be the most valid index of impaired respiratory control in MD. Unfortunately, this parameter was not available in their study.

We conducted a prospective study of the prevalence of chronic hypercapnia in relation to muscular disability in a population from the Saguenay-Lac-St.-Jean region of Québec, in which the prevalence of MD is 30 to 60 times higher than its world prevalence (7). The large sample was expected to allow comparison of steady-state patients with MD of different degrees of severity in adequate numbers and to lead to a better characterization of the shape of some relationships linking expiratory lung volumes, respiratory muscle force, and daytime sleepiness to alveolar hypoventilation.

	METHODS

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One hundred and thirty-four individuals with a diagnosis of MD were assessed at the neuromuscular clinic of the Complexe Hospitalier de la Sagamie in 1992 and 1993. This included 125 patients with the adult form of MD (first symptoms after the age of 12 yr) and nine subjects without clinical impairment. Given the referral system of our public health system, a large majority of the affected individuals in the Saguenay area and some asymptomatic siblings are followed at the clinic.

All individuals were examined by a neurologist (J.M.) and categorized according to a previously published muscular disability rating scale (MDRS) (8). This MDRS was developed in our clinic in accord with the clinical presentation and the unique distal-to-proximal progression of MD. Table 1 describes the MDRS and shows the distribution of patients, anthropometric data, time elapsed since the first appearance of symptoms (usually handgrip myotonia), and prevalence of daytime sleepiness as assessed by requesting naps on most days. Seventeen of the subjects were taking the oral medication methylphenidate in a dose of 10 mg once or twice daily for severe sleepiness. Handgrip dynamometry was done with a direct-reading dial gauge.

All measurements of respiratory function parameters were made with subjects in the sitting position. Arterialized capillary blood-gas analysis was performed first, following a 5-min rest period. A fingertip capillary blood sample was drawn after vasodilation induced by warm water. Blood-gas analysis was done with a Model 1312 blood-gas manager (Instrumental Laboratory, Lexington, MA). Forced expiratory lung volumes were then measured with an Eagle II 10L water spirometer (Warren E. Collins, Braintree, MA). The best test, based on the largest sum of FEV₁ and FVC from three reproducible tracings, was selected. The variability of FVC between the two best efforts was found to be only 3% in a subset of 10 subjects. Normal spirometric values were taken from Morris and colleagues (9). Maximal respiratory pressures were measured as described by Black and Hyatt (10). Maximal inspiratory pressure (PI_max) was measured against an occluded airway at RV, and maximal expiratory pressure (PE_max) was measured at TLC. We used a direct-reading dial gauge calibrated with a water manometer. Five to eight measurements were made until maximal values were reproducible. PI_max was reported as the most negative value occurring after the first second, and PE_max as the most positive value, ignoring the transient maximum value. The coefficients of variation (CVs) of the last three PI_max and PE_max measurements were studied in a subset of 25 patients and were found to be 12.0 ± 8.2% and 8.3 ± 5.7% (mean ± SEM), respectively. However, when expressed as a fraction of the previous measurements done 17 ± 7 mo earlier in 79 patients, FVC was found to be 0.95 ± 0.02 and PI_max 1.06 ± 0.09 (mean ± SEM), suggesting a small residual training effect on PI_max. Measurements were expressed as percent predicted, using Black and Hyatt's data (10). Respiratory muscle strength (RMS % predicted) was defined as the mean of PI_max and PE_max, expressed as a percent of the predicted values. The theoretical effect of proportional inspiratory and expiratory muscle weakness on FVC was calculated from published data (11), and FVC was expressed as a function of the expected value. Statistical analysis involved linear regression and analysis of variance (ANOVA) using SAS/STAT (SAS Institute Inc., Cary, NC).

	RESULTS

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Muscle-strength, spirometric, and blood-gas data for each MDRS group are shown in Table 2. Inspiratory and expiratory muscle weakness were detected even in patients with minimal signs of muscular disability, with a preferential impairment of PE_max until proximal muscle weakness occurred. Indeed, PE_max was found to be larger than PI_max both in subjects without clinical impairment (p < 0.05) and in those with proximal weakness (p < 0.001), but not at intermediate MDRS values. FVC was found to be maintained at close to normal values until proximal muscle weakness occurred, and was then found to be reduced out of proportion to RMS. The FEV₁/FVC ratio and Pa_CO2 progressively increased with muscular disability.

Figure 1 illustrates the progressive decline of FVC as a function of respiratory muscle weakness. The solid curve indicates the theoretical effect of proportional inspiratory and expiratory muscle weakness on FVC, assuming normal respiratory-system recoil (11). The dashed curve results from linear regression after logarithmic transformation of FVC and RMS. FVC was found to be reduced to a greater degree than anticipated from the degree of respiratory muscle weakness, even more in subjects with a higher degree of muscular disability (closed symbols), as summarized in the following multiple regression analysis: log FVC (% predicted) = 1.60 MDRS + 0.22 log RMS (% predicted) (r = 0.68).

View larger version (20K): [in this window] [in a new window]   Figure 1.   Relationship between FVC and RMS (% predicted). The solid curve (11) indicates the theoretical effect of respiratory muscle weakness, with proportionate effects on inspiratory and expiratory muscles, on FVC. This relationship is calculated from the standard maximal pressure-volume curve, assuming a normal respiratory-system recoil. The fitted dashed curve was obtained by linear regression analysis after logarithmic transformation: log FVC (% pred) = 1.16 + 0.39 log RMS (% pred) (r = 0.56, p < 0.001). Means ± SEM for nine subjects with MDRS = 0 are shown. Individual values for MDRS = 1 are shown as open triangles, MDRS = 2 as open circles, MDRS = 3 as filled circles, and MDRS = 4 as filled inversed triangles.

Table 3 shows the same data as in Tables 1 and 2, reorganized for two groups of patients: hypercapnic and normocapnic. Hypercapnic subjects are shown to be older (p < 0.05), and more often males (p < 0.01), and to have a higher degree of muscular disability (p < 0.01) and a higher FEV₁/FVC ratio (p < 0.05), but lower inspiratory and expiratory muscle strength (p < 0.01) than normocapnic subjects, and to have FVC even lower than expected for the degree of RMS (p < 0.05).

The prevalence of hypercapnia (Pa_CO2  43 mm Hg) was found to be 0%, 27%, 29% 45%, and 55% for MDRS levels 0 to 4, respectively (p = 0.03). The coefficient of correlation of Pa_CO2 with MDRS was found to be 0.35. A multiple regression analysis limited to clinical data showed that daytime hypersomnolence was a significant cofactor of MDRS (p = 0.01) in the following equation: Pa_CO2 (mm Hg) = 37.96 + 1.36 MDRS + 1.59 if somnolent (r = 0.40). Among single respiratory parameters, FVC, RMS, and PI_max were found to explain 16%, 15%, and 14% of the Pa_CO2 variance, respectively, when expressed as percent predicted values.

Figure 2 shows the relationship between Pa_CO2 and FVC (r = 0.40). Subjects with daytime sleepiness are shown by closed symbols (triangles if treated with methylphenidate). In multiple regression analysis, daytime sleepiness was associated with a small increase in Pa_CO2 (p = 0.01), independent of the level of FVC and of treatment with methylphenidate, as shown in the following equation: Pa_CO2 (mm Hg) = 46.92  0.083 FVC (% predicted) + 1.58 if somnolent (r = 0.45). Muscle disability was not found to be a significant cofactor.

View larger version (13K): [in this window] [in a new window]   Figure 2.   Relationship between PaCO2 and FVC (% predicted). One hundred twenty-five myotonic dystrophy patients with MDRS levels of 1 to 4 are shown as filled circles and open circles according to the presence or absence of daytime sleepiness, respectively. Subjects receiving the CNS stimulant methylphenidate are identified by triangles. Means ± SEM for nine subjects with MDRS = 0 are shown as in Figure 1. The linear regression equation for the whole population is: PaCO2 (mm Hg) = 47.97  0.087 FVC (% pred) (r = 0.40, p < 0.001).

Figure 3 shows the relationship between Pa_CO2 and RMS in our population (r = 0.39), in parallel with the mixed venous Pa_CO2 data reported by Gibson and colleagues in MD patients. The slope of the regression lines was found to be similar; the offset of the lines on the PCO₂ axis represents the likely difference between (our) arterial and (their) mixed venous PCO₂ values. In multiple regression analysis, the expected/observed FVC ratio was found to be a significant cofactor of RMS (p < 0.001): Pa_CO2 (mm Hg) = 41.61  0.063 RMS (% predicted) + 2.83 expected/observed FVC (r = 0.47).

View larger version (14K): [in this window] [in a new window]   Figure 3.   Relationshp between PaCO2 and RMS (% predicted). The individual arterial PaCO2 values of 125 MD patients with MDRS levels of 1 to 4 are shown as closed circles. Means ± SEM for nine subjects with MDRS = 0 are shown as in Figure 1. The full line indicates the regression equation for the whole population: PaCO2 (mm Hg) = 45.56  0.068 RMS (% pred) (r = 0.39, p < 0.001). The upper dashed regression line was calculated from the mixed venous PCO2 data of Gibson and colleagues (6) for 27 MD patients (open circles): PvCO2 (mm Hg) = 54.40  0.078 RMS (% pred) (r = 0.21, p < 0.005).

The relationship between Pa_CO2 and PI_max is shown in Figure 4 for both males (r = 0.33) and females (r = 0.35). Multiple linear regression analysis showed that sex (p < 0.001), the expected/observed FVC ratio (p = 0.002), and daytime hypersomnolence (p = 0.05) were significant cofactors of PI_max in the following equation: Pa_CO2 (mm Hg) = 38.90  0.033 PI_max (cm H₂O) + 2.23 if male + 2.76 expected/observed FVC + 1.19 if somnolent (r = 0.51).

View larger version (15K): [in this window] [in a new window]   Figure 4.   Relationship between PaCO2 and PImax. Individual values for 59 male MD patients with MDRS levels of 1 to 4 are shown as closed circles and those of 66 female patients as open circles. The right upper mean ± SEM values apply to three males with MDRS = 0, and the other mean ± SEM values refer to six females with MDRS = 0. The full regression line applies to the whole male MD population and the dashed regression line to the female population. The combined equation is PaCO2 (mm Hg) = 43.68 + 2.33 if male  0.043 PImax (r = 0.43, p < 0.001). The broken lines are those reported by Rochester and Braun (16) for a group of 33 patients with uncomplicated proximal myopathies.

	DISCUSSION

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The group of patients selected for this study provided many advantages for investigating the role of inspiratory muscle weakness and low central drive in chronic ventilatory failure. First, the population under study was in a steady state. Second, patients with the adult form of MD have normal growth, no mental retardation, and no chest-wall deformity. Third, a large majority of the affected individuals in the Saguenay area are followed at our clinic. This provides access to patients with a large range of muscular disability and virtually eliminates reference bias. Moreover, the large number of patients allowed us to evaluate the predictive value of a simple MDRS; to better appreciate the shape of the relationships between force, volume displacement, and alveolar ventilation; and to apply multiple regresison analysis for assessing cofactors.

The results of the present study indicate a high prevalence of mild chronic hypercapnia in patients with MD, increasing in relation with the severity of muscular disability. Hypercapnia was found in about half of the patients with overt proximal limb weakness. Together, muscular disability and daytime hypersomnolence, two parameters easily assessed by the clinician, explained 16% of the variance of Pa_CO2. Although we found a significant reduction of VC in the hypercapnic subjects, it was only moderate. Our data suggest that inspiratory muscle weakness, increased respiratory elastance, and, presumably, low central ventilatory drive are involved in the pathogenesis of chronic hypercapnia in this population.

Inspiratory Muscle Weakness and Hypercapnia

Approximately half of patients with MD die from a respiratory problem, mainly pneumonia or acute respiratory failure (12). We found chronic respiratory failure to be more prevalent in advanced MD at the time that proximal limb (i.e., generalized) muscle weakness could be recognized. Our data show that respiratory muscle weakness may occur even without obvious limb weakness. As previously reported (13, 14), MD patients usually have more weakness of the expiratory muscles than of the inspiratory muscles. However, when proximal limb weakness becomes apparent, inspiratory muscle force declines severely and the likelihood of hypercapnia increases sharply.

Numerous reports on various neuromuscular disorders have confirmed that VC decreases as RMS declines (1, 11, 15). This curvilinear relationship, described by a logarithmic regression (1, 11), was confirmed in our study. However, the volume restriction was more important than expected from the normal static pressure-volume curve of the respiratory system, as explained by increased lung elastance and decreased passive recoil of the chest wall (11).

Braun and colleagues (1) suggested that in various forms of proximal myopathies, Pa_CO2 is a discontinuous function of RMS, with a linear increase of Pa_CO2 below an RMS value of 50% predicted (r = 0.59, p < 0.02). Since expiration is passive during rest, they later rearranged their data to show that this relationship was based on inspiratory muscle strength (16). Were inspiratory muscles to limit alveolar ventilation, a hyperbolic relationship between Pa_CO2 and PI_max (or RMS) would be expected, reminiscent of the ventilation hyperbola. Indeed, this can be recognized from Braun and colleagues' data (1), and Gibson and coworkers' mixed cases of neuromuscular disorders (6). In the latter study, MD and other neuromuscular diseases were considered together after no significant difference was found between their PCO₂-versus-VC regression lines. However, the hyperbolic function resulting from the linear regression of Pa_CO2 on RMS¹ gave us lower coefficients of correlation and more systematic deviation of residuals than did the linear function calculated with RMS, both for our data (r = 0.32) and Gibson and coworkers' MD data (r = 0.20). Given the high reproductibility of PI_max and PE_max values in our study, the precision of RMS measurements is unlikely to explain weaker correlations nor these different shapes of relationship. A possible reason for a weak Pa_CO2/PI_max relationship is that values were measured at RV, when PI_max is slightly higher than at FRC, being overestimated by the amount of the elastic recoil of the respiratory system, which in turn largely depends on PE_max. Neither of these factors may limit the actual tidal force developed by the inspiratory muscles during breathing at rest. However, the presence of CO₂ retention could not be clearly attributed to weakness of the diaphragm in a previous smaller series of MD patients (13), in contrast to patients with motor-neuron disease, suggesting that other factors play a role in MD.

Intrinsic Loads and Hypercapnia

In COPD, the likelihood of hypercapnia largely depends upon the balance between inspiratory muscle loads and strength. This balance was expressed by Bégin and Grassino (3) as the ratio of lung resistance (RL) to PI_max (RL/PI_max). They also found that hypercapnic COPD patients generated a higher portion of their inspiratory force during quiet breathing (i.e., a higher inspiratory tension-time index [TTI] of the inspiratory muscles [TTI = TI/Ttot × I/PI_max, where I is the mean inspiratory driving pressure developed by the inspiratory muscles]), which is likely to maintain a similar level of resting ventilation despite weaker inspiratory muscles and increased loads. However, their TTI was kept below the fatigue threshold described for normal subjects during endurance runs. This was interpreted as if hypercapnic subjects behaved as "wise fighters" who weigh their options and choose alveolar hypoventilation rather than respiratory muscle fatigue (3).

If we want to express the balance between inspiratory muscle loads and strength in MD in a way that includes the loads acting on the entire respiratory system, then the impedance of the respiratory system (Zrs) and the Zrs/PI_max ratio are more appropriate parameters. Bégin and associates (17) reported a 2-fold increase in estimated Zrs in MD patients, and a reduction of PI_max to half the values of control subjects. In the present study, the increase in FEV₁/FVC and the lower-than-expected FVC for the degree of RMS suggest the presence of increased lung and respiratory-system elastance, and hence an increased Zrs, both in our subjects with a higher degree of disability (Table 2) and in those with hypercapnia (Table 3). The association between these mechanical factors and volume restriction in longstanding and severe respiratory weakness was recognized by De Troyer and colleagues (11), who found a high degree of correlation (r = 0.79) between VC and static lung compliance in neuromuscular diseases. Increased respiratory-system elastance may be explained by microatelectasis (11) and chest-wall ankylosis (18) rather than by myotonia of the respiratory muscles (19). Additionally, body mass index (BMI) in our subjects tended to increase in parallel with muscle disability (Table 1), despite the opposite effect of muscle wasting, suggesting some obesity in subjects with more severe disease. Obesity might result in a threshold load on the chest wall (20). However, BMI does not closely reflect mass loading in this population because of muscle wasting, and was not found to be a significant cofactor for Pa_CO2.

Resting ventilation in MD patients has been found to be increased (17) or not significantly different (13) than that in control subjects. As discussed earlier for COPD patients, the only way in which they could maintain ventilation despite an unfavorable balance between inspiratory loads and strength was to generate a higher proportion of their inspiratory force during quiet breathing. In fact, measurements of the mouth occulsion pressure at 0.1 s after the onset of inspiration (P_0.1) during rest (which is accepted as representative of the pressure output during the whole breath in conscious subjects) have shown either normal (6, 21) or increased values (17). In either case, taking into account that PI_max is lower in MD patients than in normal subjects, the P_0.1/PI_max ratio in the patients has to be higher.

We have been able to do some calculations of TTI and Zrs/ PI_max based on mean values from MD patients published by Bégin and associates (17). From the data in Table 1 and Figure 2 (17), we were able to obtain TI/Ttot, P_0.1, VT/TI, and PI_max data for both MD patients and control subjects in the sitting position. For MD patients, TI/Ttot = 0.47, P_0.1 = 1.95 cm H₂O, VT/TI = 0.40 L/s, and PI_max = 38 cm H₂O. For control subjects, TI/Ttot = 0.41, P_0.1 = 0.85 cm H₂O, VT/TI = 0.39 L/s, and PI_max = 80 cm H₂O. Although P_0.1 is not a direct measurement of I, it has been used instead to estimate I and then TTI, assuming a linear rate of increase of the pressure output during inspiration: I = 5 × P_0.1 × TI (22). We also used the estimated I to calculate Zrs as follows: Zrs = I/(VT/TI). The values for inspiratory time (TI) reported by Bégin and associates (17) were 1.42 s and 1.64 s for MD patients and control subjects, respectively. Calculations yielded values of I = 13.8 cm H₂O, TTI = 0.171, and Zrs/PI_max = 0.91 (L/s)¹ for MD patients. For control subjects, I = 6.97 cm H₂O, TTI = 0.036, and Zrs/ PI_max = 0.22 (L/s)¹. Since the authors did not provide individual values for all of these parameters, statistical analysis was not possible. Our hypercapnic patients seemed to have a higher PI_max value (57 ± 26 cm H₂O) than did the MD subjects of Bégin and colleagues, and their TTI would therefore be expected to be lower and thus not to exceed the fatigue threshold. Nevertheless, their inspiratory muscle force reserve appears to be smaller than that of normocapnic MD subjects. MD patients with respiratory muscle weakness are at risk of acquiring acute bronchitis and pneumonia (12). These infections increase airway resistance and/or ventilation-perfusion (A/) mismatch and therefore TT I, and may precipitate acute respiratory failure.

To summarize, these estimations are in accord with the current working hypothesis, based on COPD data (3), that inspiratory muscle fatigue plays no role in the pathogenesis of chronic hypercapnia, whereas inspiratory muscle weakness and loading definitely do (23).

Daytime Hypersomnolence and Hypercapnia

Hypercapnic patients were found to have a PI_max value of 56 ± 25% predicted and an FVC as high as 62% ± 19% predicted. Our results confirm the data of Kilburn and coworkers (5), who noticed a relative preservation of VC and maximum breathing capacity in chronic hypercapnic MD patients. By contrast, chronic hypercapnia usually occurs with severe inspiratory muscle weakness in other types of proximal myopathies (16), and is rare in Duchenne muscular dystrophy, even with major respiratory muscle weakness (13). These findings are in accord with the suggestion by several authors (24) that central ventilatory control mechanisms are abnormal in MD and contribute to chronic alveolar hypoventilation. This hypothesis was largely supported by the recent finding of neuronal loss in the dorsal central, ventral central, and subtrigeminal medullary nuclei in MD patients with alveolar hypoventilation (28).

Disentangling peripheral from possible central influences on respiratory function in MD patients has proved a challenge for many years; among features suggesting impaired respiratory control in MD, it was suggested that daytime hypersomnolence may be the only one that has a truly central basis (6). Daytime sleepiness in MD appears to be related to a dysfunction of the central nervous system (CNS) (6, 27, 29, 30) and to severe neuronal loss and gliosis in the tegmentum of the brainstem (29). It was reported in association with central alveolar hypoventilation (25, 27), and may exceptionally precede it by two decades (26) or persist after hypercapnia is eased (25). Hypercapnia may be eased by using the CNS stimulant methylphenidate (27, 30), a known respiratory stimulant (31). Like others (30), we found that daytime hypersomnolence is highly prevalent in symptomatic MD patients, in whom it is unrelated to the degree of the muscular disablity (Table 1). In addition, hypercapnia in our subjects was not severe enough to induce CO₂ narcosis. In our multiple regression analyses, daytime sleepiness was found to explain a small increment in Pa_CO2 of 1.6 mm Hg after taking into account muscular disability or FVC. However, the importance of central alveolar hypoventilation might have been underestimated in our study, since 17 of our subjects were taking methylphenidate for severe daytime sleepiness.

Daytime hypersomnolence also bore some relationship to nightime events in a sleep questionnaire answered 5 yr before our study (before the use of methylphenidate at our clinic) by 201 MD patients, including 66 who participated in the present study. It revealed a self-reported prevalence of snoring (at least sometimes) of 54.2%. In addition, 25.2% of 135 patients taking naps admitted "choking or stopping breathing" (at least sometimes)a greater prevalence than the 7.6% value found in the 66 patients not having naps (p < 0.01). Some sleep studies (27, 30, 32) have suggested the involvement of a central neurogenic abnormality in the appearance of daytime hypersomnolence. Rapid eye movement (REM) periods at the onset of sleep occur in these patients, as in narcoleptic patients, suggesting a common abnormality (34). More recent sleep studies did not show a significant relationship between daytime hypersomnolence and sleep apnea, nor abnormal sleep architecture in myotonic patients (30, 35). However, none of these studies included more than four patients in both the somnolent and nonsomnolent groups. Our data suggest that disruption of sleep might be one factor contributing to daytime somnolence, although a larger number of subjects participating in controlled sleep studies might be needed to confirm this hypothesis.

Our data point to an integrative mechanism in which alveolar hypoventilation is partly explained by inspiratory muscle weakness, inspiratory loads, and, presumably, low ventilatory drive. However, the higher prevalence of self-reported disturbed breathing during sleep in subjects with daytime hypersomnolence suggests that this parameter is not specific to low central drive, and bears some association with a sleep disorder.

Conclusion

In MD, weakness of the respiratory muscles may be detected even in patients with minimal signs of muscular disability. Weakness of the inspiratory muscles is usually severe when proximal limb weakness is clinically evident. Inspiratory capacity then declines, increasing the likelihood of alveolar hypoventilation.

Our study suggests that the combination of inspiratory muscle weakness and loading plays a predominant role in the pathogenesis of chronic alveolar hypoventilation in MD patients. The occurrence of daytime hypersomnolence suggests that other factors, such as low central ventilatory drive or sleep apnea, might play an additional role.