PEDIATRICS Vol. 119 No. 2 February 2007, pp. e320-e324 (doi:10.1542/10.1542/peds.2006-1400)
ARTICLE |
Effect of Long-term Steroids on Cough Efficiency and Respiratory Muscle Strength in Patients With Duchenne Muscular Dystrophy
a Departments of Pulmonary Medicine
c Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
b Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVE. The objective of this study was to determine whether long-term steroid therapy is associated with increased peak cough flow in patients with Duchenne muscular dystrophy and to determine which pulmonary function test variable is most predictive of peak cough flow.
METHODS. In this case-control study, the medical charts of patients who had Duchenne muscular dystrophy and had pulmonary function tests at our institution in the previous 2 years were examined. Steroid-treated patients were on therapy for at least 1 year. The measured pulmonary function tests included forced vital capacity, maximum expiratory pressure, maximum inspiratory pressure, maximum voluntary ventilation, and peak cough flow. Multiple linear regression analysis was used to determine which pulmonary function test measure was most predictive of peak cough flow and assess the influence of steroid treatment and patient age on peak cough flow.
RESULTS. Ten steroid-treated and 25 untreated patients were analyzed. Peak cough flow and maximum expiratory pressure were significantly higher in the steroid-treated patients. Each of the pulmonary function test variables was significantly associated with peak cough flow. The linear model that had the highest adjusted r2 value included only 2 variables: maximum voluntary ventilation and steroid treatment, demonstrating that steroid-treated patients had peak cough flow values that were 27 L/min higher than the untreated patients. The interaction between maximum voluntary ventilation and steroid was not statistically significant, suggesting that the steroid-associated increase in peak cough flow was approximately constant over the observed range of maximum voluntary ventilation values. The effects of maximum voluntary ventilation and treatment group on peak cough flow were not confounded with the patient age.
CONCLUSIONS. Long-term steroid therapy is associated with improved peak cough flow and respiratory muscle strength in patients with Duchenne muscular dystrophy. Maximum voluntary ventilation may be a useful predictor of lung function in Duchenne muscular dystrophy.
Key Words: cough • Duchenne muscular dystrophy • pulmonary • steroids
Abbreviations: DMD—Duchenne muscular dystrophy • FVC—forced vital capacity • PCF—peak cough flow • PFT—pulmonary function test • ATS—American Thoracic Society • MVV—maximum voluntary ventilation • MIP—maximum inspiratory pressure • MEP—maximum expiratory pressure • IRLS—iteratively reweighted least squares
Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder with an incidence of 1:3000 live male births. It is characterized by progressive loss of muscle function that eventually causes respiratory insufficiency and death frequently from respiratory failure.1,2 Patients often succumb to acute or chronic respiratory failure that is brought on by respiratory tract infections.3 Typically these exacerbations result from impaired airway clearance by a weakened cough and further weakening of respiratory muscles. Bach et al4 demonstrated prolongation of survival in patients who had DMD with cough augmentation and noninvasive ventilatory support. Since the advent of steroid therapy for treatment of DMD, several studies have shown higher forced vital capacity (FVC) percent predicted, an excellent measure of respiratory function, in treated patients.5–7 Our objective was to determine whether patients who have DMD and are treated with long-term steroids have improved peak cough flow (PCF) and respiratory muscle strength as compared with the untreated group. We also sought to determine which pulmonary function test (PFT) variable was most predictive of PCF.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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A case-control study was proposed and approved by the institutional review board. A retrospective review of the medical charts of patients who had DMD and were treated at our institution in the previous 2 years was performed. DMD was diagnosed by DNA testing or demonstration of lack of dystrophin in the patients' muscle biopsy specimen. Only patients who had PFTs that were acceptable per the American Thoracic Society (ATS) criteria performed at our institution were included.8,9 Because patients with DMD are weak and therefore often unable to sustain exhalation for 6 seconds, as required by ATS to meet PFT acceptability criteria, we arbitrarily chose a
3-second exhalation criterion for acceptability. For the steroid-treated patients, informed decisions regarding therapy were obtained from the caregivers after reviewing the benefits and risks of therapy. Patients had to have been on therapy for at least 1 year for inclusion in the study. Because all of the patients were started on steroids before publication of the practice parameter statement from the American Academy of Neurology,10 the steroid regimen (intermittent versus daily) was not standardized. Prednisone was started at a dosage of 0.75 mg/kg per day and deflazacort at 0.9 mg/kg per day. As patients grew, the dosage was not increased for weight gain but clinically adjusted for optimal motor function. FVC, maximum voluntary ventilation (MVV), maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), and PCF data were collected. PFTs were performed by qualified respiratory therapists using a Sensormedics (Yorba Linda, CA) pneumotachograph that is calibrated daily as per ATS recommendations. PCF was performed using a portable peak flow meter (Astech, New York, NY). Tests were conducted in the sitting position, over 30 minutes to 1 hour, to allow for patient recovery from each maneuver. The order of testing was respiratory muscle strength and PCF, followed by spirometry and, last, MVV. For muscle strength testing, patients performed repeat maneuvers until a 10% reproducibility criterion was met (up to 3 maneuvers, with the highest value reported). An unassisted PCF value was measured on our patients. Patients on average had PFTs tested twice a year; however, to avoid biases from missed follow-up visits, we chose the most recent PCF and PFT results on record for group comparison.
Data analysis was performed using SAS 9.1 (SAS Institute, Cary, NC). A Wilcoxon rank sum test was performed to evaluate whether any of the PFT variables differed between treatment groups (1-sided test with 
= .05). Multiple linear regression analysis was used to identify which combination of our 6 independent variables (MIP, MEP, FVC, MVV, age, and treatment group) was most predictive of PCF. The Pearson adjusted r2 values for each of the 63 possible 1-factor through 6-factor models were obtained using the ADJRSQ selection option of PROC REG. The final model was chosen by selecting the model that had the highest adjusted r2 value and the fewest explanatory variables. The assumptions of normality and homogeneity of variance were tested using the Shapiro-Wilk and the Brown-Forsythe tests, respectively. Influential observations were detected using Cook's distance measure. Iteratively reweighted least squares (IRLS) regression was applied using the Huber weight function to dampen the influence of outlying observations. The IRLS assigned lower weights to observations that had higher error estimates. Model coefficients whose t statistics had P < .05 were considered to be statistically significant.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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A total of 49 patients, 15 steroid-treated and 34 untreated, initially were identified. A total of 35 patients (10 steroid-treated and 25 steroid untreated) met inclusion criteria and were included in the final analysis. The age range of the steroid-treated group was 7 to 21 years. The mean duration of steroid therapy was 8.2 years (range: 1–14 years). Three patients had been treated exclusively with prednisone and 5 exclusively with deflazacort. Two patients initially had been started on intermittent prednisone and then were switched to daily deflazacort. Two patients who were on steroid therapy were started on a regimen at a different medical center, before transfer of care to our program. The age range of the untreated group was 8 to 26 years. MVV and MEP data were missing for 2 patients in the steroid-treated group. MVV data were missing for 4 patients and PCF as well as muscle strength data for 1 patient in the untreated group. On the basis of flow-volume loop analysis and forced expiratory volume in 1 second/FVC ratio, none of the patients had evidence of obstructive ventilatory limitation. Our results (Table 1) show that 2 of the pulmonary function variables measured, PCF (P = .047) and MEP (P = .021), were significantly higher in the steroid-treated patients than in the untreated patients.
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The linear correlation between PCF and each of the pulmonary function variables was significant. Pearson correlation coefficients between PCF and MVV, MIP, FVC, and MEP had values of 0.545 (P = .003), 0.537 (P = .002), 0.527 (P = .002), and 0.430 (P = .016), respectively. A multiple linear regression model was used to identify the combination of variables that best predicted PCF. The model that had the highest adjusted r2 value (0.430) and the fewest explanatory variables included only 2 variables: MVV and a categorical variable that corresponded to the treatment group (1 = steroid-treated; 0 = untreated). The best 3-variable model (MVV, steroid treatment group, and MIP) decreased the adjusted r2 value to 0.418, indicating that no additional benefit was obtained by adding more than 2 explanatory variables to the model.
Diagnostic tests indicated that both the assumptions of the normality of error terms and the homogeneity of variance were met. However, Cook's distance measure identified 2 observations as outlying cases. One of these cases was in the steroid-treated group and had an unusually high PCF (340 L/min); the other case was in the untreated group and had an unusually low PCF (140 L/min) for its associated MVV. Consequently, we used IRLS regression to produce more conservative estimates of the influence of steroid treatment on PCF. The results for the IRLS regression model that contained MVV and the treatment group as explanatory variables are shown in Table 2. The model suggests that the steroid-treated group had PCF values 
27 L/min higher than the untreated group (95% confidence interval: 2–52 L/min; P = .0328). The Pearson r2 value for the model was 0.526, indicating that MVV and steroid treatment could account for >50% of the variance in PCF. Although we tested for a possible interaction between MVV and treatment group, this interaction was not found to be significant (P = .591). Therefore, a model with 2 parallel lines, 1 for each treatment group, was found to describe the data best, indicating that the influence of steroid treatment remained approximately constant over the range of MVV values observed (Fig 1).
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The median age of the untreated group (13 years) was higher than that of the steroid-treated group (10 years). Consequently, we introduced age as a third explanatory variable into the model to investigate its possible influence as a confounder. The estimated coefficient for the age variable was not statistically significant (P = .418), indicating that age explained little of the variance in PCF. In addition, the introduction of age into the model failed to alter the coefficients for MVV and treatment group by >10% (ie, a 4% increase for MVV and a 7% decrease for treatment group). This finding suggested that age was not confounded with either MVV or treatment group; therefore, we eliminated age from our final model as an explanatory variable.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Cough is a vital protective reflex and plays an important role in airway clearance with prevention of atelectasis and pulmonary infection. Inhaling to large lung volumes followed by isometric contraction of expiratory muscles against a closed glottis results in high intrathoracic pressures with dynamic compression of airways. Glottic release initiates the expiratory phase, which is characterized by high airflow velocity that clears the airways of secretions.11 Integrity of cough requires adequate inspiratory and expiratory muscle strength with an intact cough pathway. Because modest increases in intrathoracic pressures are sufficient to cause dynamic airway compression with augmentation of cough flow, it is possible to preserve such airway clearance with mild to moderate respiratory muscle weakness.12 Pulmonary morbidity has been shown to be improved in patients with DMD by supporting respiratory muscles.4
DMD results from absence of the muscle protein dystrophin.13 Increased calcium permeability of dystrophin-depleted cells has been observed in cell cultures,14,15 and elevated inflammatory mediators have been observed in dystrophin-deficient muscles.16 The abnormal calcium homeostasis in DMD is believed to activate signaling cascades that are involved in inflammation.17 Motor and respiratory outcomes have been shown to be preserved by steroid therapy in patients with DMD,18 and immune modulation to improve ventilatory function has been suggested in patients with muscular dystrophy.19 Biggar et al6 demonstrated improved FVC percent predicted in patients who had DMD and were treated with long-term steroids. We therefore attempted to ascertain whether the beneficial effects of steroid therapy translated to preservation of cough efficiency and respiratory muscle strength. Our results show that respiratory muscle strength, as well as PCF, in the steroid-treated group of patients with DMD was higher than that in untreated patients. The correlations of MIP and MEP with PCF suggest that preservation of respiratory muscle strength should translate into better cough efficiency.
Respiratory outcome studies of patients who have DMD and are treated with steroids have shown improved FVC percent predicted. Because the FVC maneuver requires integrity of both inspiratory and expiratory muscles, it is an excellent measure of respiratory function reserve and correlated with PCF in our data (Pearson r = 0.526, P = .002). The limitation of FVC percent predicted is that its value is subject to error when the reference is changed from height to arm span as patients become nonambulatory. We therefore attempted to establish correlation of PCF with other PFT variables and found MVV to be most predictive. Because both MVV and FVC require adequate inspiratory and expiratory muscle function, they both represent respiratory function reserve; however, MVV probably is a better measure of endurance. Unlike the assisted PCF technique described by Bach et al, we test unassisted PCF because we believe that it reflects real-life cough for our patients. Dystrophic muscle demonstrates a predominance of type I muscle fibers (slow twitch/oxidative),20,21 which are recruited for submaximal endurance activity. Because cough-mediated airway clearance can be accomplished with mild to moderate muscle weakness, it is likely that type I muscle fibers participate to a greater extent in the weak cough, which is characteristic of patients with DMD. Given the histopathologic bias toward type I fibers in dystrophic muscle and our study results, MVV may be a useful addition to FVC in monitoring respiratory function in DMD.
Our study's limitations are the retrospective design and thus risk for selection bias, small patient number in each of the study groups, and the nonstandardized steroid regimen. The longitudinal effect of age on PCF could not be assessed because of the study design. The small number of patients, differing duration, and regimens of therapy also limit comparisons between prednisone and deflazacort. A larger prospective study needs to be conducted to confirm our findings. Our results show meaningful interpretation using a shortened exhalation criterion for PFTs; therefore, it may be worthwhile to consider a 3-second exhalation criterion when assessing PFTs in patients with neuromuscular disorders.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Steroid therapy seems to be beneficial in preserving respiratory muscle strength and cough efficiency in DMD. In the event that patients are unable to perform ATS-acceptable FVC maneuvers, MVV may be a useful additional parameter to monitor for a global perspective on respiratory function in patients with DMD. A study with larger patient numbers is warranted to reproduce our demonstrated benefits in respiratory muscle strength and cough efficiency and establish the magnitude of effect.
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ACKNOWLEDGMENTS |
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This study was performed in partial fulfillment of requirements for the Master of Science in Clinical Research Training Program, University of Cincinnati (Cincinnati, OH).
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FOOTNOTES |
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Accepted Aug 25, 2006.
Address correspondence to Ameet S. Daftary, MBBS, Department of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, MLC 2021, Cincinnati, OH 45246. E-mail: ameet.daftary{at}cchmc.org
The authors have indicated they have no financial relationships relevant to this article to disclose.
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