Current Practices in Treating Cardiomyopathy and Heart Failure in Duchenne Muscular Dystrophy (DMD): Understanding Care Practices in Order to Optimize DMD Heart Failure Through ACTION.

Cardiac disease has emerged as a leading cause of mortality in Duchenne muscular dystrophy in the current era. This survey sought to identify the diagnostic and therapeutic approach to DMD among pediatric cardiologists in Advanced Cardiac Therapies Improving Outcomes Network. Pediatric cardiology providers within ACTION (a multi-center pediatric heart failure learning network) were surveyed regarding their approaches to cardiac care in DMD. Thirty-one providers from 23 centers responded. Cardiac MRI and Holter monitoring are routinely obtained, but the frequency of use and indications for ordering these tests varied widely. Angiotensin converting enzyme inhibitor and aldosterone antagonist are generally initiated prior to onset of systolic dysfunction, while the indications for initiating beta-blocker therapy vary more widely. Seventeen (55%) providers report their center has placed an implantable cardioverter defibrillator in at least 1 DMD patient, while 11 providers (35%) would not place an ICD for primary prevention in a DMD patient. Twenty-three providers (74%) would consider placement of a ventricular assist device (VAD) as destination therapy (n = 23, 74%) and three providers (10%) would consider a VAD only as bridge to transplant. Five providers (16%) would not consider VAD at their institution. Cardiac diagnostic and therapeutic approaches vary among ACTION centers, with notable variation present regarding the use of advanced therapies (ICD and VAD). The network is currently working to harmonize medical practices and optimize clinical care in an era of rapidly evolving outcomes and cardiac/skeletal muscle therapies.

Large-scale serum protein biomarker discovery in Duchenne muscular dystrophy.

Serum biomarkers in Duchenne muscular dystrophy (DMD) may provide deeper insights into disease pathogenesis, suggest new therapeutic approaches, serve as acute read-outs of drug effects, and be useful as surrogate outcome measures to predict later clinical benefit. In this study a large-scale biomarker discovery was performed on serum samples from patients with DMD and age-matched healthy volunteers using a modified aptamer-based proteomics technology. Levels of 1,125 proteins were quantified in serum samples from two independent DMD cohorts: cohort 1 (The Parent Project Muscular Dystrophy-Cincinnati Children's Hospital Medical Center), 42 patients with DMD and 28 age-matched normal volunteers; and cohort 2 (The Cooperative International Neuromuscular Research Group, Duchenne Natural History Study), 51 patients with DMD and 17 age-matched normal volunteers. Forty-four proteins showed significant differences that were consistent in both cohorts when comparing DMD patients and healthy volunteers at a 1% false-discovery rate, a large number of significant protein changes for such a small study. These biomarkers can be classified by known cellular processes and by age-dependent changes in protein concentration. Our findings demonstrate both the utility of this unbiased biomarker discovery approach and suggest potential new diagnostic and therapeutic avenues for ameliorating the burden of DMD and, we hope, other rare and devastating diseases.

Autonomic dysfunction: a driving force for myocardial fibrosis in young Duchenne muscular dystrophy patients?

Cardiac manifestations of Duchenne muscular dystrophy (DMD) include progressive cardiac dysfunction and an elevated resting heart rate (HR). We hypothesized this elevated HR reflects autonomic dysfunction that can be identified by heart rate variability (HRV) analyses which will be associated with myocardial fibrosis by cardiac magnetic resonance imaging (cMR). DMD patients (N = 74) and controls (N = 17) had time and frequency domain HRV analyses calculated via Holter monitoring. Cardiac magnetic resonance imaging was performed on DMD cases only. χ (2) test, T test, ANOVA, and logistic regression were used to perform comparisons between groups. A p value of <0.05 was used for statistical significance. DMD cases had higher resting average HR than controls (99.4 ± 8.9, 85.4 + 6.2, p < 0.001). Among HRV variables, decreases were seen in the following: standard deviation of R to R intervals, the percent RR intervals differing by >50 ms from previous RR interval, the root-meansquare of successive differences of RR intervals, the standard deviation of the mean R to R segment (SDANN), low frequency, and high frequency domain, all p values 0.001. Maximum HR and SDANN most significantly associated with positive LGE on cMR (p = 0.008, p = 0.016). DMD cases on beta blocker had an average HR lower than those not on beta blocker (p = 0.009), but with no difference in HRV analysis. DMD patients have reduced HRV and therefore autonomic dysfunction prior to the onset of heart failure which is associated with myocardial fibrosis.

Regional circumferential strain is a biomarker for disease severity in duchenne muscular dystrophy heart disease: a cross-sectional study.

The aim of this study is to determine the contribution of strain ε cc in mid left ventricular (LV) segments to the reduction of composite LV circumferential ε cc in assess severity of duchenne muscular dystrophy (DMD) heart disease as assessed by cardiac magnetic resonance imaging (CMR). DMD patients and control subjects were stratified by age, LV ejection fraction, and late gadolinium enhancement (LGE) status. Tagged CMR images were analyzed for global ventricular function, LGE imaging, and composite and segmental ε cc. The relationship between changes in segmental ε cc changes and LGE across patient groups was assessed by a statistical step-down model. LV ε cc exhibited segmental heterogeneity; in control subjects and young DMD patients, ε cc was greatest in LV lateral free wall segments. However, with increasing age and cardiac disease severity as demonstrated by decreased EF and development of myocardial strain the segmental differences diminished. In subjects with advanced heart disease as evidenced by reduced LV ejection fraction and presence of LGE, very little segmental heterogeneity was present. In control subjects and young DMD patients, ε cc was greatest in LV lateral free wall segments. Increased DMD heart disease severity was associated with reduced composite; ε cc diminished regional ε cc heterogeneity and positive LGE imaging. Taken together, these findings suggest that perturbation of segmental, heterogeneous ε cc is an early biomarker of disease severity in this cross-section of DMD patients.

Co-occurring Duchenne muscular dystrophy and hypertrophic cardiomyopathy in an adult with atypical cardiac phenotype.

We present the case of a 29-year-old man with mutation-positive Duchenne muscular dystrophy and mutation-positive hypertrophic cardiomyopathy. His cardiac phenotype has characteristics of both disorders; he manifests sub-epicardial left ventricular free wall late gadolinium enhancement that is consistent with Duchenne cardiomyopathy, as well as asymmetric ventricular septal hypertrophy, hyperdynamic left ventricular systolic function, and septal mid-myocardial late gadolinium enhancement, which are characteristic of hypertrophic cardiomyopathy.

Pan-valvulitis in Children With Kawasaki Disease: A Case Report and Review of the Literature.

We present a rare case of pan-valvular involvement in a 5-month-old female with Kawasaki disease shock syndrome despite early treatment with intravenous immunoglobulin and corticosteroids. She experienced a favorable outcome after the addition of infliximab, which was guided based on clinical, laboratory and echocardiogram findings, rather than recrudescence of fever, the most common indicator of intravenous immunoglobulin resistance.

Rate of Change in Cardiac Magnetic Resonance Imaging Measures Is Associated With Death in Duchenne Muscular Dystrophy.

BACKGROUND: Cardiovascular disease is the leading cause of death among patients with Duchenne muscular dystrophy (DMD). Identifying patients at risk of early death could allow for increased monitoring and more intensive therapy. Measures that associate with death could serve as surrogate outcomes in clinical trials. METHODS AND RESULTS: Duchenne muscular dystrophy subjects prospectively enrolled in observational studies were included. Models using generalized least squares were used to assess the difference of cardiac magnetic resonance measurements between deceased and alive subjects. A total of 63 participants underwent multiple cardiac magnetic resonance imaging and were included in the analyses. Twelve subjects (19.1%) died over a median follow-up of 5 years (interquartile range, 3.1-7.0). Rate of decline in left ventricular ejection fraction was faster in deceased than alive subjects (P<0.0001). Rate of increase in indexed left ventricular end-diastolic (P=0.0132) and systolic (P<0.0001) volumes were higher in deceased subjects. Faster worsening in midcircumferential strain was seen in deceased subjects (P=0.049) while no difference in global circumferential strain was seen. The rate of increase in late gadolinium enhancement, base T1, and mid T1 did not differ between groups. CONCLUSIONS: Duchenne muscular dystrophy death is associated with the rate of change in left ventricular ejection fraction, midcircumferential strain, and ventricular volumes. Aggressive medical therapy to decrease the rate of progression may improve the mortality rate in this population. A decrease in the rate of progression may serve as a valid surrogate outcome for therapeutic trials.

Left ventricular noncompaction in Duchenne muscular dystrophy.

BACKGROUND: Left ventricular noncompaction (LVNC) describes deep trabeculations in the left ventricular (LV) endocardium and a thinned epicardium. LVNC is seen both as a primary cardiomyopathy and as a secondary finding in other syndromes affecting the myocardium such as neuromuscular disorders. The objective of this study is to define the prevalence of LVNC in the Duchenne Muscular Dystrophy (DMD) population and characterize its relationship to global LV function. METHODS: Cardiac magnetic resonance (CMR) was used to assess ventricular morphology and function in 151 subjects: DMD with ejection fraction (EF) > 55% (n = 66), DMD with EF < 55% (n = 30), primary LVNC (n = 15) and normal controls (n = 40). The non-compacted to compacted (NC/C) ratio was measured in each of the 16 standard myocardial segments. LVNC was defined as a diastolic NC/C ratio > 2.3 for any segment. RESULTS: LVNC criteria were met by 27/96 DMD patients (prevalence of 28%): 11 had an EF > 55% (prevalence of 16.7%), and 16 had an EF < 55% (prevalence of 53.3%). The median maximum NC/C ratio was 1.8 for DMD with EF > 55%, 2.46 for DMD with EF < 55%, 1.54 for the normal subjects, and 3.69 for primary LVNC patients. Longitudinal data for 78 of the DMD boys demonstrated a mean rate of change in NC/C ratio per year of +0.36. CONCLUSION: The high prevalence of LVNC in DMD is associated with decreased LV systolic function that develops over time and may represent muscular degeneration versus compensatory remodeling.

Prevalence and distribution of late gadolinium enhancement in a large population of patients with Duchenne muscular dystrophy: effect of age and left ventricular systolic function.

BACKGROUND: Duchenne muscular dystrophy (DMD), an X-linked disorder affects approximately 1 in 5000 males, is universally associated with heart disease. We previously identified myocardial disease by late gadolinium enhancement (LGE) in DMD subjects at various stages of disease, but the true prevalence is unclear. Cardiovascular magnetic resonance (CMR) is well established for both assessment of ventricular function and myocardial fibrosis by LGE. We sought to establish i) prevalence and distribution of LGE in a large DMD population and ii) relationship among LGE, age, LVEF by CMR and current living status. METHODS: Current living status, demographic and CMR data including ventricular volumes, LVEF and LGE from 314 DMD patients undergoing evaluation at a single large tertiary referral center were analyzed. RESULTS: 113 of 314 (36%) of DMD subjects showed LGE positivity with prevalence increasing from 17% of patients <10 years to 34% of those aged 10-15 years and 59% of those >15 years-old. Patients with LVEF ≥55% were LGE positive in 30% of cases; this increased to 84% for LVEF <55%. LGE was more prevalent in the free wall (531/1243, 42.7%) vs. septal segments (30/565, 5.3%). Patients with septal involvement were significantly older and had lower LVEF than those with isolated free wall LGE. Ten percent (11/113) patients who had LGE died 10.8 months after CMR. Only one patient from the LGE negative group died. Patients who died had higher heart rate, larger left ventricular volume and mass, greater number of positive LGE segment and increase incident of septal LGE compared to those who remained alive. CONCLUSION: In DMD patients, LGE occurs early, is progressive and increases with both age and decreasing LVEF. Segmentally, the incidence of the number of positive LGE segments increase with age and lower LVEF. Older patients and those who died during the study period had more septal LGE involvement. The current studies suggest that the time course and distribution of LGE-positivity may be an important clinical biomarker to aid in the management of DMD-associated cardiac disease.

Cardiac considerations in the operative management of the patient with Duchenne or Becker muscular dystrophy.

Duchenne muscular dystrophy/Becker muscular dystrophy (DMD/BMD) is a progressive multisystem neuromuscular disorder. In addition to the skeletal muscle, the myocardium in the DMD/BMD patient is dystrophin deficient which results in a progressive cardiomyopathy. The myopathic myocardium poses significant risk of increased morbidity and mortality at the time of major surgical procedures. Careful attention must be given to the DMD/BMD patient during the intraoperative and postoperative period. Anesthesia selection is critical and anesthetics should be avoided which have been shown to be harmful in this patient population. Preanesthesia assessment should include cardiac consultation and detailed preoperative evaluation. Intraoperative management needs to insure that the weakened myocardium is not compromised by physiologic changes such as hypotension or major fluid shifts. Finally, attention to the cardiac status of the patient must continue into the postoperative period. The surgical care of the DMD/BMD patient requires a multispecialty approach to insure operative success.

Abnormal circumferential strain is present in young Duchenne muscular dystrophy patients.

Advances in management of non-cardiac issues in Duchenne muscular dystrophy (DMD) have improved such that DMD-associated cardiac disease has become the leading cause of death for such patients. Cardiac dysfunction measured by standard transthoracic echocardiographic methods, e.g., fractional shortening (FS) and ejection fraction (EF), is rarely present during the first decade of life. The current study used transthoracic echocardiogram (TTE) to assess strain (ε), an indicator of regional ventricular function, in young DMD patients. A retrospective review of the TTE database was performed. TTE results from DMD patients <8 years (n = 63) performed during 2009 to 2010 were compared with TTE results from an unaffected control group (n = 61). Feature tracking analysis software was used to measure total circumferential strain (ε cc) as well as segmental ε cc based on the American Society of Echocardiography 16-segment model. Although there were no differences in FS, the absolute value for left-ventricular (LV) ε cc at the mid-chamber level was decreased in DMD (-21.7 % ± 3.8 % vs. -19.8 % ± 4.2 %, p < 0.01; unaffected vs. DMD). Segmental ε(cc) was similarly affected in the anteroseptal segment (-23.0 % ± 6.1 % vs. -18.9 % ± 7.0 %, p = 0.001; controls vs. DMD), the inferior segment (-20.7 % ± 5.16 % vs. -17.7 % ± 6.1 %, p = 0.003; controls vs. DMD), and the inferolateral segment (-18.3 % ± 6.2 % vs. -15.9 % ± 6.7 %, p = 0.04; controls vs. DMD). In the present study we demonstrate both total and segmental LV ε cc (anteroseptal, inferior, and inferolateral segments) abnormalities at the mid-chamber level in a large group of young DMD patients with normal FS. These novel findings substantiate that the disease process is present and results in abnormal myocardial function before standard measures detect global dysfunction.

Cardiovascular Measures of All-Cause Mortality in Duchenne Muscular Dystrophy.

BACKGROUND: Cardiopulmonary failure is the leading cause of death in Duchenne muscular dystrophy (DMD). Research into DMD-specific cardiovascular therapies is ongoing, but there are no Food and Drug Administration-approved cardiac end points. To adequately power a therapeutic trial, appropriate end points must be chosen and the rate of change for these end points reported. The objective of this study was to evaluate rate of change for cardiac magnetic resonance and blood biomarkers and to determine which measures associate with all-cause mortality in DMD. METHODS: Seventy-eight DMD subjects underwent 211 cardiac magnetic resonance studies analyzed for left ventricular (LV) ejection fraction, indexed LV end diastolic and systolic volumes, circumferential strain, late gadolinium enhancement presence and severity (global severity score, and full width half maximum), native T1 mapping, T2 mapping, and extracellular volume. Blood samples were analyzed for BNP (brain natriuretic peptide), NT-proBNP (N-terminal pro-B-type natriuretic peptide), and troponin I. Cox proportional hazard regression modeling was performed with all-cause mortality as the outcome. RESULTS: Fifteen subjects (19%) died. LV ejection fraction, indexed end systolic volumes, global severity score, and full width half maximum worsened at 1 and 2 years while circumferential strain and indexed LV end diastolic volumes worsened at 2 years. LV ejection fraction, indexed LV end diastolic and systolic volumes, late gadolinium enhancement full width half maximum, and circumferential strain associated with all-cause mortality (P<0.05). NT-proBNP was the only blood biomarker that associated with all-cause mortality (P<0.05). CONCLUSIONS: LV ejection fraction, indexed LV volumes, circumferential strain, late gadolinium enhancement full width half maximum, and NT-proBNP are associated with all-cause mortality in DMD and may be the best end points for use in cardiovascular therapeutic trials. We also report change over time of cardiac magnetic resonance and blood biomarkers.

Initial multicenter experience with ventricular assist devices in children and young adults with muscular dystrophy: An ACTION registry analysis.

PURPOSE: Cardiac disease results in significant morbidity and mortality in patients with muscular dystrophy (MD). Single centers have reported their ventricular assist device (VAD) experience in specific MDs and in limited numbers. This study sought to describe the outcomes associated with VAD therapy in an unselected population across multiple centers. METHODS: We examined outcomes of patients with MD and dilated cardiomyopathy implanted with a VAD at Advanced Cardiac Therapies Improving Outcomes Network (ACTION) centers from 9/2012 to 9/2020. RESULTS: A total of 19 VADs were implanted in 18 patients across 12 sites. The majority of patients had dystrophinopathy (66%) and the median age at implant was 17.2 years (range 11.7-29.5). Eleven patients were non-ambulatory (61%) and 6 (33%) were on respiratory support pre-VAD. Five (28%) patients were implanted as a bridge to transplant, 4 of whom survived to transplant. Of 13 patients implanted as bridge to decision or destination therapy, 77% were alive at 1 year and 69% at 2 years. The overall frequencies of positive outcome (transplanted or alive on device) at 1 year and 2 years were 84% and 78%, respectively. Two patients suffered a stroke, 2 developed sepsis, 1 required tracheostomy, and 1 experienced severe right heart failure requiring right-sided VAD. CONCLUSIONS: This study demonstrates the potential utility of VAD therapies in patients with muscular dystrophy. Further research is needed to further improve outcomes and better determine which patients may benefit most from VAD therapy in terms of survival and quality of life.

Pediatric cardiomyopathy: importance of genetic and metabolic evaluation.

BACKGROUND: Cardiomyopathy is a heterogeneous disease with a strong genetic component. A research-based pediatric cardiomyopathy registry identified familial, syndromic, or metabolic causes in 30% of children. However, these results predated clinical genetic testing. METHODS AND RESULTS: We determined the prevalence of familial, syndromic, or metabolic causes in 83 consecutive unrelated patients referred for genetic evaluation of cardiomyopathy from 2006 to 2009. Seventy-six percent of probands (n = 63) were categorized as familial, syndromic, or metabolic. Forty-three percent (n = 18) of hypertrophic cardiomyopathy (HCM) patients had mutations in sarcomeric genes, with MYH7 and MYBPC3 mutations predominating. Syndromic (17%; n = 7) and metabolic (26%; n = 11) causes were frequently identified in HCM patients. The metabolic subgroup was differentiated by decreased endocardial shortening fraction on echocardiography. Dilated cardiomyopathy (DCM) patients had similar rates of syndromic (20%; n = 5) and metabolic (16%; n = 4) causes, but fewer familial cases (24%; n = 6) compared with HCM patients. CONCLUSIONS: The cause of cardiomyopathy is identifiable in a majority of affected children. An underlying metabolic or syndromic cause is identified in >35% of children with HCM or DCM. Identification of etiology is important for management, family-based risk assessment, and screening.

Electrocardiographic prediction of late gadolinium enhancement on cardiac magnetic resonance in Becker muscular dystrophy.

Dystrophin deficiency results in cardiomyopathy and fibrosis with variable onset. Little is known about electrocardiographic abnormalities in Becker muscular dystrophy and their relationship to underlying cardiac pathology. We hypothesized QRS fragmentation is associated with myocardial fibrosis on cardiac magnetic resonance imaging in Becker muscular dystrophy patients. We retrospectively evaluated 44 patients, and extracted data from clinically obtained electrocardiogram and cardiac magnetic resonance. Ventricular function and presence or absence late gadolinium enhancement representing myocardial fibrosis were recorded from imaging. Nearly half (19/42, 45%) of patients interrogated had myocardial fibrosis on cardiac magnetic resonance. Total number of electrocardiogram leads with QRS fragmentation (median 1 vs 4, p < 0.001) and either right or left axis deviation from median was significantly increased (13.6 vs. 44.8°, p < 0.001) in patients with myocardial fibrosis. Decreased leftward voltage in V6 correlated to both increased fibrosis and decreased cardiac function (p < 0.01). The positive likelihood ratio for underlying myocardial fibrosis in patients with two of the three findings on electrocardiogram was 8.47 (p < 0.0001). QRS fragmentation and axis deviation on electrocardiography are strongly predictive of myocardial fibrosis in Becker muscular dystrophy and may inform the use of advanced imaging in evaluation of these patients.

Cardiorespiratory management of Duchenne muscular dystrophy: emerging therapies, neuromuscular genetics, and new clinical challenges.

The life-limiting complications of Duchenne muscular dystrophy (DMD) include loss of lung function and progressive cardiomyopathy; when patients are treated with assisted ventilation, cardiac function becomes the main determinant of survival. Therapy for DMD is changing rapidly, with the emergence of new genetic and molecular therapeutic options, the proliferation of which has fostered the perception that DMD is a potentially curable disease. However, data for respiratory and cardiac outcomes are scarce and available evidence is not uniformly positive. Patients who share a dystrophin (DMD) genotype can have highly divergent cardiorespiratory phenotypes; genetic modifiers of DMD gene expression are a probable cause of respiratory and cardiac phenotypic variability and discordance. In this Personal View, we provide an overview of new and emerging DMD therapies, highlighting the limitations of current research and considering strategies to incorporate cardiorespiratory assessments into clinical trials. We explore how genetic modifiers could be used to predict cardiorespiratory natural history and how manipulation of such modifiers might represent a promising therapeutic strategy. Finally, we examine the changing role of respiratory physicians, cardiologists, and intensive care clinicians on the frontline of a challenging new clinical landscape.

Effects of steroids and angiotensin converting enzyme inhibition on circumferential strain in boys with Duchenne muscular dystrophy: a cross-sectional and longitudinal study utilizing cardiovascular magnetic resonance.

BACKGROUND: Steroid use has prolonged ambulation in Duchenne muscular dystrophy (DMD) and combined with advances in respiratory care overall management has improved such that cardiac manifestations have become the major cause of death. Unfortunately, there is no consensus for DMD-associated cardiac disease management. Our purpose was to assess effects of steroid use alone or in combination with angiotensin converting enzyme inhibitors (ACEI) or angiotension receptor blocker (ARB) on cardiovascular magnetic resonance (CMR) derived circumferential strain (εcc). METHODS: We used CMR to assess effects of corticosteroids alone (Group A) or in combination with ACEI or ARB (Group B) on heart rate (HR), left ventricular ejection fraction (LVEF), mass (LVM), end diastolic volume (LVEDV) and circumferential strain (εcc) in a cohort of 171 DMD patients >5 years of age. Treatment decisions were made independently by physicians at both our institution and referral centers and not based on CMR results. RESULTS: Patients in Group A (114 studies) were younger than those in Group B (92 studies)(10 ± 2.4 vs. 12.4 ± 3.2 years, p < 0.0001), but HR, LVEF, LVEDV and LVM were not different. Although εcc magnitude was lower in Group B than Group A (-13.8 ± 1.9 vs. -12.8 ± 2.0, p = 0.0004), age correction using covariance analysis eliminated this effect. In a subset of patients who underwent serial CMR exams with an inter-study time of ~15 months, εcc worsened regardless of treatment group. CONCLUSIONS: These results support the need for prospective clinical trials to identify more effective treatment regimens for DMD associated cardiac disease.

The effect of emerging molecular and genetic therapies on cardiopulmonary disease in Duchenne muscular dystrophy.

Gene therapy is an attractive approach being intensively studied to prevent muscle deterioration in patients with Duchenne muscular dystrophy. While clinical trials are only in early stages, initial reports are promising for its effects on ambulation. Cardiopulmonary failure, however, is the most common cause of mortality in Duchenne muscular dystrophy (DMD) patients, and little is known regarding the prospects for gene therapy on alleviating DMD-associated cardiomyopathy and respiratory failure. Here we review current knowledge regarding effects of gene therapy on DMD cardiomyopathy and discuss respiratory endpoints that should be considered as outcome measures in future clinical trials.

A 17-Year-Old With Becker Muscular Dystrophy and Unusual Polysomnography Findings.

CASE PRESENTATION: A 17-year-old male patient who was diagnosed with Becker muscular dystrophy (nonsense mutation [c.3822C>A] within exon 28 of the DMD gene) at 6 years of age was evaluated in the multidisciplinary neuromuscular clinic for loss of ambulation for 1 year. From a pulmonary perspective, there were no acute or chronic respiratory symptoms, and no history of pneumonia or aspiration. Clinical examination revealed a nonambulant teenager, with normal oxygen saturation and end-tidal CO2 when awake, no respiratory distress, and symmetrically diminished aeration due to obesity (BMI 40 kg/m2). Results of pulmonary function testing revealed FVC of 83% predicted with actual volume of 3.5 L and peak cough flow of 445 L/min (all within normal limits).