Hemant Sawnani

Implantation of the HeartMate II and HeartWare left ventricular assist devices in patients with duchenne muscular dystrophy: lessons learned from the first applications.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder affecting 1 in 3,500 males, characterized by progressive skeletal muscle weakness and death secondary to cardiac or respiratory failure in the 2nd or 3rd decade. Being a progressive disease, patients are rarely candidates for cardiac transplantation and death from dilated cardiomyopathy (DCM) is common. Implantation of left ventricular assist device (LVAD) offers the potential to alter clinical trajectory by alleviating heart failure symptoms. We report implantation of HeartMate II device in a 29-year-old male patient and HeartWare device in a 23-year-old female patient, each with DMD and end-stage DCM. By improving cardiac output, we were able to achieve resolution of the symptoms of heart failure and improve their quality of life. Preoperative planning and patient selection played a significant role in the postoperative course for these patients. These cases represent the first use for each device in this patient population and the first reported LVAD implantations in patients with DMD in North America.

Growth hormone treatment in boys with Duchenne muscular dystrophy and glucocorticoid-induced growth failure

This study evaluated efficacy and safety of growth hormone treatment in Duchenne muscular dystrophy boys with glucocorticoid-induced growth failure. We reviewed 39 consecutive boys (average age 11.5 years; 32 ambulatory) treated with growth hormone for 1 year during a four-year period. Boys were on long-term daily deflazacort or prednisone (mean duration 5 ± 2.2 years; dosing regimen prednisone 0.75 mg/kg/day equivalent). Primary outcomes were growth velocity and height-for-age z-scores (height SD) at 1 year. Height velocity increased from 1.3 ± 0.2 to 5.2 ± 0.4 cm/year on growth hormone (p<0.0001). Pre-growth hormone decline in height SD (-0.5 ± 0.2SD/year) stabilized at height SD -2.9 ± 0.2 on growth hormone (p<0.0001). The rate of weight gain was unchanged, at 2.8 ± 0.6 kg/year pre-growth hormone and 2.6 ± 0.7 kg/year at 1 year. Motor function decline was similar pre-growth hormone and at 1 year. Cardiopulmonary function was unchanged. Three experienced side effects. In this first comprehensive report of growth hormone in Duchenne muscular dystrophy, growth hormone improved growth at 1 year, without detrimental effects observed on neuromuscular and cardiopulmonary function.

Sleep Disordered Breathing in Young Boys with Duchenne Muscular Dystrophy

OBJECTIVES To describe sleep-disordered breathing (SDB) in young boys with Duchenne muscular dystrophy (DMD) and its relationship with pulmonary function tests (PFTs). STUDY DESIGN This retrospective study examined diagnostic polysomnogram and PFT data of boys younger than 18 years with DMD and treated with steroids. Spirometry, respiratory muscle strength, body mass index (BMI), sleep architecture variables, and indices of SDB were analyzed. We examined the effect of PFT measures on the risk of each type of respiratory event using logistic regression and have reported results as OR (95% CI). RESULTS Subjects included 110 boys with DMD, mean age 11.5 (5.6-17.9) years. Mean (±SD) percent forced vital capacity predicted was 79.5% ± 29.1%. Mean BMI for all subjects was 21.9 ± 7.0 kg/m(2), and mean BMI z-score was 0.65 ± 1.93. Seventy (63.6%) subjects had obstructive sleep apnea; 37 (33.6%) subjects had central sleep apnea; 18 (17%) subjects had hypoventilation. Median (IQR) Apnea Hypopnea Index was 2.9 (1.6-6.9) and median Obstructive Index was 1.5 (0.5-3.8). Obstructive Index during rapid eye movement sleep positively correlated with BMI (r = 0.33, P = .002), BMI z-score (r = 0.22, P = .04), and age (r = 0.31, P = .004). Lower forced vital capacity was associated with increased risk of hypoventilation (OR 0.8, P = .001). CONCLUSION SDB is common in young boys with DMD treated with steroids. It is manifest with rapid eye movement-obstructive sleep apnea, often severe, and strongly influenced by BMI.

Long-Term Outcome of Interdisciplinary Management of Patients with Duchenne Muscular Dystrophy Receiving Daily Glucocorticoid Treatment

Objective To evaluate clinical outcomes and steroid side effects in a cohort of patients with Duchenne muscular dystrophy (DMD) treated with long‐term daily glucocorticoid therapy. Although daily glucocorticoid therapy has been shown to extend ambulatory function in DMD, less frequent dosing is often used because of side effect concerns. Study design Retrospective study of 97 patients with DMD aged 10 to <16 years treated with daily glucocorticoid (89% on deflazacort) for a mean of 8.5 years. Outcome measures were motor, pulmonary, and cardiac function, and scoliosis. Side effects were growth failure and weight gain, facial fullness, blood pressure, bone health, cataracts, gastrointestinal symptoms, behavior, hypertrichosis, and need for medication interventions. Results For 13‐ to 16‐year‐old patients, 40% could rise from the floor and 50% could perform the 30‐foot run test. Forced vital capacity for the entire cohort was well preserved. Thirteen percent of younger (10‐ to <13‐year‐old) and 21% of older patients had findings of left ventricle systolic dysfunction. Six percent (all aged 16 years) developed scoliosis (Cobb angle >20 degrees). Eighty‐six percent had normal weight velocities; 30% had no increased facial fullness; 72% had short stature; and 19% had asymptomatic cataracts. Asymptomatic spine compression deformities were noted in 76% and long bone fractures in 30%. One patient stopped glucocorticoid because of behavioral concerns. Conclusions With evidence for improved outcomes and manageable side effects, we recommend use of daily glucocorticoid therapy for patients with DMD with anticipatory management of side effects and a coordinated interdisciplinary care approach.

Pulmonary Endpoints in Duchenne Muscular Dystrophy. A Workshop Summary

Abstract Development of novel therapeutics for treatment of Duchenne muscular dystrophy (DMD) has led to clinical trials that include pulmonary endpoints that allow assessment of respiratory muscle status, especially in nonambulatory subjects. Parent Project Muscular Dystrophy (PPMD) convened a workshop in Bethesda, Maryland, on April 14 and 15, 2016, to summarize published respiratory data in DMD and give guidance to clinical researchers assessing the effect of interventions on pulmonary outcomes in DMD.

Variable phenotype in a novel mutation in PHOX2B

We evaluated a family with three siblings, two of whom ages 2 years and 19 months, had long segment colonic agangliosis and anisocoria. The mother also had anisocoria. All three affected family members were mildly dysmorphic with a flat facial profile, square appearance to the face, depressed nasal bridge, and anteverted nares. Genetic testing identified a novel heterozygous mutation, c.234C>G, resulting in a premature stop codon in exon 1 of the PHOX2B gene. Screening for neural crest tumors was performed in the siblings and to date has been negative. This family supports a strong association between non polyalanine tract mutations, autonomic dysfunction, and Hirschsprung disease, but suggests mutation outside of the polyalanine tract may not dictate severe phenotype with significant respiratory compromise. A unique finding in this family is the association of congenital heart disease in two of the affected patients. These malformations may be a sporadic isolated finding or the result of environmental factors or a modifying allele. Given the association between congenital heart disease and aberrant neural crest cell development, however, findings are suggestive that congenital heart disease may be a rare feature of PHOX2B mutation which has not been previously reported.

Implementation of Postoperative Respiratory Care for Pediatric Orthopedic Patients

BACKGROUND AND OBJECTIVES: At our institution, one-fifth of pediatric patients undergoing hip and spine surgery require prolonged oxygen supplementation, most likely due to postoperative atelectasis. Using quality improvement methodology, we aimed to implement an innovative postoperative respiratory care algorithm for hip and spine surgery patients, with a global aim of improving respiratory outcomes. METHODS: A multidisciplinary team developed a care algorithm that relied on an activated respiratory therapist (RT) and engagement of patients and families. The algorithm was implemented via multiple rapid tests of change. Process measures representing the beginning and end of the care algorithm were plotted on standard run charts. We evaluated the association of algorithm implementation with a primary outcome of prolonged (>10 hours) oxygen supplementation via a quasi-experimental design using Fisher’s exact and t tests. RESULTS: The team successfully implemented the algorithm, with a reliability to process of 80%. Key interventions included education of RTs, a daily huddle, and implementation of automated orders. Among all hip and spine patients, algorithm implementation was associated with a small, non–statistically significant decrease in prolonged oxygen use (21% to 16%). Among patients with underlying chronic conditions, there was a significant decrease in prolonged oxygen use from 22% to 6% after algorithm implementation (P = .04). CONCLUSIONS: We implemented an innovative respiratory care algorithm in hip and spine surgery patients by empowering RTs and engaging families to participate in care. We found that this approach was associated with decreased prolonged oxygen use in patients with chronic underlying conditions.

The Performance of the Upper Limb scores correlate with pulmonary function test measures and Egen Klassifikation scores in Duchenne muscular dystrophy

The Performance of the Upper Limb scale was developed as an outcome measure specifically for ambulant and non-ambulant patients with Duchenne muscular dystrophy and is implemented in clinical trials needing longitudinal data. The aim of this study is to determine whether this novel tool correlates with functional ability using pulmonary function test, cardiac function test and Egen Klassifikation scale scores as clinical measures. In this cross-sectional study, 43 non-ambulatory Duchenne males from ages 10 to 30 years and on long-term glucocorticoid treatment were enrolled. Cardiac and pulmonary function test results were analyzed to assess cardiopulmonary function, and Egen Klassifikation scores were analyzed to assess functional ability. The Performance of the Upper Limb scores correlated with pulmonary function measures and had inverse correlation with Egen Klassifikation scores. There was no correlation with left ventricular ejection fraction and left ventricular dysfunction. Body mass index and decreased joint range of motion affected total Performance of the Upper Limb scores and should be considered in clinical trial designs.

Influence of gender on pharyngeal airway length in obese adolescents.

Objectives: Although pharyngeal airway length has been implicated in an increased male predisposition for obstructive sleep apnea (OSA) in adults, data in obese children and adolescents are lacking. Our objective was to determine the influence of gender on pharyngeal airway length in obese adolescents, and to apply computational simulations to better understand the effect of pharyngeal airway length on the airways predisposition to collapse in this select group. Methods: Obese subjects without OSA were recruited from our Sleep Center. Their pharyngeal airway length was measured on midline sagittal magnetic resonance images as the distance between the hard palate and the base of the epiglottis. Computational fluid dynamics analysis was used to study the effect of pharyngeal airway length on airflow characteristics. The gender groups were compared for anthropometric measurements and pharyngeal airway length by an unpaired Students t-test. Results: Our study group included 18 female and 16 male obese adolescents with a mean (±SD) age of 14.7 ± 2.3 years and a mean body mass index of 38.9 ± 6.9 kg/m2. The groups did not differ in age, body weight, or normalized pharyngeal airway length (0.44 ± 0.08 mm/cm in girls versus 0.44 ± 0.11 mm/cm in boys; p = 0.9). The computational fluid dynamics simulation indicated that the 3-dimensional flow field and airway wall pressures were not significantly affected by pharyngeal airway lengthening of up to 10 mm. Conclusions: Our results indicate that in obese adolescents, there is no influence of gender on pharyngeal airway length, and pharyngeal airway length alone does not significantly affect the airways predisposition to collapse. These findings suggest that pharyngeal airway length may not explain the increased male gender predisposition for OSA in this select group.

Respiratory Management of the Patient With Duchenne Muscular Dystrophy

Building on the 2018 DMD Care Considerations, we provide detailed guidance on respiratory management of patients with DMD. In 2010, Care Considerations for Duchenne Muscular Dystrophy, sponsored by the Centers for Disease Control and Prevention, was published in Lancet Neurology, and in 2018, these guidelines were updated. Since the publication of the first set of guidelines, survival of individuals with Duchenne muscular dystrophy has increased. With contemporary medical management, survival often extends into the fourth decade of life and beyond. Effective transition of respiratory care from pediatric to adult medicine is vital to optimize patient safety, prognosis, and quality of life. With genetic and other emerging drug therapies in development, standardization of care is necessary to accurately assess treatment effects in clinical trials. This revision of respiratory recommendations preserves a fundamental strength of the original guidelines: namely, reliance on a limited number of respiratory tests to guide patient assessment and management. A progressive therapeutic strategy is presented that includes lung volume recruitment, assisted coughing, and assisted ventilation (initially nocturnally, with the subsequent addition of daytime ventilation for progressive respiratory failure). This revision also stresses the need for serial monitoring of respiratory muscle strength to characterize an individual’s respiratory phenotype of severity as well as provide baseline assessments for clinical trials. Clinical controversies and emerging areas are included.