Daniel W. Sheehan

Oral Corticosteroids and Onset of Cardiomyopathy in Duchenne Muscular Dystrophy

OBJECTIVE To estimate the age when cardiomyopathy develops in boys with Duchenne muscular dystrophy (DMD) and to analyze the effect of corticosteroid treatment on the age of cardiomyopathy onset. STUDY DESIGN We identified a population-based sample of 462 boys with DMD, born between 1982 and 2005, in 5 surveillance sites in the US. Echocardiographic and corticosteroid treatment data were collected. Cardiomyopathy was defined by a reduced fractional shortening (<28%) or ejection fraction (<55%). The age of cardiomyopathy onset was determined. Survival analysis was performed to determine the effects of corticosteroid treatment on cardiomyopathy onset. RESULTS The mean (SD) age of cardiomyopathy onset was 14.3 (4.2) years for the entire population and 15.2 (3.4) years in corticosteroid-treated vs 13.1 (4.8) in non-treated boys. Survival analysis described a significant delay of cardiomyopathy onset for boys treated with corticosteroids (P < .02). By 14.3 years of age, 63% of non-treated boys had developed cardiomyopathy vs only 36% of those treated. Among boys treated with corticosteroids, there is a significant positive effect of duration of corticosteroid treatment on cardiomyopathy onset (P < .0001). For every year of corticosteroid treatment, the probability of developing cardiomyopathy decreased by 4%. CONCLUSIONS Oral corticosteroid treatment was associated with delayed cardiomyopathy onset. The duration of corticosteroid treatment also correlated positively with delayed cardiomyopathy onset. Our analysis suggests that a boy with DMD treated for 5 years with corticosteroids might experience a 20% decrease in the likelihood of developing cardiomyopathy compared with untreated boys.

Effects of hypoxia on energy state and pH in resting pulmonary and femoral arterial smooth muscles

To determine the effects of hypoxia on energy state and intracellular pH (pHi) in resting pulmonary and systemic arterial smooth muscles, we used31P nuclear magnetic resonance spectroscopy and colorimetric and enzymatic assays to measure pHi; intracellular concentrations of ATP, phosphocreatine, creatine, and Pi; and phosphorylation potential in superfused tissue segments from porcine proximal intrapulmonary and superficial femoral arteries. Under baseline conditions ([Formula: see text] 467 ± 12.1 mmHg), energy state and total creatine (phosphocreatine + creatine) concentration were lower and pHi was higher in pulmonary arteries. During hypoxia ([Formula: see text] 23 ± 2.4 mmHg), energy state deteriorated more in femoral arteries than in pulmonary arteries. pHi fell in both tissues but was always more alkaline in pulmonary arteries. Reoxygenation reversed the changes induced by hypoxia. These results suggest that production and/or elimination of ATP and H+ was different in resting pulmonary and systemic arterial smooth muscles under baseline and hypoxic conditions. Because energy state and pHi affect a wide variety of cellular processes, including signal transduction, contractile protein interaction, and activities of ion pumps and channels, further investigation is indicated to determine whether these differences have functional significance.

Respiratory Care Received by Individuals With Duchenne Muscular Dystrophy From 2000 to 2011

BACKGROUND: Duchenne muscular dystrophy (DMD) causes progressive respiratory muscle weakness and decline in function, which can go undetected without monitoring. DMD respiratory care guidelines recommend scheduled respiratory assessments and use of respiratory assist devices. To determine the extent of adherence to these guidelines, we evaluated respiratory assessments and interventions among males with DMD in the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) from 2000 to 2011. METHODS: MD STARnet is a population-based surveillance system that identifies all individuals born during or after 1982 residing in Arizona, Colorado, Georgia, Hawaii, Iowa, and western New York with Duchenne or Becker muscular dystrophy. We analyzed MD STARnet respiratory care data for non-ambulatory adolescent males (12–17 y old) and men (≥18 y old) with DMD, assessing whether: (1) pulmonary function was measured twice yearly; (2) awake and asleep hypoventilation testing was performed at least yearly; (3) home mechanical insufflation-exsufflation, noninvasive ventilation, and tracheostomy/ventilators were prescribed; and (4) pulmonologists provided evaluations. RESULTS: During 2000–2010, no more than 50% of both adolescents and men had their pulmonary function monitored twice yearly in any of the years; 67% or fewer were assessed for awake and sleep hypoventilation yearly. Although the use of mechanical insufflation-exsufflation and noninvasive ventilation is probably increasing, prior use of these devices did not prevent all tracheostomies, and at least 18 of 29 tracheostomies were performed due to acute respiratory illnesses. Fewer than 32% of adolescents and men had pulmonologist evaluations in 2010–2011. CONCLUSIONS: Since the 2004 publication of American Thoracic Society guidelines, there have been few changes in pulmonary clinical practice. Frequencies of respiratory assessments and assist device use among males with DMD were lower than recommended in clinical guidelines. Collaboration of respiratory therapists and pulmonologists with clinicians caring for individuals with DMD should be encouraged to ensure access to the full spectrum of in-patient and out-patient pulmonary interventions.

Local pulmonary blood flow: control and gas exchange.

We studied the local response of the pulmonary vasculature to combined changes in alveolar PO2 and PCO2 in the right apical lobe (RAL) of six conscious sheep. That lobe inspired an O2-CO2-N2 mixture adjusted to produce one of 12 alveolar gas compositions: end-tidal PCO2 (PETCO2) of 40, 50, and 60 Torr, each coupled with end-tidal PO2 (PETO2) of 100, 75, 50, and 25 Torr. In addition, at each of the four PETO2, the inspired CO2 was set to 0 and PETCO2 was allowed to vary as RAL perfusion changed. The remainder of the lung, which served as control (CL) inspired air. Fraction of the total pulmonary blood flow going to the RAL (%QRAL) was obtained by comparing the methane elimination from the RAL to that of the whole lung, and expressed as a percentage of that fraction at PETCO2 = 40, PETO2 = 100. Cardiac output, pulmonary vascular pressures, and CL gas tensions were unaffected or only minimally affected by changes in RAL gas composition. A drop in PO2 from 100 to 50 Torr decreased local blood flow by 60% in normocapnia and by 66% at a PCO2 of 60. At all levels of oxygenation, an increase in PCO2 from 40 to 60 reduced QRAL by nearly 50%. With these stimulus-response data, we developed a model of gas exchange, which takes into account the effects of test segment size on blood flow diversion. This model predicts that: (1) when the ventilation to one compartment of a two compartment lung is progressively decreased, PAO2 remains above 60 Torr for up to 60% reductions in alveolar ventilation, irrespective of compartment size; (2) the decrease in PAO2 that occurs at altitude is accompanied by a drop in PACO2 that limits the decrease in conductance and minimizes the pulmonary hypertension; and (3) as we stand, local blood flow control by the alveolar gas tensions halves the alveolar-arterial PO2 and PCO2 differences imposed by gravity.

Pulmonary hypoxic vasoconstriction: How strong? how fast?☆

We have developed a minimally invasive technique for studying regional blood flow in conscious sheep, bypassing the complications of open-chest surgery, flow probes and tracer infusion. We quantitate regional perfusion continuously on the basis of regional clearance of methane (methane is produced in the sheep rumen, enters the circulation and is eliminated nearly completely (greater than 95%) in the lung). Tracheal intubation with a dual-lumen catheter isolates the gas exchange of the right apical lobe (RAL; less than 15% of the lung) from that of the remainder of the lung, which serves as a control (CL). We measure RAL and CL methane elimination by entraining expirates in constant flows, sampled continuously for methane. Results obtained with this technique and from regional oxygen uptake are in excellent agreement. We have found that hypoxic vasoconstriction is far more potent and stable during eucapnic hypoxia than during hypocapnic hypoxia. The time course of the vasoconstriction suggests that many of the data in the literature may have been obtained prior to steady state.

Pulmonary Circulation and Systemic Circulation: Similar Problems, Different Solutions

Both the systemic and the pulmonary circulations respond to local hypoxia in the appropriate manner, the former by vasodilating, thereby providing more oxygen, and the latter by constricting and rerouting blood flow to areas where more O2 is available. In either case, changes in local conductance affect total conductance, and through that variable, the perfusing pressure; as a result, the effects of local vasomotion should be reduced. In the systemic circulation, arterial pressure can be prevented from falling by two important mechanisms: vasoconstriction of other vascular beds, and an increase in cardiac output. There are no similar means for protecting pulmonary arterial pressure against a rise when vessels in hypoxic areas contract; the only defense is provided by passive expansion of the vascular bed. Thus, in the lung regional circulatory readjustments conflict with the need to maintain a reasonably low pulmonary arterial pressure and local regulation (and maintenance of arterial oxygenation) may be subordinate to prevention of pulmonary hypertension.

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.

Airway clearance techniques in neuromuscular disorders: A state of the art review

This is a unique state of the art review written by a group of 21 international recognized experts in the field that gathered during a meeting organized by the European Neuromuscular Centre (ENMC) in Naarden, March 2017. It systematically reports the entire evidence base for airway clearance techniques (ACTs) in both adults and children with neuromuscular disorders (NMD). We not only report randomised controlled trials, which in other systematic reviews conclude that there is a lack of evidence base to give an opinion, but also include case series and retrospective reviews of practice. For this review, we have classified ACTs as either proximal (cough augmentation) or peripheral (secretion mobilization). The review presents descriptions; standard definitions; the supporting evidence for and limitations of proximal and peripheral ACTs that are used in patients with NMD; as well as providing recommendations for objective measurements of efficacy, specifically for proximal ACTs. This state of the art review also highlights how ACTs may be adapted or modified for specific contexts (e.g. in people with bulbar insufficiency; children and infants) and recommends when and how each technique should be applied.

Sibling concordance for clinical features of Duchenne and Becker muscular dystrophies.

Introduction: The correlation of markers of disease severity among brothers with Duchenne or Becker muscular dystrophy has implications for clinical guidance and clinical trials. Methods: Sibling pairs with Duchenne or Becker muscular dystrophy (n = 60) were compared for ages when they reached clinical milestones of disease progression, including ceased ambulation, scoliosis of ≥ 20°, and development of cardiomyopathy. Results: The median age at which younger brothers reached each milestone, compared with their older brothers ranged from 25 months younger for development of cardiomyopathy to 2 months older for ceased ambulation. For each additional month of ambulation by the older brother, the hazard of ceased ambulation by the younger brother decreased by 4%. Conclusions: The ages when siblings reach clinical milestones of disease vary widely between siblings. However, the time to ceased ambulation for older brothers predicts the time to ceased ambulation for their younger brothers. Muscle Nerve 49: 814–821, 2014

Associations between timing of corticosteroid treatment initiation and clinical outcomes in Duchenne muscular dystrophy

The long-term efficacy of corticosteroid treatment and timing of treatment initiation among Duchenne muscular dystrophy (DMD) patients is not well-understood. We used data from a longitudinal, population-based DMD surveillance program to examine associations between timing of treatment initiation (early childhood [before or at age 5 years], late childhood [after age 5 years], and naïve [not treated]) and five clinical outcomes (age at loss of ambulation; ages at onset of cardiomyopathy, scoliosis, and first fracture; and pulmonary function). Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using survival analysis. DMD patients who initiated corticosteroid treatment in early childhood had a higher risk of earlier onset cardiomyopathy compared to cases who initiated treatment in late childhood (HR = 2.0, 95% CI = [1.2, 3.4]) or treatment naïve patients (HR = 1.9, 95% CI = [1.1, 3.2]), and higher risk of suffering a fracture (HR = 2.3, 95% CI = [1.4, 3.7] and HR = 2.6, 95% CI = [1.6, 4.2], respectively). Patients with early childhood treatment had slightly decreased respiratory function compared with those with late childhood treatment. Ages at loss of ambulation or scoliosis diagnosis did not differ statistically among treatment groups. We caution that the results from our study are subject to several limitations, as they were based on data abstracted from medical records. Further investigations using improved reporting of disease onset and outcomes are warranted to obtain a more definitive assessment of the association between the timing of corticosteroid treatment and disease severity.