Richard M. Kravitz

Efficacy of aerosolized tobramycin in patients with cystic fibrosis.

BACKGROUND Direct aerosol delivery of aminoglycosides such as tobramycin to the lower airways of patients with cystic fibrosis may control infection with Pseudomonas aeruginosa and improve pulmonary function, with low systemic toxicity. We conducted a randomized crossover study to evaluate the safety and efficacy of aerosolized tobramycin in patients with cystic fibrosis and P. aeruginosa infections. METHODS Seventy-one patients with stable pulmonary status were recruited from seven U.S. centers for the treatment of cystic fibrosis and randomly assigned to one of two crossover regimens. Group 1 received 600 mg of aerosolized tobramycin for 28 days, followed by half-strength physiologic saline (placebo) for two 28-day period. Group 2 received placebo for 28 days, followed by tobramycin for two 28-day periods. Pulmonary function, the density of P. aeruginosa in sputum, ototoxicity, nephrotoxicity, and the emergence of tobramycin-resistant P. aeruginosa were monitored. RESULTS In the first 28-day period, treatment with tobramycin was associated with an increase in the percentage of the value predicted for forced expiratory volume in one second (9.7 percentage points higher than the value for placebo; P < 0.001), forced vital capacity (6.2 percentage points higher than the value for placebo; P = 0.014), and forced expiratory flow at the midportion of the vital capacity (13.0 percentage points higher than the value for placebo; P < 0.001). A decrease in the density of P. aeruginosa in sputum by a factor of 100 (P < 0.001) was found during all periods of tobramycin administration. Neither ototoxicity nor nephrotoxicity was detected. The frequency of the emergence of tobramycin-resistant bacteria was similar during both tobramycin and placebo administration. CONCLUSIONS The short-term aerosol administration of a high dose of tobramycin in patients with clinically stable cystic fibrosis is an efficacious and safe treatment for endobronchial infection with P. aeruginosa.

Pompe disease diagnosis and management guideline

Disclaimer: ACMG standards and guidelines are designed primarily as an educational resource for physicians and other health care providers to help them provide quality medical genetic services. Adherence to these standards and guidelines does not necessarily ensure a successful medical outcome. These standards and guidelines should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the geneticist should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. It may be prudent, however, to document in the patient’s record the rationale for any significant deviation from these standards and guidelines.

Congenital malformations of the lung.

Congenital malformations of the lung are a frequent cause of abnormal chest radiographs in neonates and young children as well as a common cause for recurrent pneumonia in older patients. Based on the mode of presentation and clinical findings along with an understanding of lung embryology, one can develop a thorough differential diagnosis that allows for the evaluation of the lesion in question. Appropriate management of the patient can then be undertaken with a minimum of diagnostic studies and without any delay in treatment.

The respiratory management of patients with duchenne muscular dystrophy: a DMD care considerations working group specialty article.

In 2001, the Muscular Dystrophy Community Assistance, Research and Education Amendments (MD‐CARE Act) was enacted, which directed federal agencies to coordinate the development of treatments and cures for muscular dystrophy. As part of the mandate, the Centers for Disease Control and Prevention (CDC) initiated surveillance and educational activities, which included supporting development of care considerations for Duchenne muscular dystrophy (DMD) utilizing the RAND/UCLA Appropriateness Method (RAM). This document represents the consensus recommendations of the projects 10‐member Respiratory Panel and includes advice on necessary equipment, procedures and diagnostics; and a structured approach to the assessment and management of the respiratory complications of DMD via assessment of symptoms of hypoventilation and identification of specific thresholds of forced vital capacity, peak cough flow and maximum expiratory pressure. The document includes a set of Figures adaptable as “pocket guides” to aid clinicians. This article is an expansion of the respiratory component of the multi‐specialty article originally appearing in Lancet Neurology, comprising respiratory recommendations from the CDC Care Considerations project. Pediatr. Pulmonol. 2010; 45:739–748.

Electrocardiographic response to enzyme replacement therapy for Pompe disease

Purpose: Electrocardiogram (ECG) abnormalities are universal in infantile Pompe disease or glycogen storage disease type II, a fatal genetic muscle disorder caused by deficiency of acid α-glucosidase (GAA). Hallmarks of this disease include a shortened PR interval, an increased QT dispersion (QTd), and large left ventricular (LV) voltages. We evaluated the effect of recombinant human GAA (rhGAA) enzyme replacement therapy (ERT) on these ECG parameters in patients with infantile-onset Pompe disease.Methods: A total of 134 ECGs were evaluated from 19 patients (5 females and 14 males) with a median age of 5.5 months at the time of enrollment in open-label clinical trials exploring the safety and efficacy of ERT at a single center from 1999 to 2004. rhGAA was purified from genetically engineered Chinese hamster ovary cells overproducing GAA and infused intravenously at doses ranging from 10 mg/kg per week to 20 to 40 mg/kg every 2 weeks in patients with infantile-onset Pompe disease. The PR interval, QTd (longest to shortest QT), and LV voltage (SV1+RV6) were blindly determined by two independent observers.Results: The median follow-up period was 6 months (range 2–30 months). The PR interval lengthened from 83 (42–110) ms to 107 (95–130) ms (P < .001), and the QTd decreased from 83 (40–125) ms to 53 (20–80) ms (P = .003). There were significant decreases in LV voltage (67 [17–83] mV vs. 48 [18–77] mV, P = .03), which correlated with decrease in LV mass on two-dimensional echocardiogram. There was no evident change in the QTc interval (429 [390–480] ms vs. 413 [370–450] ms, P = not significant).Conclusion: rhGAA ERT for infantile Pompe disease results in an increase in PR interval and a decrease in both the QTd and the LV voltage. These results suggest that these ECG parameters may be useful markers of the severity of cardiac disease and the response to ERT treatment in patients with infantile Pompe disease.

EUR-1008 pancreatic enzyme replacement is safe and effective in patients with cystic fibrosis and pancreatic insufficiency

BACKGROUND EUR-1008 (Zenpep [pancrelipase]) is a new, enteric-coated, porcine-derived pancreatic enzyme product (PEP) developed for the treatment of cystic fibrosis (CF) patients with malabsorption associated with exocrine pancreatic insufficiency (EPI). Unlike currently marketed PEPs, EUR-1008 contains the label-claimed lipase content. Safety and efficacy were assessed in younger (<7 years) and older (> or =7 years) CF patients with EPI. METHODS Two multicenter studies were conducted: a randomized, double-blind, placebo-controlled, crossover trial in patients > or =7 years of age (N=34) and a supplemental, open-label study in children <7 years of age (N=19). Use of any medications altering gastric pH/motility was prohibited during the studies. Outcome measures in the randomized trial included changes in the coefficient of fat absorption (CFA), coefficient of nitrogen absorption (CNA), and signs/symptoms of malabsorption for EUR-1008 vs. placebo. Outcome measures in the supplemental study included safety and response (defined as no steatorrhea and no overt signs/symptoms of malabsorption) to EUR-1008 vs. previous enzyme treatment. RESULTS In the randomized trial, EUR-1008 treatment compared to placebo resulted in a significantly higher mean CFA (88.3% vs. 62.8%, respectively) and CNA (87.2% vs. 65.7%, respectively) (both p<0.001) and reduced the incidence of malabsorption signs and symptoms in 32 evaluable patients. In the supplemental study, 11 of 19 patients met the criteria for responder with EUR-1008 at the end of the study vs. 10 of 19 patients at screening (previous PEP), and improvements in clinical symptoms were reported with EUR-1008 treatment. EUR-1008 was safe and well tolerated, and no serious drug-related AEs were reported in either study. CONCLUSIONS EUR-1008 was safe, well tolerated, and effective in CF patients of all ages with EPI-associated malabsorption in two clinical trials. Treatment led to clinically and statistically significant improvements in CFA and CNA in the randomized study, and control of malabsorption and clinical symptoms in both studies.

Physician-targeted program on inhaled therapy for childhood asthma ☆ ☆☆ ★

BACKGROUND Inhaled medications are the mainstay of asthma therapy, but significant deficiencies exist in the knowledge and skills of physicians regarding use of metered-dose inhalers (MDI) and spacer devices. OBJECTIVE We developed, implemented, and evaluated the effects of a physician-targeted educational program on inhaled therapy in a group of pediatric residents in our institution. METHODS Patient-directed instruction sheets on aerosol therapy were developed on the basis of literature review and expert guidelines. These served to establish a consistent foundation for the educational curriculum. The program was delivered through one-on-two teaching sessions (45 minutes). Residents were provided with a summary of theoretical and practical information and with devices for practice (a placebo MDI, InspirEase and AeroChamber holding chambers, and the AeroChamber device with mask). Each session included review of an educational monograph, demonstration of proper technique, and practice with the different devices. The program was evaluated by a randomized-control design. Assessment of practical skills included number of correct steps for the use of MDI (maximum score, 7), InspirEase (maximum, 7) and AeroChamber (maximum, 6). Theoretical knowledge was assessed with 25 multiple-choice questions. RESULTS Pretest scores in the experimental group (n = 24) were 3.7 of 7, 1.9 of 7, and 0.3 of 6 steps correct for MDI, InspirEase, and AeroChamber devices, respectively, and 13 of 25 for the theoretical knowledge assessment. The control group (n = 26) had similar pretest scores. After the program the experimental group significantly improved in all parameters: 6.3 of 7, 5.9 of 7, and 4.5 of 6 steps correct for MDI, InspirEase, and AeroChamber devices, respectively, and 18 of 25 questions correct (p < 0.01 for all parameters). CONCLUSIONS Implementation of a simple educational program among pediatric residents can significantly increase their skills in the use of inhalational therapy.

Bronchiectasis in Children

Bronchiectasis (BR) is a descriptive term for abnormal, irreversibly dilated, and often thick walled bronchi, usually associated with inflammation. Causes are varied but include cystic fibrosis, aspiration, post infectious airway obstruction, immune abnormalities, immotile cilia, posttransplantation states, and congenital bronchial lesions. Although BR is uncommon in children, it causes significant mortality when present. Following a period of presumed decline due to antibiotics and vaccines, BR may increase in prevalence because of AIDS, organ transplantation complications, and changing patterns of childhood immunization. As with adults, high resolution CT (HRCT) is the most useful imaging tool for diagnosis and evaluation of bronchiectasis in children.

Airway Clearance in Duchenne Muscular Dystrophy

This is a summary of the presentation on airway clearance in neuromuscular disorders presented as part of the program on airway clearance in Duchenne muscular dystrophy at the 30th annual Carrell-Krusen Neuromuscular Symposium on February 20, 2008.

An Official American Thoracic Society Clinical Practice Guideline: Pediatric Chronic Home Invasive Ventilation.

BACKGROUND Children with chronic invasive ventilator dependence living at home are a diverse group of children with special health care needs. Medical oversight, equipment management, and community resources vary widely. There are no clinical practice guidelines available to health care professionals for the safe hospital discharge and home management of these complex children. PURPOSE To develop evidence-based clinical practice guidelines for the hospital discharge and home/community management of children requiring chronic invasive ventilation. METHODS The Pediatric Assembly of the American Thoracic Society assembled an interdisciplinary workgroup with expertise in the care of children requiring chronic invasive ventilation. The experts developed four questions of clinical importance and used an evidence-based strategy to identify relevant medical evidence. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to formulate and grade recommendations. RESULTS Clinical practice recommendations for the management of children with chronic ventilator dependence at home are provided, and the evidence supporting each recommendation is discussed. CONCLUSIONS Collaborative generalist and subspecialist comanagement is the Medical Home model most likely to be successful for the care of children requiring chronic invasive ventilation. Standardized hospital discharge criteria are suggested. An awake, trained caregiver should be present at all times, and at least two family caregivers should be trained specifically for the childs care. Standardized equipment for monitoring, emergency preparedness, and airway clearance are outlined. The recommendations presented are based on the current evidence and expert opinion and will require an update as new evidence and/or technologies become available.