Anatole D. Martin

Pompe disease gene therapy

Pompe disease is an autosomal recessive metabolic myopathy caused by the deficiency of the lysosomal enzyme acid alpha-glucosidase and results in cellular lysosomal and cytoplasmic glycogen accumulation. A wide spectrum of disease exists from hypotonia and severe cardiac hypertrophy in the first few months of life due to severe mutations to a milder form with the onset of symptoms in adulthood. In either condition, the involvement of several systems leads to progressive weakness and disability. In early-onset severe cases, the natural history is characteristically cardiorespiratory failure and death in the first year of life. Since the advent of enzyme replacement therapy (ERT), the clinical outcomes have improved. However, it has become apparent that a new natural history is being defined in which some patients have substantial improvement following ERT, while others develop chronic disability reminiscent of the late-onset disease. In order to improve on the current clinical outcomes in Pompe patients with diminished clinical response to ERT, we sought to address the cause and potential for the treatment of disease manifestations which are not amenable to ERT. In this review, we will focus on the preclinical studies that are relevant to the development of a gene therapy strategy for Pompe disease, and have led to the first clinical trial of recombinant adeno-associated virus-mediated gene-based therapy for Pompe disease. We will cover the preliminary laboratory studies and rationale for a clinical trial, which is based on the treatment of the high rate of respiratory failure in the early-onset patients receiving ERT.

Expiratory Muscle Training Increases Pressure Support in High School Band Students

An experiment to increase expiratory muscle strength for instrumentalists, using a high-intensity, low-repetition expiratory training method, was conducted with 40 healthy high school band players. Subjects trained five days per week for 2 weeks using four sets of six training breaths for a total of 24 training breaths with a spring-loaded pressure relief valve that provided an adjustable threshold. The training valve pressure was set at 75% of the subjects measured maximum expiratory pressure (up to 80 cm H2O). Results demonstrated that high-intensity, low-repetition expiratory exercises significantly increased expiratory pressure generating capacity in these subjects and the degree of the training effect was similar regardless of the instrument the band member played. The training effect occurred within 2 weeks of initiating expiratory muscle training. Thus, this simple method of expiratory-specific strength training is effective and efficient for increasing expiratory pressure support in high school band students and has possibilities of a respiratory support device for many high pressure generating purposes. The potential mechanisms of the training effect are discussed.

Respiratory-related evoked potential elicited in tracheostomised lung transplant patients

The present study investigated the role of removal of upper airway and lung vagal afferents in the respiratory-related evoked potential (RREP) response to inspiratory occlusions in two patients with a tracheostomy, who had undergone double lung transplantation (DLT). The patients were 1.5 and 3 months post-DLT and surgical placement of the tracheostomy. RREP recordings in response to inspiratory occlusions were obtained under four conditions: mouth breathing ignore trial; mouth breathing attend trial; tracheostomy breathing attend trial; and tracheostomy breathing ignore trial. The RREP peak components, Nf, P1 and N1, were present in both mouth and tracheostomy ignore breathing trials. The P300 was present in both mouth and tracheostomy attend trials. RREP peak latencies were similar between conditions. The peak amplitudes were greater with mouth breathing due to greater occlusion-related inspiratory pressure. These results demonstrate that the respiratory-related evoked potential can be elicited with inspiratory occlusion in the absence of mouth, upper airway and lung vagal afferent input. This suggests that inspiratory occlusion can elicit cortical activity with activation of inspiratory pump mechanoreceptors.

Effect of Training on Inspiratory Load Compensation in Weaned and Unweaned Mechanically Ventilated ICU Patients

BACKGROUND: While inspiratory muscle weakness is common in prolonged mechanical ventilation, inspiratory muscle strength training (IMST) can facilitate strengthening and ventilator weaning. However, the inspiratory load compensation (ILC) responses to threshold loads are not well characterized in patients. We retrospectively compared ILC responses according to the clinical outcomes of IMST (ie, maximum inspiratory pressure [PImax], weaning outcome), in difficult-to-wean ICU patients. METHODS: Sixteen tracheostomized subjects (10 weaned, 6 unweaned) from a previous clinical trial underwent IMST 5 days/week, at the highest tolerated load, in conjunction with daily, progressive spontaneous breathing trials. PImax and ILC with a 10 cm H2O load were compared in the subjects before and after IMST. Changes in ILC performance were further characterized (5, 10, 15 cm H2O loads) in the trained subjects who weaned. RESULTS: Demographics, respiratory mechanics, and initial PImax (52 ± 26 cm H2O vs 42 ± 13 cm H2O) did not significantly differ between the groups. Upon enrollment, PImax significantly correlated with flow ILC responses with the 10 cm H2O load (r = 0.64, P = .008). After IMST, PImax significantly increased in the entire sample (P = .03). Both before and after IMST, subjects who weaned generated greater flow and volume ILC than subjects who failed to wean. Additionally, ILC flow, tidal volume, and duty cycle increased upon ventilator weaning, at loads of 5, 10, and 15 cm H2O. CONCLUSIONS: Flow ILC at a threshold load of 10 cm H2O in ventilated, tracheostomized subjects positively correlated with PImax. Although PImax improved in both groups, the flow and volume ILC responses of the weaned subjects were more robust, both before and after IMST. The results suggest that ILC response is different in weaned and unweaned subjects, reflecting dynamic inspiratory muscular efforts that could be influential in weaning.

Respiratory motor function in individuals with centronuclear myopathies.

Introduction: Individuals with X‐linked myotubular myopathy (XLMTM) and other centronuclear myopathies (CNMs) frequently have profound respiratory insufficiency that requires support early in life. Still, few quantitative data exist to characterize respiratory motor function in CNM. Methods: We evaluated the reliance upon mechanical ventilation (MV), ventilatory kinematics, unassisted tidal volumes, and maximal respiratory pressures in 14 individuals with CNMs, including 10 boys with XLMTM. Results: Thirteen participants required full‐time, invasive MV. Maximal inspiratory pressures were higher in subjects who breathed unsupported at least 1 hour/day as compared with 24‐hour MV users [33.7 (11.9–42.3) vs. 8.4 (6.0–10.9) cm H2O, P < 0.05]. Years of MV dependence correlated significantly with MEP (r = −0.715, P < 0.01). Conclusions: Respiratory function in CNMs may be related to deconditioning from prolonged MV and/or differences in residual respiratory muscle strength. Results from this study may assist in evaluating severe respiratory insufficiency in neuromuscular clinical care and research. Muscle Nerve 53: 214–221, 2016

54: CLOSED-LOOP PRESSURE SUPPORT DECISION SUPPORT SYSTEM

Crit Care Med 2016 • Volume 44 • Number 12 (Suppl.) Macrolide therapy was not associated with decreased hospital length of stay, length of ventilation, or hospital costs (p>0.05 for all). Conclusions: Macrolide antibiotic utilization in severe AECOPD was associated with lower readmissions, but not mortality. Prospective investigations are required to determine mechanisms and confirm the clinical impact observed in this study.