What Are the Implications of Blunted Load Compensation Responses in Prolonged-Weaning Patients?

Sassoon, Catherine S. H.

doi:10.4187/respcare.03001

Cited by 1 publication

(1 citation statement)

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“…The gains in flow and volume LC observed at Day 180 could be especially beneficial when patients must maintain ventilation during periods of increased breathing demands, such as during bronchoconstriction or mucus obstruction. (Sassoon, 2014; Smina et al, 2003) However, flow and volume LC improved only in the subjects with partial or no MV dependence upon enrollment. Since ventilatory independence is typically progressively lost in children maintained with standard doses of ERT,(Nicolino et al, 2009) we interpret these findings to suggest a potential benefit of AAV1-CMV-GAA for some of the subjects.…”

Section: Discussionmentioning

confidence: 96%

Inspiratory muscle conditioning exercise and diaphragm gene therapy in Pompe disease: Clinical evidence of respiratory plasticity

Smith

Martin

Lawson

et al. 2017

Experimental Neurology

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Pompe disease is an inherited disorder due to a mutation in the gene that encodes acid α-glucosidase (GAA). Children with infantile-onset Pompe disease develop progressive hypotonic weakness and cardiopulmonary insufficiency that may eventually require mechanical ventilation (MV). Our team conducted a first in human trial of diaphragmatic gene therapy (AAV1-CMV-GAA) to treat respiratory neural dysfunction in infantile-onset Pompe. Subjects (aged 2-15 years, full-time MV: n=5, partial/no MV: n=4) underwent a period of preoperative inspiratory muscle conditioning exercise. The change in respiratory function after exercise alone was compared to the change in function after intramuscular delivery of AAV1-CMV-GAA to the diaphragm with continued exercise. Since AAV-mediated gene therapy can reach phrenic motoneurons via retrograde transduction, we hypothesized that AAV1-CMV-GAA would improve dynamic respiratory motor function to a greater degree than exercise alone. Dependent measures were maximal inspiratory pressure (MIP), respiratory responses to inspiratory threshold loads (load compensation: LC), and physical evidence of diaphragm activity (descent on MRI, EMG activity). Exercise alone did not change function. After AAV1-CMV-GAA, MIP was unchanged. Flow and volume LC responses increased after dosing (p<0.05 to p<0.005), but only in the subjects with partial/no MV use. Changes in LC tended to occur on or after 180 days. At Day 180, the four subjects with MRI evidence of diaphragm descent had greater maximal voluntary ventilation (p<0.05) and tended to be younger, stronger, and use fewer hours of daily MV. In conclusion, combined AAV1-CMV-GAA and exercise training conferred benefits to dynamic motor function of the diaphragm. Children with a higher baseline neuromuscular function may have greater potential for functional gains.

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Section: Discussionmentioning

confidence: 96%