Diaphragm pacing and rehabilitation in Pompe disease

庞贝病的膈肌起搏和康复

• 批准号: 9225722
• 负责人: Barbara K Smith
• 金额: $ 22.27万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-23 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9225722
• 关键词: Adult; Axon; Blood; Brain; Breathing; Chronic; Clinical; Controlled Clinical Trials; Crossover Design; Data; Dependence; Disease; Electric Stimulation; Electrodes; Electrophysiology (science); Environmental air flow; Enzymes; Etiology; Evaluation; Failure; Foundations; Frequencies; Functional disorder; Future; Generations; Glucan 1,4-alpha-Glucosidase; Glycogen; Glycogen storage disease type II; Goals; Human; Impairment; Implant; Inherited; Intramuscular; Investigation; Measurement; Measures; Mechanical ventilation; Motor; Motor Activity; Muscle; Neuromuscular Diseases; Neuromuscular Junction; Outcome; Pacemakers; Pathology; Patients; Public Health; Quality of life; Recovery; Recovery of Function; Recruitment Activity; Regimen; Rehabilitation therapy; Research; Respiratory Diaphragm; Respiratory Insufficiency; Series; Sleep; Structure of phrenic nerve; Testing; Therapeutic Uses; Tidal Volume; Time; Ventilator; Ventilator Weaning; Work; awake; base; conditioning; design; diaphragm pacing; enzyme deficiency; enzyme replacement therapy; high risk; implantation; improved; innovation; insight; mortality; neuromuscular; neuromuscular activity; neuromuscular function; neuromuscular plasticity; neuropathology; novel; novel therapeutic intervention; patient population; pulmonary function; research study; respiratory; tool

ABSTRACT Pompe disease is an inherited neuromuscular disorder caused by a deficiency of the enzyme acid α- glucosidase, which results in progressive phrenic neuropathology. Since available enzyme replacement therapy does not treat this neuropathology, diaphragm/phrenic neuromuscular dysfunction ultimately leads to ventilatory insufficiency and ventilator dependence. Consequently, respiratory complications are the leading cause of mortality in Pompe disease. Diaphragm pacing is an alternative approach to treat critical ventilatory insufficiency, activating phrenic axons through intramuscular electrodes. Exciting preliminary data from patients with Pompe disease who have undergone diaphragm pacing suggests it may do more than replace the need for mechanical ventilation. It may have a rehabilitative effect on diaphragm/phrenic activity, restoring some independence from ventilatory support of any kind. While these initial findings are encouraging, pacing-induced neuromuscular plasticity has scarcely been studied. The fundamental hypothesis guiding this proposal is that diaphragm pacing is a novel rehabilitative tool to increase diaphragm/phrenic activity, thereby improving the capacity for independent tidal volume generation. In this way, diaphragm pacing may promote ventilator weaning in Pompe disease. We will recruit patients with Pompe disease who have undergone intramuscular pacemaker implantation to replace chronic mechanical ventilation, and then evaluate the rehabilitative effects of pacing over 12 weeks on diaphragm/phrenic neuromuscular activity and recovery of independent breathing ability. During spontaneous breathing and maximal voluntary efforts, we will investigate pacing effects on breathing function. In addition, direct recordings of human diaphragm EMG activity using an innovative application of the diaphragm intramuscular electrodes will enable longitudinal evaluations of diaphragm/phrenic activity. To test our central hypothesis, we propose two specific aims: 1) test the hypothesis that a single bout of diaphragm pacing has lasting effects on diaphragm/phrenic activation and ventilation, and 2) test the hypothesis that these effects accumulate over 12 weeks of repeated, daily diaphragm pacing sessions. This high risk/high impact proposal will evaluate diaphragm pacing as a rehabilitative tool to increase diaphragm/phrenic activity and improve independent breathing ability. This work will provide the first controlled, empirical evidence concerning the ability of diaphragm pacing to rehabilitate phrenic neuromuscular function in Pompe disease, and may have profound implications for the use of diaphragm stimulation in other clinical disorders that compromise breathing. Our hope is that data generated in this study will form the basis for a future mechanistic study of diaphragm pacing to promote ventilator weaning in neuromuscular disease.

抽象的 庞贝病是一种遗传性神经肌肉疾病，由α-酸酶缺乏引起 葡萄糖苷酶，自从可用酶替代品以来，导致进行性膈神经病理学。 治疗不能治疗这种神经病理学，膈肌/膈神经肌肉功能障碍最终导致 经测试，通气不足和呼吸机依赖是导致呼吸系统并发症的主要原因。 膈肌起搏是治疗危重通气的另一种方法。 功能不全，通过肌内电极激活膈轴突来自患者的令人兴奋的初步数据。 患有庞贝病且接受过膈肌起搏的患者表明，它的作用可能不仅仅是替代需求 对于机械通气，它可能对膈肌/膈肌活动有康复作用，恢复一些功能。 虽然这些初步发现令人鼓舞，但起搏引起的。 神经肌肉可塑性几乎没有被研究过。 指导该提议的基本假设是膈肌起搏是一种新颖的康复方法 增加隔膜/膈活动的工具，从而提高独立潮汐的能力 通过这种方式，膈肌起搏可能会促进庞贝病患者的呼吸机脱机。 招募接受肌内起搏器植入术的庞贝病患者来替代 慢性机械通气，然后评估起搏超过 12 周的康复效果 膈肌/膈神经肌肉活动和自主呼吸能力的恢复。 呼吸和最大自主努力，我们将研究起搏对呼吸功能的影响。 使用隔膜的创新应用直接记录人体隔膜肌电图活动 肌内电极将能够纵向评估膈肌/膈肌活动，以测试我们的中枢。 假设，我们提出两个具体目标：1）检验单次膈肌起搏的假设 对膈肌/膈激活和通气有持久影响，并且 2) 检验以下假设： 这些影响在 12 周的每日重复膈肌起搏过程中累积。 风险/高影响提案将评估膈肌起搏作为增强膈肌/膈肌的康复工具 这项工作将提供第一个受控的经验证据。 关于膈肌起搏恢复庞贝病膈神经肌肉功能的能力， 并且可能对膈肌刺激在其他临床疾病中的使用产生深远的影响 我们希望这项研究中产生的数据将为未来的机制奠定基础。 膈肌起搏促进神经肌肉疾病呼吸机脱机的研究。