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 庞贝病是由酶酸α-缺乏引起的一种遗传性神经肌肉疾病 葡萄糖酶，导致进行性衰变神经病理学。由于可用的酶更换 治疗不会治疗这种神经病理学，隔膜/phrenic神经肌肉功能障碍最终导致 通气功能不全和呼吸机依赖性。因此，呼吸并发症是领先的 庞贝疾病死亡率的原因。隔膜起搏是治疗关键通气的另一种方法 功能不全，通过肌内电极激活Phrenic轴突。来自患者的令人兴奋的初步数据 患有隔膜起搏的庞贝疾病表明，它可能做得不仅取代需求 用于机械通气。它可能对膜片/phrenig活性具有康复作用，从而恢复了一些 独立于任何形式的通风支持。这些初步发现令人鼓舞，但起搏引起 神经肌肉可塑性几乎没有研究。 基本的假设指导了这一建议，即隔膜起搏是一种新颖的康复性 增加膜片/phren型活性的工具，从而提高了独立潮汐的能力 体积产生。这样，隔膜起搏就可以促进庞贝疾病中的呼吸机断奶。我们将 招募患有肌内起搏器植入的庞贝疾病患者以取代 慢性机械通气，然后评估12周超过12周的起搏的康复作用 diaphragm/phrenic神经肌肉活性和独立呼吸能力的恢复。在自发的过程中 呼吸和最大的自愿努力，我们将研究对呼吸功能的起搏影响。此外， 使用隔膜的创新应用人类隔膜EMG活性的直接记录 肌内电极将实现隔膜/phrenic活性的纵向评估。测试我们的中央 假设，我们提出了两个具体目的：1）测试单个隔膜起搏的假设 对膜片/phren型激活和通风具有持久的影响，以及2）检验以下假设： 这些效果在每天重复的，每天的隔膜起搏会话的12周内积累。这个高 风险/高影响力提案将评估隔膜起搏，作为增加膜片/phrenic的康复工具 活动并提高独立的呼吸能力。这项工作将提供第一个受控的经验证据 关注隔膜起搏在庞贝疾病中恢复神经肌肉功能的能力， 并且可能对在其他临床疾病中使用膜片刺激有深远的影响 折衷的呼吸。我们希望本研究生成的数据将构成未来机械的基础 diaphragm膜起搏的研究，以促进神经肌肉疾病中的呼吸机断奶。