Diaphragm pacing and rehabilitation in Pompe disease

摘要 庞贝病是一种遗传性神经肌肉疾病，由酸性α酶缺乏引起。 葡萄糖苷酶，导致进行性膈神经病变。因为有可用的酶替代品 治疗不能治疗这种神经病理，隔膜/膈神经肌肉功能障碍最终导致 呼吸机功能不全和呼吸机依赖。因此，呼吸道并发症是主要的 庞培病的死亡原因。隔膜起搏是治疗危重呼吸机的一种替代方法 功能不全，通过肌肉内电极激活膈神经轴突。来自患者的令人兴奋的初步数据 接受过隔膜起搏的庞贝病患者建议，它可能不仅仅取代了需要 用于机械通风。它可能对隔膜/膈活动有康复作用，恢复一些 独立于任何种类的通风支撑。虽然这些初步发现令人鼓舞，但起搏诱导的 神经肌肉可塑性几乎没有被研究过。 指导这一提议的基本假设是，隔膜起搏是一种新的康复方法 增加横隔膜/膈活动的工具，从而提高独立潮汐的能力 卷生成。这样，隔膜起搏可能会促进庞贝病患者的呼吸机脱机。我们会 招募植入肌内起搏器的庞贝病患者接替 慢性机械通气，然后评估起搏超过12周的康复效果。 隔膜/膈神经肌肉活动和独立呼吸能力的恢复。在自发过程中 呼吸和最大的自愿努力，我们将调查起搏对呼吸功能的影响。此外, 使用创新的横隔膜应用直接记录人体横隔膜肌电活动 肌内电极将能够纵向评估横隔膜/膈的活动。为了测试我们的中央 假设，我们提出了两个具体的目标：1)检验假设，即单次膈肌起搏 对隔膜/膈肌的激活和通风有持久的影响，以及2)检验假设 这些效应累积在每日重复的隔膜起搏治疗的12周内。这么高 风险/高影响提案将评估隔膜起搏作为增加横隔膜/膈肌的康复工具 活动，提高自主呼吸能力。这项工作将提供第一个可控的经验证据 关于隔膜起搏恢复庞贝病患者膈神经肌肉功能的能力， 并可能对隔膜刺激在其他临床疾病中的使用具有深远的意义 妥协呼吸。我们希望，这项研究中产生的数据将为未来的机械论奠定基础 隔肌起搏促进神经肌肉疾病呼吸机撤机的研究。

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.