The Effect of an Oral Beta-2 Agonist on Respiratory Muscle Strength in SCI

口服 Beta-2 激动剂对 SCI 呼吸肌力量的影响

• 批准号: 9132626
• 负责人: Gregory J. Schilero
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9132626
• 关键词: Abdominal Muscles; Acute; Adrenergic Agonists; Adverse effects; Agonist; Albuterol; Atelectasis; Attention; Breathing; Cervical; Chest; Chronic Phase; Coughing; Crossover Design; Data; Devices; Dose; Double-Blind Method; Effectiveness; Environmental air flow; Gases; Generations; Hand; Hour; Individual; Injury; Inspiratory Capacity; Intercostal Muscles; Intervention; Lead; Length; Lesion; Lung; Measurement; Measures; Metabolic; Morbidity - disease rate; Mucous body substance; Multicenter Trials; Muscle; Muscle Contraction; Muscle Fibers; Muscle Weakness; Muscle function; Oral; Oral Administration; Oral cavity; Paralysed; Paraplegia; Patients; Persons; Pharmaceutical Preparations; Placebo Control; Placebos; Pneumonia; Population; Property; Quadriplegia; Randomized; Research Design; Residual state; Resistance; Respiratory Diaphragm; Respiratory Muscles; Rest; Salmeterol; Spinal cord injury; Spinal cord injury patients; Subgroup; Testing; Thick; Thoracic spinal cord structure; Training; Translating; Ultrasonography; Vital capacity; Work; Work of Breathing; clinical application; design; discontinuation study; effective intervention; follow-up; improved; indexing; lung volume; mortality; muscle strength; pectoralis major muscle; pressure; public health relevance; pulmonary function; respiratory; thoracic pressure

 DESCRIPTION (provided by applicant): Spinal cord injury (SCI), especially involving the cervical and upper thoracic segments, can significantly compromise respiratory muscle function. Respiratory complications can ensue, including lung collapse and pneumonia, which are the primary cause for mortality in association with traumatic SCI both during the acute (< 12 months) and chronic phases post-injury. Lesions at the level of the cervical or high thoracic spinal cord result in respiratory muscle weakness, which is associated with ineffective cough, mucus retention, and mucus plugging. Residual expiratory pressure-generating capacity in persons with tetraplegia has been attributed to the clavicular portion of the pectoralis major muscle, with contraction of this muscle during cough necessary for generation of dynamic airway compression and expulsion of mucus. Inspiratory muscle function may also be compromised, as paralysis of intercostal and abdominal muscles can change the resting configuration and muscle fiber length of the diaphragm, the major muscle of inspiration, thereby impeding maximal force generation and contributing to reduction in vital capacity. Cough effectiveness is contingent upon both inspiratory and expiratory muscle strength; increasing the pressure-generating capacity of the inspiratory and expiratory muscles in persons with tetraplegia and high paraplegia may, therefore, translate to improved cough effectiveness and reduction in the propensity for atelectasis and, possibly, pneumonia. The work of breathing can be calculated by measuring change in intra-thoracic pressure due to inspiration, and the volume of gas displaced, and provides a way to determine if interventions reduce metabolic demand. Despite the fact that pulmonary complications are a major cause of morbidity and mortality in this population, there is a paucity of effective interventions in the SC population known to improve respiratory muscle strength. Respiratory muscle training, often utilizing simple hand-held portable resistive or threshold training devices, appears to have marginal effects on vital capacity and maximal static mouth inspiratory and expiratory pressures (MIP and MEP, respectively), although data is inconclusive. Pharmacologic intervention has comparatively received little attention. In a preliminary study, the inhaled long-acting beta-2 adrenergic agonist, salmeterol, was shown in a double-blind, placebo-controlled crossover design after four weeks of treatment to be associated with significant increases in lung volumes and maximal static mouth pressures suggestive of improvement in respiratory muscle strength. We recently completed a follow-up study using an oral form of a beta-2 agonist (sustained-release albuterol 4mg every 12 hours) in persons with tetraplegia and high paraplegia (injury T6 and above), that demonstrated significant improvement in MIP compared to placebo with minimal side effects. The improvements were most evident in the subgroup of SCI patients with the most profound inspiratory muscle weakness at baseline, as determined by baseline measurement of MIP, thereby identifying a subset of individuals who stand to potentially derive the greatest benefit from the intervention. Therefore, our primary aim is to identify persons with tetraplegia and high paraplegia who have significant baseline respiratory muscle weakness (baseline MIP of < 90 cmH2O) and by use of a randomized, double- blind, placebo-controlled, parallel group design determine if 16 weeks of treatment with sustained release albuterol improves: (1) inspiratory and expiratory muscle strength, (2) cough effectiveness, and (3) work of breathing. An exploratory aim will be to determine if there are sustained effects upon surrogate measures of respiratory muscle strength two weeks after discontinuation of study drug. We hypothesize that 16 weeks of oral beta-2 agonist use in SCI individuals with moderately to severely compromised respiratory muscle function will lead to a significant improvement in both inspiratory and expiratory muscle strength, as well as an improvement in cough effectiveness and decreased work of breathing compared to placebo.

 描述（由申请人提供）： 脊髓损伤 (SCI)，特别是累及颈段和上胸段的损伤，可显着损害呼吸肌功能，随之而来的是呼吸系统并发症，包括肺萎陷和肺炎，这是急性期与创伤性 SCI 相关的死亡的主要原因。损伤后（< 12 个月）和慢性期 颈段或高胸段脊髓损伤导致呼吸肌无力，这与无效咳嗽、粘液潴留和粘液有关。四肢瘫痪患者的残余呼气压力产生能力归因于胸大肌的锁骨部分，咳嗽期间该肌肉的收缩是产生动态气道压缩和排出粘液所必需的。受到损害，因为肋间肌和腹部肌肉的麻痹会改变膈肌（吸气的主要肌肉）的静息形态和肌纤维长度，从而阻碍最大力量的产生并有助于减少咳嗽效果取决于吸气和呼气肌肉的力量；因此，增加四肢瘫痪和高位截瘫患者的吸气和呼气肌肉的压力产生能力可能会改善咳嗽效果并减少咳嗽的倾向。肺不张，可能还有肺炎，可以通过测量吸气引起的胸腔内压力的变化和排出的气体量来计算呼吸功，并提供一种确定干预措施是否会减少代谢的方法。尽管肺部并发症是该人群发病和死亡的一个主要原因，但在 SC 人群中缺乏已知的可改善呼吸肌力量的有效干预措施，通常使用简单的手持式便携式阻力训练。或阈值训练装置，尽管对肺活量和最大静态口吸气和呼气压力（分别为 MIP 和 MEP）有边际影响，但在初步研究中，药物干预的数据相对较少受到关注。吸入长效 β2 肾上腺素能激动剂沙美特罗在双盲、安慰剂对照交叉设计中显示，治疗 4 周后与肺容量和最大静态口腔压力显着增加相关，提示呼吸系统改善我们最近完成了一项针对四肢瘫痪和高位患者口服 β-2 激动剂（每 12 小时缓释沙丁胺醇 4 毫克）的后续研究。截瘫（损伤 T6 及以上），与安慰剂相比，MIP 显着改善，副作用最小，在基线时吸气肌无力最严重的 SCI 患者亚组中最为明显，这是通过 MIP 基线测量确定的。 ，从而确定可能从干预中获得最大收益的个体子集，因此，我们的主要目标是确定基线呼吸肌无力（基线 MIP < ）的四肢瘫痪和高位截瘫患者。 90 cmH2O）并通过使用随机、双盲、安慰剂对照、平行组设计确定缓释沙丁胺醇治疗 16 周是否改善：（1）吸气和呼气肌力，（2）咳嗽有效性，以及（ 3) 呼吸功。一个探索性的目标是确定停止研究药物两周后呼吸肌力量的替代指标是否有持续影响。我们记录了 16 周的口服药物。与安慰剂相比，呼吸肌功能中度至重度受损的 SCI 个体使用 β-2 激动剂将显着改善吸气和呼气肌力，并改善咳嗽效果并减少呼吸功。