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; 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），尤其是涉及宫颈和上胸部片段的脊髓损伤，可能会严重损害呼吸肌功能。可能随后发生呼吸并发症，包括肺塌陷和肺炎，这是急性（<12个月）和受伤后慢性阶段的创伤性SCI死亡的主要原因。宫颈或高胸脊髓水平的病变会导致呼吸肌无力，这与无效的咳嗽，粘液保留和粘液塞有关。四肢瘫痪者的残留到期压力产生能力归因于胸大肌主要肌肉的锁骨部分，在产生动态气道压缩和粘液驱动所必需的咳嗽过程中，这种肌肉的收缩。吸气性肌肉功能也可能受到损害，因为肋间和腹部肌肉的瘫痪可以咳嗽的效率取决于灵感和呼气性肌肉力量。因此，增加四脑和截瘫患者的灵感和呼气肌肉的压力产生能力可能会转化为提高咳嗽的有效性，并降低了对amateracis以及可能是肺炎的诺言。呼吸的工作可以通过测量因灵感引起的胸内压力的变化以及流离失所的气体来计算，并提供了一种方法来确定干预措施是否减少了代谢需求。尽管事实是肺部并发症是该人群发病率和死亡率的主要原因，但在已知可以改善呼吸肌强度的SC人群中，有效的干预措施很少。呼吸道肌肉训练通常使用简单的手持便携式电阻或阈值训练设备，似乎对生命力和最大静态嘴灵感和到期压力（MIP和MEP）具有边缘影响，尽管数据尚无定论。药理干预措施相对较少关注。在一项初步研究中，遗传性的长效β-2肾上腺激动剂Salmeterol在经过四个星期的治疗后，以双盲，安慰剂对照的跨界设计显示，与肺部体积的显着增加和最大的静态静态肌肉压力相关。我们最近使用β-2激动剂的口服形式（每12小时持续释放的紫proer 4mg）对四链磷酸根和高副瘫痪（损伤T6及以上）进行了一项随访研究，与安慰剂相比，MIP与安慰剂相比有了显着改善。这些改进是基线肌肉弱点的SCI患者亚组中的最大证据，这是通过MIP的基线测量确定的，从而确定了一部分，这些个体有可能从干预措施中获得最大的好处。因此，我们的主要目的是确定四脑血统和高瘫痪的人具有明显的基线呼吸道肌肉无力（基线MIP的MIP <90 cmh2O），并使用随机，双盲，安慰剂对照，平行的组设计，是否可以持续释放效果，并提高了效率的效率（1（1）2（1）（1）（1）（1），（1）呼吸。探索性的目的是确定在停止研究药物后两周对呼吸道肌肉力量的替代措施是否持续影响。我们假设16周的口服β-2激动剂在具有适度且严重损害的呼吸肌功能的SCI中使用，将导致灵感和到期肌肉力量的显着改善，以及与安慰剂相比的咳嗽效果和呼吸效果的改善。