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

 描述（由申请人提供）： 脊髓损伤（SCI），特别是涉及颈段和上胸段，可显著损害呼吸肌功能。呼吸系统并发症可能随之而来，包括肺萎陷和肺炎，这是与创伤性SCI相关的急性（< 12个月）和慢性期损伤后死亡的主要原因。颈髓或高位胸髓水平的病变导致呼吸肌无力，这与无效咳嗽、粘液潴留和粘液堵塞有关。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对于产生动态气道压缩和粘液排出是必要的。吸气肌功能也可能受损，因为肋间肌和腹肌的麻痹可以改变膈肌（吸气的主要肌肉）的静息构型和肌纤维长度，从而阻碍最大力的产生并导致肺活量的降低。咳嗽的有效性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吸气和呼气肌肉的压力产生能力可能会改善咳嗽的有效性，减少肺不张和可能的肺炎的倾向。呼吸功可以通过测量由于吸气引起的胸内压变化和排出的气体体积来计算，并提供了一种确定干预是否减少代谢需求的方法。尽管肺部并发症是该人群发病率和死亡率的主要原因，但在SC人群中缺乏已知可改善呼吸肌力量的有效干预措施。呼吸肌训练，通常使用简单的手持便携式阻力或阈值训练设备，似乎对肺活量和最大静态口腔吸气和呼气压力（MIP和MEP，分别）有边际效应，尽管数据是不确定的。药物干预相对较少受到关注。在一项初步研究中，在一项双盲、安慰剂对照交叉设计中，吸入长效β-2肾上腺素能激动剂沙美特罗治疗4周后与肺容量和最大静态口腔压力显著增加相关，提示呼吸肌力量改善。我们最近完成了一项随访研究，在四肢瘫痪和高位截瘫（损伤T6及以上）患者中使用口服形式的β-2激动剂（缓释沙丁胺醇4 mg，每12小时一次），与安慰剂相比，MIP显着改善，副作用最小。根据MIP的基线测量结果，在基线时具有最严重吸气肌无力的SCI患者亚组中，改善最为明显，从而确定了一个可能从干预中获得最大益处的个体亚组。因此，我们的主要目的是确定有明显基线呼吸肌无力的四肢瘫和高位截瘫患者（基线MIP < 90 cmH 2 O），并通过使用随机、双盲、安慰剂对照、平行组设计确定用缓释沙丁胺醇治疗16周是否改善：（1）吸气和呼气肌肉强度，（2）咳嗽有效性，和（3）呼吸功。探索性目的是确定研究药物停药后两周是否对呼吸肌强度的替代指标存在持续影响。我们假设，与安慰剂相比，中度至重度呼吸肌功能受损的SCI患者口服β-2激动剂16周将导致吸气和呼气肌力的显著改善，以及咳嗽有效性的改善和呼吸功的减少。

 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.