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)，尤其是累及颈段和上胸段，可显著损害呼吸肌功能。呼吸系统并发症可能随之而来，包括肺衰竭和肺炎，这是创伤后急性(12个月)和慢性阶段与创伤性脊髓损伤相关的死亡的主要原因。颈髓或上胸段脊髓水平的病变会导致呼吸肌无力，这与无效咳嗽、粘液滞留和粘液堵塞有关。四肢瘫痪患者的剩余呼气压力产生能力被归因于胸大肌的锁骨部分，在咳嗽时这块肌肉的收缩是产生动态呼吸道压缩和排出粘液所必需的。吸气肌功能也可能受损，因为肋间和腹肌瘫痪会改变主要吸气肌--横隔肌的休息形态和肌纤维长度，从而阻碍最大的力量产生，并导致肺活量减少。咳嗽的有效性取决于吸气和呼气肌肉的力量；因此，增加四肢瘫痪和高度截瘫患者吸气和呼气肌肉的压力产生能力可能会转化为改善咳嗽效果，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入而引起的胸腔内压的变化和排气量来计算，并提供了一种确定干预是否减少代谢需求的方法。尽管肺部并发症是这一人群发病率和死亡率的主要原因，但在SC人群中缺乏已知的有效干预措施来改善呼吸肌力量。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(分别为MIP和MEP)有轻微影响，尽管数据尚不确定。药物干预相对较少受到关注。在一项初步研究中，吸入的长效β-2肾上腺素能激动剂沙美特罗在四周的治疗后以双盲、安慰剂对照的交叉设计显示与肺容量的显著增加和表明呼吸肌肉力量改善的最大静态口腔压力有关。我们最近完成了一项使用口服形式的β-2激动剂(每12小时缓释沙丁胺醇4毫克)在四肢瘫痪和高度截瘫(T6及以上损伤)患者中的随访研究，结果显示，与副作用最小的安慰剂相比，MIP有显著改善。这些改善在SCI患者亚组中最为明显，根据MIP的基线测量确定，基线时吸气肌无力最严重，从而确定了可能从干预中获得最大好处的一组个体。因此，我们的主要目标是确定有显著基线呼吸肌无力(基线MIP为90 cmH2O)的四肢瘫痪和高度截瘫患者，并使用随机、双盲、安慰剂对照、平行分组设计，确定沙丁胺醇缓释治疗16周是否改善：(1)吸气和呼气肌力，(2)咳嗽有效性，(3)呼吸功。一个探索性的目标将是确定在停止研究药物两周后，呼吸肌力量的替代测量是否有持续的影响。我们假设，与安慰剂相比，在呼吸肌肉功能中度到严重受损的脊髓损伤患者中，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.