Influence of weaning modes on diaphragmatic remodeling in an animal model of ventilator-induced diaphragmatic dysfunction

机械通气(MV)对呼吸衰竭患者是一种挽救生命的干预措施。当隔膜不活动或仅部分活动时，呼吸支持时间可持续数周。先前涉及动物和人类的研究表明，与MV相关的快速肌肉萎缩。部分激活横隔膜可以减少萎缩，但并不能完全阻止萎缩。据我们所知，所有检查横隔膜激活的研究都没有模仿MV前已经萎缩的横隔膜和/或预先存在的损伤，尽管这在重症监护病房中很常见。因此，拟议的实验将检验脱机模式对经历了12小时机械通气的损伤前或健康的横隔肌再生的影响。两个实验环境将研究健康大鼠或患有肺气肿的大鼠。后一种动物由于几个月的长期阻性呼吸，建立了不同的横隔膜质地。所有动物将被分配到接受MV诱导横隔膜萎缩的实验组，然后直接或逐步地对横隔膜进行重新加载。将对萎缩、肌肉生成和细胞损伤的变化进行调查。由于神经肌肉阻滞剂加剧了MV过程中的病理生理，这些过程将在使用健康动物的实验环境中进行测试。总体结果将提供对断奶模式的有效性的洞察，特别是在考虑到ICU环境中存在额外的共病和潜在的有害药物使用的情况下。

Mechanical ventilation (MV) is a life saving intervention in patients with respiratory failure. Ventilatory support time can last for weeks while the diaphragm is inactive or only partially active. Previous studies involving animals and humans demonstrate the rapid muscle atrophy associated with MV. Partial activation of the diaphragm reduces atrophy but does not prevent it completely. To our knowledge, all studies examining diaphragmatic activation did not mimic an already atrophic diaphragm and/or pre-existent injury prior to MV, although this is common in intensive care units. Therefore, the proposed experiments will examine the influence of weaning modes on the regeneration of a pre-injured or healthy diaphragmatic muscle that underwent 12 h of mechanical ventilation. Two experimental settings will investigate either healthy rats or rats with lung emphysema. Latter animals establish a differing diaphragmatic texture due to long term resistive breathing over several months. All animals will be assigned to experimental groups undergoing MV to induce diaphragmatic atrophy, after which the diaphragm will be reloaded either directly or stepwise. Changes in atrophy, myogenesis and cell damage will be investigated. Due to the fact that neuromuscular blocking agents aggravate the pathohphysiology occurring during MV, these processes will be tested in the experimental setting that uses healthy animals. Overall results will provide insight in the effectiveness of weaning modalities, especially under the consideration of an ICU setting with additional comorbidities and potentially harmful drug use .