Diaphragm and Leg Strength Rehabilitation in Chronically Critically Ill Patients

项目摘要 需要ICU护理14天或更长时间的脓毒症患者最近被定义为慢性危重病 (CCI)患者CCI患者的一个亚组发生持续性炎症/免疫抑制， 癫痫综合征（PICS），并且它们具有病态的长期结局（项目#1）。CCI伴PICS患者 通常会出现严重的膈肌和骨骼肌萎缩和虚弱。PICS患者还表现出 减少肌肉线粒体功能和加速蛋白质分解。PICS中的肌肉功能障碍是 这是由于许多因素，包括肌肉减少症、脓毒症/炎症、蛋白水解、细胞凋亡和不活动。 膈肌无力可延迟患者脱离机械通气，并增加炎症和 医院感染的风险。肢体肌肉无力阻止患者达到功能活动 这是一个里程碑，延迟了他们的康复和恢复正常功能。尽管横膈膜的严重性 在接受机械通气的CCI患者中，对于治疗这种情况的运动策略知之甚少 功能障碍我们对力量训练如何影响炎症的了解也很有限， CCI患者中的免疫抑制和卡他霉素。在项目#4中，我们将进行I/II期随机 在24名接受机械通气的CCI患者中进行长达28天的特定吸气肌力量训练（IMST）试验， 确定他们是否能对先前已证明能改善断奶结果的训练计划做出反应， 慢性通气患者。此外，由于CCI患者也会出现严重的下肢 肌肉无力，对于力量训练的有效性知之甚少，我们建议进行 一项在另外24名通气CCI患者中进行的下肢力量训练的I/II期随机试验， 28天训练后，将从四头肌获得肌肉活检，并在 力量训练组和SHAM组检查线粒体功能障碍，合成代谢和分解代谢的标志物， 活性和凋亡。这两项试验还将评估运动对炎症标志物的影响， 免疫抑制和蛋白质催化剂。 项目#4的主要功能如下： � 确定IMST对治疗和对照CCI患者膈肌强度的影响。 � 确定膝关节伸展强化练习是否会引起肌肉特性的变化，包括 形态学、蛋白质表达和生物能量学。 � 确定膝关节伸展强化训练对CCI患者股四头肌的影响 以及全身炎症、免疫抑制和分解代谢标志物。 这个项目将进一步了解如何治疗CCI相关的肌肉无力与力量训练 不仅可以改善肌肉功能，还可以潜在地减轻炎症，免疫抑制， PICS的目录。

PROJECT ABSTRACT Septic patients requiring 14 or more days of ICU care have been recently defined as chronically critically ill (CCI) patients. A subgroup of CCI patients develops persistent inflammation/immunosuppression and catabolism syndrome (PICS), and they have morbid long-term outcomes (Project #1). CCI patients with PICS often develop severe diaphragm and skeletal muscle atrophy and weakness. PICS patients also demonstrate diminished muscle mitochondrial function and accelerated protein catabolism. Muscle dysfunction in PICS is due to many factors including sarcopenia, sepsis/inflammation, proteolysis, apoptosis, and inactivity. Diaphragm weakness can delay patients' weaning from mechanical ventilation, and increase inflammation and the risk of nosocomial infection. Limb-muscle weakness prevents patients from reaching functional activity milestones, delaying their rehabilitation and return to normal function. Despite the seriousness of diaphragm weakness in CCI patients receiving mechanical ventilation, little is known about exercise strategies to treat this dysfunction. We also have limited knowledge about how strength training impacts inflammation, immunosuppression, and catabolism in CCI patients. In Project #4, we will conduct a Phase I/II randomized trial of specific inspiratory muscle strength training (IMST) for up to 28 days in 24 ventilated CCI patients to determine if they can respond to a training program that has previously shown to improve weaning outcome in chronically ventilated patients. Furthermore, because CCI patients also develop profound lower-extremity muscle weakness, for which little is known about the effectiveness of strength training, we propose to conduct a Phase I/II randomized trial of lower-extremity strength training in an additional 24 ventilated CCI patients for 28 days. Following training, muscle biopsies will be obtained from the quadriceps and contrasted between strength-trained and SHAM groups examining mitochondrial dysfunction, markers of anabolic and catabolic activity, and apoptosis. Both trials will also assess the effect of exercise on markers of inflammation, immunosuppression, and protein catabolism. Project #4's main functions will be the following: � Determine the effects of IMST on diaphragm strength in treated and control CCI patients. � Determine whether knee extension strengthening exercises induce changes in muscle properties including morphology, protein expression, and bioenergetics. � Determine the effects of knee extension strengthening exercises on the quadriceps muscle in CCI patients and on systemic inflammatory, immunosuppressive and catabolic markers. This project will further our understanding of how treating CCI-related muscle weakness with strength training can not only improve muscle function, but also potentially blunt the inflammation, immunosuppression, and catabolism of PICS.