Diaphragm and Leg Strength Rehabilitation in Chronically Critically Ill Patients

项目摘要 最近，需要14天或更长时间ICU护理的脓毒症患者被定义为慢性危重患者 (CCI)患者。CCI患者的亚组出现持续性炎症/免疫抑制和 分解代谢综合征(PICS)，它们具有病态的长期结果(项目1)。CCI合并PICS患者 经常出现严重的横隔肌和骨骼肌萎缩和无力。PICS患者还展示了 肌肉线粒体功能减弱，蛋白质分解代谢加快。PICS的肌肉功能障碍是 由于许多因素，包括骨质疏松症、脓毒症/炎症、蛋白分解、细胞凋亡和不活跃。 隔膜无力会推迟患者脱离机械通气，并增加炎症和 医院感染的风险。四肢肌肉无力妨碍患者达到功能活动 里程碑，推迟他们的康复和恢复正常功能。尽管横隔膜很严重 接受机械通气的CCI患者的虚弱，对治疗这一问题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也知之甚少， CCI患者的免疫抑制和分解代谢。在项目4中，我们将进行第一阶段/第二阶段随机 24例接受呼吸机治疗的CCI患者进行长达28天的特定吸气肌力训练的试验 确定他们是否可以对先前显示可改善脱机效果的培训计划做出反应 长期使用呼吸机的病人。此外，由于CCI患者还会出现深层次的下肢 肌肉无力，对于力量训练的有效性知之甚少，我们建议进行 一项对另外24名接受机械通气的CCI患者进行下肢力量训练的I/II期随机试验 28天。训练结束后，将从股四头肌获得肌肉活组织检查，并与 力量训练组和假训练组检测线粒体功能障碍、合成代谢和分解代谢的标志物 活性和细胞凋亡。这两项试验还将评估锻炼对炎症标志物的影响， 免疫抑制和蛋白质分解代谢。 项目#4‘S的主要职能如下： �测定了IMST对治疗和对照慢性脑梗塞患者的横隔膜强度的影响。 �确定膝关节伸展强化运动是否会导致肌肉特性的变化，包括 形态、蛋白质表达和生物能量学。 �测定膝关节伸展加强训练对慢性脑梗塞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。 这个项目将进一步加深我们对如何通过力量训练治疗CCI相关性肌肉无力的理解 不仅可以改善肌肉功能，还可以潜在地钝化炎症、免疫抑制和 PICS的分解代谢。

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.