Muscle and physical function recovery after acute critical illness

急性危重病后肌肉和身体机能的恢复

• 批准号: 10584022
• 负责人: Esther E Dupont-Versteegden
• 金额: $ 45.04万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-18 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584022
• 关键词: Acceleration; Acute; Acute Lung Injury; Acute Respiratory Distress Syndrome; Acute respiratory failure; Adult; Age; Area; Attention; Automobile Driving; Awareness; Biopsy; COVID-19; Cells; Characteristics; Clinical; Collagen; Communities; Critical Illness; Data; Deposition; Deuterium Oxide; Development; Disabled Persons; Disparate; Environment; Equilibrium; Etiology; Extracellular Matrix; Fatigue; Fibrosis; Functional disorder; Future; Goals; Growth; Hospitalization; Hospitals; Immune; Immune response; Impairment; Inflammation; Inflammatory; Influenza; Intensive Care Units; Intervention; Knowledge; Label; Mass Spectrum Analysis; Measurement; Measures; Metabolic; Mission; Mitochondria; Muscle; Muscle Fibers; Muscle Weakness; Muscle function; Muscle satellite cell; National Institute of Arthritis, and Musculoskeletal, and Skin Diseases; Observational Study; Outcome; Patients; Pattern; Pharmacological Treatment; Phenotype; Physical Function; Pneumonia; Proteins; Quality of life; Recovery; Recovery of Function; Rehabilitation therapy; Research; Research Project Grants; Respiration; Sepsis; Severity of illness; Signal Pathway; Skeletal Muscle; Survivors; Therapeutic Intervention; Time; Tissue Sample; Tissues; United States; Work; comorbidity; disability; evidence base; improved; interest; muscle strength; nutrition; participant enrollment; patient subsets; pharmacologic; physically handicapped; predictive modeling; protein biomarkers; protein degradation; proteostasis; response; sepsis induced ARDS; skeletal muscle wasting; stable isotope; therapeutic development; therapy development

Many patients who survive critical illness, including sepsis and acute respiratory failure, have arduous recoveries plagued by an inability to recover muscle and physical function after hospital discharge, resulting in lower quality of life, inability to return to work and disability. The number of patients surviving critical illnesses in the United States continues to rise each year and therefore it is critically important to develop interventions that will support their recovery. Clinical and muscle cellular factors driving skeletal muscle dysfunction are relatively unknown after an acute critical illness, but are necessary to inform intervention development. We will address this knowledge gap by studying myofibrillar and collagen protein turnover, cellular signaling pathways, and markers of damage, inflammation and immune response in the first year of recovery. The unique aspect of this proposal is the serial, intra-patient muscle tissue sampling paired with simultaneously obtained clinical functional parameters over the first year of recovery post hospital discharge. Physical function and quality of life outcomes will be assessed to understand why some patients recover muscle function, yet others develop severe disability. The overall goal of this clinical observational study is to elucidate the cellular environment and the patient’s clinical characteristics contributing to failed muscle recovery and physical disability in survivors of critical illness. Our central hypothesis is that alterations in myofibrillar, mitochondrial and collagen protein homeostasis are underlying muscle and physical dysfunction in patients surviving critical illness. In Aim 1, we will identify trajectory of recovery for muscle strength and power, as well as physical function in patients surviving ICU-related critical illness including pneumonia, sepsis, and COVID-19 etiologies. We hypothesize that patients with a higher initial severity of illness will show poor recovery of muscle strength and physical function during the first year of recovery. In Aim 2, we will determine mechanisms of skeletal muscle deficiencies contributing to disparate recovery in patients surviving ICU-related COVID-19 or other acute lung injury etiologies. We hypothesize that patients with longer ICU durations will show poor recovery of muscle size and increased collagen deposition during the first year of recovery. In addition, we hypothesize that patients with persistent weakness and fatigue have prolonged impairments in mitochondrial function compared to patients who recover their muscle function. Finally, we hypothesize that patients with long-term disability have an inability to recover muscle function due to a cellular environment of that is not permissive to a positive protein balance. We will use stable isotope mass spectroscopy measurements of muscle biopsies to determine synthesis of myofibrillar, mitochondrial and collagen protein. Findings from this study, will inform why some patients develop persistent disability and others gradually improve. The results from this research will guide future development of therapeutic interventions that are specific to skeletal muscle deficits with consideration for patient related factors such as age and co-morbid burden.

许多在危重疾病中幸存下来的患者，包括败血症和急性呼吸衰竭，都面临着 康复受到出院后肌肉和身体功能无法恢复的困扰，导致 生活质量较低、无法重返工作岗位和残疾。在危重疾病中幸存下来的患者数量 美国每年都在继续崛起，因此至关重要的是制定干预措施 将支持他们的恢复。导致骨骼肌功能障碍的临床和肌肉细胞因素相对较多 在急性危重疾病后未知，但对于通知干预发展是必要的。我们将解决 通过研究肌原纤维和胶原蛋白的周转、细胞信号通路和 损伤、炎症和免疫反应的标志在康复的第一年。它的独特之处在于 建议是患者内的肌肉组织连续采样与同时获得的临床数据配对。 出院后恢复第一年的功能参数。身体机能和身体素质 将对生活结果进行评估，以了解为什么一些患者肌肉功能恢复，而另一些患者则发展 严重残疾。这项临床观察性研究的总体目标是阐明细胞环境。 以及导致肌肉恢复失败和身体残疾的患者的临床特征 危重疾病的幸存者。我们的中心假设是肌原纤维、线粒体和胶原的改变 蛋白质动态平衡是危重患者潜在的肌肉和身体功能障碍。在AIM 1、我们将确定患者肌肉力量和力量以及身体功能的恢复轨迹 在重症监护病房相关危重疾病中幸存下来，包括肺炎、脓毒症和新冠肺炎病因。我们假设 初始病情严重程度较高的患者肌肉力量和体能恢复较差 在恢复的第一年中发挥作用。在目标2中，我们将确定骨骼肌的机制 缺陷导致重症监护病房相关新冠肺炎或其他急性肺病患者康复情况不同 受伤原因。我们假设ICU持续时间较长的患者肌肉大小恢复较差。 在康复的第一年，胶原沉积增加。此外，我们假设患者 与持续虚弱和疲劳的人相比，线粒体功能损害时间更长 恢复肌肉功能的病人。最后，我们假设长期残疾的患者有 由于细胞环境而无法恢复肌肉功能，这是不允许阳性的 蛋白质平衡。我们将使用肌肉活组织的稳定同位素质谱学测量来确定 肌原纤维、线粒体和胶原蛋白的合成。这项研究的发现将告诉我们为什么一些 患者会出现持续性残疾，其他人会逐渐好转。这项研究的结果将指导 考虑到针对骨骼肌缺陷的治疗干预的未来发展 与患者相关的因素，如年龄和并存负担。