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.

许多患有危害疾病的患者，包括败血症和急性呼吸衰竭，艰巨 住院后无法恢复肌肉和身体机能困扰的恢复，导致 较低的生活质量，无法恢复工作和残疾。幸存的重症患者人数 美国每年继续上升，因此，制定干预措施至关重要 将支持他们的恢复。临床和肌肉细胞因素驱动骨骼肌功能障碍是相对的 急性重症疾病后未知，但对于干预发展提供了必要的必要性。我们将解决 通过研究肌原纤维和胶原蛋白更新，细胞信号通路以及 恢复第一年的损害，炎症和免疫反应的标记。这个独特的方面 提案是串行的，患者内肌肉组织采样，与简单获得的临床配对 医院后出院第一年的功能参数。身体功能和质量 将评估生活成果，以了解为什么有些患者恢复肌肉功能，而另一些患者则发展 严重的残疾。这项临床检查研究的总体目标是阐明细胞环境 患者的临床特征导致肌肉恢复失败和身体残疾失败 重症疾病的幸存者。我们的中心假设是肌原纤维，线粒体和胶原蛋白的改变 蛋白质稳态是患者生存危重疾病的潜在肌肉和身体功能障碍。目标 1，我们将确定肌肉力量和力量恢复的轨迹，以及患者的身体功能 幸存的ICU相关危害疾病，包括肺炎，败血症和Covid-19病因。我们假设 疾病初期严重程度较高的患者将表现出肌肉力量和身体的恢复不良 恢复第一年的功能。在AIM 2中，我们将确定骨骼肌的机制 在与ICU相关的Covid-19或其他急性肺的患者中有助于不同恢复的缺陷 伤害病因。我们假设ICU持续时间较长的患者的肌肉大小恢复不良 并增加胶原蛋白恢复的第一年。此外，我们假设患者 与持续的无力和疲劳相比 恢复肌肉功能的患者。最后，我们假设长期残疾患者患有 由于细胞环境而无法恢复肌肉功能 蛋白质平衡。我们将使用稳定的同位素质谱测量肌肉活检来确定 肌原纤维，线粒体和胶原蛋白的合成。这项研究的结果将告知为什么有些 患者会出现持续的残疾，而其他患者则逐渐改善。这项研究的结果将指导 考虑到骨骼肌定义的理论干预措施的未来发展 对于患者相关的因素，例如年龄和联合性伯恩。