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

基本信息

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
项目类别：
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

项目摘要

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（包括败血症和急性呼吸衰竭）中幸存下来的患者都面临着艰巨的任务出院后无法恢复肌肉和身体功能，导致康复过程受到困扰生活质量下降、无法重返工作岗位和残疾。美国的经济增长率每年都在持续上升，因此制定干预措施至关重要将支持他们的康复驱动骨骼肌功能障碍的临床和肌肉细胞因素是相对的。急性危重疾病后未知，但对于制定干预措施是必要的，我们将解决这一问题。通过研究肌原纤维和胶原蛋白周转、细胞信号传导途径以及恢复第一年的损伤、炎症和免疫反应的标志物是其独特之处。该提案是连续的患者体内肌肉组织采样，并与同时获得的临床数据相结合出院后恢复第一年的功能参数身体功能和质量。将评估生活结果，以了解为什么一些患者恢复肌肉功能，而另一些患者则发展这项临床观察研究的总体目标是阐明细胞环境。以及患者的临床特征导致肌肉恢复失败和身体残疾我们的中心假设是肌原纤维、线粒体和胶原蛋白的变化。蛋白质稳态是危重病患者潜在的肌肉和身体功能障碍。 1、我们将确定患者肌肉力量和力量以及身体机能的恢复轨迹幸存 ICU 相关危重疾病，包括肺炎、败血症和 COVID-19 病因。初始病情严重程度较高的患者，肌肉力量和体力恢复较差在目标 2 中，我们将确定骨骼肌的机制。导致 ICU 相关的 COVID-19 或其他急性肺病患者康复情况不同的缺陷我们勇敢地面对 ICU 住院时间较长的患者肌肉尺寸恢复情况不佳的情况。并在恢复的第一年增加胶原蛋白沉积。与持续虚弱和疲劳的人相比，线粒体功能长期受损最后，我们再次认识到，长期残疾的患者具有恢复肌肉功能的能力。由于细胞环境不允许积极的结果而无法恢复肌肉功能我们将使用肌肉活检的稳定同位素质谱测量来确定蛋白质平衡。这项研究的结果将解释为什么肌原纤维、线粒体和胶原蛋白的合成。患者出现持续性残疾，而其他人则逐渐改善。这项研究的结果将为我们提供指导。未来开发针对骨骼肌缺陷的治疗干预措施，并考虑到针对患者相关因素，例如年龄和共病负担。