Muscle and Physical Function Recovery after Acute Critical Illness (ALN 93.859)

Patients who have survived critical illness, including COVID-19, have arduous recoveries that are often plagued by an inability to recover muscle mass and function after hospital discharge. The reduced or inability to recover muscle after hospital discharge reduces the likelihood of patients returning to their pre-hospital functional level and increases the risk of secondary complications such as readmission and death. 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 may recover muscle function, yet others develop severe disability. The overall goal of this clinical observational study is therefore to determine cellular processes of the underlying failure to recover muscle function and understand the relationships between the presence of dysfunctional cellular mechanisms with physical dysfunction in survivors of critical illness. This work is a necessary step in order to refine the current approach to post-critical illness rehabilitation therapy in which a template prescription is applied to all survivors. 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 6-months 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. The overarching goal of this proposal focuses on elucidating the cellular processes and markers that lead to muscle mass dysregulation in early, intermediate and long-term recovery of critical illness. Findings from this study, will inform why some patients develop persistent disability and others gradually improve. The research will guide future development of therapeutic interventions that may be specific to skeletal muscle deficits with consideration for patient related factors such as age and co-morbid burden. It is a long-term goal of our research team to develop and test interventions that mitigate impairments and stimulate recovery for ICU survivors.