RETURN: RECOVERY TO PHYSICALFUNCTION AFTER CRITICAL ILLNESS IN OLDER ADULTS

About This Grant

RETURN: Recovery To physical fUntion afteR critical illNess in older adults Previously healthy adults who enter the intensive care unit (ICU) are at risk of exiting the hospital with impairments in physical function and activities of daily living (ADLs) that persists for years. It remains unknown why a subset of survivors of critical illness has a positive trajectory of recovery and return to their baseline physical function status, while others develop persistent disability. Age is a critical component of disparate physical recovery as older survivors are less likely to return to ADLs and participate in societal roles. Despite awareness of age being a contributor to functional recovery, interventional strategies to mitigate or prevent dysfunction are equivocal. Elucidating the clinical and cellular factors contributing to disparate recovery patterns in older survivors provides the foundation to develop and test interventions that are individualized to the specific deficits. Therefore, we will perform a longitudinal study in humans as well as a translational murine model of critical illness to identify clinical and cellular factors of poor functional and ADL recovery. Aim 1: we will determine the long-term trajectory of physical function and ADL performance in ICU survivors. We hypothesize that older ICU survivors with high acuity of illness in ICU will have persistent inflammation and failed recovery of physical function. Patients will participate in a battery of tests and self-reported questionnaire for muscle and physical function, ADLs, and quality of life. Aim 2: we will assess the cellular changes in skeletal muscle that contribute to long-term physical dysfunction, in a subset of ICU survivors. Aim 3: in a murine model of critical illness recovery, we will determine cellular mechanisms that drive failed muscle and physical recovery in older compared to intermediate age. Subsequently, we will determine if metabolite supplementation with Urolithin A in early recovery period can prevent or mitigate mitochondrial dysfunction and sensecence. The murine model of polymicrobial sepsis is used since it mimics the initial inflammatory phase followed by onset of mitochondria dysfunction that is observed in our preliminary data in humans. The murine model provides comprehensive mechanistic insight that cannot be achieved in humans because of multiple safety criteria prohibiting muscle biopsies in the sickest patients. Results from this study will define mechanisms that lead to physical decline after an ICU admission for older adults. We expect to demonstrate that physical dysfunction after ICU admission is driven by persistent immune dysregulation leading to muscle mitochondrial dysfunction and cellular senescence. Understanding who is at risk for physical decline following critical illness improves the ability to develop and deliver targeted interventions to mitigate, reverse or prevent long-term deleterious effects.