Molecular Correlates and Outcomes Associated with Striated Muscle Atrophy in Post Surgical Critical Illness A Longitudinal Study
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PROJECT SUMMARY Approximately one-third of the nearly five million annual critical care admissions result from a primary surgical diagnosis. Because the age and comorbid complexity of surgical patients is increasing, so are the challenges faced by those who require post-surgical intensive care. Among patients requiring post-surgical intensive care, some require only a short stay and experience rapid recovery while others experience a more protracted intensive care unit (ICU) course followed by persistent functional impairment. In fact, among all patients requiring post-operative ICU care, well over a third experience severe physical and cognitive disability for months to years after hospitalization, leading to a substantial and growing healthcare and economic burden. Now referred to as post-intensive care syndrome (PICS), the problem is increasingly recognized among clinicians. Interventions have yet to be developed for PICS given our still nascent understanding its drivers and determinants. It remains unclear, for instance, why it is the spectrum of functional disability varies widely among ICU survivors. Emerging data from our group and others suggest that, extending beyond pre-operative and operative risk factors, certain features of post-operative critical illness distinguish between patients who are more versus less likely to develop longer-term disability. Based on prior and ongoing work, we hypothesize that in critical illness, atrophy of both central and peripheral striated muscle is common and that a more rapid rate of global (i.e. combined central and peripheral) striated muscle mass loss is associated with the development of more severe disability as well as frailty among post-surgical ICU survivors. Additionally, we hypothesize that marked decrements in global striated muscle mass are related not only to pre-existing traits and operative factors but also to a substantial and protracted post-operative imbalance of circulating pro- versus anti-inflammatory mediators, which normally serve as bioactive lipid regulators of endogenous response to stress and injury. To test our hypotheses, we will conduct a prospective longitudinal study designed to examine clinical trajectories and outcomes in relation to global striated muscle atrophy patterns and alterations in circulating molecular measures of inflammation, metabolic stress, and tissue injury. The proposed research will be conducted as part of a comprehensive K23 career development program, designed to provide the PI with the experience and skills needed to become an independently funded physician-scientist focused on clinical-translational approaches to identifying underlying mechanisms of and therapeutic targets for preventing functional disability among survivors of critical illness.
