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Patients who survive the acute phase of sepsis frequently acquire new organ dysfunction and enter a state or persistent critical illness, or fail to recover from their acute injuries and experience post-intensive care syndrome. Current attempts to mitigate these effects have focused on reducing harms done in the ICU and maximizing rehabilitation. Can specific pathways be leveraged to ameliorate the morbidity and mortality experienced by critical illness survivors? This session will describe the emerging understanding of the mechanisms that set the stage for persistent organ dysfunction in survivors of acute critical illness.