Circulatory shock is one of the most common reasons for admission to an intensive care unit (ICU) and results from inadequate blood pressure and blood flow to support organ function. Causes of circulatory shock include heart failure, sepsis, and hemorrhage. Prompt treatment is required to restore adequate blood pressure to prevent severe organ injury and death. Consensus guidelines for treatment of shock provide general targets for mean arterial pressure (MAP) that can be used to adjust medications, but optimal individual pressure goals for patients with various diseases and comorbidities remain uncertain. Prospective randomized clinical trials looking at different patient populations have generally failed to show a mortality benefit for higher versus lower MAP goals, and MAP alone has therefore proven an inadequate single measure of tissue perfusion. This project seeks to develop a novel hemodynamic metric called tissue perfusion pressure (TPP) for use in patients with circulatory shock. This metric defines the pressure drop across the systemic circulation as the difference between MAP and the critical closing pressure (Pcrit), which is the arterial pressure when blood flow stops and the circulation collapses. It has generally not been possible to measure Pcrit in patients with an intact circulation, however, and this physiology has been largely ignored in clinical practice. The proposed approach, developed using analyses from thousands of patients, now allows estimation of Pcrit from standard blood pressure monitors in the ICU and enables continuous calculation of TPP to augment standard hemodynamic measures. The fundamental hypothesis of this project is that TPP can provide individualized blood pressure targets for critically-ill patients and can therefore guide titration of fluid and vasoactive therapies. This hypothesis will be tested in three specific aims. Aim 1 will investigate the physiology of Pcrit and TPP in preclinical animal models of circulatory shock and resuscitation using extensive physiologic phenotyping. Measured data will be incorporated into new circuit models of organ perfusion during shock. Aim 2 will next analyze distinct shock cohorts using computational approaches applied to a large clinical database of ICU patients, with the goal of identifying patterns in TPP response in various forms of shock and to standard of care therapeutics. Aim 3 will then develop a computational pipeline to perform real-time analysis of TPP for implementation in clinical decision support tools. Clinical feedback on the novel metrics will be obtained from expert critical care clinicians. If successful, this project will advance TPP as a potential therapeutic target for diagnosis and management of circulatory shock and set the foundation for design of future prospective clinical trials.