Severe sepsis is the syndrome of acute organ dysfunction secondary to infection. It affects 750,000 Americans each year, with a mortality of 30%. Despite considerable understanding of the pathophysiology of sepsis, current efforts to improve care are hampered by limited empiric data regarding the amount and timing of sepsis therapies. This stands in stark contrast to other acute conditions, such as acute coronary syndromes, where standardized, prompt, rigorous care has led to a large improvement in outcome and paved the way for better clinical and translational research. We have amassed for this Center proposal a multidisciplinary group of investigators and consortium of leading institutions. Our goal is to address the overarching hypothesis that there are 'golden hours'in the initial management of sepsis and septic shock where prompt, rigorous, standardized care can reduce unwanted downstream consequences and improve clinical outcomes. Our efforts capitalize on the findings of a recent 'proof-of-concept'trial by Rivers et al. They demonstrated in a single center randomized trial that 6 h of protocolized resuscitation for subjects presenting to the Emergency Department (ED) with early septic shock dramatically improved mortality when compared to usual care. While this study was revolutionary, it left unanswered whether the findings are generalizable and whether all elements of the protocol are necessary, especially the use of central venous catheterization and blood transfusion. The apparent success of the Rivers protocol also prompts questions about the mechanisms by which resuscitation techniques affect outcome. And, there are important questions regarding the logistic and economic constraints to widespread implementation of protocolized resuscitation across the US. We will tackle these questions directly through execution of a large multicenter trial. We will randomize 1950 subjects who present to the ED in septic shock to 3 arms (650/arm): the 'Rivers'protocol;a simpler, less invasive protocol (using esophageal Doppler monitoring and no blood transfusion);and usual care. Protocols will be implemented using best evidence regarding guideline dissemination. We have organized our efforts under 3 integrated subprojects. Subproject #1 (Clinical Efficacy) will conduct the trial and test whether protocolized care improves mortality compared to usual care and whether the full Rivers protocol is necessary. Subproject #2 (Mechanisms of Action) will measure concentrations over time of carefully selected circulating markers of four fundamental pathways implicated in sepsis-related organ dysfunction (cellular hypoxia, oxidative stress, inflammation, and coagulation/thrombosis) and test whether protocolized resuscitation reduces expression of these markers and whether the clinical efficacy of these protocols is associated with reduced expression of these markers. Subproject #3 (Costs and Cost-effectiveness) will measure the incremental costs and resource use of protocolized resuscitation and determine the value, or cost-effectiveness, of the alternative strategies. These subprojects are supported by 3 cores: administration, human subjects, and data management and analysis. This project will generate new, important, and comprehensive data on the clinical, biologic, and pragmatic aspects of standard, prompt, rigorous resuscitation for septic shock. Our findings will aid scientists, clinicians, families and policymakers and will immediately affect care of the critically ill. As the number of Americans dying with sepsis is similar to that of acute myocardial infarction, the proposed study has enormous implications for the public health of the country and is consistent with the recent NIH emphasis on translational research.