All the participating sites were academic hospitals with more than 40,000 emergency department visits yearly. To be eligible, the study sites had to use the measurement of serum lactate levels as the method for screening for cryptogenic shock and had to adhere to the Surviving Sepsis Campaign guidelines9 (link),10 (link) for nonresuscitation aspects of care but could have no routine resuscitation protocols for septic shock and could not routinely use continuous Scvo2 catheters. We recruited patients in the emergency department in whom sepsis was suspected according to the treating physician, who were at least 18 years of age, who met two or more criteria for systemic inflammatory response syndrome11 (link) (see the Methods section in the Supplementary Appendix), and who had refractory hypotension or a serum lactate level of 4 mmol per liter or higher. We defined refractory hypotension as a systolic blood pressure that either was less than 90 mm Hg or required vasopressor therapy to maintain 90 mm Hg even after an intravenous fluid challenge. We initially required the fluid challenge to be 20 ml or more per kilogram of body weight, administered over the course of 30 minutes, but in April 2010, we simplified the requirement to a challenge of 1000 ml or more administered over the course of 30 minutes. Patients did not have to be in shock on arrival in the emergency department but had to be enrolled in the study in the emergency department within 2 hours after the earliest detection of shock and within 12 hours after arrival. The exclusion criteria are listed in the Methods section in the Supplementary Appendix. All patients or their legally authorized representatives provided written informed consent. Randomization was performed with the use of a centralized Web-based program in variable block sizes of 3, 6, or 9, with stratification according to site and race.