Vasodilatory shock, that is decreased end organ perfusion characterized by peripheral vasodilation and hypotension in the setting of preserved cardiac output, is the most common cause of shock. Current treatment dictates restoration of blood pressure while the underlying cause of shock is treated. Currently, catecholamines and vasopressin are the two classes of vasopressors available with which to address shock by inducing peripheral vasoconstriction. Unfortunately, a very narrow therapeutic window and significant side effects limit vasopressor efficacy. This is reflected in a mortality rate approaching 50% at one month in those patients requiring high-dose vasopressors for the treatment of vasodilatory shock. Fortunately, early studies of angiotensin II (ATII) – part of the human body’s own renin-angiotensin-aldosterone system (RAAS) - have shown its administration to produce more consistent vasopressor effects in patients with shock. The 2017 Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) trial was a larger randomized control trial designed to assess the usefulness of ATII in the treatment of severe vasodilatory shock. The goal of the ATHOS-3 trial was to determine the efficacy and safety of angiotensin II in improving hemodynamics in severe vasodilatory shock. This was a prospective, multi-center, double blind, randomized, placebo-controlled, phase III trial conducted in 75 medical centers throughout North America, Australia, Europe and Asia from May 2015 to January 2017 in collaboration with the trial sponsor, La Jolla Pharmaceutical Company. Eligible patients were at least 18 years of age and had catecholamine-resistant vasodilatory shock, defined as receiving more than 0.2 μg of norepinephrine per kilogram of body weight per minute, despite adequate fluid resuscitation in the past 24 hours. Excluded were patients with greater than 20% total body surface area burns, acute coronary syndrome, bronchospasm, liver failure, mesenteric ischemia, active bleeding, abdominal aortic aneurysm, immunosuppression or patients receiving extracorporeal membrane oxygenation. Enrolled patients were randomly assigned to receive infusions of either angiotensin II or a placebo. The primary end point was a measured increase in mean arterial pressure (MAP) of at least 10mm Hg or to at least 75mm Hg within 3 hours without an increase dose of vasopressors. Secondary endpoints included changes in the cardiovascular Sequential Organ Failure Assessment (SOFA) score and total SOFA score at 48 hours. And safety was evaluated by assessing serious adverse events, event-related drug discontinuations, and all-cause mortality at 7 and 28 days. A total of 344 patients were enrolled in the study with 321 receiving an intervention (angiotensin II (163) and placebo (158)). The primary endpoint, MAP responsiveness, was reached by 114 (69.9%) patients receiving ATII versus 37 patients (23.4%) in the placebo arm (odds ratio (OR) 7.95; 95% confidence interval (CI) 4.76-13.3). Furthermore, at 48 hours, the cardiovascular SOFA score had a significant improvement in the ATII group as compared to the placebo group (-1.75 vs.-1.28). In multivariate analysis adjusted for age, sex and other variables, treatment assignment was the most significant predictor of response. Hypoalbuminemia and elevated vasopressor requirements were the most significant negative predictors. In terms of safety, there were similar rates of dysrhythmias and distal ischemia between the two groups. Furthermore, there was no significant difference in all-cause mortality by day 7 or by day 28 between the two groups. The authors of this study conclude that angiotensin II was effective at increasing blood pressure in patients with vasodilatory shock that in unresponsive to high dose vasopressors. Comment: This is the first RCT examining the efficacy and safety of angiotensin II use in vasodilatory shock and demonstrated the effectiveness of ATII at increasing mean arterial pressure. However, the small size of the study and its short duration of follow up limited the study’s ability to detect differences in outcomes such as mortality and to draw any conclusions about the longer-term efficacy and safety of ATII. As emergency physicians, we are often the first line of defense in cases of shock. While this study may not change our immediate approach to vasodilatory shock; it is important to keep in mind that once larger studies with longer follow up have answered the lingering questions above, angiotensin II may become an important tool in our armamentarium.