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Septic shock patients often require two or more vasopressors to maintain hemodynamic stability. Norepinephrine is the recommended first-line vasopressor. The purpose of this study is to determine whether the choice of the additional second vasopressor has an impact on mortality.We hypothesize that the choice of the second vasopressor after reaching optimal norepinephrine dose in septic shock will affect outcome.This study was a retrospective chart review of septic shock patients requiring multiple vasopressor therapy in the ICU from July 2010 to June 2012. Patients who received norepinephrine within 24 hours of admission and a second vasopressor (vasopressin, dopamine, dobutamine, or phenylephrine) within 48 hours were enrolled. The primary outcome was in-hospital mortality. The effect of 36 variables on mortality in the 4 vasopressor groups was assessed using logistic regression.One-hundred seventeen patients were enrolled, age 61+/-17 years, APACHE IV 102+/-26, 84.6% mechanically ventilated, and 66.9% in-hospital mortality. Within 96 hours 2.9+/-1.1 vasopressors were administered. 46, 18, 27, and 26 patients received vasopressin, dopamine, dobutamine, or phenylephrine as the second vasopressor within 48 hours; with in-hospital mortality 76.1%, 52.6%, 51.9%, and 76.9%, respectively, p=0.06. Bilirubin, hemoglobin, total fluids at 48 and 96 hours had statistically significant effect on outcome amongst the 4 vasopressor groups. After adjusting for hemoglobin, total fluids at 48 and 96 hours, dobutamine showed significant decreased odds ratio (OR) for mortality compared to vasopressin: OR 0.32 (95% CI 0.12,0.90), OR 0.32 (0.11,0.89), and OR 0.35 (0.12,0.97), respectively. When adjusted for total fluids at 96 hours, dopamine had decreased odds ratio for mortality compared to vasopressin: OR 0.31 (0.10, 0.99).In septic shock patients requiring multiple vasopressors, hemoglobin, total fluids at 48 and 96 hours have significant effect on outcome. Dobutamine or dopamine may be the preferred second vasopressor when norepinephrine alone is inadequate. A prospective randomized trial examining the choice of second vasopressor is needed.