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Refractory shock is a lethal manifestation of cardiovascular failure defined by an inadequate hemodynamic response to high doses of vasopressor medications. Approximately 7% of critically ill patients will develop refractory shock, with short-term mortality exceeding 50%. Refractory vasodilatory shock develops from uncontrolled vasodilation and vascular hyporesponsiveness to endogenous vasoconstrictors, causing failure of physiologic vasoregulatory mechanisms. Standard approaches to the initial management of shock include fluid resuscitation and initiation of norepinephrine. When these measures are inadequate to restore BP, vasopressin or epinephrine can be added. Few randomized studies exist to guide clinical management and hemodynamic stabilization in patients who do not respond to this standard approach. Adjunctive therapies, such as hydrocortisone, thiamine, and ascorbic acid, may increase BP in severe shock and should be considered when combination vasopressor therapy is needed. Novel vasopressor agents, such as synthetic human angiotensin II, can increase BP and reduce the need for high doses of catecholamine vasopressors in severe or refractory vasodilatory shock. Few effective rescue therapies exist for established refractory shock, which emphasizes the importance of aggressive intervention before refractory shock develops, including the earlier initiation of rational combination vasopressor therapy. The present review discusses the diagnosis and management of refractory shock to offer guidance for management of this important clinical problem and to provide a framework for future research.