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Purpose: Sepsis and septic shock are significant health issues in the United States. Novel treatment options focusing on mitigating the dysregulated host response while reducing the need for vasopressor support are needed. This review discusses ascorbic acid, thiamine, and steroids as monotherapy and in combination for the treatment of sepsis and septic shock. Summary: The results of clinical studies using ascorbic acid, thiamine, and steroids as monotherapy or in combination are reviewed. High doses of IV ascorbic acid improved organ failure evidenced by changes in SOFA scores, declining CRP and PCT levels, and reduced vasopressor use. Thiamine initiation improved lactate levels in thiamine deficient patients in one study and demonstrated quicker lactate clearance and lower 28-day mortality in another study. Steroid studies demonstrated greatest benefit when initiating hydrocortisone and fludrocortisone early in septic shock. Combination therapy with ascorbic acid, thiamine and steroids reduced hospital mortality and vasopressor use in sepsis and septic shock in a small single-center study. Conclusion: Initial studies in patients with sepsis and septic shock demonstrated beneficial effects of ascorbic acid, thiamine, and steroids as monotherapy or in combination without safety concerns. However, the efficacy and safety of these therapies warrant further validation in larger clinical studies. [ABSTRACT FROM AUTHOR]