Early Administration of Hydrocortisone, Vitamin C, and Thiamine in Adult Patients With Septic Shock

A Randomized Controlled Clinical Trial

Qing-Quan Lyu; Rui-Qiang Zheng; Qi-Hong Chen; Jiang-Quan Yu; Jun Shao; Xiao-Hua Gu


Crit Care. 2022;26(295) 

In This Article

Abstract and Introduction


Background: The combination therapy of hydrocortisone, vitamin C, and thiamine has been proposed as a potential treatment in patients with sepsis and septic shock. However, subsequent trials have reported conflicting results in relation to survival outcomes. Hence, we performed this randomized controlled trial (RCT) to evaluate the efficacy and safety of early combination therapy among adult patients with septic shock.

Methods: This single-center, double-blind RCT enrolled adult patients with diagnosis of septic shock within 12 h from Northern Jiangsu People's Hospital between February 2019 and June 2021. Recruited patients were randomized 1:1 to receive intervention (hydrocortisone 200 mg daily, vitamin C 2 g every 6 h, and thiamine 200 mg every 12 h) or placebo (0.9% saline) for 5 days or until ICU discharge. The primary endpoint was 90-day mortality. The secondary endpoints included mortality at day 28, ICU discharge, and hospital discharge; shock reversal; 72-h Delta SOFA score; ICU-free days, vasopressor-free days, and ventilator support -free days up to day 28; ICU length of stay (LOS) and hospital LOS.

Results: Among 426 patients randomized, a total of 408 patients with septic shock were included in the per-protocol (PP) analysis, of which 203 were assigned to the intervention group and 205 to the placebo group. In the PP population, the primary outcome of 90-day mortality was 39.9% (81/203) and 39.0% (80/205) in the intervention and the placebo groups, respectively, and was not significantly different (P = 0.86). There was no significant difference between two groups in 28-day mortality (36.5% vs. 36.1%, P = 0.94) or the ICU mortality (31.5% vs. 28.8%, P = 0.55) and hospital mortality (34.5% vs. 33.2%, P = 0.78). No other secondary outcomes showed significant differences between two groups, including shock reversal, vasopressor-free days, and ICU LOS. Intention-to-treat analysis included all the 426 patients and confirmed these results (all P > 0.05).

Conclusion: Among adult patients with septic shock, early use of hydrocortisone, vitamin C, and thiamine combination therapy compared with placebo did not confer survival benefits.

Trial Registration: ClinicalTrials.gov: NCT03872011, registration date: March 12, 2019.

Graphic Abstract


Sepsis is a life-threatening condition that occurs due to a dysregulated host response to infection.[1] There were approximately 49 million cases of sepsis and 11 million sepsis-related deaths worldwide annually.[2] Septic shock, a subset of sepsis, is characterized by circulatory and cellular/metabolic abnormalities that are associated with a higher risk of mortality.[3]

At present, there are no treatments directly targeting the pathogenesis of sepsis; therefore, management relies on early identification and treatment of infection through appropriate antibiotic therapy and/or source control, as well as the reversal of hemodynamic instability through fluid resuscitation and vasopressors, if necessary.[3] Therefore, safe, effective, affordable adjuvant interventions that focus on mitigating dysregulated host responses in addition to standard therapy are urgently required.

A previous retrospective before–after study of 94 patients showed that early use of combination therapy with intravenous vitamin C, hydrocortisone, and thiamine might prove to be effective in preventing progressive organ dysfunction including acute kidney injury and reducing the mortality of patients with severe sepsis and septic shock.[4] The promising results of this study have aroused great interest of the therapeutic effects of the combination therapy with vitamin C, thiamine, and hydrocortisone among sepsis and septic shock patients. However, recently published prospective, randomized controlled trials (RCTs) conducted since then reported conflicting results in relation to survival outcomes,[5–8] and limited specific data are available in septic shock patients. The VITAMINS and ACTS trials, which included patients diagnosed of septic shock within 24 h, both demonstrated no significant mortality difference between the combination therapy and control groups.[5,9] It was assumed that beneficial effect could be achieved if the combination therapy initiated early.[6] Therefore, we performed this randomized controlled clinical trial to evaluate the efficacy of early administration of hydrocortisone, vitamin C, and thiamine combination therapy for patients with diagnosis of septic shock within 12 h.