Early administration of hydrocortisone, vitamin C, and thiamine in adult patients with septic shock: a randomized controlled clinical trial

Abstract

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

The outcome of IV vitamin C therapy in patients with sepsis or septic shock: a meta-analysis of randomized controlled trials

“…We acknowledge some limitations. First of all, 10 RCTs [16,25,26,29,[31][32][33][36][37][38] were all singlecenter studies, which may result in selective bias, so as to obtain a large beneficial therapeutic effect conclusion. Second, RCTs in this meta-analysis used different doses of vitamin C. Most RCTs administered 1.5 g vitamin C every 6 h or 25 mg/kg every 6 h, whereas other RCTs administered 50 mg/kg every 6 h or 200 mg/kg daily.…”

“…We initially identified 803 records, and 192 identical duplicate articles were deleted before screening; 582 studies were excluded by screening titles and abstracts; 11 studies were further removed during the assessment of the full text. Ultimately, 18 eligible RCTs [15][16][17][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] enrolling 3364 patients were included in this metaanalysis. The PRISMA 2020 flowchart of this study is presented in Fig.…”

“…No study administered a dose of < 25 mg/kg/d, 14 studies [16,17,[24][25][26][27][28][29][30][31][32][33][34]37] (15 studies for short-term mortality [16, 17, 24-34, 36, 37]) administered 25-100 mg/ kg/d, and 3 studies [15,35,38] administered > 100 mg/ kg/d. 25-100 mg/kg/d IVVC administration was associated with reduced delta SOFA score (MD, − 0.85; 95% CI, − 1.23 to − 0.46; p < 0.0001; I 2 = 42%) and shortterm mortality (OR, 0.80; 95% CI, 0.65 to 0.97; p = 0.03; I 2 = 36%) as shown in Table 1.…”

“…One study [32] analyzed sepsis patients. Ten studies [16,17,25,26,28,30,33,34,36,38] tested septic shock patient (9 studies for delta SOFA score [16,17,25,26,28,30,33,34,38]). Seven studies [15,24,27,29,31,35,37] analyzed unclear patients.…”

Manejo de shock séptico refractario con Glucocorticoides en pacientes adultos ingresados en Unidades de Cuidados Intensivos

“…En cuanto a la mortalidad a los 28 días, Liang H. et al(34), Lyu Q. et al(35), y Wen Y. et al(36), concuerdan que el uso de glucocorticoides en pacientes con shock séptico refractario no resultó en la disminución significativa de mortalidad en este período de tiempo. Venkatesh B. et al (37) y Lian X. et al(39), concuerdan que el uso de glucocorticoides acortan el tiempo de estancia en UCI y este último autor también asocia esta terapia con disminución de la estancia hospitalaria en pacientes con shock séptico refractario.…”