Table 2.

Randomized clinical trials evaluating thiamine supplementation as adjunctive therapy in septic shock.

Authors	Diagnosis, number of patients and design	Nutrients. dose and time	Results	Strong points/limitations
VITAMINS Trial. Fugii et al. (61). JAMA	Septic shock n = 216 Multicentre, open-label, randomized clinical trial Primary outcomes: duration of time alive and free of vasopressor administration up to day 7 Secondary outcomes: 28-day, 90-day ICU, and hospital mortality, 28-day cumulative vasopressor-free days, 28-day cumulative mechanical ventilation-free days, 28-day renal replacement therapy–free days, change in SOFA score at day 3, 28-day ICU free-days, and hospital LOS	Intervention group: IV vitamin C (1.5 g every 6 h), hydrocortisone (50 mg every 6 h) and thiamine (200 mg every 12 h) Control group: IV hydrocortisone (50 mg every 6 h) Until shock resolution or up to 10 days	There was no significant difference in time alive and free of vasopressors up to day 7 (−0.6 h [95% CI, −8.3 to 7.2 h; p = 0.83]). There was no statistically significant difference in secondary outcomes.	Patients with septic shock within 24 h of diagnosis to maximize the possible effects of the intervention No serious adverse events were reported
HYVCTTSSS study. Chang et al. (62). CHEST	Sepsis and septic shock n = 80 Single-blind, randomized controlled trial Primary outcome: 28-day mortality. Secondary outcomes: duration of vasopressor use, ICU LOS, change in SOFA score within 72 h after experimental intervention, and PCT clearance rate within 72 h after experimental intervention	Intervention group: IV vitamin C (1.5 g every 6 h), hydrocortisone (50 mg every 6 h) and thiamine (200 mg every 12 h) Control group: placebo Hydrocortisone for 7 days and vitamin C and B1 for 4 days	There was no difference in mortality between the treatment and control groups (relative risk [RR],0.79; 95% CI, 0.41–1.52; p = 0.47) Thiamine treatment was associated with a significant improvement of 72-h change in ΔSOFA score (3.5 ± 3.3 vs. 1.8 ± 3.0; p = 0.02) and exhibited more incidents of hypernatremia (13 vs. 3; p = 0.005) In a subgroup diagnosed with sepsis within 48 h at ICU admission, an improvement in mortality in the treatment group was observed (13.6% vs 47.6%; RR, 0.29; 95% CI,0.09-0.90; p = 0.02)	Small sample size, single-blind and terminated early Did not include corticosteroids in the control group
ORANGES trial Iglesias et al. (55). CHEST	Sepsis and septic shock n = 137 Double-blind, randomized clinical trial Primary outcomes: resolution of shock and change in SOFA score Secondary outcomes: ICU mortality, hospital mortality, procalcitonin clearance (PCT-c), LOS, ICU LOS, and ventilator-free day	Intervention group: IV vitamin C (1.5 g every 6 h), hydrocortisone (50 mg every 6 h) and thiamine (200 mg every 12 h) Control group: placebo Maximum of 4 days	No statistically significant change in SOFA score was found between groups (p = 0.17) Intervention group showed quicker reversal of shock (27 ± 22 h vs 53 ± 38 h; p < 0.001) No significant differences were found between study mortality, length of stay and ventilator-free days	Baseline ascorbic acid and thiamine levels were evaluated Homogenous (primarily white) cohort size, limiting the ability to detect differences in hospital mortality and length of stay Did not include corticosteroids in the control group
Wani et al. (63). Infectious Disease	Sepsis and septic shock n = 100 Open-label, randomized controlled trial Primary outcomes: hospital mortality Secondary outcomes: 30-day mortality, duration of hospital stay, duration of vasopressor therapy, lactate clearance, change in serum lactate and the SOFA score over the first 4 days	Intervention group: IV vitamin C (1.5 g every 6 h), hydrocortisone (50 mg every 6 h) and thiamine (200 mg every 12 h) Control group: placebo Vitamin C and B1 for 4 days or until discharge from hospital; hydrocortisone for 7 days or until discharge from hospital	There was no difference between groups regarding hospital mortality (p = 0.82) and 30-day mortality (p = 1.00) Intervention group had shorter vasopressor use (96.13 ± 40.50 h vs. 75.72 ± 30.29 h; p = 0.010) and greater lactate clearance compared to control (41.8% vs. 56.8%; p = 0.031) No difference in mortality, length of stay and SOFA score	Geographical area (India) with high prevalence of antimicrobial resistance and mortality from sepsis Open-label and small sample size Did not include corticosteroids in the control group
ACTS trial Moskowitz et al. (38). JAMA	Septic shock n = 200 Multicentre, randomized, blinded clinical trial Primary outcome: change in the SOFA score between enrolment and 72-hour follow-up Secondary outcomes: kidney failure, 30-day mortality, ventilator-free days, and shock-free days during the first 7 days, days free of ICU stay, all-cause mortality to ICU and hospital discharge, post hospitalization disposition in survivors to hospital discharge, 72-hour change in individual SOFA score components, and delirium on day 3	Intervention group: IV vitamin C (1.5 g every 6 h), hydrocortisone (50 mg every 6 h) and thiamine (100 mg every 6 h) Control group: placebo For 4 days or until discharge from ICU	There was no statistically significant difference in SOFA score between groups (p = 0.12) The median number of shock-free days was higher in the intervention group compared with the placebo group (5 [IQR, 3–5] days vs 4 [IQR, 1–5] days; median difference, 1.0 days; 95% CI, 0.2-1.8 days; p < 0.01) There was no statistically significant difference in any other secondary outcomes	Conducted at 14 centres Adverse events were hyperglycaemia, hypernatremia and new hospital-acquired infection Large number of patients were screened (n = 4,569) but not randomized Did not include corticosteroids in the control group
ATESS trial. Hwang et al. (68). Intensive Care Medicine	Septic shock n = 111 Multicentre, double-blind, randomized clinical trial Primary outcomes: ΔSOFA score Secondary outcomes: 7-day, 28-day, 90-day, in-hospital and ICU mortality, shock reversal, vasopressor free days, vasopressor dose, duration of mechanical ventilation, ventilator-free days, AKI, RRT, RRT-free days, LOS ICU, ICU-free days, hospital LOS, reduction of C-reactive protein (CRP) and procalcitonin for 72 h	Intervention group: IV vitamin C (50 mg/kg, every 12 h, maximum daily dose 6 g) and thiamine (200 mg every 12 h) Control group: placebo For 48 h	There was no significant difference in ΔSOFA scores between the treatment group and the placebo group (3, interquartile range IQR – 1 to 5 vs. 3, IQR 0–4, respectively, p=0.96]) There was no significant difference in any secondary outcomes.	Glucocorticoid was administered to over half of the patients Interval for vitamin administration was longer (12 h vs. 6 h), while the duration of treatment was shorter (48 h vs. 96 h or more) compared to previous studies Intra-abdominal infection, either solid cancer or hematologic malignancy, accounted for almost half of the cases of septic shock
VICTAS Randomized Clinical Trial. Sevransky et al. (69). JAMA	Sepsis n = 501 Multicentre, double-blind, randomized clinical trial Primary outcomes: ventilator- and vasopressor-free days in the first 30 days Secondary outcomes: 30-day mortality	Intervention group: IV vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) every 6 h Control group: hydrocortisone (of at least 200 mg) or matching placebo equivalent For 96 h or until discharge or death	There was no statistically significant difference between the intervention and control groups regarding ventilator- and vasopressor-free days (median difference of −1 day [95% CI, −4 to 2 days; p = 0.85]) There was no difference between groups in 30-day mortality (intervention = 22% vs placebo = 24%, p = 0.619)	Trial was terminated early for administrative reasons and may have been underpowered to detect a clinically important difference

AKI, Acute kidney injury; CI, confidence interval; CRP, C-reactive protein; IV, intravenous; ICU, intensive care unit; LOS, length of stay; PCT-c, Procalcitonin clrearence; RR, razard ratio; IQR, interquartile range; RRT, Renal replacement treatment; SOFA, sequential organ failure assessment.