Current role of high dose vitamin C in sepsis management: A concise review

Table 2 Randomized Trials of vitamin C in sepsis

No.	Title	Ref.	Acronym	Country of origin	Study design	Sample size in control arm	Sample size in intervention arm	Intervention summary	Results in brief
Studies using isolated vitamin C
1	Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit	Lamontagne et al[20], 2022	LOVIT Trial	Canada	RCT	437	435	Intravenous vitamin C (at a dose of 50 mg/kg body weight) 6 hourly for 96 h	This trial reported significantly higher composite primary outcome (risk of mortality OR persistent organ dysfunction at 28 d) in vitamin C group. One patient had a severe hypoglycemic episode and another had a serious anaphylaxis event.
2	Intravenous vitamin C administration to patients with septic shock: a pilot randomised controlled trial	Rosengrave et al[19], 2022		New Zealand	RCT	20	20	Intravenous vitamin C (at a dose of 25 mg/kg of body weight every 6 h) for up to 96 h, or until death or discharge	Treatment with intravenous vitamin C did not result in reduction of mean dose and duration of vasopressor infusion. Both the groups were comparable for rise in inflammatory markers, length of ICU stay, length of hospital stay, and mortality.
3	Early use of high-dose vitamin C is beneficial in treatment of sepsis	Lv et al[18], 2020		China	RCT	56	61	Intravenous vitamin C 3.0 g in 5% dextrose (100 ml/time, 2 times/d)	Treatment with vitamin C resulted in a significant reduction in the 28-d mortality. There was a significant reduction in SOFA score at 72 h and duration of vasopressor use, also there was increased clearance of procalcitonin.
4	Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial	Fowler et al[17], 2019	CITRIS-ALI RCT	United States	RCT	83	84	Intravenous infusion of vitamin C (50 mg/kg in dextrose 5% in water, n = 84) every 6 h for 96 h	There was no significant difference in SOFA score at 96 h, and levels of marker of inflammation (CRP) and vascular injury (thrombomodulin) at 168 h.
5	Effect of vitamin C administration on neutrophil apoptosis in septic patients after abdominal surgery	Ferrón-Celma et al[21], 2008		Spain	PD interventions RCT study	10	10	The vitamin C group received 450 mg/d of the vitamin in 3 doses	Vitamin C treatment in postoperative septic abdominal surgery patients have an antiapoptotic effect on peripheral blood neutrophils, reducing caspase-3 and PARP levels, and increasing BCL-2 levels. However this effect is not maintained all the time.
Studies using vitamin C in combination therapy
6	Effect of Supplementation of Vitamin C and Thiamine on the Outcome in Sepsis: South East Asian Region	Ap et al[27], 2022		India	RCT	20	20 + 20 + 20	Intervention group received vitamin C, thiamine, both, and neither, respectively. Vitamin C (2 g 8 hourly) and thiamine (200 mg 12 hourly) were given intravenously for 5 d	Intervention with vitamin C and thiamine did not reduce mortality. The vitamin C level and thiamine level were significantly lower than those in healthy controls.
7	Biomarker Analysis for Combination Therapy of Vitamin C and Thiamine in Septic Shock: A Post-Hoc Study of the ATESS Trial	Park et al[34], 2022	Post hoc ATESS	South Korea	RCT (post hoc analysis)	52	45	Intravenous vitamin C (50 mg/kg, maximum single dose 3 g) and thiamine (200 mg) administration every 12 h for a total of 48 h	Baseline biomarker levels (IL-6, IL-10, AP2, and S100β) at 72 h were not significantly different between the treatment and the placebo groups, also the rate of reduction was not significantly different between the two groups.
8	Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis: The VICTAS Randomized Clinical Trial	Sevransky JE et al[25], 2021	VICTAS Trial	United States	RCT	252	249	Vitamin C (1.5 G), thiamine (100 mg), and hydrocortisone (50 mg) every 6 h	In patients with sepsis and septic shock, treatment with combination therapy did not reduce ventilator days and vasopressor use. Mortality at 30 d was also comparable between the groups.
9	Vitamin C Therapy for Routine Care in Septic Shock (ViCTOR) Trial: Effect of Intravenous Vitamin C, Thiamine, and Hydrocortisone Administration on Inpatient Mortality among Patients with Septic Shock	Mohamed et al[33], 2020	ViCTOR Trial	India	RCT	43	45	Intravenous combination of vitamin C (1.5 g every 6 h), thiamine (200 mg every 12 h), and hydrocortisone (50 mg every 6 h) within 6 h of onset of septic shock admission	This trial found no difference in all-cause mortality in the two groups. The data reported earlier reversal of septic shock but no difference in improvement of SOFA score at 72 h, use of vasoactive substances, or use of mechanical ventilation.
10	Combined Treatment with Hydrocortisone, Vitamin C, and Thiamine for Sepsis and Septic Shock: A Randomized Controlled Trial	Chang et al[32], 2020	HYVCTTSSS	China	RCT	40	40	Combination therapy with hydrocortisone (50 mg every 6 h for 7 d), vitamin C (1.5 g every 6 h for 4 d), and thiamine (200 mg every 12 h for 4 d)	Combination therapy did not reduce 28 d all-cause mortality in sepsis and septic shock patients. However, it was associated with 72-h change in Sequential Organ Failure Assessment score improvement. The treatment group exhibited more incidents of hypernatremia.
11	Usefulness of Antioxidants as Adjuvant Therapy for Septic Shock: A Randomized Clinical Trial	Aisa-Alvarez et al[28], 2020		Mexico	RCT	18	18 + 18 + 18 + 18	Enterally administered tablets of NAC 600 mg every 12 hourly. Further, 50 mg of MT in capsules of 5 mg were given to patients once a day, and 1 mg vitamin C tablets were administered every 6 h. Vitamin E capsules of 400 units were given every 8 h for 5 d	Antioxidant therapy helps to regulate inflammation in septic patients with shock. Vitamin C therapy in pulmonary sepsis increases vitamin C serum levels and decreases levels of inflammatory marker like CRP, PCT, and NO3−/NO2−.
12	Effect of Ascorbic Acid, Corticosteroids, and Thiamine on Organ Injury in Septic Shock: The ACTS Randomized Clinical Trial	Moskowitz et al[24], 2020	ACTS RCT	United States	RCT	102	103	Parenteral vitamin C (1500 mg), hydrocortisone (50 mg), and thiamine (100 mg) every 6 h for 4 d	Combination therapy with ascorbic acid, corticosteroids, and thiamine did not lead to a significant reduction of SOFA score in septic shock patients during the first 72 h after enrolment. Data from this trial do not support routine use of combination therapy in septic shock.
13	Combination therapy of vitamin C and thiamine for septic shock: a multi-centre, double-blinded randomized, controlled study	Hwang et al[26], 2020	ATESS Trial	South Korea	RCT	58	53	Vitamin C (50 mg/kg, maximum single dose 3 g) and thiamine (200 mg) administration every 12 h for a total of 48 h intravenously	Vitamin C therapy and thiamine administration did not improve organ function and need for organ support despite improvement in levels of these vitamins in early phase of septic shock.
14	Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis: The ORANGES Trial	Iglesias et al[29], 2020	ORANGES trial	United States	RCT	69	68	Ascorbic acid 1500 mg q6h, thiamine 200 mg every 12 h, and hydrocortisone 50 mg q6h for a maximum of 4 d	Combination therapy resulted in quicker reversal of shock; however, no difference was found in reversal of organ dysfunction or other secondary outcomes.
15	Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock: The VITAMINS Randomized Clinical Trial	Fujii et al[23], 2020	VITMAINS RCT	Japan	RCT	107	109	Intravenous vitamin C (1.5 g every 6 h), hydrocortisone (50 mg every 6 h), and thiamine (200 mg every 12 h), given in intervention group and intravenous hydrocortisone (50 mg every 6 h) alone in comparison group until shock resolution or up to 10 d	Findings from this trial suggest that combination therapy does not lead to rapid resolution of septic shock in comparison to hydrocortisone alone with no significant improvement in overall mortality with intervention. No serious adverse events were reported.
16	Combination of vitamin C, thiamine and hydrocortisone added to standard treatment in the management of sepsis: results from an open label randomised controlled clinical trial and a review of the literature	Wani et al[30], 2020		India	RCT	50	50	Combination of vitamin C (1.5 g q6h for 4 d), thiamine (200 mg q12h for 4 d), and hydrocortisone (50 mg q6h for 7 d/ICU discharge, taper over 3 d)	Combination therapy does not improve in hospital mortality and mortality at 30 d. However, lactate clearance was faster and vasopressor use was lower in intervention group.
17	The effects of intravenous antioxidants in patients with septic shock	Galley HF al[31], 1997		United Kindom	RCT	14	16	Antioxidants (n-acetylcysteine 150 mg/kg for 30 min then 20 mg/kg/h plus bolus doses of 1 g ascorbic acid and 400 mg α-tocopherol)	Basal vitamin C was low and redox-reactive iron was elevated in all patients. Levels of vitamin C were increased but overall antioxidant capacity was unaffected after supplementation. Heart rate cardiac index increased and systemic vascular resistance index decreased in patients treated with antioxidants.

AP2: Angiopoietin-2; CRP: C-reactive Protein; DOI: Digital object identifier; ICU: Intensive care unit; IL-10: Interleukin-10; IL-6: Interleukin-6; MT: Melatonin; NAC: N-acetyl cysteine; NO2: Nitrite; NO3: Nitrate; PARP: Poly (ADP-ribose) polymerase; PCT: Procalcitonin; PMID: PubMed unique identifier; S100β: S100 calcium-binding protein B; SOFA: Sequential organ failure assessment score.