Table 3.

Non randomized studies of vitamin C in sepsis

No.	Title	Ref.	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	High dose intravenous vitamin C treatment in Sepsis: associations with acute kidney injury and mortality	McCune et al[35], 2021	United States	Cohort study (retrospective cohort)	1178		212	Cohort of patients who have received at least one dose of 1.5 g IV vitamin C	Vitamin C therapy was associated with significant chances of AKI and death.
2	Effect of high-dose intravenous vitamin C on point-of-care blood glucose level in septic patients: a retrospective, single-center, observational case series	He et al[38], 2020	China	Observational case series			82	Patients with septic shock on admission received 100 mg/kg/d, while other patients received < 100 mg/kg/d	High-dose vitamin C therapy may interfere with point-of-care glucose testing results.
3	Pharmacokinetic data support 6-hourly dosing of intravenous vitamin C to critically ill patients with septic shock	Hudson EP et al[36], 2019	Australia	Observational PK study			11	Patients received 1.5 g intravenous vitamin C every 6 h	Injectable vitamin C 1.5 g every 6 h helps in correction of vitamin C deficiency and hypovitaminosis C, and it also provides appropriate dosing schedule for vitamin C supplementation in septic shock.
4	Accuracy of Point-of-Care Blood Glucose Level Measurements in Critically Ill Patients with Sepsis Receiving High-Dose Intravenous Vitamin C	Smith et al[37], 2018	United States	Observational PK study			5	Patients who have received vitamin C 1500 mg intravenously two or more doses and had point of care blood glucose checked and laboratory venous BG levels measured within 1 h of each other during vitamin C therapy	The accuracy and agreement of POC BG did not have significant interreference during vitamin C treatment in sepsis.
5	Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis	Fowler et al[39], 2014	United States	Phase I safety trial			24 total in 1:1:1 ratio	Patients with severe sepsis in the medical intensive care unit were randomized 1:1:1 to receive intravenous infusions every 6 h for 4 d of ascorbic acid: Lo-AscA (50 mg/kg/24 h, n = 8), or Hi-AscA (200 mg/kg/24 h, n = 8), or placebo (5% dextrose/water, n = 8)	Intravenous vitamin C infusion is safe and tolerated well and may have a positive impact on endothelial injury, the extent of multiple organ failure, and levels of inflammatory biomarkers.
Studies using combination therapies including vitamin C
6	Adding vitamin C to hydrocortisone lacks benefit in septic shock: a historical cohort study	Chang et al[40], 2020	Canada	Cohort study (retrospective cohort)	88		52	Retrospective cohorts of vitamin C with hydrocortisone and hydrocortisone therapies for 72 h were compared in patients with sepsis or septic shock	Outcomes for hospital mortality, ICU mortality, ventilator free days, vasopressor free days, dialysis use, and duration of ICU admission were comparable between the groups.
7	Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study	Marik et al[22], 2017	United States	Cohort study (before and after study)	47		47	Intravenous vitamin C (1.5 g q6h for 4 d or until ICU discharge), hydrocortisone (50 mg q6h for 7 d or until ICU discharge followed by a taper over 3 d) as well as intravenous thiamine (200 mg q12h for 4 d or until ICU discharge)	Results of this study suggest that the early use of intravenous vitamin C, together with corticosteroids and thiamine, prevents progressive organ dysfunction, including acute kidney injury, and reduces the mortality of patients with severe sepsis and septic shock.
Other studies
9	Plasma Cortisol, Aldosterone, and Ascorbic Acid Concentrations in Patients with Septic Shock Do Not Predict Treatment Effect of Hydrocortisone on Mortality. A Nested Cohort Study	Cohen et al[42], 2020	Australia and NZ	Cohort Study (nested cohort study)				Levels of total and free plasma cortisol and aldosterone were measured along with quantitatively measured vitamin C levels	In patients with septic shock, plasma aldosterone and ascorbic acid concentrations are not associated with outcome.
10	Vitamin C levels amongst initial survivors of out of hospital cardiac arrest	Gardner et al[43], 2020	United States	Observational study	34		25 post arrest, 25 post sepsis	Observational	Vitamin C levels are lower in cardiac arrest patients in comparison to healthy patients.
11	Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes	Carr et al[8], 2017	New Zealand	Observational study	20		24	Patients with septic shock and non-septic aetiology	Critically sick patients have low levels of vitamin C, and septic shock patients have significantly depleted levels.
12	Colistin-associated Acute Kidney Injury in Severely Ill Patients: A Step Toward a Better Renal Care? A Prospective Cohort Study	Dalfino et al[41], 2015	Italy	Cohort (prospective cohort)	39 non AKI		31 AKI	Intervention cohort patients have received colistin at a median daily dose of 9 million IU	Independent renal-protective role emerged for ascorbic acid among other factors responsible for higher chances of AKI.

AKI: Acute kidney injury; Hi-AscA: High dose ascorbic acid; ICU: Intensive care unit; Lo-AscA: Low dose ascorbic acid; POC BG: Point of care blood glucose.