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

Table 4 Meta-analyses of trials on vitamin C in sepsis

No.	Title	Ref.	Country of origin	Study design	Included studies	Included sample size	Intervention summary	Results in brief
Studies with isolated vitamin C therapy
1	IV Vitamin C in Critically Ill Patients: A Systematic Review and Meta-Analysis	Patel et al[45], 2022	United States	Meta-analysis	15 RCTs	2490 participants	Compared intravenous vitamin C at high and low doses with placebo among pooled study participants	Intravenous vitamin C therapy is associated with a trend toward reduced overall mortality. Data further reveals that High-dose IV vitamin C was associated with a significant reduction in overall mortality. None of the included trials reported an increase in adverse events related to IV vitamin C therapy.
2	Efficacy of intravenous vitamin C intervention for septic patients: A systematic review and meta-analysis based on randomized controlled trials	Li et al[47], 2021	China	Meta-analysis of RCTs	10 RCTs	1400 patients	Studies that have intravenous vitamin C supplementation were included	Data from this meta-analysis reports improved SOFA score within 72 h but no significant improvement in short term (28-30 d) mortality, long term mortality (90 d), hospital stay, ventilator-free days, ICU-stay in sepsis or septic shock patients.
3	Effect of vitamin C in critically ill patients with sepsis and septic shock: A meta-analysis	Feng et al[48], 2021	China	Meta-analysis of RCTs	9 RCTs	584 patients	Studies with vitamin C treatment in critically sick sepsis and septic shock patients were included	Data from this study finds significant differences in 28-d mortality and dose of vasopressors. However, the ICU length of stay was the same between the two groups.
4	Efficacy of vitamin C in patients with sepsis: An updated meta-analysis	Wei et al[46], 2020	China	Meta-analysis	6 RCTs and 6 observational studies	1176 in control group	This analysis included data from RCTs and observational studies that evaluated the effect of vitamin C in patients with sepsis	This study reports no significant improvement in 28-d or in-hospital mortality. There was also no difference in vasopressor duration and ICU or hospital stay.
Vitamin C as a combination therapy
5	Thiamine, Ascorbic Acid, and Hydrocortisone As a Metabolic Resuscitation Cocktail in Sepsis: A Meta-Analysis of Randomized Controlled Trials With Trial Sequential Analysis	Assouline B et al[49], 2021	Switzerland	Meta-analysis	8 RCTs	1335 patients	Combination of thiamine, ascorbic acid, and hydrocortisone compared to in patients with sepsis or septic shock	Data in this study was homogenous and intervention led to improved change in SOFA score at 72 h; however, there was no difference in ICU mortality and renal composite outcome (incidence of AKI 3 or need for Renal replacement therapy).
6	The Efficacy of vitamin C, thiamine, and corticosteroid therapy in adult sepsis patients: a systematic review and meta-analysis	Somagutta et al[50], 2021	United States	Meta-analysis	15 studies (8 RCTs and 7 cohort studies)	67349 patients	Combination of HAT treatment in patients with sepsis	Meta-analysis from RCTs concluded that hospital mortality, ICU stay, hospital stay, and renal replacement therapy was not significant. Results from cohort studies have also concluded that hospital mortality, ICU mortality, ICU length of stay, length of hospital stay, change in SOFA score, the use of renal replacement therapy, or vasopressor duration was not significant.
7	Vitamin C, Thiamine, and Hydrocortisone in the Treatment of Sepsis: A Meta-Analysis and Trial Sequential Analysis of Randomized Controlled Trials	Zayed et al[51], 2021	United States	Meta-analysis	6 RCTs	839 patients	Vitamin C, thiamine, and steroid in combination for sepsis and septic shock	Data from this study concluded that there is no significant difference in long term mortality, ICU mortality, incidence of acute kidney injury, hospital length of stay, ICU length of stay, and ICU free days on day 28 between the intervention and control groups. However, there was a significant reduction in SOFA score on 3rd day.
8	Mortality in septic patients treated with vitamin C: a systematic meta-analysis	Scholz et al[52], 2021	Germany	Meta-analysis	17 studies (randomized and non-randomized, blinded and unblinded, prospective and retrospective, and single- and multi-centre studies)	3133 patients	Vitamin C 1.5 g every 6 h, 100 mg thiamine every 6 h, and 50 mg hydrocortisone every 6 h. However, initiation and duration of the intervention differed considerably within the studies	Pooled analysis in this study indicated no mortality benefit; however, a subgroup analyses revealed an improved survival, if vitamin C treatment was applied for 3-4 d.
9	Effect of adjunctive vitamin C, glucocorticoids, and vitamin B1 on longer-term mortality in adults with sepsis or septic shock: a systematic review and a component network meta-analysis	Fujii et al[53], 2021	Japan	Meta-analysis (network meta-analysis)	43 RCTs	10257 patients	Compared networked interventions of very high dose vitamin C, high dose vitamin C, vitamin C, vitamin B1, and glucocorticoids	This study found that metabolic resuscitation with vitamin C, glucocorticoids, vitamin B1, or combinations of these drugs have no difference in long term mortality. Also they did not find effect of vitamin C or B1 on organ dysfunction or ICU length of stay. However, adding glucocorticoid to the combination therapies reduces the duration of vasopressor therapy and ICU stay.
10	Steroid, ascorbic acid, and thiamine in adults with sepsis and septic shock: a systematic review and component network meta-analysis	Fong et al[54], 2021	Hong Kong	Meta-analysis (component network meta-analysis)	33 RCTs	9898 patients	Additive network meta -analysis was performed, adding vitamin C, glucose corticoid, and thiamine sequentially	Data from this study reveals that combination of glucocorticoid and fludrocortisone improved short-term and longer-term mortality in sepsis and septic shock patients. Steroids shortened the time to resolution of shock and duration of mechanical ventilation. However, there was no evidence to support use of thiamine and vitamin C in sepsis and septic shock.
11	Effect of Combined Hydrocortisone, Ascorbic Acid and Thiamine for Patients with Sepsis and Septic Shock: A Systematic Review and Meta-Analysis	Wu et al[55], 2021	China	Meta-analysis of RCT and observational studies	6 RCTs and 7 observational studies	1559 participants.	This study compared hydrocortisone, thiamine, and ascorbic acid use to usual care or hydrocortisone	Combination therapy associated with significant reductions in duration of vasopressor in RCTs, but not in observational studies. It was associated with lower SOFA score at 72 h both in RCTs and observational studies. Combination therapy associated with lower hospital mortality and higher PCT clearance in observational studies.
12	Thiamine combined with vitamin C in sepsis or septic shock: a systematic review and meta-analysis	Ge et al[56], 2021	China	Systematic review and meta-analysis	7 RCTs	868 patients	Thiamine combined with vitamin C in patients with sepsis or septic shock	Data from this study found no significant differences for in hospital mortality, but have shorter duration of vasopressor use and reduced SOFA score during 72 h.

HAT: Hydrocortisone; ascorbic acid and thiamine combination; ICU: Intensive care unit; IV: Intravenous; RCT: Randomized control trial; SOFA: Sequential organ failure assessment score.