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

by Baofang Liang, Jianwei Su, Hanquan Shao, Huiying Chen and Baocheng Xie 

Critical Care volume 27, Article number: 109 (2023) Published: 13 March 2023

Background

To update a meta-analysis of randomized controlled trials (RCTs) and further explore the outcome of IV vitamin C (IVVC) administration in sepsis or septic shock patients.

Methods

This study is a meta-analysis of RCTs. The RCTs of vitamin C therapy in sepsis or septic shock were searched in PubMed, EMBASE and Clinical Trials.gov from inception to January 16, 2023. We registered the protocol with PROSPERO (CRD42022354875). The primary outcome was delta Sequential Organ Failure Assessment (SOFA) score at 72–96 h. Two reviewers independently assessed RCTs according to eligibility criteria: (1) study type: RCT; (2) patient population: patients ≥ 18 years with sepsis or septic shock; (3) intervention: IVVC at any doses as monotherapy or combined with thiamine or and hydrocortisone compared with standard of care, no intervention or placebo (defined as control group); (4) the RCT described short-term mortality or SOFA score. Then, two authors independently extracted related information from RCTs.

Results

Eighteen RCTs (n = 3364 patients) were identified in this meta-analysis. There were significant effects in the delta SOFA score from baseline to 72–96 h (MD, − 0.62; 95% CI, − 1.00 to − 0.25; p = 0.001) and the duration of vasopressor use (MD, − 15.07; 95% CI, − 21.59 to − 8.55; p < 0.00001) with IVVC therapy. Treatment with IVVC was not shown to improve short-term mortality (OR, 0.89; 95% CI, 0.77 to 1.04; p = 0.14); nevertheless, dose at 25–100 mg/kg/d subgroup associated with a significant reduction in short-term mortality (OR, 0.80; 95% CI, 0.65 to 0.97; p = 0.03). An increase adverse event was observed in IVVC therapy (OR, 1.98; 95% CI, 1.06 to 3.68; p = 0.03).

Conclusion

In this meta-analysis, IVVC in sepsis or septic shock patients significantly improved delta SOFA score and reduced the duration of vasopressor use, whereas it was not associated with reduction in short-term mortality and had higher adverse events.

 

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

 

by Qing-Quan Lyu, Rui-Qiang Zheng, Qi-Hong Chen, Jiang-Quan Yu, Jun Shao and Xiao-Hua Gu 

 

Critical Care volume 26, Article number: 295 (2022) 

 

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.

 

 

IV Vitamin C in Critically Ill Patients: A Systematic Review and Meta-Analysis

by Patel, Jayshil J.; Ortiz-Reyes, Alfonso; Dhaliwal, Rupinder; Clarke, John; Hill, Aileen; Stoppe, Christian; Lee, Zheng-Yii; Heyland, Daren K. 

 

Critical Care Medicine: March 2022 - Volume 50 - Issue 3 - p e304-e312

OBJECTIVES: 

To conduct a systematic review and meta-analysis to evaluate the impact of IV vitamin C on outcomes in critically ill patients.

DATA SOURCES: 

Systematic search of MEDLINE, EMBASE, CINAHL, and the Cochrane Register of Controlled Trials.

STUDY SELECTION: 

Randomized controlled trials testing IV vitamin C in critically ill patients.

Two independent reviewers abstracted patient characteristics, treatment details, and clinical outcomes.

DATA SYNTHESIS: 

Fifteen studies involving 2,490 patients were identified. Compared with placebo, IV vitamin C administration is associated with a trend toward reduced overall mortality (relative risk, 0.87; 95% CI, 0.75–1.00; p = 0.06; test for heterogeneity I2 = 6%). High-dose IV vitamin C was associated with a significant reduction in overall mortality (relative risk, 0.70; 95% CI, 0.52–0.96; p = 0.03), whereas low-dose IV vitamin C had no effect (relative risk, 0.94; 95% CI, 0.79–1.07; p = 0.46; test for subgroup differences, p = 0.14). IV vitamin C monotherapy was associated with a significant reduction in overall mortality (relative risk, 0.64; 95% CI, 0.49–0.83; p = 0.006), whereas there was no effect with IV vitamin C combined therapy. No trial reported an increase in adverse events related to IV vitamin C.

CONCLUSIONS: 

IV vitamin C administration appears safe and may be associated with a trend toward reduction in overall mortality. High-dose IV vitamin C monotherapy may be associated with improved overall mortality, and further randomized controlled trials are warranted.

 

Intravenous vitamin C administration to patients with septic shock: a pilot randomised controlled trial

 

by Patrice Rosengrave, Emma Spencer, Jonathan Williman, Jan Mehrtens, Stacey Morgan, Tara Doyle, Kymbalee Van Der Heyden, Anna Morris, Geoff Shaw and Anitra C. Carr 

 

Critical Care volume 26, Article number: 26 (2022) 

 

Background

Intravenous vitamin C administration in septic shock may have a sparing effect on vasopressor requirements, and vitamin C’s enzyme cofactor functions provide a mechanistic rationale. Our study aimed to determine the effect of intravenous vitamin C administration on vasopressor requirements and other outcomes in patients with septic shock.

Methods

This was a double-blind, randomised placebo-controlled trial in 40 patients with septic shock who were randomised (1:1) to receive intravenous vitamin C (at a dose of 25 mg/kg of body weight every 6 h) or placebo (intravenous 5% dextrose) for up to 96 h, or until death or discharge. The primary outcome was intravenous vasopressor requirements (dose and duration), and secondary outcomes included Sequential Organ Failure Assessment (SOFA) scores, intensive care unit (ICU) and hospital length of stay, and mortality. In addition, blood samples were collected to determine vitamin C kinetics and inflammatory marker concentrations.

Results

Median plasma vitamin C concentrations were deficient at baseline (9.2 [4.4, 12] µmol/L) and increased to 408 (227, 560) µmol/L following 72 h of intervention. The mean duration of intravenous vasopressor infusion in the vitamin C group was 48 (95% CI 35–62) hours and in the placebo group was 54 (95% CI 41–62) hours (p = 0.52). The dose of vasopressor delivered over time was comparable between the two groups, as were SOFA scores (p > 0.05). The median ICU length of stay in the intervention group was 3.8 (2.2, 9.8) days versus 7.1 (3.1, 20) days in the placebo group (p = 0.12). The median hospital length of stay for the vitamin C group was 18 (11, 35) days versus 22 (10, 52) days for the placebo group (p = 0.65). Mortality was comparable between the two groups (p > 0.05). Of the inflammatory markers, neutrophil counts were elevated in the vitamin C group relative to placebo by 72 h (p = 0.01). C-reactive protein and myeloperoxidase concentrations were elevated at baseline, however, the two groups were comparable over time (p > 0.05).

Conclusions

Our pilot study indicated that intravenous vitamin C did not provide significant decreases in the mean dose or duration of vasopressor infusion. Further research that takes into account the potential impact of intervention timing, dose and duration, and location of trial, may provide more definitive evidence.

 

 

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

Tomoko Fujii, Georgia Salanti, Alessandro Belletti, Rinaldo Bellomo, Anitra Carr, Toshi A. Furukawa, Nora Luethi, Yan Luo, Alessandro Putzu, Chiara Sartini, Yasushi Tsujimoto, Andrew A. Udy, Fumitaka Yanase & Paul J. Young 

 

Intensive Care Medicine (2021) Published: 09 November 2021

 

We aimed to compare the effects of vitamin C, glucocorticoids, vitamin B1, combinations of these drugs, and placebo or usual care on longer-term mortality in adults with sepsis or septic shock. MEDLINE, Embase, CENTRAL, ClinicalTrials.gov and WHO-ICTRP were searched. The final search was carried out on September 3rd, 2021. Multiple reviewers independently selected randomized controlled trials (RCTs) comparing very-high-dose vitamin C (≥ 12 g/day), high-dose vitamin C (< 12, ≥ 6 g/day), vitamin C (< 6 g/day), glucocorticoid (< 400 mg/day of hydrocortisone), vitamin B1, combinations of these drugs, and placebo/usual care. We performed random-effects network meta-analysis and, where applicable, a random-effects component network meta-analysis. We used the Confidence in Network Meta-Analysis framework to assess the degree of treatment effect certainty. The primary outcome was longer-term mortality (90-days to 1-year). Secondary outcomes were severity of organ dysfunction over 72 h, time to cessation of vasopressor therapy, and length of stay in intensive care unit (ICU). Forty-three RCTs (10,257 patients) were eligible. There were no significant differences in longer-term mortality between treatments and placebo/usual care or between treatments (10 RCTs, 7,096 patients, moderate to very-low-certainty). We did not find any evidence that vitamin C or B1 affect organ dysfunction or ICU length of stay. Adding glucocorticoid to other treatments shortened duration of vasopressor therapy (incremental mean difference, − 29.8 h [95% CI − 44.1 to − 15.5]) and ICU stay (incremental mean difference, − 1.3 days [95% CI − 2.2 to − 0.3]). Metabolic resuscitation with vitamin C, glucocorticoids, vitamin B1, or combinations of these drugs was not significantly associated with a decrease in longer-term mortality.

 

Measuring vitamin C in critically ill patients: clinical importance and practical difficulties—Is it time for a surrogate marker?

 

by Sander Rozemeijer, Frans A. L. van der Horst and Angélique M. E. de Man 

 

Critical Care volume 25, Article number: 310 (2021) Published: 31 August 2021

Interest in intravenous vitamin C administration has rapidly increased in the field of critical care medicine over recent years. The first studies investigating the effect of intravenous vitamin C in septic (shock) patients showed a decrease in organ dysfunction, vasopressor dependency, and even a reduction in mortality [1,2,3]. Within a short period of time, multiple trials in septic patients were conducted to confirm these promising findings, but results were not uniform [4,5,6,7,8,9,10,11,12]. The inconsistencies in effects on outcome may partially be explained by differences in study design [8], in particular the dosing regimens (timing, duration and dose) and choice of co-medication. For example, vitamin C administration has been investigated alone, or in combination with thiamine and/or hydrocortisone, sometimes with uncontrolled use of hydrocortisone in the control group. There is also considerable variety among septic patients as sepsis is a heterogeneous syndrome. Therefore, some subgroups of patients might benefit more than others from intravenous vitamin C therapy. A recently published meta-analysis on mortality performed subgroup analyses and found a beneficial effect of vitamin C on short-term mortality (< 30 days). Additionally, survival was improved by a treatment duration of 3–4 days [13]. The results of vitamin C alone versus combination therapy were not different. A particular subgroup of interest is patients with vitamin C deficiency. None of the studies performed subgroup analyses on vitamin C deficient patients. This is unfortunate, but understandable, since the measurement of plasma vitamin C concentration is difficult.

In this chapter, we discuss the practical problems and pitfalls of measuring vitamin C and describe a novel potential surrogate marker that can estimate vitamin C status.

Letter: High-dose intravenous vitamin C may help in cytokine storm in severe SARS-CoV-2 infection

 

Letter: High-dose intravenous vitamin C may help in cytokine storm in severe SARS-CoV-2 infection

 

by Adriana Françozo de Melo and Mauricio Homem-de-Mello 

 

Critical Care volume 24, Article number: 500 (2020) 

 

The complete mechanism of action of the SARS-CoV-2 remains unclear. The severity of the disease is probably linked to the “cytokine storm” that leads to the acute respiratory distress syndrome. Cytokine storm is an overwhelming increase of several inflammatory markers at once, and it is a cause of severity in some conditions such as sepsis, acute pancreatitis, and multiple sclerosis, among others.

These conditions, characterized by a variety of inflammatory etiologies, have the common prognostic of hemodynamic abnormalities, multiple organs failure, and high mortality rates. Treatment of cytokine storm associated syndromes usually focuses in this environment: intensive care of hemodynamic parameters, uphold of damaged organs, and supervision of coagulopathy. The main cause of the cytokine induction, however, must yet be treated and is the main reason why in bacterial sepsis antibiotics are used.

High doses of intravenous vitamin C, higher than 6 g per day (however, even 15 g/day, or more, are reported), have demonstrated efficacy in treatment of sepsis and acute pancreatitis [1, 2]. To the best of our knowledge, oral formulations cannot exert the same effects.

In parenteral administration of high doses, vitamin C may decrease several inflammatory parameters (cytokines, cellular response, and homeostatic control), already observed in human and animal models. As adverse effect, ascorbic acid may cause oxalate accumulation in the kidneys that can be prevented with the concomitant use of thiamine.

Recovery Trial [3] recently finished its dexamethasone arm in severe COVID-19 patients and has shown decrease in mortality among patients that requires mechanical ventilation and support of oxygen. We are convinced about a possible synergistic effect of vitamin C and this corticosteroid.

Recently, Dr. Carr commented [4] about a new clinical trial in development in China, using intravenous vitamin C in high dose. This trial, registered by Dr. Peng (Wuhan University), is now closed, since new severe cases became rare in Wuhan. (Confirmed by Dr. Peng by e-mail, even if in clinicaltrials.gov the status of the trial is yet as “recruiting”).

Dr. Hernández and colleagues proposed a protocol including vitamin C in high dose to be used in COVID-19 patients [5]. However, the manuscript is in Spanish, decreasing the accessibility of the information.

The protocol using intravenous high dosage of vitamin C, thiamine and a glucocorticoid (as dexamethasone) seems to be useful, not expensive, with low risk of severe adverse effects. The aim is providing further discussion about the recovery of complicated cases of cytokine storm associated to the SARS-CoV-2.

The Effect of Vitamin C on Clinical Outcome in Critically Ill Patients: A Systematic Review With Meta-Analysis of Randomized Controlled Trials*

The Effect of Vitamin C on Clinical Outcome in Critically Ill Patients: A Systematic Review With Meta-Analysis of Randomized Controlled Trials*

Critical Care Medicine: June 2019 - Volume 47 - Issue 6 - p 774–783

Objectives: The effects of vitamin C administration on clinical outcome in critically ill patients remain controversial.

Data Sources: Online databases were searched up to October 1, 2018.

Study Selection: We included randomized controlled trials on the use of vitamin C (any regimen) in adult critically ill patients versus placebo or no therapy.

Data Extraction: Risk ratio for dichotomous outcome and standardized mean difference for continuous outcome with 95% CI were calculated using random-effects model meta-analysis.

Data Synthesis: Forty-four randomized studies, 16 performed in ICU setting (2,857 patients) and 28 in cardiac surgery (3,598 patients), published between 1995 and 2018, were included in the analysis. In ICU patients, vitamin C administration was not associated with a difference in mortality (risk ratio, 0.90; 95% CI, 0.74–1.10; p = 0.31), acute kidney injury, ICU or hospital length of stay compared with control. In cardiac surgery, vitamin C was associated to a reduction in postoperative atrial fibrillation (risk ratio, 0.64; 95% CI, 0.52–0.78; p < 0.0001), ICU stay (standardized mean difference, –0.28 d; 95% CI, –0.43 to –0.13 d; p = 0.0003), and hospital stay (standardized mean difference, –0.30 d; 95% CI, –0.49 to –0.10 d; p = 0.002). Furthermore, no differences in postoperative mortality, acute kidney injury, stroke, and ventricular arrhythmia were found.

Conclusions: In a mixed population of ICU patients, vitamin C administration is associated with no significant effect on survival, length of ICU or hospital stay. In cardiac surgery, beneficial effects on postoperative atrial fibrillation, ICU or hospital length of stay remain unclear. However, the quality and quantity of evidence is still insufficient to draw firm conclusions, not supporting neither discouraging the systematic administration of vitamin C in these populations. Vitamin C remains an attractive intervention for future investigations aimed to improve clinical outcome.