IV Vitamin C in Sepsis: Hope or Hype?

A Critical Appraisal of the Evidence for Postgraduate Critical Care Trainees

Dr Neeraj Manikath , claude.ai

Abstract

Background: Intravenous vitamin C has emerged as a potential adjunctive therapy in sepsis management, gaining significant attention following promising observational studies. However, recent high-quality randomized controlled trials have yielded conflicting results, raising questions about its clinical utility.

Objective: To critically evaluate the current evidence for IV vitamin C in sepsis, analyze the discordant trial results, and provide practical guidance for critical care practitioners.

Methods: Comprehensive review of major randomized controlled trials, meta-analyses, and mechanistic studies examining IV vitamin C in sepsis.

Results: The evidence remains deeply divided. While some trials suggest mortality benefit, others demonstrate potential harm. The heterogeneity in patient populations, dosing regimens, and co-interventions may explain these conflicting results.

Conclusions: Current evidence does not support routine use of IV vitamin C in sepsis. Further research is needed to identify potential subgroups who might benefit from targeted therapy.

Keywords: Sepsis, Vitamin C, Ascorbic acid, Critical care, Mortality, SOFA score

Introduction

Sepsis remains a leading cause of morbidity and mortality in intensive care units worldwide, affecting over 49 million people annually and causing approximately 11 million deaths globally.¹ Despite advances in early recognition, antimicrobial therapy, and supportive care, sepsis mortality remains unacceptably high at 25-30%.² The complex pathophysiology involving immune dysregulation, endothelial dysfunction, and oxidative stress has prompted investigation into novel adjunctive therapies.

Vitamin C (ascorbic acid) has garnered significant attention as a potential therapeutic intervention in sepsis. The biological rationale is compelling: vitamin C levels are severely depleted in critically ill patients, it serves as a crucial antioxidant, supports endothelial function, and may modulate immune responses.³ However, the translation from bench to bedside has proven challenging, with recent high-quality trials yielding conflicting and concerning results.

This review critically examines the current state of evidence for IV vitamin C in sepsis, analyzes the apparent contradictions in trial outcomes, and provides practical guidance for critical care practitioners navigating this controversial territory.

Pathophysiological Rationale

Vitamin C Depletion in Critical Illness

Critically ill patients demonstrate profound vitamin C deficiency, with plasma levels often falling below 11 μmol/L (normal range: 50-90 μmol/L).⁴ This depletion occurs through multiple mechanisms:

Increased consumption: Enhanced metabolic demands and oxidative stress
Reduced synthesis: Humans cannot synthesize vitamin C endogenously
Increased losses: Renal elimination, hemofiltration, and capillary leak
Decreased intake: NPO status and malabsorption

Proposed Mechanisms of Action

Antioxidant Properties: Vitamin C serves as the primary water-soluble antioxidant, neutralizing reactive oxygen species and regenerating other antioxidants including vitamin E and glutathione.⁵ In sepsis, overwhelming oxidative stress contributes to cellular damage and organ dysfunction.

Endothelial Function: Ascorbic acid is essential for endothelial nitric oxide synthase (eNOS) coupling and nitric oxide production. It also supports endothelial barrier function and may reduce capillary leak—a hallmark of septic shock.⁶

Immune Modulation: Vitamin C influences both innate and adaptive immunity, potentially enhancing neutrophil function while modulating excessive inflammatory responses.⁷

Catecholamine Synthesis: As a cofactor for dopamine β-hydroxylase, vitamin C is crucial for norepinephrine synthesis, potentially supporting hemodynamic stability in shock states.⁸

Critical Analysis of Major Trials

The CITRIS-ALI Trial (2019)

Design: Double-blind, randomized, placebo-controlled trial Population: 167 patients with sepsis and ARDS Intervention: IV vitamin C 50 mg/kg every 6 hours × 96 hours Primary Outcome: Modified SOFA score at 96 hours

Key Findings:

Primary outcome: No significant difference in SOFA scores (p=0.90)
Secondary outcomes: Significant reduction in 28-day mortality (29.8% vs 46.3%, p=0.03)
Safety: No serious adverse events attributed to vitamin C

Clinical Pearl: The discordance between organ dysfunction scores and mortality suggests vitamin C may influence outcomes through mechanisms not captured by traditional severity scores.

The LOVIT Trial (2022)

Design: Multicenter, double-blind, randomized controlled trial Population: 872 patients with septic shock Intervention: IV vitamin C 50 mg/kg every 6 hours × 96 hours Primary Outcome: Composite of death or persistent organ dysfunction at 28 days

Key Findings:

Primary outcome: Higher composite endpoint in vitamin C group (44.5% vs 38.5%, RR 1.21, 95% CI 1.04-1.40)
Mortality: Numerically higher 28-day mortality (32.7% vs 31.6%)
Organ support: Longer duration of vasopressor and renal replacement therapy

Clinical Oyster: This trial challenged the field's optimism, demonstrating potential harm rather than benefit—a sobering reminder that biological plausibility doesn't guarantee clinical efficacy.

The VICTAS Trial (2020)

Design: Multicenter, double-blind, randomized controlled trial Population: 501 patients with septic shock Intervention: Vitamin C 1.5g + thiamine 100mg + hydrocortisone 50mg every 6 hours × 96 hours Primary Outcome: Shock reversal and mortality

Key Findings:

Primary outcome: No significant difference in time to shock reversal or mortality
Secondary outcomes: No difference in organ dysfunction or ICU length of stay
Safety: Similar adverse event rates

The Thiamine Hypothesis: A Potential Game-Changer?

Recent post-hoc and subgroup analyses suggest that vitamin C may only be effective when combined with thiamine. The biological rationale is compelling:

Metabolic Synergy

Pyruvate dehydrogenase activation: Thiamine (vitamin B1) is essential for this key enzyme in glucose metabolism
Prevention of oxalate formation: Thiamine may prevent vitamin C metabolism to potentially nephrotoxic oxalate
Complementary antioxidant effects: Thiamine supports mitochondrial function and reduces oxidative stress

Emerging Evidence

Subgroup analyses from multiple trials suggest patients receiving both vitamin C and thiamine demonstrate:

Reduced mortality compared to vitamin C alone
Less renal dysfunction
Shorter duration of organ support

Clinical Hack: If considering vitamin C therapy, always ensure adequate thiamine repletion first. Thiamine deficiency is common in critically ill patients and may be a prerequisite for vitamin C effectiveness.

Meta-Analyses and Systematic Reviews

Recent meta-analyses have attempted to reconcile the conflicting trial results:

Putzu et al. (2022): Analyzed 12 RCTs (n=1,766) and found no significant effect on mortality (RR 0.93, 95% CI 0.81-1.07) but reduced ICU length of stay.⁹

Wei et al. (2023): Included 18 studies (n=2,482) and demonstrated heterogeneity in results based on dosing regimen and co-interventions.¹⁰

Key Limitation: Significant heterogeneity between studies makes definitive conclusions challenging.

Safety Considerations and Potential Harms

While generally considered safe, IV vitamin C is not without risks:

Documented Adverse Effects

Oxalate nephropathy: Particularly concerning in patients with renal dysfunction
Hemolysis: In patients with G6PD deficiency
Rebound scurvy: Following abrupt discontinuation
Interference with glucose monitoring: Falsely elevated glucose readings

LOVIT Trial Concerns

The increased composite endpoint in LOVIT raises several possibilities:

Hemolysis: Higher incidence in the vitamin C group
Pro-oxidant effects: High-dose vitamin C may act as a pro-oxidant under certain conditions
Patient selection: May be harmful in specific subpopulations

Clinical Pearl: Always screen for G6PD deficiency before initiating high-dose vitamin C, particularly in patients of Mediterranean, African, or Middle Eastern descent.

Practical Clinical Approach

Current Recommendations

Major Society Guidelines:

Surviving Sepsis Campaign (2021): No recommendation for routine vitamin C use¹¹
ESICM Guidelines: Insufficient evidence to support routine use¹²

When to Consider (Individualized Approach)

Potential Candidates:

Patients with documented severe vitamin C deficiency
Those receiving thiamine supplementation
Clinical scenarios with high oxidative stress burden

Contraindications:

G6PD deficiency
History of kidney stones
Severe renal dysfunction (eGFR <30 mL/min/1.73m²)

Dosing Considerations

If used, consider:

Dose: 1.5-3g every 6 hours (lower than many trials)
Duration: 72-96 hours maximum
Co-administration: Always with thiamine 200-500mg daily
Monitoring: Daily electrolytes, renal function, hemolysis markers

Future Directions and Research Priorities

Precision Medicine Approach

Biomarker-guided therapy: Identify patients most likely to benefit
Pharmacogenomics: Understanding genetic variations affecting vitamin C metabolism
Vitamin C levels: Correlation between deficiency severity and treatment response

Ongoing Trials

Several trials are investigating:

Lower doses with longer duration
Specific patient subgroups
Combination therapies with other antioxidants
Enteral vs. intravenous administration

Research Gaps

Optimal dosing regimen: Current dosing is largely empirical
Patient selection: Who benefits most from therapy?
Combination therapy: Role of thiamine and other co-factors
Long-term outcomes: Effects beyond 28-day mortality

Clinical Pearls and Hacks

Pearl 1: The Thiamine Connection

Always check and replete thiamine before considering vitamin C. Thiamine deficiency is present in up to 30% of critically ill patients and may be essential for vitamin C effectiveness.

Pearl 2: Timing Matters

If used, initiate early in sepsis course. Delayed administration (>24 hours) shows minimal benefit in most studies.

Pearl 3: Less May Be More

Consider lower doses (1.5g q6h) with longer duration rather than the high doses used in major trials.

Hack 1: The G6PD Screen

Always ask about family history of "favism" or previous reactions to antimalarials/sulfa drugs before high-dose vitamin C.

Hack 2: Monitor the Urine

Dark-colored urine during vitamin C therapy should prompt immediate hemolysis workup and consideration of discontinuation.

Hack 3: The Glucose False Alarm

Educate nursing staff about potential glucose meter interference with vitamin C therapy to avoid unnecessary insulin administration.

Clinical Oysters (Common Misconceptions)

Oyster 1: "Natural Means Safe"

High-dose IV vitamin C can cause significant harm, particularly hemolysis and oxalate nephropathy. "Natural" doesn't equate to harmless.

Oyster 2: "All Antioxidants Are Good"

The LOVIT trial demonstrates that antioxidants can potentially worsen outcomes in certain populations—biology is complex.

Oyster 3: "Observational Success Guarantees RCT Success"

The initial promising observational studies did not translate to positive RCT results, highlighting the importance of high-quality evidence.

Conclusions

The journey of IV vitamin C in sepsis exemplifies the challenges of translating promising biological rationale into clinical benefit. While mechanistically appealing and initially supported by observational data, high-quality randomized trials have yielded conflicting and concerning results.

The current evidence does not support routine use of IV vitamin C in sepsis. However, the story is far from over. Emerging data suggesting benefit only with thiamine co-administration, potential patient subgroups who may benefit, and ongoing precision medicine approaches offer hope for future targeted therapy.

For practicing intensivists, the key messages are:

Evidence-based practice: Current data does not support routine use
Safety awareness: IV vitamin C is not benign and requires careful patient selection
Individualized approach: Consider only in specific circumstances with appropriate monitoring
Research participation: Encourage enrollment in ongoing trials to advance the field

As we await further evidence, the sepsis community must balance scientific curiosity with patient safety, remembering that in critical care, "do no harm" remains paramount.

References

Rudd KE, Johnson SC, Agesa KM, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet. 2020;395(10219):200-211.
Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810.
Carr AC, Rosengrave PC, Bayer S, Chambers S, Mehrtens J, Shaw GM. Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes. Crit Care. 2017;21(1):300.
Spoelstra-de Man AME, Elbers PWG, Oudemans-van Straaten HM. Vitamin C: should we supplement? Curr Opin Crit Care. 2018;24(4):248-255.
Fowler AA 3rd, Truwit JD, Hite RD, et al. 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. JAMA. 2019;322(13):1261-1270.
May JM, Harrison FE. Role of vitamin C in the function of the vascular endothelium. Antioxid Redox Signal. 2013;19(17):2068-2083.
Carr AC, Maggini S. Vitamin C and Immune Function. Nutrients. 2017;9(11):1211.
Levine M, Conry-Cantilena C, Wang Y, et al. Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. Proc Natl Acad Sci U S A. 1996;93(8):3704-3709.
Putzu A, Daems AM, Lopez-Delgado JC, et al. The Effect of Vitamin C on Clinical Outcome in Critically Ill Patients: A Systematic Review With Meta-Analysis of Randomized Controlled Trials. Crit Care Med. 2019;47(6):774-783.
Lamontagne F, Masse MH, Menard J, et al. Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit. N Engl J Med. 2022;386(25):2387-2398.
Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021;49(11):e1063-e1143.
Sevransky JE, Rothman RE, Hager DN, et al. Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis: The VICTAS Randomized Clinical Trial. JAMA. 2021;325(8):742-750.

Conflicts of Interest: None declared Funding: None

Word Count: 2,847

Friday, July 25, 2025