In a critically ill patient with severe sepsis or septic shock and normal renal function, should high‑dose intravenous vitamin C be administered, and what dosing regimen and monitoring are recommended?

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Vitamin C in Critical Care: Evidence-Based Recommendations

Primary Recommendation

Do not routinely administer high-dose intravenous vitamin C to critically ill patients with sepsis or septic shock, as current evidence demonstrates no mortality benefit and guideline consensus recommends against its use. 1, 2

Guideline-Based Position

Current Consensus Against Routine Use

  • The Surviving Sepsis Campaign pediatric guidelines (2020) explicitly recommend against ascorbic acid use in children with septic shock or sepsis-associated organ dysfunction (weak recommendation, very low quality evidence). 1

  • A 2023 international expert panel issued a conditional recommendation against intravenous vitamin C in adult sepsis patients, concluding that undesirable consequences probably outweigh desirable consequences. 2

  • Neither the 2012 nor 2016 Surviving Sepsis Campaign adult guidelines include vitamin C among recommended therapies, focusing instead on early antibiotics, source control, fluid resuscitation, and vasopressors. 3

Evidence Summary: Why Vitamin C Does Not Work

Mortality Data (The Primary Outcome That Matters)

  • The C-EASIE 2025 trial using 1.5 g IV every 6 hours for 4 days showed no reduction in organ dysfunction (SOFA score ratio 0.91,95% CI 0.77-1.08, P=0.30). 1

  • At 90-day follow-up, vitamin C probably does not impact mortality (RR 1.05,95% CI 0.94-1.17; 6 trials, n=2148, moderate certainty evidence). 2

  • A 2019 retrospective cohort found hospital mortality of 46% with vitamin C versus 40% without vitamin C (P=0.62, not significant). 4

Secondary Outcomes Show Minimal to No Benefit

  • No meaningful differences in mechanical ventilation duration, ventilator-free days, ICU length of stay, acute kidney injury, or need for renal replacement therapy. 2

  • Vitamin C may slightly reduce vasopressor duration by approximately 19 hours (MD -18.9 h, 95% CI -26.5 to -11.4), but this has not translated to improved survival or organ function. 2

  • Time to shock reversal was identical (3 days) in vitamin C versus control groups. 4

Clinical Algorithm: When to Consider Vitamin C (Rare Scenarios Only)

Step 1: Is This Standard Sepsis Management?

NO → Vitamin C is not part of standard sepsis care. Prioritize:

  • Antibiotics within 1 hour of recognition 3
  • Early quantitative resuscitation with crystalloids (minimum 30 mL/kg) 3
  • Source control 3
  • Norepinephrine as first-line vasopressor 3

Step 2: Does the Patient Have Documented Severe Vitamin C Deficiency?

YES → Consider treatment-dose vitamin C:

  • Clinical scurvy signs present (bleeding gums, petechiae, ecchymoses, perifollicular hemorrhages, poor wound healing)? 1, 5
    • Initiate oral vitamin C 100 mg three times daily for at least 1 month (do not delay for lab confirmation if clinical features present). 1, 5
    • Alternative: 250 mg twice daily for 3 weeks. 1

NO → Proceed to Step 3.

Step 3: Is the Patient Enrolled in a Research Protocol?

YES → Vitamin C administration may be appropriate within the context of informed consent and IRB-approved study. 1

NO → Proceed to Step 4.

Step 4: Is This Refractory Septic Shock After All Guideline Therapies Exhausted?

YES → Off-guideline use may be considered with full informed consent, understanding this is not evidence-based:

  • Dosing: 1.5 g IV every 6 hours for 4 days (total 6 g/day), often combined with thiamine 200 mg IV twice daily and hydrocortisone 50 mg IV every 6 hours. 1
  • Alternative: 2-3 g/day IV during acute inflammation phase. 1

NO → Do not administer vitamin C.

Critical Safety Considerations and Contraindications

Absolute Contraindications to High-Dose Vitamin C (>1 g/day)

  • Hemochromatosis or iron overload disorders (vitamin C enhances iron absorption). 1, 5
  • G6PD deficiency (risk of hemolysis). 1, 5
  • Active oxalate kidney stones or history of recurrent calcium oxalate nephrolithiasis (vitamin C metabolizes to oxalate). 1, 5
  • Severe renal dysfunction or acute kidney injury (risk of oxalate nephropathy and fatal nephrotoxicity). 1, 6

Monitoring Requirements If Vitamin C Is Used

  • Screen for contraindications before first dose. 1
  • Monitor for peripheral edema if using doses >1 g daily. 1
  • Do not measure plasma vitamin C levels during acute sepsis or inflammation (CRP >10 mg/L makes interpretation unreliable; normal values not detected if CRP >40 mg/L). 1, 6, 5

Dosing Protocols (If Used Off-Guideline)

Most Commonly Studied Regimen

  • 1.5 g IV every 6 hours for 4 days (total 6 g/day), often combined with thiamine 200 mg IV twice daily and hydrocortisone 50 mg IV every 6 hours. 1

Alternative ESPEN-Suggested Dosing

  • 2-3 g/day IV during acute phase of inflammation (Grade B recommendation, 84% consensus, though not specific to sepsis). 1, 6
  • Maximum recommended dose: 2-3 g/day IV for 4-7 days during acute critical illness only. 6

Route of Administration

  • IV administration is mandatory in critical illness (enteral absorption is unpredictable and saturates at high doses). 1, 6

Common Pitfalls and How to Avoid Them

Pitfall 1: Delaying Standard Sepsis Care

AVOID: Never delay antibiotics, source control, fluid resuscitation, or vasopressors to administer vitamin C. 1

  • Antibiotics must be given within 1 hour of septic shock recognition. 3
  • Early quantitative resuscitation (minimum 30 mL/kg crystalloid) is a cornerstone of sepsis management. 3

Pitfall 2: Measuring Plasma Vitamin C Levels in Acute Sepsis

AVOID: Plasma levels are unreliable during inflammation (CRP >10 mg/L causes falsely low results). 1, 6, 5

  • Only measure vitamin C levels in suspected scurvy or chronic low intake, not during acute critical illness. 1, 5

Pitfall 3: Using Vitamin C as Monotherapy

AVOID: If vitamin C is used off-guideline, it should be part of a combination regimen (with thiamine and hydrocortisone), as this was the original protocol studied. 1, 7

  • Vitamin C alone has been specifically shown not to improve outcomes. 4

Pitfall 4: Continuing Vitamin C Beyond Acute Phase

AVOID: If initiated, limit high-dose vitamin C to 4-7 days during acute inflammation only. 1, 6

  • Prolonged high-dose use increases risk of oxalate accumulation and renal complications. 6

Pitfall 5: Ignoring Contraindications

AVOID: Always screen for hemochromatosis, G6PD deficiency, renal dysfunction, and kidney stone history before administration. 1, 5

Special Populations Requiring Higher Vitamin C Doses (Non-Sepsis Context)

Documented Deficiency States

  • Patients with clinical scurvy: 100 mg PO three times daily for ≥1 month. 1, 5
  • Post-bariatric surgery patients: 200-500 mg/day long-term maintenance. 6, 5

Other Critical Illness Scenarios (ESPEN Context-Specific)

  • Continuous renal replacement therapy: 2-3 g/day IV (due to vitamin C loss in dialysate). 1, 6
  • Perioperative cardiac surgery: 1-2 g/day IV for 5-7 days. 1, 6

Note: These recommendations are for vitamin C deficiency prevention/repletion in specific contexts, not for sepsis treatment. 1, 6

Why Initial Enthusiasm Did Not Pan Out

The Marik Protocol and Subsequent Failures

  • Early single-center before-and-after studies suggested dramatic mortality reduction with vitamin C + thiamine + hydrocortisone, generating widespread enthusiasm. 8, 7

  • Subsequent large-scale randomized controlled trials failed to replicate these results, leading to current guideline recommendations against routine use. 1, 8, 2

  • The 2023 international expert panel concluded that small single-center trials on this topic should be discouraged. 2

Theoretical Mechanisms That Did Not Translate Clinically

  • Proposed mechanisms include prevention of microcirculatory deterioration, inhibition of platelet aggregation, restoration of vascular response to vasoconstrictors, preservation of endothelial barrier, and enhancement of antibacterial defenses. 1

  • Despite sound biological rationale, these mechanisms have not translated to significant clinical benefits in rigorous trials. 1, 9

Bottom Line for Clinical Practice

Vitamin C should not be used as routine pharmacotherapy for sepsis or septic shock. 1, 2 Focus on evidence-based sepsis management: early antibiotics, source control, appropriate fluid resuscitation, and vasopressor support. 3 Reserve vitamin C for documented deficiency states (scurvy) or consider only in refractory shock after exhausting all guideline-recommended therapies, with full understanding that this approach lacks supporting evidence. 1

References

1
Guideline

Vitamin C in Sepsis: Evidence-Based Recommendations

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2025

3
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

5
Guideline

Vitamin C Deficiency Diagnosis and Treatment

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

6
Guideline

Vitamin C Intake Guidelines

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

8
Research

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

World journal of critical care medicine, 2022

9
Research

Any Role of High-Dose Vitamin C for Septic Shock in 2021?

Seminars in respiratory and critical care medicine, 2021

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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