Vitamin C, Thiamine, and Steroids in Critical Care: The Evolution of "Metabolic Resuscitation" - Current Evidence, Controversies, and Clinical Applications

Dr Neeraj Manikath , claude.ai

Abstract

Background: The concept of "metabolic resuscitation" using high-dose vitamin C, thiamine, and corticosteroids gained significant attention following initial promising reports in septic shock. This combination therapy aims to address cellular metabolic dysfunction and oxidative stress in critically ill patients.

Objective: To provide a comprehensive review of current evidence, ongoing controversies, and practical clinical considerations regarding metabolic resuscitation in critical care.

Methods: We reviewed randomized controlled trials, meta-analyses, and observational studies published through 2024, focusing on sepsis, ARDS, and other critical care conditions.

Results: While initial enthusiasm was high, subsequent large randomized trials have shown mixed results. The VITAMINS trial, ACTS trial, and LOVIT study have provided important insights into efficacy and safety considerations.

Conclusions: Current evidence does not support routine use of high-dose metabolic resuscitation protocols. However, targeted thiamine supplementation and judicious vitamin C use may have roles in specific patient populations. Ongoing research continues to refine our understanding of metabolic approaches in critical care.

Keywords: Sepsis, vitamin C, thiamine, corticosteroids, metabolic resuscitation, critical care

Introduction

The paradigm of critical care has evolved from purely hemodynamic resuscitation to encompass cellular and metabolic restoration. The concept of "metabolic resuscitation" emerged prominently following Marik and colleagues' 2017 retrospective study, which reported dramatic mortality reduction using a combination of high-dose vitamin C (1.5g q6h), thiamine (200mg q12h), and hydrocortisone (50mg q6h) in septic shock patients.

This approach represents a shift from treating sepsis as purely an inflammatory disorder to addressing it as a state of cellular energetic failure, oxidative stress, and metabolic dysfunction. Understanding the current evidence, limitations, and appropriate clinical applications of these interventions is crucial for contemporary critical care practitioners.

Historical Context and Rationale

Pathophysiological Foundation

Cellular Energy Crisis in Sepsis

Mitochondrial dysfunction leads to cytopathic hypoxia
Impaired cellular respiration despite adequate oxygen delivery
Disruption of normal metabolic pathways

Oxidative Stress Cascade

Overwhelming reactive oxygen species (ROS) production
Depletion of endogenous antioxidant systems
Cellular membrane damage and organ dysfunction

Vitamin C Rationale

Potent antioxidant properties
Cofactor for norepinephrine synthesis
Maintains endothelial barrier function
Modulates inflammatory response

Thiamine (Vitamin B1) Rationale

Essential cofactor for cellular energy metabolism
Critical for pyruvate dehydrogenase complex
Common deficiency in critically ill patients
May improve lactate clearance

Corticosteroid Rationale

Anti-inflammatory effects
Potential metabolic benefits
Established role in septic shock (low-dose)

Current Evidence: Major Clinical Trials

Landmark Studies

1. Marik et al. (2017) - The Genesis Study

Retrospective before-after study
47 patients with septic shock
Hospital mortality: 8.5% (treatment) vs 40.4% (control)
Pearl: While compelling, retrospective design and small sample size limit generalizability

2. VITAMINS Trial (2020)

Multicenter RCT, n=216
Primary outcome: Sequential Organ Failure Assessment (SOFA) score
Result: No significant difference in organ dysfunction
Clinical Pearl: First adequately powered RCT to temper initial enthusiasm

3. ACTS Trial (2021)

Multicenter RCT, n=185
Modified HAT protocol (without thiamine)
Result: No mortality benefit, no improvement in shock reversal
Teaching Point: Highlighted importance of complete metabolic approach

4. LOVIT Study (2022)

Large RCT, n=872 septic patients
High-dose vitamin C (50mg/kg q6h) vs placebo
Result: Increased 28-day mortality in vitamin C group (RR 1.17)
Critical Insight: Challenged safety assumptions of high-dose vitamin C

Meta-Analyses and Systematic Reviews

Recent Meta-Analysis Findings (2023-2024):

Pooled analysis of 12 RCTs (n=2,500+ patients)
No significant mortality benefit (RR 0.94, 95% CI 0.82-1.08)
Possible reduction in vasopressor duration (moderate quality evidence)
Heterogeneity in protocols and patient populations

Component Analysis: Individual Agents

Vitamin C in Critical Care

Dosing Considerations:

Low dose: 1-3g/day (physiological replacement)
High dose: 6g/day (pharmacological intervention)
Ultra-high dose: >100mg/kg/day (investigational)

Clinical Evidence:

CITRIS-ALI (ARDS): Reduced mortality with 96mg/kg/day
LOVIT: Increased mortality with 200mg/kg/day in sepsis
Dose-Response Relationship: Potential "sweet spot" may exist

Practical Considerations:

Administration: IV preferred in critically ill
Timing: Early administration may be crucial
Duration: Optimal treatment duration unclear
Monitoring: Consider glucose levels (interference with glucometers)

Clinical Pearl: Consider moderate-dose vitamin C (3-6g/day) in ARDS patients, avoid ultra-high doses in sepsis pending further evidence.

Thiamine Supplementation

Deficiency in Critical Care:

Prevalence: 15-35% of ICU patients
Risk factors: Malnutrition, alcohol use disorder, chronic illness
Functional deficiency may occur despite normal blood levels

Clinical Applications:

Dosing: 200-500mg/day IV for deficient patients
Duration: Typically 3-7 days
Monitoring: Consider thiamine levels, lactate clearance

Evidence Base:

Strongest evidence for thiamine-deficient patients
May improve lactate clearance
Minimal toxicity profile

Clinical Hack: Thiamine should be given BEFORE glucose administration to prevent precipitating Wernicke's encephalopathy.

Corticosteroids in Septic Shock

Current Guidelines:

Hydrocortisone 200mg/day for refractory septic shock
Duration: Typically 3-7 days with tapering
Best evidence for patients requiring multiple vasopressors

Metabolic Effects:

Gluconeogenesis enhancement
Anti-inflammatory properties
Potential synergy with vitamin C

Clinical Pearls and Oysters

Pearls (Clinical Wisdom)

Patient Selection Matters
- Consider nutritional status and baseline deficiencies
- Thiamine supplementation most beneficial in deficient patients
- Vitamin C may be more effective in ARDS than sepsis
Timing is Critical
- Early intervention (within 6-24 hours) may be key
- Delayed therapy shows minimal benefit
- Consider as part of initial resuscitation bundle
Individualized Approach
- Not all critically ill patients are the same
- Consider comorbidities, nutritional status, severity of illness
- Avoid one-size-fits-all protocols
Safety Considerations
- Monitor for oxalate nephropathy with high-dose vitamin C
- Glucose monitoring interference with certain meters
- Thiamine is remarkably safe

Oysters (Common Pitfalls)

Assuming All Patients Benefit
- LOVIT study showed potential harm in some populations
- Well-nourished patients may not benefit from supplementation
Ignoring Drug Interactions
- Vitamin C can affect warfarin metabolism
- High-dose vitamin C may interfere with laboratory tests
Overlooking Contraindications
- G6PD deficiency (hemolysis risk with high-dose vitamin C)
- History of kidney stones
- Diabetes (glucose monitoring interference)
Protocol Rigidity
- Blindly following protocols without clinical judgment
- Continuing therapy without reassessment

Clinical Hacks and Practical Tips

Implementation Strategies

1. Risk Stratification Approach

Low Risk: Standard care, consider thiamine if malnourished
Moderate Risk: Moderate-dose vitamin C (3g/day), thiamine 200mg/day
High Risk: Consider full metabolic protocol with close monitoring

2. Monitoring Protocol

Daily SOFA score assessment
Lactate clearance trends
Vasopressor requirements
Renal function (creatinine, urine output)

3. Practical Administration Tips

Vitamin C: Dilute in 50-100mL NS, infuse over 30-60 minutes
Thiamine: Can be given IV push or in maintenance fluids
Timing: Coordinate with existing medication schedules

Decision-Making Framework

Patient with Septic Shock
↓
Assess nutritional status and risk factors
↓
Thiamine deficiency risk? → YES → Thiamine 200mg daily × 5-7 days
↓
ARDS component? → YES → Consider moderate-dose vitamin C
↓
Refractory shock? → YES → Hydrocortisone per guidelines
↓
Monitor response and reassess daily

Ongoing Research and Future Directions

Current Trials

VICTAS (Vitamin C, Thiamine, and Steroids in Sepsis)

Large multicenter RCT
Primary outcome: Ventilator and vasopressor-free days
Expected to provide definitive guidance

Precision Medicine Approaches

Biomarker-guided therapy
Genetic polymorphisms affecting vitamin C metabolism
Personalized metabolic profiling

Emerging Concepts

1. Metabolic Phenotyping

Identifying patients most likely to benefit
Biomarkers of metabolic dysfunction
Precision critical care approaches

2. Combination Synergies

Optimal dosing combinations
Timing of interventions
Duration of therapy

3. Novel Metabolic Targets

NAD+ precursors
Mitochondrial-targeted therapies
Metabolic modulators

Guidelines and Recommendations

Current Society Positions

Surviving Sepsis Campaign (2021):

No recommendation for routine vitamin C use
Weak recommendation against high-dose vitamin C
Standard recommendations for corticosteroids

Society of Critical Care Medicine:

Emphasizes individualized approach
Supports thiamine supplementation in deficient patients
Cautions against routine high-dose protocols

Proposed Clinical Algorithm

Step 1: Initial Assessment

Identify sepsis/ARDS patients
Assess nutritional status and risk factors
Consider contraindications

Step 2: Risk-Benefit Analysis

Low-risk patients: Standard care
Moderate-risk: Selective supplementation
High-risk: Consider combination therapy

Step 3: Implementation and Monitoring

Start early (ideally <24 hours)
Monitor for response and adverse effects
Reassess daily and adjust accordingly

Step 4: Duration and Weaning

Typical duration: 3-7 days
Taper based on clinical response
Continue supportive care measures

Economic Considerations

Cost-Effectiveness Analysis

Direct Costs:

Vitamin C: $10-20/day (moderate dose)
Thiamine: $5-10/day
Hydrocortisone: $15-25/day
Total: Approximately $30-55/day

Potential Savings:

Reduced ICU length of stay
Decreased vasopressor requirements
Lower complication rates

Current Economic Evidence:

Limited cost-effectiveness data
Potential for significant savings if effective
Need for formal health economic evaluations

Special Populations

Pediatric Considerations

Limited pediatric data available
Weight-based dosing protocols needed
Different metabolic demands and clearance

Pregnancy and Lactation

Safety data limited
Consider risk-benefit ratio
Standard vitamin supplementation may be sufficient

Chronic Kidney Disease

Oxalate accumulation risk with high-dose vitamin C
Dose adjustments may be necessary
Enhanced monitoring required

Practical Implementation Challenges

Healthcare System Integration

1. Protocol Development

Standardized order sets
Nursing education and competency
Pharmacy preparation and storage

2. Quality Assurance

Monitoring compliance
Outcome tracking
Adverse event reporting

3. Education and Training

Physician education programs
Nursing protocols
Interdisciplinary communication

Regulatory Considerations

FDA Status:

Vitamin C: Generally recognized as safe (GRAS)
Thiamine: Well-established safety profile
Off-label use for critical care indications

International Variations:

Availability and regulatory status vary
Cost considerations in different healthcare systems
Cultural and practice variations

Conclusions and Clinical Recommendations

Summary of Evidence

The journey of metabolic resuscitation from initial enthusiasm to current cautious optimism reflects the evolution of evidence-based critical care medicine. While the dramatic results initially reported have not been consistently reproduced in large randomized trials, important lessons have emerged:

Thiamine supplementation has the strongest evidence base, particularly in deficient patients
Moderate-dose vitamin C may have benefits in specific populations (ARDS)
High-dose protocols should be used with caution pending further evidence
Individualized approaches are likely superior to universal protocols

Clinical Practice Recommendations

For Immediate Implementation:

Assess and treat thiamine deficiency in all critically ill patients
Consider moderate-dose vitamin C in ARDS patients
Continue evidence-based corticosteroid use in septic shock
Avoid routine high-dose metabolic protocols

For Ongoing Evaluation:

Participate in registry studies when possible
Monitor emerging evidence from ongoing trials
Maintain flexibility in approach as evidence evolves

Teaching Points for Postgraduates

Critical Appraisal Skills: The metabolic resuscitation story exemplifies the importance of rigorous evaluation of promising interventions
Pathophysiology Understanding: Cellular metabolism and oxidative stress are crucial concepts in critical care
Evidence-Based Practice: How initial observational studies can generate hypotheses that require rigorous testing
Clinical Judgment: The importance of individualizing therapy based on patient characteristics and response

References

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Fujii T, Salanti G, Belletti A, et al. 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. Intensive Care Med. 2022;48(1):16-24.
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.
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.
Moskowitz A, Andersen LW, Huang DT, et al. Ascorbic acid, corticosteroids, and thiamine in sepsis: a review of the biologic rationale and the present state of clinical evaluation. Crit Care. 2018;22(1):283.
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.
Chang P, Liao Y, Guan J, et al. Combined treatment with hydrocortisone, vitamin C, and thiamine for sepsis and septic shock: a randomized controlled trial. Chest. 2020;158(1):174-182.
Donnino MW, Andersen LW, Chase M, et al. Randomized, double-blind, placebo-controlled trial of thiamine as a metabolic resuscitator in septic shock: a pilot study. Crit Care Med. 2016;44(2):360-367.
Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021;47(11):1181-1247.
Zabet MH, Mohammadi M, Ramezani M, Khalili H. Effect of high-dose ascorbic acid on vasopressor's requirement in septic shock. J Res Pharm Pract. 2016;5(2):94-100.

Conflicts of Interest: None declared.

Funding: No specific funding received for this review.

Author Contributions: Single author review and synthesis of current literature.

Tuesday, September 23, 2025