Article Identification

• Article Title: "Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock: The VITAMINS Randomized Clinical Trial"
• Citation: Fujii T, Luethi N, Young PJ, et al. JAMA. 2020;323(5):423-431.
• DOI: 10.1001/jama.2019.22176
• PMID: 31950979

Quick Reference Summary

• The VITAMINS trial assessed if intravenous vitamin C, hydrocortisone, and thiamine combined improves time alive and free of vasopressor support within seven days in septic shock patients, compared to hydrocortisone alone.
• The study found no significant difference in the primary outcome between groups (122.1 vs. 124.6 hours; median difference: –0.6 hours; 95% CI: –8.3 to 7.2 hours; P=0.83).

Core Clinical Question

Does the combination of vitamin C, hydrocortisone, and thiamine increase the duration of time alive and free of vasopressor support within seven days compared to hydrocortisone alone in patients with septic shock?

Background

• Sepsis and Septic Shock: Life-threatening organ dysfunction from infection, causing 5 million deaths annually. Septic shock increases mortality risk.
• Vitamin C in Sepsis: Studies suggest potential benefits of high-dose vitamin C, but results are inconsistent.
• Thiamine Deficiency: Present in about 20% of septic patients, linked with improved lactate clearance when supplemented.
• Corticosteroids: Hydrocortisone helps hasten shock resolution in septic shock.
• Knowledge Gaps: Unclear if adding vitamin C and thiamine to hydrocortisone is superior for septic shock.
• Study Rationale: Need for RCTs to validate combination therapy efficacy from retrospective studies.

Methods Summary

• Study Design: Multicenter, open-label, randomized.
• Setting: 10 ICUs in Australia, New Zealand, and Brazil, May 2018 - July 2019.
• Population: 216 septic shock patients.
• Inclusions/Exclusions: SOFA ≥2, lactate >2 mmol/L, vasopressors ≥2 hours. Excluded if <18 or other contraindications.
• Interventions: Vitamin C, hydrocortisone, thiamine vs. hydrocortisone only.
• Outcomes: Primary was time alive/free of vasopressors. Secondary included 90-day mortality.
• Statistics: Non-parametric, Cox regression, adjusted analyses.
• Sample Size: 216 for 90% power; 25-hour difference detectable.
• Ethics & Funding: Ethics approved, funded by various trusts.

Detailed Results

• Flow & Demographics: 216 randomized (109 intervention, 107 control), 211 completed primary result, mean age 61.7, mostly male.
• Primary Outcome:
  • Intervention: 122.1 h (IQR 76.3-145.4)
  • Control: 124.6 h (IQR 82.1-147.0)
  • Median difference: –0.6 h (95% CI, –8.3 to 7.2; P=0.83)
• Secondary Outcomes: No significant mortality differences at various time points. Slight SOFA score improvement at day 3 (>control).
• Safety: Few mild adverse events, no serious adverse events reported.

Outcome	Intervention Group	Control Group	Difference (95% CI)	P-value
Primary Outcome	122.1 h (IQR 76.3-145.4)	124.6 h (IQR 82.1-147.0)	-0.6 h (-8.3 to 7.2)	0.83
28-day Mortality	22.6%	20.4%	2.3% (-8.9 to 13.4)	0.69
90-day Mortality	28.6%	24.5%	4.1% (-8.0 to 16.1)	0.51
ICU Mortality	19.6%	18.3%	1.4% (-9.2 to 11.9)	0.80
Hospital Mortality	23.4%	20.4%	3.0% (-8.2 to 14.1)	0.60
28-day Vasopressor-Free	25.6 (IQR 17.8-26.8)	25.8 (IQR 19.6-26.8)	-0.2 (-1.7 to 1.2)	0.66
28-day Mech. Vent-Free	25.3 (IQR 5.2-28.0)	24.8 (IQR 9.5-28.0)	0.4 (-2.6 to 3.4)	0.73
28-day Renal Replacement-Free	28.0 (IQR 23.5-28.0)	28.0 (IQR 21.0-28.0)	0.0 (-0.6 to 0.6)	0.71
Change in SOFA Score at Day 3	-2 (IQR -4 to 0)	-1 (IQR -3 to 0)	-1.0 (-1.9 to -0.1)	0.02

Authors' Conclusions

The combination of intravenous vitamin C, hydrocortisone, and thiamine did not provide added benefit over hydrocortisone alone for vasopressor support freedom in septic shock patients. The addition of vitamin C and thiamine does not enhance septic shock resolution above hydrocortisone monotherapy effects.

Critical Analysis

A. Strengths

• Methodological: Multicenter design enhances generalizability; randomized controlled trial minimizes biases; rigorous statistical approach.
• Internal Validity: High protocol adherence; minimal follow-up loss ensures data reliability.
• External Validity: Inclusion of multiple centers provides applicability across various settings.
• Comprehensive Outcomes: Broad range of outcomes evaluated, including efficacy and safety measures.

B. Limitations

• Study Design: Open-label nature may introduce bias; separate assessments for individual vitamin C/thiamine effects were not conducted.
• Generalizability: Limited to high/middle-income countries; less applicability in low-resource settings.
• Statistical: Underpowered to detect some secondary outcome differences; risk of Type I error due to multiple outcomes.
• Missing Data: No imputation for missing data risks bias.
• Other Constraints: No baseline thiamine levels measured; no standardized MAP target collection.

Literature Review

A. Positioning the Current Study in Existing Evidence

The VITAMINS trial is positioned within a complex landscape of sepsis management. Early studies like Marik et al. showed substantial mortality reductions with combined vitamin C, hydrocortisone, and thiamine therapy, sparking interest. However, robust RCTs such as VICTAS, LOVIT, and ACTS, along with VITAMINS, have not replicated these results, aligning with the cautions outlined in the Surviving Sepsis Campaign guidelines.

Comparison with Supporting Trials:

• VICTAS Trial: No significant difference in vasopressor/ventilator-free days or mortality. Aligns with VITAMINS findings of no added benefit from combination therapy.
• LOVIT Trial: Higher mortality and organ dysfunction with vitamin C, contradicting early positive studies. Raises safety concerns.
• ADRENAL Trial: Supports hydrocortisone use alone, with no additional benefit from vitamins as in VITAMINS control group.
• CITRIS-ALI & ACTS Trials: Mixed or neutral results on vitamin C benefits; reinforce need for cautious interpretation of early positive findings.
• HYVITS Trial: Partial support for combination therapy, but largely contrasts VITAMINS' results.
• Meta-Analyses: Mixed results; slight outcome improvements but no consistent mortality benefits, revealing the inconsistency of support for combination therapy.
• Early Observational Studies: Early promise in reduced mortality from observational studies contrasts with the overall lack of RCT validation.

B. Comprehensive Synthesis of Findings

RCTs, including VITAMINS and others, consistently show no significant benefits from combining vitamin C, hydrocortisone, and thiamine compared to hydrocortisone alone. Potential minor benefits in vasopressor duration have not translated into meaningful clinical gains. LOVIT trial outcomes highlight possible safety concerns with high-dose vitamin C, urging careful consideration of routine combination therapy use. Meta-analyses confirm the inconsistency, with no substantial mortality advantages.

Clinical Applicability: These results align with SSC guidelines. Resources should be allocated to proven therapies, not combination regimens lacking definitive evidence.

C. Gaps and Future Directions

• Subgroup Identification: Need to identify potential benefit-bearing subgroups.
• Optimal Dosing and Timing: Requires standardization across studies to ascertain potential benefits.
• Long-term Outcomes: Further investigation needed into cognitive and functional consequences.
• Combination vs. Individual Effects: Elucidating the individual contributions of treatment components beneficial.

Large-scale, well-designed RCTs focusing on these gaps are fundamental to advancing septic shock management nuances.

Clinical Application

• The VITAMINS trial findings indicate that adding vitamin C and thiamine does not enhance treatment benefits of hydrocortisone alone for septic shock.
• Adherence to Surviving Sepsis Campaign guidelines is recommended, focusing on proven interventions like antibiotics, fluid resuscitation, and corticosteroid use.

How To Use This Info In Practice

Practitioners should continue utilizing hydrocortisone per guidelines and refrain from adding vitamin C and thiamine until further evidence emerges supporting their benefit. Ongoing trials and meta-analyses should be monitored for future therapeutic updates.