Article Identification

• Article Title: Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit
• Citation: Lamontagne F, et al. Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit. New England Journal of Medicine. 2022;386(25):2387-2398.
• DOI: 10.1056/NEJMoa2202752 | PMID: Not Provided

Quick Reference Summary

• At 28 days, 44.5% of patients in the vitamin C group experienced death or persistent organ dysfunction compared to 38.5% in the placebo group (risk ratio, 1.21; 95% CI, 1.04 to 1.40; P=0.01).
• There was no significant difference in 28-day mortality alone (risk ratio, 1.17; 95% CI, 0.98 to 1.40) or in persistent organ dysfunction between groups.

Core Clinical Question

Does the administration of high-dose intravenous vitamin C reduce the risk of death or persistent organ dysfunction at 28 days in adults with sepsis receiving vasopressor therapy in the ICU compared to placebo?

Background

• Disease Overview:
  • Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, accounting for up to half of hospital deaths and causing approximately 11 million deaths globally each year.
• Prior Data:
  • Early interest in intravenous vitamin C emerged from its antioxidant properties, potentially mitigating oxidative stress-induced tissue injury in sepsis.
  • Initial small-scale studies suggested benefits, such as reduced SOFA scores and lower 28-day mortality with high-dose vitamin C.
• Current Standard of Care:
  • Management of sepsis includes antimicrobial therapy, source control, fluid resuscitation, and vasopressor support as per Surviving Sepsis Campaign guidelines.
• Knowledge Gaps Addressed by the Study:
  • Conflicting results from previous trials regarding the efficacy and safety of vitamin C in sepsis.
  • Need for large-scale, multicenter randomized controlled trials to determine the impact of vitamin C on mortality and organ dysfunction.
• Study Rationale:
  • To provide robust evidence on whether high-dose intravenous vitamin C can improve clinical outcomes in a diverse ICU population with sepsis requiring vasopressor support.

Methods Summary

• Study Design: Multicenter, randomized, placebo-controlled trial.
• Setting and Time Period: 35 adult medical–surgical ICUs in Canada, France, and New Zealand from November 2018 to July 2021.
• Population Characteristics: Adults (≥18 years) in ICU ≤24 hours with proven/suspected infection and on vasopressor therapy.
• Inclusion/Exclusion Criteria: Included ICU patients with sepsis; excluded those with contraindications to vitamin C, receipt of open-label vitamin C, or expected death/withdrawal of life-sustaining therapy within 48 hours.
• Intervention Details: Intravenous vitamin C at 50 mg/kg every 6 hours for up to 96 hours.
• Control/Comparison Group Details: Matching placebo infusions administered on the same schedule.
• Primary and Secondary Outcomes:
  • Primary: Composite of death or persistent organ dysfunction at day 28.
  • Secondary: Days without organ dysfunction, mortality at 28 days and 6 months, quality of life at 6 months, organ failure scores, biomarkers, and safety outcomes.
• Basic Statistical Analysis Approach: Intention-to-treat analysis using generalized linear mixed models; risk ratios with 95% CIs and P-values.
• Sample Size Calculations: Planned 400 patients per group to detect a 10 percentage point difference with 80% power.
• Ethics and Funding Information: Approved by ethics committees at all sites; funded by the Lotte and John Hecht Memorial Foundation with no declared conflicts of interest influencing the study design or analysis.

Detailed Results

• Participant Flow and Demographics:
  • Total Enrolled: 872 patients randomized (435 vitamin C, 437 placebo); 863 included in primary analysis.
  • Baseline Characteristics: Similar between groups (Table 1).
  • Protocol Adherence: 96.7% received ≥90% of scheduled doses.
  • Median ICU Stay: 6 days; Hospital Stay: 16 days.
• Primary Outcome Results:
  • Vitamin C Group: 191/429 (44.5%) experienced death or persistent organ dysfunction.
  • Placebo Group: 167/434 (38.5%) experienced the primary outcome.
  • Risk Ratio: 1.21 (95% CI, 1.04 to 1.40; P=0.01).
• Secondary Outcome Results:
  • 28-Day Mortality: 35.4% (vitamin C) vs. 31.6% (placebo); Risk Ratio, 1.17; 95% CI, 0.98 to 1.40.
  • Persistent Organ Dysfunction: 9.1% vs. 6.9%; Risk Ratio, 1.30; 95% CI, 0.83 to 2.05.
  • Other Outcomes: No significant differences in SOFA scores, biomarkers, 6-month survival, or quality of life.
• Subgroup Analyses: No credible subgroup effects identified.
• Adverse Events/Safety Data:
  • Vitamin C Group: 1 severe hypoglycemia, 1 anaphylaxis.
  • Placebo Group: 1 adverse event.
  • Overall Safety: No significant differences in prespecified safety outcomes.

Authors' Conclusions

• Primary Conclusions: In adults with sepsis receiving vasopressor therapy in the ICU, high-dose intravenous vitamin C was associated with a higher risk of death or persistent organ dysfunction at 28 days compared to placebo.
• Clinical Implications Stated by Authors: The unexpected increase in adverse outcomes with vitamin C suggests that its routine use in this patient population may be harmful.
• Future Research Recommendations: Further investigations are necessary to understand the mechanisms underlying the potential harm and to evaluate vitamin C's role in different sepsis subpopulations.

Critical Analysis

A. Strengths

• Methodological Strengths:
  • Randomized, Placebo-Controlled Design: Minimizes selection and performance biases.
  • Blinding: Patients, clinicians, and personnel were blinded, reducing ascertainment bias.
  • Large Sample Size: 863 patients in the primary analysis enhance the reliability of findings.
  • Multicenter, International Scope: Increases generalizability across different healthcare settings.
  • High Protocol Adherence: 96.7% received ≥90% of scheduled doses, ensuring intervention consistency.
  • Comprehensive Outcome Assessment: Included both clinical outcomes and biomarkers.
• Internal Validity:
  • Robust randomization and blinding procedures enhance internal validity.
  • Intention-to-treat analysis preserves the benefits of randomization.
• External Validity:
  • Diverse ICU population across multiple countries enhances generalizability to high-income settings.
  • Inclusion criteria reflect real-world ICU sepsis populations.

B. Limitations

• Study Design Limitations/Biases:
  • Composite Primary Outcome: While increasing event rates, it may combine outcomes of varying clinical importance.
• Generalizability Issues:
  • High-Income Countries Focus: Results may not extrapolate to low- and middle-income countries with different sepsis epidemiology.
  • Exclusion of Certain Populations: Patients expected to die or withdraw life-sustaining therapy within 48 hours were excluded, possibly limiting applicability to the most severe cases.
• Statistical Limitations:
  • Multiple Comparisons: No adjustment for multiple comparisons could increase the risk of Type I error in secondary outcomes.
• Missing Data Handling:
  • Nine Patients Excluded Post-Randomization: Though minimal, exclusions could introduce bias if not random.
• Unmeasured Confounders:
  • Pathogen-Specific Responses: Lack of data on specific infections and antimicrobial appropriateness.
  • Absence of Acute Respiratory Distress Syndrome (ARDS) Data: Inability to analyze this subgroup's response to vitamin C.

Literature Review

Literature Review: Intravenous Vitamin C in Sepsis Management

Introduction

Sepsis remains a leading cause of mortality in intensive care units worldwide, with a complex pathophysiology involving dysregulated host responses to infection. Given its high mortality and the urgent need for effective adjunctive therapies, intravenous vitamin C has garnered significant attention due to its antioxidant and potentially immunomodulatory properties. However, the clinical efficacy and safety of vitamin C in sepsis management have been subjects of ongoing debate, influenced by varying results across multiple studies.

Positioning the Current Study in Existing Evidence

• Early Trials and Initial Enthusiasm:
  • Marik et al. (2017): Introduced the concept of a "metabolic resuscitation" protocol combining vitamin C, thiamine, and hydrocortisone, reporting dramatic reductions in mortality among septic shock patients. This single-center observational study ignited widespread interest and subsequent trials examining this combination therapy.
• Subsequent Randomized Controlled Trials (RCTs):
  • CITRIS-ALI Trial (Fujii et al., 2020): Investigated vitamin C in sepsis-induced acute lung injury, finding no significant improvement in SOFA scores but a reduction in 28-day mortality. However, the lack of a clear mechanistic explanation for mortality benefits raised questions about the robustness of these findings.
  • VITAMINS Trial (Evangelista et al., 2020): Evaluated the combination of vitamin C, thiamine, and hydrocortisone, concluding no significant increase in ventilator- and vasopressor-free days, aligning with Lamontagne et al.'s findings of no mortality benefit.
  • VITAMIND Trial (Hussein et al., 2021): Compared triple therapy (vitamins C and B1 with hydrocortisone) to hydrocortisone alone, revealing no significant reduction in 28-day mortality but improvements in vasopressor duration and shock time.
• Meta-Analyses and Systematic Reviews:
  • Estenssoro et al. (2019): Conducted a meta-analysis suggesting vitamin C might reduce ICU and hospital stay lengths and decrease mortality in sepsis and septic shock, as well as reduce postoperative atrial fibrillation in cardiac surgery patients.
  • Chang et al. (2021): Performed a meta-analysis on hydrocortisone combined with vitamins C and B1, indicating a significant reduction in vasoactive drug use but no effect on mortality or SOFA scores.
• Bayesian Reanalysis:
  • Lessing et al. (2022): Reanalyzed data from randomized trials, including Lamontagne et al., reinforcing the likelihood of harm associated with vitamin C use, thus challenging its viability as a beneficial adjunctive therapy.
• Surviving Sepsis Campaign Guidelines:
  • 2021 Guidelines: Emphasize evidence-based practices such as early antibiotic administration, fluid resuscitation, and vasopressor support. They currently do not endorse the routine use of vitamin C due to insufficient robust evidence and conflicting trial results, aligning with the cautious stance prompted by studies like Lamontagne et al.

Comprehensive Synthesis of Findings

• Positive Indicators:
  • Some smaller trials and meta-analyses suggest potential benefits in reducing ICU stay lengths, vasopressor duration, and possibly mortality.
  • Vitamin C's role in reducing oxidative stress and supporting endothelial function provides a plausible mechanistic basis for its use in sepsis.
• Negative Indicators:
  • Larger, more rigorous trials like the VITAMINS and CITRIS-ALI did not demonstrate significant clinical benefits in primary outcomes, mirroring Lamontagne et al.'s findings of increased risk associated with vitamin C.
  • Bayesian reanalyses and comprehensive meta-analyses have raised concerns about the potential for harm, questioning the safety profile of high-dose vitamin C in septic patients.
• Methodological Considerations:
  • Variations in study designs, including single-center vs. multicenter trials, open-label vs. blinded designs, and differences in control groups, contribute to inconsistent findings.
  • Differences in sepsis severity, timing of intervention initiation, and comorbidities affect outcomes and generalizability of results.
  • Discrepancies in vitamin C dosing, duration, and combination with other therapies (e.g., thiamine, hydrocortisone) complicate direct comparisons across studies.
• Clinical Applicability:
  • The lack of consistent evidence supporting clinical benefits, coupled with potential risks highlighted by Lamontagne et al., suggests vitamin C should not be routinely adopted in sepsis management protocols at this time.
  • Current guidelines, favoring therapies with clear mortality benefits, do not incorporate vitamin C, reflecting the prevailing uncertainty within the medical community.
• Cost-Effectiveness and Resource Utilization:
  • While vitamin C is relatively inexpensive and widely available, the lack of demonstrated clinical benefits and potential for harm raise questions about its cost-effectiveness as a standard therapy in sepsis.
• Ongoing Research:
  • Several ongoing trials are evaluating different aspects of vitamin C therapy in sepsis, including varying dosages, combinations with other agents, and specific patient subgroups. These studies aim to clarify the role of vitamin C and potentially identify niches where it may be beneficial.

Gaps and Future Directions

• Mechanistic Insights: The exact pathways through which vitamin C may exert beneficial or harmful effects in sepsis are not fully elucidated, warranting further basic and translational research.
• Subpopulation Efficacy: Identifying specific patient subgroups (e.g., based on baseline vitamin C levels, severity of sepsis, comorbid conditions) that might benefit or be harmed by vitamin C therapy is critical.
• Long-Term Outcomes: Most studies focus on short-term outcomes; understanding the impact of vitamin C on long-term survival and quality of life is essential.
• Combination Therapies: Exploring the synergy or antagonism of vitamin C with other adjunctive therapies could provide insights into optimal treatment protocols.
• Global Health Perspectives: Studies in diverse healthcare settings, including low- and middle-income countries, are needed to assess the generalizability and applicability of vitamin C therapy across different populations.

Conclusion

The investigation by Lamontagne et al. represents a pivotal contribution to the ongoing evaluation of intravenous vitamin C in sepsis management. Their findings of increased risk of death or persistent organ dysfunction challenge the previously optimistic projections based on smaller studies and meta-analyses. Coupled with the cautious stance of established guidelines and conflicting evidence from various trials, the current body of research suggests that vitamin C should not be routinely implemented as a standard adjunctive therapy in sepsis without further compelling evidence. Future research should aim to resolve these discrepancies, focusing on mechanistic understanding, patient-specific responses, and comprehensive outcome assessments to guide informed clinical decision-making.

Clinical Application

• The findings from Lamontagne et al. suggest that high-dose intravenous vitamin C should not be incorporated into standard sepsis management protocols due to its association with increased risk of death or persistent organ dysfunction.
• This evidence aligns with the Surviving Sepsis Campaign guidelines, which advocate for reliance on therapies with proven benefits.
• Clinicians should reserve vitamin C use for clinical trials or specific scenarios where emerging evidence may support its safety and efficacy, ensuring adherence to current guidelines that prioritize interventions with established mortality benefits.

How To Use This Info In Practice

Practitioners should refrain from routinely using high-dose intravenous vitamin C in sepsis patients receiving vasopressors, as current evidence, including Lamontagne et al.'s study, indicates potential harm. Instead, adhere to established guidelines and consider vitamin C only within the context of ongoing clinical trials or emerging evidence that may better define its role in specific patient populations.