LOVIT: Vitamin C in Sepsis (2022)

“In adult patients with sepsis receiving vasopressor therapy in the ICU, treatment with an intravenous infusion of vitamin C did not lead to a lower risk of death or persistent organ dysfunction at 28 days than treatment with placebo.”

  • The LOVIT Investigators

1. Publication Details

  • Trial Title: Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit
  • Citation: 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. DOI: 10.1056/NEJMoa2200644
  • Published: June 23, 2022, in The New England Journal of Medicine
  • Author: François Lamontagne, M.D., M.Sc.
  • Funding: The Lotte and John Hecht Memorial Foundation; Canadian Institutes of Health Research; and others.

2. Keywords

  • Sepsis, Septic Shock, Vitamin C, Ascorbic Acid, Organ Dysfunction, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with sepsis who are receiving vasopressor therapy in the ICU (Population), does a high-dose intravenous infusion of vitamin C (Intervention) compared to placebo (Comparison) reduce the composite risk of death or persistent organ dysfunction at 28 days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Sepsis is characterized by a profound inflammatory response and oxidative stress. Vitamin C is a potent antioxidant, and it was hypothesized that high doses could mitigate this pathological process. The CITRIS-ALI trial (2019), while negative for its primary outcome, had shown a surprising and controversial reduction in 28-day mortality as a secondary outcome.
  • Knowledge Gap: A large, definitive randomized controlled trial, powered for a patient-centered clinical outcome, was urgently needed to confirm or refute the potential life-saving benefit of high-dose vitamin C in sepsis suggested by the CITRIS-ALI trial.
  • Proposed Hypothesis: The authors hypothesized that high-dose intravenous vitamin C would be superior to placebo in reducing the risk of death or persistent organ dysfunction at 28 days.

5. Study Design and Methods

  • Design: A multicenter, international, prospective, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: 35 intensive care units (ICUs) in Canada, France, and New Zealand.
  • Trial Period: Enrollment ran from March 2018 to September 2021.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) admitted to the ICU with a proven or suspected infection who were receiving a vasopressor infusion for at least 2 hours.
    • Exclusion Criteria: Included known allergy to vitamin C, pregnancy, and a history of oxalate kidney stones.
  • Intervention: Patients received a continuous intravenous infusion of vitamin C (50 mg/kg) every 6 hours for 96 hours.
  • Control: Patients received a matching intravenous placebo (5% dextrose or 0.9% saline).
  • Management Common to Both Groups: All other aspects of care for sepsis were at the discretion of the treating clinicians according to local guidelines.
  • Power and Sample Size: The authors calculated that a sample size of 800 patients would provide 90% power to detect a 9% absolute risk reduction in the primary outcome. (Power is a study’s ability to find a real difference between treatments if one truly exists; 90% power means the study had a 90% chance of detecting the specified effect, which is considered very high).
  • Outcomes:
    • Primary Outcome: A composite of death or persistent organ dysfunction (defined as continued vasopressor support, dialysis, or mechanical ventilation) at 28 days.
    • Secondary Outcomes: Included 28-day mortality, 6-month mortality, and organ dysfunction scores.

6. Key Results

  • Enrollment and Baseline: 872 patients were randomized (435 to vitamin C and 437 to placebo). The groups were well-matched at baseline.
  • Trial Status: The trial was stopped for harm by the data and safety monitoring board after a pre-planned interim analysis, based on a higher incidence of the primary outcome and death in the vitamin C group.
  • Primary Outcome: The primary composite outcome of death or persistent organ dysfunction at 28 days was significantly higher in the vitamin C group: 191 of 429 patients (44.5%) in the vitamin C group met the primary endpoint, compared with 166 of 431 patients (38.5%) in the placebo group (p=0.07).
  • Secondary Outcomes: 28-day mortality was also higher in the vitamin C group (35.4% vs. 31.6%).
  • Adverse Events: The primary adverse events were death and persistent organ dysfunction, which were more common in the vitamin C group.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a Bayesian statistical model.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of patients who met the composite endpoint between the two groups.
  • Key Statistic(s) Reported: Relative Risk (RR) for the primary outcome: 1.21 (95% CI, 1.04 to 1.40).
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk in Intervention Group) / (Risk in Control Group).
      • Calculation: The paper reports the result as 1.21.
      • Clinical Meaning: The RR of 1.21 means that patients in the vitamin C group had a 21% higher relative risk of dying or having persistent organ dysfunction at 28 days compared to the placebo group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 1.04 to 1.40.
      • Clinical Meaning: Since this entire range is above the line of no effect (1.0), it suggests that the result is statistically significant and demonstrates a clear signal of harm.
  • Clinical Impact Measures:
    • Absolute Risk Increase (ARI):
      • Formula: ARI = (Risk in Intervention Group) – (Risk in Control Group)
      • Calculation: ARI = 44.5% – 38.5% = 6.0%.
      • Clinical Meaning: For every 100 patients with sepsis treated with high-dose vitamin C, about 6 additional patients died or had persistent organ failure.
    • Number Needed to Harm (NNH):
      • Formula: NNH = 1 / ARI
      • Calculation: NNH = 1 / 0.06 = 16.7, which is rounded up to 17.
      • Clinical Meaning: You would only need to treat 17 patients with this vitamin C regimen to cause one additional case of death or persistent organ dysfunction.
  • Subgroup Analyses: The signal of harm was consistent across all pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The large, multicenter, randomized, double-blind, placebo-controlled design is the gold standard and provided a massive amount of high-quality data.
  • Generalizability: The pragmatic design and inclusion of 35 diverse ICUs across three countries make the findings highly generalizable to a wide range of patients with sepsis.
  • Statistical Power: The study was large and adequately powered, and ultimately found a clear signal of harm.
  • Patient-Centered Outcomes: The primary outcome was a composite of death and persistent organ dysfunction, which are robust and highly relevant patient-centered endpoints.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a very low risk of bias.
  • External Validity (Generalizability): The findings are highly generalizable to the broad population of patients with sepsis requiring vasopressor support.
  • Other: The trial was stopped early for harm, which was ethically necessary.

10. Conclusion of the Authors

  • The authors concluded that in critically ill patients with sepsis receiving vasopressor therapy, intravenous vitamin C did not lead to a lower risk of death or persistent organ dysfunction and may be harmful.

11. To Summarize

  • Impact on Current Practice: This was a profoundly practice-changing trial. It provided definitive evidence that high-dose intravenous vitamin C is not beneficial and may be harmful in patients with sepsis. It effectively ended the widespread enthusiasm and off-label use of this therapy that had been generated by the CITRIS-ALI trial.
  • Specific Recommendations:
    • Patient Selection: For adult patients with sepsis requiring vasopressor support.
    • Actionable Intervention: Do not administer high-dose intravenous vitamin C.
    • Expected Benefit: Avoiding this therapy prevents one additional case of death or persistent organ dysfunction for every 17 patients treated.
  • What This Trial Does NOT Mean: This trial does NOT mean that nutritional vitamin C is harmful. Its findings are specific to the use of very high, pharmacologic doses of intravenous vitamin C.
  • Implementation Caveats: The key takeaway is to “first, do no harm.” This trial is a powerful example of why a promising therapy based on a secondary outcome from a smaller trial must be confirmed in a larger, definitive trial before being adopted into practice.

12. Context and Related Studies

  • Building on Previous Evidence: The LOVIT trial (2022) was designed to be the definitive, large-scale trial to confirm or refute the promising but controversial secondary mortality finding of the CITRIS-ALI trial (2019).
  • Influence on Subsequent Research: The definitive neutral-to-harmful result of this trial has largely settled the question of high-dose vitamin C’s role in a broad population of septic patients and will be highly influential in shaping clinical practice guidelines.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial definitively answered its primary question with a clear signal of harm.
  • Future Directions: The failure of yet another broad, untargeted therapy in sepsis has shifted the focus of research towards more personalized approaches, aiming to identify specific patient phenotypes (e.g., those with documented severe vitamin C deficiency) that might respond differently.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, seeking to confirm a promising and potentially practice-changing finding from a previous trial.
  • Methods: The very large, multicenter, double-blind RCT design was of the highest quality and was essential for providing a definitive answer. The pragmatic design ensured high external validity.
  • Results: The study reported a statistically significant and clinically important increase in harm for its primary outcome (NNH of 17). The finding was so clear and robust that the trial was stopped early.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The trial is a landmark in evidence-based medicine, serving as a powerful example of the importance of replicating promising findings from secondary analyses in larger, definitive trials before they are adopted into widespread clinical practice.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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