CITRIS-ALI: Vitamin C in Sepsis and ARDS (2019)

“In this preliminary randomized clinical trial of patients with sepsis and ARDS, a 96-hour infusion of vitamin C, compared with placebo, did not significantly improve the primary end point of SOFA scores. However, patients in the vitamin C group had significantly lower 28-day mortality.”

  • The CITRIS-ALI Trial Investigators

1. Publication Details

  • Trial Title: 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
  • Citation: 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. DOI: 10.1001/jama.2019.11825
  • Published: October 1, 2019, in The Journal of the American Medical Association (JAMA)
  • Author: Alpha A. Fowler III, M.D.
  • Funding: National Institutes of Health (NIH) and others.

2. Keywords

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

3. The Clinical Question

  • In adult patients in the ICU with sepsis and ARDS (Population), does a 96-hour infusion of high-dose intravenous vitamin C (Intervention) compared to placebo (Comparison) improve organ dysfunction scores and biomarkers of inflammation (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Sepsis and ARDS are 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 and improve organ function. Previous, small observational studies had suggested a potential benefit.
  • Knowledge Gap: There was no high-quality evidence from a multicenter randomized controlled trial to determine if high-dose vitamin C was an effective and safe therapy for patients with sepsis and ARDS.
  • Proposed Hypothesis: The authors hypothesized that high-dose intravenous vitamin C would reduce organ failure, as measured by the Sequential Organ Failure Assessment (SOFA) score, and decrease biomarkers of inflammation and vascular injury.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: 7 medical intensive care units (ICUs) in the United States.
  • Trial Period: Enrollment ran from September 2014 to November 2017.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) admitted to the ICU with sepsis (based on SepsIS-2 criteria) and ARDS who were receiving mechanical ventilation.
    • Exclusion Criteria: Included pregnancy, known allergy to vitamin C, 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).
  • Management Common to Both Groups: All other aspects of care for sepsis and ARDS were at the discretion of the treating clinicians according to local guidelines.
  • Power and Sample Size: The authors calculated that a sample size of 166 patients would provide 80% power to detect a 1.5-point difference in the primary outcome (change in SOFA score). (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: The change in the modified SOFA score from baseline to 96 hours.
    • Secondary Outcomes: Included 28-day all-cause mortality, ventilator-free days, ICU-free days, and changes in inflammatory biomarkers.

6. Key Results

  • Enrollment and Baseline: 167 patients were randomized (84 to vitamin C and 83 to placebo). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in the primary outcome. The change in the modified SOFA score at 96 hours was not significantly different between the vitamin C group and the placebo group (p=0.86).
  • Secondary Outcomes: A key secondary outcome, 28-day mortality, was significantly lower in the vitamin C group: 13 of 84 patients (15.5%) died, compared with 25 of 83 patients (30.1%) in the placebo group (p=0.03). Patients in the vitamin C group also had more ICU-free days and hospital-free days.
  • Adverse Events: The incidence of adverse events was similar in both groups.

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 linear mixed-effects model. Mortality was analyzed with a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the mean change in SOFA scores between the two groups.
  • Key Statistic(s) Reported: The key statistics were the change in SOFA scores for the primary outcome and the absolute mortality rates for the key secondary outcome.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.86 for the primary outcome is much higher than the 0.05 threshold, indicating a clear neutral result. The p-value of 0.03 for the secondary outcome of 28-day mortality is below the 0.05 threshold, suggesting a statistically significant difference (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures (for the secondary outcome of mortality):
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = 30.1% – 15.5% = 14.6%.
      • Clinical Meaning: For every 100 patients treated with vitamin C, about 15 additional deaths were prevented at 28 days.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.146 = 6.8, which is rounded up to 7.
      • Clinical Meaning: You would need to treat 7 patients with this vitamin C regimen to prevent one additional death.
  • Subgroup Analyses: Not a major feature of this publication.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, double-blind, placebo-controlled design is the gold standard for minimizing bias.
  • Generalizability: The inclusion of 7 different academic medical centers increases the external validity of the findings.
  • Patient-Centered Outcomes: The study included the crucial patient-centered outcome of mortality, in addition to its physiological primary outcome.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The primary outcome was a surrogate marker (SOFA score) rather than a direct patient-centered outcome. The study was powered for this surrogate outcome, not for mortality. Therefore, the statistically significant mortality finding must be interpreted with caution as it is a secondary outcome from a trial that was technically “negative” on its primary endpoint.
  • External Validity (Generalizability): The study population was specific to patients with both sepsis and ARDS, and the results may not apply to patients with sepsis without ARDS.
  • Other: The study was relatively small, and the mortality benefit, while statistically significant, requires confirmation in a larger trial powered for mortality.

10. Conclusion of the Authors

  • The authors concluded that in patients with sepsis and ARDS, a 96-hour infusion of vitamin C did not significantly improve organ dysfunction scores. They noted that the observed reduction in mortality was a secondary outcome that requires further investigation.

11. To Summarize

  • Impact on Current Practice: This trial generated intense interest and controversy. While it failed to meet its primary endpoint, the large and statistically significant mortality benefit seen in a secondary analysis led many clinicians to consider using high-dose vitamin C, despite the lack of definitive evidence.
  • Specific Recommendations:
    • Patient Selection: For adult patients in the ICU with sepsis and ARDS.
    • Actionable Intervention: The results are not strong enough to recommend the routine use of high-dose vitamin C. However, given the potential for a large mortality benefit and the low risk of harm, it may be considered as a potential therapy.
  • What This Trial Does NOT Mean: This trial does NOT definitively prove that vitamin C saves lives in sepsis and ARDS. Because mortality was a secondary outcome in a trial that was negative for its primary outcome, this finding is considered hypothesis-generating and requires confirmation.
  • Implementation Caveats: If vitamin C is used, it should be administered as a high-dose infusion as was done in the trial.

12. Context and Related Studies

  • Building on Previous Evidence: The CITRIS-ALI trial (2019) was one of the first multicenter RCTs to test the promising but unproven hypothesis that high-dose vitamin C could benefit septic patients.
  • Influence on Subsequent Research: The controversial but promising mortality signal in this trial directly led to the design of several larger trials powered for mortality, such as the LOVIT trial (2022), which ultimately failed to confirm a survival benefit with high-dose vitamin C in a broader population of septic patients.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question from this trial is whether the observed mortality benefit was a real treatment effect or a chance finding (a false positive).
  • Future Directions: The definitive negative result of the subsequent, much larger LOVIT trial has largely answered this question, suggesting that high-dose vitamin C is not beneficial for the majority of patients with sepsis.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, testing a promising and low-cost therapy for a deadly condition.
  • Methods: The multicenter, double-blind RCT design was of high quality. The main methodological issue is the choice of a surrogate primary outcome (SOFA score) instead of a patient-centered outcome like mortality. This decision significantly complicates the interpretation of the results.
  • Results: The study was negative for its primary outcome. The statistically significant finding for the secondary outcome of mortality is the most important and controversial result. A positive secondary outcome in a trial that is negative for its primary outcome should always be interpreted with extreme caution, as it has a higher probability of being a false-positive result due to multiple comparisons.
  • Conclusions and Applicability: The authors’ cautious conclusion is a fair and appropriate interpretation of their data. The trial is a classic example of the challenges of interpreting a study with a “negative” primary outcome but a “positive” and clinically important secondary outcome. It highlights the principle that trials should always be powered for their most important patient-centered endpoint.

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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