REDOXS: Glutamine and Antioxidants in Critical Illness (2013)

“In critically ill adults with multiorgan failure, we found that 28-day mortality was significantly higher among patients who received glutamine than among those who did not. Supplementation with antioxidants alone or with glutamine and antioxidants had no effect on mortality.”

  • The REDOXS Study Investigators

1. Publication Details

  • Trial Title: A Randomized Trial of Glutamine and Antioxidants in Critically Ill Patients
  • Citation: Heyland D, Muscedere J, Wischmeyer PE, et al. A randomized trial of glutamine and antioxidants in critically ill patients. N Engl J Med. 2013;368(16):1489-1497. DOI: 10.1056/NEJMoa1212722
  • Published: April 18, 2013, in The New England Journal of Medicine
  • Author: Daren Heyland, M.D., on behalf of the REDOXS Study Investigators
  • Funding: The Canadian Institutes of Health Research.

2. Keywords

  • Critical Illness, Sepsis, Multiple Organ Dysfunction Syndrome (MODS), Glutamine, Antioxidants, Selenium, Randomized Controlled Trial

3. The Clinical Question

  • In critically ill adult patients with multiple organ dysfunction (Population), does supplementation with glutamine, antioxidants, or both (Intervention) compared to placebo (Comparison) reduce 28-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Critical illness is characterized by a profound state of oxidative stress and depletion of certain nutrients, including glutamine. It was hypothesized that this depletion contributed to organ failure. Supplementation with glutamine and antioxidants (like selenium) was thought to be a promising “immunonutrition” strategy to restore function and improve outcomes.
  • Knowledge Gap: Previous trials on glutamine and antioxidant supplementation were small, often single-center, and had produced conflicting results. A large, definitive, multicenter trial was needed to clarify the true risk-benefit balance of this common practice.
  • Proposed Hypothesis: The authors hypothesized that supplementation with glutamine, antioxidants, or both would be superior to placebo in reducing 28-day mortality in critically ill patients with multiple organ failure.

5. Study Design and Methods

  • Design: A large, multicenter, prospective, 2×2 factorial, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: 40 intensive care units (ICUs) in Canada, the United States, and Europe.
  • Trial Period: Enrollment ran from March 2007 to January 2012.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) admitted to the ICU with two or more organ failures.
    • Exclusion Criteria: Included pregnancy, end-stage renal disease on chronic dialysis, and severe liver failure.
  • Intervention: Patients were randomized in a factorial design to one of four groups for 28 days:
  • Glutamine: Intravenous and enteral glutamine.
  • Antioxidants: Intravenous and enteral antioxidants (including selenium, zinc, and vitamins).
  • Combination: Both glutamine and antioxidants.
  • Double Placebo: Placebo for both interventions.
  • Control: The placebo groups served as the controls.
  • Management Common to Both Groups: All patients received standard nutritional support and other ICU care according to local guidelines.
  • Power and Sample Size: The authors calculated that a sample size of 1200 patients would provide 80% power to detect a 6.5% absolute risk reduction in 28-day mortality for each intervention. (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: All-cause mortality at 28 days.
    • Secondary Outcomes: Included 6-month mortality, duration of organ support, and length of ICU stay.

6. Key Results

  • Enrollment and Baseline: 1223 patients were randomized. The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome:
    • Glutamine: 28-day mortality was significantly higher in the group receiving glutamine: 211 of 609 patients (34.6%) died, compared with 172 of 609 patients (28.2%) in the no-glutamine group (p=0.02).
    • Antioxidants: There was no significant difference in 28-day mortality for the antioxidant comparison (30.8% with antioxidants vs. 32.1% with no antioxidants; p=0.57).
  • Secondary Outcomes: In-hospital and 6-month mortality were also significantly higher in the glutamine group.
  • Adverse Events: The primary adverse event was death, which was more common in the glutamine 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 chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of death between the groups for each intervention.
  • Key Statistic(s) Reported: Odds Ratio (OR) for death at 28 days for glutamine vs. no glutamine: 1.28 (95% CI, 1.05 to 1.57; P-value: 0.02).
  • Interpretation of Key Statistic(s):
    • Odds Ratio (OR):
      • Formula: Conceptually, OR = (Odds of Death in Intervention Group) / (Odds of Death in Control Group).
      • Calculation: The paper reports the result as 1.28.
      • Clinical Meaning: An OR of 1.28 means that patients who received glutamine had a 28% higher odds of dying at 28 days compared to those who did not.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 1.05 to 1.57.
      • Clinical Meaning: Since this entire range is above the line of no effect (1.0), it confirms that the result is statistically significant and demonstrates a clear signal of harm.
    • P-value: The p-value of 0.02 is below the 0.05 threshold, indicating the result is statistically significant (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures (for glutamine):
    • Absolute Risk Increase (ARI):
      • Formula: ARI = (Risk in Intervention Group) – (Risk in Control Group)
      • Calculation: ARI = 34.6% – 28.2% = 6.4%.
      • Clinical Meaning: For every 100 critically ill patients with organ failure treated with glutamine, about 6 additional deaths occurred.
    • Number Needed to Harm (NNH):
      • Formula: NNH = 1 / ARI
      • Calculation: NNH = 1 / 0.064 = 15.6, which is rounded up to 16.
      • Clinical Meaning: You would only need to treat 16 patients with glutamine to cause one additional death.
  • Subgroup Analyses: The harm associated with glutamine was most pronounced in patients with primary septic shock and multiple organ failure.

8. Strengths of the Study

  • Study Design and Conduct: The large, multicenter, randomized, double-blind, placebo-controlled, factorial design is the gold standard and provided a massive amount of high-quality data.
  • Generalizability: The pragmatic design and inclusion of a large, international population of critically ill patients make the findings highly generalizable.
  • Statistical Power: The large sample size provided definitive power to detect even small but clinically important differences, ultimately revealing a clear signal of harm.
  • Patient-Centered Outcomes: The primary outcome of 28-day mortality is a robust and patient-centered endpoint.

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 critically ill patients with multiple organ failure.
  • Other: The study found a clear signal of harm for glutamine, which is a critical finding.

10. Conclusion of the Authors

  • The authors concluded that in critically ill patients with multiple organ failure, neither glutamine nor antioxidant supplementation provided any benefit, and that glutamine supplementation was associated with a significant increase in mortality.

11. To Summarize

  • Impact on Current Practice: This was a profoundly practice-changing trial. It provided definitive evidence that a common and physiologically plausible “immunonutrition” strategy was not just ineffective, but actively harmful in the sickest ICU patients. It led to the immediate de-adoption of routine glutamine supplementation.
  • Specific Recommendations:
    • Patient Selection: For the broad population of adult ICU patients with multiple organ failure.
    • Actionable Intervention: Do not administer supplemental glutamine or antioxidants.
    • Expected Benefit: Avoiding glutamine supplementation prevents one additional death for every 16 patients treated.
  • What This Trial Does NOT Mean: This trial does NOT mean that nutrition is not important. It only argues against the routine supplementation of these specific high-dose micronutrients.
  • Implementation Caveats: The key takeaway is to “first, do no harm.” This trial is a powerful example of why even logical-sounding therapies must be tested in rigorous trials before being adopted into routine practice.

12. Context and Related Studies

  • Building on Previous Evidence: The REDOXS trial (2013) was designed to definitively resolve the major clinical controversy surrounding immunonutrition, which was based on numerous smaller, conflicting, and often industry-sponsored trials.
  • Influence on Subsequent Research: The definitive finding of harm in this trial has been a cornerstone of all subsequent international critical care nutrition guidelines, which now strongly recommend against the routine use of supplemental glutamine and antioxidants in the ICU.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial definitively answered its primary questions with a clear signal of harm for one intervention and neutrality for the other.
  • Future Directions: The failure of this and other broad, untargeted nutritional interventions has shifted the focus of research towards more personalized approaches, such as identifying specific nutrient deficiencies and targeting replacement to those specific patients.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was of the highest relevance, testing a very common and expensive practice that lacked high-quality evidence.
  • Methods: The very large, multicenter, double-blind, factorial 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 profound increase in harm (NNH of 16) for one of its primary interventions.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The trial is a landmark in evidence-based critical care, serving as a powerful example of how a logical, physiologically-based therapy can be harmful, and how only a very large, rigorous, placebo-controlled trial can reveal such a truth.

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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