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Cited by 125Clinical Nutrition and GastroenterologySepsis Diagnosis and TreatmentHyperglycemia and glycemic control in critically ill and hospitalized patients

Glutamine and Antioxidants in the Critically Ill Patient: A Post Hoc Analysis of a Large‐Scale Randomized Trial

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Heyland, Daren K., Elke, Gunnar, Cook, Deborah, Berger, Mette M., Wischmeyer, Paul E., Albert, Martin, Muscedere, John, Jones, Gwynne +2 more·2015·Journal of Parenteral and Enteral Nutrition
DOI 10.1177/0148607114529994PMC PMC6800175
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Abstract

Background: The recent large randomized controlled trial of glutamine and antioxidant supplementation suggested that high‐dose glutamine is associated with increased mortality in critically ill patients with multiorgan failure. The objectives of the present analyses were to reevaluate the effect of supplementation after controlling for baseline covariates and to identify potentially important subgroup effects. Materials and Methods : This study was a post hoc analysis of a prospective factorial 2 × 2 randomized trial conducted in 40 intensive care units in North America and Europe. In total, 1223 mechanically ventilated adult patients with multiorgan failure were randomized to receive glutamine, antioxidants, both glutamine and antioxidants, or placebo administered separate from artificial nutrition. We compared each of the 3 active treatment arms (glutamine alone, antioxidants alone, and glutamine + antioxidants) with placebo on 28‐day mortality. Post hoc, treatment effects were examined within subgroups defined by baseline patient characteristics. Logistic regression was used to estimate treatment effects within subgroups after adjustment for baseline covariates and to identify treatment‐by‐subgroup interactions (effect modification). Results : The 28‐day mortality rates in the placebo, glutamine, antioxidant, and combination arms were 25%, 32%, 29%, and 33%, respectively. After adjusting for prespecified baseline covariates, the adjusted odds ratio of 28‐day mortality vs placebo was 1.5 (95% confidence interval, 1.0–2.1, P = .05), 1.2 (0.8–1.8, P = .40), and 1.4 (0.9–2.0, P = .09) for glutamine, antioxidant, and glutamine plus antioxidant arms, respectively. In the post hoc subgroup analysis, both glutamine and antioxidants appeared most harmful in patients with baseline renal dysfunction. No subgroups suggested reduced mortality with supplements. Conclusions: After adjustment for baseline covariates, early provision of high‐dose glutamine administered separately from artificial nutrition was not beneficial and may be associated with increased mortality in critically ill patients with multiorgan failure. For both glutamine and antioxidants, the greatest potential for harm was observed in patients with multiorgan failure that included renal dysfunction upon study enrollment.

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  • The REDOXS study randomization was associated with higher severity with more organ failures in the GLN groups upon enrollment, largely explaining the higher mortality.

    “The REDOXS study [85], designed as a 2 x 2 factorial trial, generated concerns for several reasons, including the fact that the randomization was associated with higher severity with more organ failures in the GLN groups upon enrollment, largely explaining the higher mortality.”

    From ESPEN practical and partially revised guideline: Clinical nutrition in the intensive care unit (2023) · cites this paper as [85]

    The Discussion (page unavailable) acknowledges a random imbalance in organ failures across groups but says the increased mortality associated with glutamine persisted after adjustment and was independent of the number of organ failures. It explicitly says that the imbalance did not affect the authors’ main inference, contrary to the claim that it largely explains the higher mortality. (LLM, conf=0.90)

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  • Rodas et al. showed a U-shaped association between plasma GLN levels and outcome.

    “Rodas et al. (208) showed a U-shaped association between plasma GLN levels and outcome.”

    From ESPEN guideline on clinical nutrition in the intensive care unit. (2019) · cites this paper as [208]

    The Discussion (page unavailable) cites Rodas et al. as reference 21 and reports a possible U-shaped relationship between plasma glutamine levels and 6-month mortality in critically ill patients. The claim captures that relationship but says Rodas et al. “showed” it without the source’s uncertainty qualifier (“may be”). (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • A post hoc analysis of REDOXS confirmed the harmful effect of both glutamine and antioxidants, particularly in patients with renal dysfunction.

    “A post hoc analysis by the same group confirmed the harmful effect of both glutamine and antioxidants, particularly in patients with renal dysfunction [49].”

    From Nutrition in Sepsis: A Bench-to-Bedside Review. (2020) · cites this paper as [49]

  • Plasma GLN levels have repeatedly been shown to be low during critical illness, and low values to be associated with poor outcome.

    “Plasma GLN levels have repeatedly been shown to be low during critical illness, and low values to be associated with poor outcome (206,207,208).”

    From ESPEN guideline on clinical nutrition in the intensive care unit. (2019) · cites this paper as [208]

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Research works printed but not linked: 27

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Authors
Heyland, D. K., Elke, G., Cook, D., Berger, M. M., Wischmeyer, P. E., Albert, M., Muscedere, J., Jones, G., Day, A. G., & on behalf of the Canadian Critical Care Trials Group
Affiliations
  • Kingston General Hospital (CA)
  • University Hospital Schleswig-Holstein (DE)
  • St. Joseph’s Healthcare Hamilton (CA)
  • Centre Hospitalier Universitaire Vaudois (CH)
  • University of Colorado Anschutz (US)
  • Hôpital du Sacré-Cœur de Montréal (CA)
  • Ottawa Hospital (CA)
Corresponding author
Heyland, Daren K.
ORCID
Venue
Journal of Parenteral and Enteral Nutrition
Publisher
Wiley
Published
2014-05-05
Volume
39
Issue
4
Pages
401-409
ISSN
  • 0148-6071 (ISSN-L)
  • 1941-2444
DOI
10.1177/0148607114529994
PMC
PMC6800175
OpenAlex
W2011280034
Cited by
125
References
0
Citations by year
2026: 2 · 2025: 3 · 2024: 14 · 2023: 14 · 2022: 5 · 2021: 10 · 2020: 8 · 2019: 7 · 2018: 8 · 2017: 10 · 2016: 18 · 2015: 20 · 2014: 5 · 2013: 1
FWCI
16.45
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Parenteral and Enteral Nutrition (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • IRIS (submittedVersion)
  • SERVAL (Université de Lausanne) (submittedVersion)
Funders
Canadian Institutes of Health Research
Topics
  • Health Sciences › Nursing › Nutrition and Dietetics › Clinical Nutrition and Gastroenterology
  • Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hyperglycemia and glycemic control in critically ill and hospitalized patients
Keywords
glutamine supplementation, antioxidant supplementation, critically ill patients, multiple organ failure, 28-day mortality, renal dysfunction, effect modification, subgroup analysis, intensive care, mechanical ventilation, dietary supplementation
MeSH terms
Aged, Antioxidants, Glutamine, Humans, Kidney, Middle Aged, Multiple Organ Failure, Prospective Studies, Logistic Models, Odds Ratio, Critical Illness, Hospital Mortality, Dietary Supplements

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