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Glutamine and Antioxidants in Critical Illness: A Review of Findings

Explore the role of glutamine and antioxidants in critical illness, their impact on patient outcomes, and the safety considerations involved. Dive into recent studies and observations to understand the potential benefits and risks associated with these treatments.

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Glutamine and Antioxidants in Critical Illness: A Review of Findings

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  1. Glutamine and Antioxidants in the critically ill: End of an Era? Daren K. Heyland MD Professor of MedicineQueen’s University, Kingston, ON Canada On behalf of the REDOXS Study Investigators

  2. Glutamine: Important Questions • Is glutamine ‘conditionally essential’? • Is glutamine safe? • Mechanism of harm? • Negative interactions between glutamine and antioxidants • What are the recommendations for glutamine in 2015?

  3. Glutamine: A conditionally essential amino acid? Glutamine levels drop: - following extreme physical exercice - after major surgery - during critical illness Low glutamine levels are associated with: • immune dysfunction • higer mortality in critically ill patients Novak F, Heyland DK, A Avenell et al., Crit Care Med 2002 Oudemans-van Straaten HM, Bosman RJ, Treskes Met al., Intensive Car Med 2001

  4. The “Oudemans-van Straaten-Study” “high” “low” => Low plasma glutamine at ICU admission is related to mortality.

  5. Plasma Levels of Glutamine in Subset of Patients P <0.001 Heyland N Engl J Med 2013;368:1489-97.

  6. Glutamine and glutathione at ICU admission in relation to outcome Rodas Clinical Science (2012) 122, 591–597

  7. Future Trials Require Bedside Testing?

  8. Double-blind, multicenter RCT • 142 trauma patients (excluded renal failure) • 0.5 gm/kg of Ala-Gln dipeptide x 5 days unrelated to PN vs. saline placebo (pharmaconutrition) • Overall, no effect on infection (primary endpoint), LOS, or mortality • No effect in subgroup of severe trauma (ISS>24) • No effect in subgroup that had low levels of GLN at baseline (n=60) • Of treated patients, 39% had low plasma levels at END of treatment – day 6 levels associated with worse outcomes

  9. Glutamine: Is it safe?

  10. The REDOXS study antioxidants Factorial 2x2 design Double blind treatment glutamine R 1200 ICU patients R Concealed Stratified by site placebo Evidence of Multi-organ failure antioxidants R placebo placebo Heyland N Engl J Med 2013;368:1489-97.

  11. The Research Protocol Inclusion Criteria • Adults (>18) • With 2 or more organ failures related to their acute illness : • Requiring mechanically ventilation (P/F<300) • Clinical evidence of hypoperfusion defined by need for vasopressor agents for more than 2hour • Renal dysfunction : Cr>171 or <500ml/24 hrs • platelet < 50

  12. Optimizing the Dose of Glutamine Dipeptides and Antioxidants In Critically Ill Patients:A Phase I dose finding study • High dose appears safe • High dose associated with • no worsening of SOFA Scores • greater resolution of oxidative stress • greater preservation of glutathione • Improved mitochondrial function Heyland JPEN Mar 2007

  13. Primary outcome of 28 day mortality using all 1218 evaluable patients (ITT) Glutamine(glut)

  14. Mortality Outcomes P=0.02 P=0.02 P=0.049 P=0.07 Note: all P values pertain to GLN vs No GLN; no significant differences between AOX vs. No AOX

  15. Other Clinical Outcomes • No differences between groups • SOFA • Need for dialysis • Duration of mechanical ventilation • PODS • infections • ICU and Hospital LOS

  16. Post-hoc Secondary Analyses

  17. Adjusted Analysis • The 28-day mortality rates in the placebo, glutamine, antioxidant and combination groups were 25%, 32%, 29% and 33% respectively. • Compared to placebo, the unadjusted OR (95% CI) of mortality was Glutamine 1.4 (1.0-2.0, P =0.063), Antioxidant 1.2 (0.8-1.7, P =0.31), Both 1.4 (1.0-2.0, P=0.049). • After adjusting for all statistically significant baseline characteristics, the corresponding adjusted ORs remained virtually unchanged at: Glutamine 1.4 (1.0-2.1, P =0.054) Antioxidant 1.2(0.8-1.8, P =0.34) Both 1.4 (0.9-2.0, P =0.10) JPEN May 2014

  18. Selected Subgroup Analyses

  19. Conclusions • Glutamine and antioxidants at doses studied in this study do not improve clinical outcomes in critically ill patients with multi-organ failure • Glutamine may be harmful • For both glutamine and antioxidants, the greatest signal of harm was in patients with multi-organ failure that included renal dysfunction upon study enrollment.

  20. Metaplus Study • 14 ICUs in the Netherlands, Germany, France, and Belgium. • 301 adult patients who were expected to be ventilated and to require enteral nutrition (EN) for more than 72 hours • Randomized to intervention feed • High-protein EN enriched with 21 grams of glutamine, extra antioxidants including an additional 275 mcg of selenium and an additional 7.5 grams of fish oils, n = 152) • or control (standard high-protein EN, n = 149). • Feeds initiated within 48 hours of ICU admission and continued for a maximum of 28 days • Intention-to-treat analysis for total population as well as predefined medical, surgical, and trauma subpopulations. Van Zanten JAMA 2014;312:514

  21. Metaplus Study • No statistically significant differences in the primary end point, incidence of new infections • 53% (95%CI, 44%-61%) in the enriched group vs 52% (95%CI, 44%-61%) in the control group (P = .96). • No differences in secondary end points included mortality, Sequential Organ Failure Assessment (SOFA) scores, mechanical ventilation duration, ICU and hospital lengths of stay, and subtypes of infections according to CDC definitions. • Only positive finding was a higher 6-month mortality rate in the medical subgroup: 54% (95%CI, 40%-67%) in the enriched group vs 35% (95%CI, 22%-49%) in the control group (P = .04). • hazard ratio of 1.57 (95%CI, 1.03-2.39; P = .04) for 6-month mortality adjusted for age and Acute Physiology and Chronic Health Evaluation II score. Van Zanten JAMA 2014;312:514

  22. 6 Month Survival Curves for REDOXS and METAPLUS Adjusted model, glutamine treated patients had higher rate of death (HR 1.57, 95% CI 1.03, 2.39, p=0.04)

  23. GLN-enriched EN GLN-enriched EN

  24. GLN-enriched EN GLN-enriched EN GLN-enriched EN

  25. Key Question • If we conclude that glutamine has potential for harm, what impact does this have on our clinical recommendations?

  26. Updated Meta-analysis of IV Glutamine (n=32 RCTs) Overall Mortality Note: Does not include EN GLN studies nor REDOXS study RR=0.87 (0.75,1.01) P=0.07)

  27. Updated Meta-analysis of IV Glutamine (n=32 RCTs) Hospital Mortality RR=0.70 (0.53,0.92) P= 0.01

  28. Updated Meta-analysis of IV Glutamine (n=32 RCTs) Influence of the number of study sites involved in the trial Hospital Mortality

  29. Updated Meta-analysis of IV Glutamine (n=32 RCTs) Influence of the type of glutamine used in the trials Hospital Mortality

  30. Updated Meta-analysis of IV Glutamine (n=32 RCTs) Infection RR=0.89 (0.77,1.03) P=0.12

  31. Updated Meta-analysis of IV Glutamine (n=32 RCTs) ICU Length of Stay Note: Does not include EN GLN studies nor REDOXS study

  32. Updated Meta-analysis of IV Glutamine (n=32 RCTs) Hospital Length of Stay WMD=-2.56 (-4.71, -0.42) P=0.02

  33. Temporal trend of short-term mortality in severely ill patients receivingparenteral glutamine supplementation All the beneficial treatment effect seen in older studies (before 2003) Fadda Clinical Nutrition 32 (2013) 492–493

  34. 2015 Canadian Nutrition CPGs: IV Glutamine Draft Recommendation: • When parenteral nutrition is prescribed to critically ill patients, we recommend parenteral supplementation with glutamine NOT be used*. • There are insufficient data to generate recommendations for intravenous glutamine in critically ill patients receiving enteral nutrition, but given the safety concerns we also recommend intravenous glutamine NOT be used in enterally fed critically ill patients. *downgraded from ‘should be considered’

  35. Updated Meta-analysis of EN Glutamine (n=11 RCTs) Mortality No overall treatment effect or in trauma subset but positive effect in burns (RR 0.19, 95% CI 0.06,0.67, p=0.01)

  36. Updated Meta-analysis of EN Glutamine (n=11 RCTs) Infection Few studies reported infection No overall treatment effect or in trauma or burns subset

  37. Updated Meta-analysis of EN Glutamine (n=11 RCTs) Hospital LOS Positive effect driven by 3 studies in burn patients

  38. 2015 Canadian Nutrition CPGs: EN Glutamine Draft Conclusions: 1) Glutamine supplemented enteral nutrition may be associated with a reduction in mortality and shorter hospital LOS in burn patients, but inconclusive in other critically ill patients. 2) No overall effect in trauma patients 3) Concerns about safety of EN glutamine given METAPLUS study Draft Recommendation: We recommend enteral glutamine NOT be used in critically ill patients*. *downgraded from ‘shouldbe considered in burn and trauma patients’

  39. A RandomizEd trial of ENtERal Glutamine to minimIZE thermal injury Double blind treatment EN glutamine 6 month mortality 2700 Burn Injury patients R Concealed Stratified by site placebo

  40. 2015 Canadian Nutrition CPGs: Combined IV+ EN Glutamine Draft Recommendation: • Based on one level 1 study (REDOXS) and 1 level 2 study, we strongly recommend that high dose combined parenteral and enteral glutamine supplementation NOT be used in critically ill patients

  41. 2015 Canadian Nutrition CPGs: Supplemental Antioxidant Nutrients Draft Recommendation: • We recommend that high dose antioxidants, specifically selenium, not be used in critically ill patients* *downgraded from ‘should be considered’

  42. Questions?

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