REDOX: A secondary analysis What did we learn?

1. REDOX: A secondary analysisWhat did we learn? Daren K. Heyland MD Professor of MedicineQueen’s University, Kingston, ON Canada On behalf of the REDOXS Study Investigators

2. Disclosures • Research grants and speaking honorarium from Fresenius Kabi, biosyn, Baxter, Abbott and Nestle • None of these companies have a decisional role in the conception, design, conduct, analysis, interpretation of results or decision to publish.

3. A RANDOMIZED TRIAL OF HIGH-DOSE GLUTAMINE AND ANTIOXIDANTS IN CRITICALLY ILL PATIENTS WITH MULTIORGAN FAILURE The REDOXS study Daren K. Heyland MD Professor of MedicineQueen’s University, Kingston, ON Canada On behalf of the REDOXS Study Investigators N Engl J Med 2013;368:1489-97.

4. 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

5. 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

6. 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

7. 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

8. Pre-specified Sub-group AnalysisGlutamine vs. No Glutamine 28 day mortality, OR with 95% CI)

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

10. Plasma Levels of Glutamine in Subset of Patients P <0.001

11. Post-hoc Secondary Analyses

12. Letter to NEJM “…Major concerns in this study are the statistical adjustment of combining the glutamine groups, showing an imbalance in baseline variables. The number of patients with more than two failing organs at baseline was much higher in the new defined glutamine group compared to the group without glutamine (n=187 vs. n=148 respectively), obviously resulting in higher mortality... In conclusion, we suggest that more severely ill patients were allocated to the glutamine groups as a result of randomization error and patients were not adequately fed. This may explain the observed higher mortality in the new defined glutamine group. Complementary data is needed to support the scientific value of this study.” by Buijs NEJM 2013

13. Adjusted Analysis Imbalance in organ failures at baseline?

14. 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)

15. Selected Subgroup Analyses

16. Additional Subgroup Analyses • Age • BMI • Comorbidities • Diabetes • Number of organ failures Subgroup analyses based on variable occurring post randomization not valid

17. Examination of Treatment Effect by Baseline Renal Dysfunction and Post-Baseline Dialysis

18. Discussion • Increased harm associated with glutamine administration have persisted despite adjustment for random imbalances in baseline covariates. • In both the pooled analysis where both glutamine-receiving groups were combined or whether considering the effect of glutamine alone vs. placebo, we confirm a trend towards increased mortality and 28 days and a significant increase in 6-month mortality associated with glutamine administration. • Our unadjusted subgroup analysis showed that the trend for a harmful glutamine effect existed among the 879 patients with ≤2 organ failures but also among the 335 patients with 3 or 4 organ failures. • Thus, the random imbalance in the number of organ failures across groups does not affect our main inference that high-dose glutamine supplementation was not beneficial, and perhaps harmful.

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. • Patients with multi-organ failure not uniformly associated with low plasma glutamine levels

20. Where does that leave Glutamine?

21. Updated Meta-analysis of IV Glutamine (n=28 RCTs) Overall Mortality Note: Does not include EN GLN studies nor REDOXS study RR=0.87 (0.75,1.02) P=0.08 In press Critical Care

22. Updated Meta-analysis of IV Glutamine (n=28 RCTs) Hospital Mortality RR=0.68 (0.51,0.89) P= 0.005 In press Critical Care

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

24. Updated Meta-analysis of IV Glutamine (n=28 RCTs) Infection RR=0.86 (0.73,1.03) P=0.10

25. Updated Meta-analysis of IV Glutamine (n=28 RCTs) ICU Length of Stay Note: Does not include EN GLN studies nor REDOXS study

26. Updated Meta-analysis of IV Glutamine (n=28 RCTs) Hospital Length of Stay WMD=-2.42 (-4.60, -0.24) P=0.03

27. 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) • Of treated patients, 39% had low plasma levels at END of treatment – day 6 levels associated with worse outcomes

28. Canadian Nutrition CPGs: IV Glutamine Recommendation: • When parenteral nutrition is prescribed to critically ill patients, parenteral supplementation with glutamine should be considered*. • However, we strongly recommend that glutamine NOT be used in critically ill patients with multi-organ failure. • here are insufficient data to generate recommendations for intravenous glutamine in critically ill patients receiving enteral nutrition. *downgraded from ‘strongly recommend’

29. Canadian Nutrition CPGs: EN Glutamine • No new studies since 2009 • Conclusions are: • 1) Glutamine supplemented enteral nutrition may be associated with a reduction in mortality in burn patients, but inconclusive in other critically ill patients. • 2) Glutamine supplemented enteral nutrition may be associated with a reduction in infectious complications in burn and trauma patients. • 3) Glutamine supplemented enteral nutrition is associated with a significant reduction in hospital length of stay in burn and trauma patients. • Recommendation: Enteral glutamine should be considered in burn and trauma patients. There are insufficient data to support the routine use of enteral glutamine in other critically ill patients.* *warning against use in multi-organ failure

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

32. Questions?