Controversies in Nutrient-Specific Therapies: Effective or Ineffective? Daren K. Heyland MD Professor of Medicine Queen’s University, Kingston, ON Canada On behalf of the REDOXS Study Investigators

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.

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 Medicine Queen’s University, Kingston, ON Canada On behalf of the REDOXS Study Investigators N Engl J Med 2013;368:

1200 ICU patients Evidence of Multi-organ failure R glutamine placebo Concealed Stratified by site R R antioxidants placebo Factorial 2x2 design Double blind treatment placebo antioxidants The REDOXS study

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

Post-hoc Secondary Analyses

Selected Subgroup Analyses OR (95% CI) compared to placeboP-values* SubgroupDeaths/n (%)GLN aloneAOX aloneGLN+AOX Overall 363/1218 (30%)1.40 ( )1.20 ( )1.42 ( ) Study Setting Region 0.37 Canada303/1044 (29%)1.41 ( )1.14 ( )1.29 ( ) USA44/131 (34%)1.56 ( )1.43 ( )3.43 ( ) Europe16/43 (37%)0.86 ( )2.40 ( )0.89 ( ) Baseline Patient Characteristics Admission category 0.52 Surgical 59/255 (23%) 2.16 ( )1.94 ( )1.58 ( ) Medical 304/963 (32%) 1.28 ( )1.08 ( )1.43 ( ) Cancer patients 0.74 No 297/1048 (28%) 1.48 ( )1.15 ( )1.42 ( ) Yes 66/170 (39%) 1.05 ( )1.43 ( )1.38 ( ) Etiology of Shock 0.71 Cardiogenic 74/240 (31%) 1.24 ( )1.62 ( )2.19 ( ) Septic 256/826 (31%) 1.43 ( )1.06 ( )1.21 ( ) Other/Unkown/None 33/152 (22%) 1.45 ( )1.45 ( )1.83 ( ) Vasopressors 0.37 <15 mcg/min162/595 (27%)1.58 ( )1.66 ( )1.50 ( ) >=15 mcg/min201/623 (32%)1.32 ( )0.92 ( )1.39 ( ) Renal dysfunction No216/776 (28%)0.93 ( )0.90 ( )1.14 ( ) Yes147/442 (33%)2.75 ( )2.16 ( )2.15 ( ) OR-odds ratio; CI-confidence interval; GLN-Glutamine; AOX-antioxidants No Positive Subgroups

Adjusted Analysis Imbalance in organ failures at baseline?

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 1.4 ( , P =0.063), 1.2 ( , P =0.31) and 1.4 ( , P=0.049) in the glutamine, antioxidant and combined groups respectively. After adjusting for all statistically significant baseline characteristics, the corresponding adjusted ORs remained virtually unchanged at: Glutamine 1.4 ( , P =0.054) Antioxidant 1.2( , P =0.34) Both 1.4 ( , P =0.10)

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 May have provided insufficient selenium

e Experimental Diet enriched with Glutamine, AOX, and Omega 3 FFAs A van Zanten, unpublished data EN glutamine associated with increased mortality?

GLN enriched

Where does that leave Glutamine?

Updated Meta-analysis of IV Glutamine (n=24 RCTs) Overall Mortality Note: Does not include EN GLN studies nor REDOXS study RR=0.88 (0.75,1.03) p=0.10 Wischmeyer et al (under review)

Updated Meta-analysis of IV Glutamine (n=13 RCTs) Hospital Mortality Note: Does not include EN GLN studies nor REDOXS study RR=0.68 (0.51,0.90) P= Wischmeyer et al (under review)

Updated Meta-analysis of IV Glutamine (n=13 RCTs) Hospital Mortality Influence of the number of study sites involved in the trial Wischmeyer et al (under review)

Updated Meta-analysis of IV Glutamine (n=12 RCTs) Infection Note: Does not include EN GLN studies nor REDOXS study RR=0.86 (0.73,1.02) P=0.10 Wischmeyer et al (under review)

Updated Meta-analysis of IV Glutamine (n=11 RCTs) ICU Length of Stay Note: Does not include EN GLN studies nor REDOXS study WMD=-1.91 (-4.10, -0.28) p=0.09 Wischmeyer et al (under review)

Updated Meta-analysis of IV Glutamine (n= 11 RCTs) Hospital Length of Stay Note: Does not include EN GLN studies nor REDOXS study WMD=-2.56 (-4.71, -0.42) P=0.02 Wischmeyer et al (under review)

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. there are insufficient data to generate recommendations for intravenous glutamine in critically ill patients receiving enteral nutrition. *downgraded from ‘strongly recommend’

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 and shock

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.

0.86 ( ) p=

0.88( )

Update Canadian CPGs: Combined Antioxidants still significant reduction in mortality & infections despite results of large RCT (REDOXS) that showed no effect (could be related to dose?) heterogeneity of the trials but high generalizability no concerns about the safety, feasibility and cost of these nutrients 2013 Recommendation: no changes: “should be considered”

Arginine 2009 Recommendation Based on 22 studies, we recommend arginine and other select nutrients not be used for critically ill patients New RCTs = : No changes in recommendation 1

Enteral Fish Oils* *Product enhanced with fish oils +borage oils + antioxidants 1

Enteral Fish Oils* *Product enhanced with fish oils +borage oils + antioxidants 2009 Recommendation Based on 5 studies, we recommend the use of enteral formula with fish oils, borage oils, and antioxidants in patients with ALI/ARDS New RCTs = 4 Rice 2011 Grau-Carmona 2011 Thiella 2011 Elamin Pontes Arruda Stapleton 2011 (fish oil only)

Timing of Feeding SUPPLEMENT “Early Full” Fast ramp up “Early Trophic” (10 ml/hr) N-3 + GLA + Antioxidants (Module delivered as bolus bid) Control Standard EN (480 cal/ 20 g pro) n = 250 NIH NHLBI

OMEGA: 60-Day Mortality P=0.05 P=0.14 Rice et al JAMA Oct 2011 bolus: dilute effect? 50% pts underfed (trophic) protein in placebo include but analyze without

 11 Spanish ICUs  89 patients with diagnosis of Sepsis on admission  Randomized to: Fish Oil/Borage Oil formula OR Standard polymeric formula  Outcomes: new organ dysfunction Grau-Carmona Clin Nutr 2011

Clinical Outcomes Grau-Carmona Clin Nutr 2011 First multicentre study to use “usual care” in control group…….no effect on mortality

Fish Oils: Effect on mortality (n = 6) 2009: RR 0.67, 95% CI 0.51, 0.97, p = No effect, statistical heterogeneity! INTERSEPT, Stapleton data not included Dhaliwal R et al NCP 2013 in press

Fish oils: effect on mortality removing bolus RCT (n =5) Significant effect, no statistical heterogeneity!

EN Fish oils with new RCTs Effect on mortality disappears when bolus study is included statistical heterogeneity present Effect on mortality is significant when bolus study excluded Infections (2 RCTs): no effect Reduction in ICU LOS still significant (heterogeneity) Concerns of control group, negative results of large studies 2013 Recommendations Fish Oils/borage oil: Downgraded recommendation to “should be considered” Fish Oils alone: insufficient data

Questions?