REDOX: A secondary analysis What did we learn?

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REDOX A secondary analysisWhat did we learn?

• Daren K. Heyland MD
• Professor of MedicineQueens University,
  Kingston, ON Canada
• On behalf of the REDOXS Study Investigators

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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.

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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 MedicineQueens University,
  Kingston, ON Canada
• On behalf of the REDOXS Study Investigators

N Engl J Med 20133681489-97.
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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
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The Research Protocol
Inclusion Criteria

• Adults (gt18)
• With 2 or more organ failures related to their
  acute illness
• Requiring mechanically ventilation (P/Flt300)
• Clinical evidence of hypoperfusion defined by
  need for vasopressor agents for more than 2 hour
• Renal dysfunction Crgt171 or lt500ml/24 hrs
• platelet lt 50

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Optimizing the Dose of Glutamine Dipeptides and
Antioxidants In Critically Ill PatientsA Phase
I dose finding study
Parenterally Enterally
Glutamine/day 0.35 gms/kg 30 gms
Antioxidants per day 500 mcg Selenium Vit C 1500 mg Vit E 500 mg B carotene 10 mg Zinc 20 mg Se 300 ug

• 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
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Primary outcome of 28 day mortality using all
1218 evaluable patients (ITT)
    Antioxidants (AOX) Antioxidants (AOX)    
    Yes No AOX OR conditioned on Glut Overall adjusted OR of AOX
Yes 101/310 (32.6) 97/301 (32.2) 1.02 (0.72, 1.43) 1.09 (0.86-1.40 p0.48)
No 89/307 (29.0) 76/309 (25.3) 1.20 (0.84, 1.72) 1.09 (0.86-1.40 p0.48)
Glut OR conditioned on AOX 1.18 (0.83-1.66) 1.40 (0.98-2.00)
Overall adjusted OR for glut 1.28 (1.00-1.64 p0.049) 1.28 (1.00-1.64 p0.049) AOX by glut interactionp0.49
  Overall adjusted OR for glut 1.28 (1.00-1.64 p0.049) 1.28 (1.00-1.64 p0.049) AOX by glut interactionp0.49
ORodds ratio. ORs are presented with 95 confidence intervals in parentheses. An ORgt1 indicates increased mortality with treatment. ORodds ratio. ORs are presented with 95 confidence intervals in parentheses. An ORgt1 indicates increased mortality with treatment. ORodds ratio. ORs are presented with 95 confidence intervals in parentheses. An ORgt1 indicates increased mortality with treatment. ORodds ratio. ORs are presented with 95 confidence intervals in parentheses. An ORgt1 indicates increased mortality with treatment. ORodds ratio. ORs are presented with 95 confidence intervals in parentheses. An ORgt1 indicates increased mortality with treatment. ORodds ratio. ORs are presented with 95 confidence intervals in parentheses. An ORgt1 indicates increased mortality with treatment.
All odds ratios adjust for presence of shock at baseline. Overall ORs also adjust for other treatment factor. To account for the two interim analyses, we pre-specified statistical significance of the final analysis at a two-sided plt0.044 in our protocol. Thus, our primary outcome did not reach statistical significance for either intervention. All odds ratios adjust for presence of shock at baseline. Overall ORs also adjust for other treatment factor. To account for the two interim analyses, we pre-specified statistical significance of the final analysis at a two-sided plt0.044 in our protocol. Thus, our primary outcome did not reach statistical significance for either intervention. All odds ratios adjust for presence of shock at baseline. Overall ORs also adjust for other treatment factor. To account for the two interim analyses, we pre-specified statistical significance of the final analysis at a two-sided plt0.044 in our protocol. Thus, our primary outcome did not reach statistical significance for either intervention. All odds ratios adjust for presence of shock at baseline. Overall ORs also adjust for other treatment factor. To account for the two interim analyses, we pre-specified statistical significance of the final analysis at a two-sided plt0.044 in our protocol. Thus, our primary outcome did not reach statistical significance for either intervention. All odds ratios adjust for presence of shock at baseline. Overall ORs also adjust for other treatment factor. To account for the two interim analyses, we pre-specified statistical significance of the final analysis at a two-sided plt0.044 in our protocol. Thus, our primary outcome did not reach statistical significance for either intervention. All odds ratios adjust for presence of shock at baseline. Overall ORs also adjust for other treatment factor. To account for the two interim analyses, we pre-specified statistical significance of the final analysis at a two-sided plt0.044 in our protocol. Thus, our primary outcome did not reach statistical significance for either intervention.
Glutamine(glut)
N Engl J Med 20133681489-97.
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Mortality Outcomes
P0.02
P0.02
P0.049
P0.07
Note all P values pertain to GLN vs No GLN no
significant differences between AOX vs. No AOX
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Pre-specified Sub-group AnalysisGlutamine vs. No
Glutamine
28 day mortality, OR with 95 CI)
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Other Clinical Outcomes

• No differences between groups
• SOFA
• Need for dialysis
• Duration of mechanical ventilation
• PODS
• infections
• ICU and Hospital LOS

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Plasma Levels of Glutamine in Subset of Patients
P lt0.001
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Plasma Levels of Selenium in Subset of Patients
P lt0.001
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Post-hoc Secondary Analyses
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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 (n187 vs. n148
  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
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Adjusted Analysis
Imbalance in organ failures at baseline?
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Kaplan-Meier Survival Curve by Treatment Arm
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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, P0.049).
• 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)

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Selected Subgroup Analyses
      OR (95 CI) compared to placebo OR (95 CI) compared to placebo OR (95 CI) compared to placebo P-values
Subgroup Subgroup Deaths/n () GLN alone AOX alone GLNAOX  
Overall Overall          
    363/1218 (30) 1.40 (0.98-2.00) 1.20 (0.84-1.72) 1.42 (1.00-2.03)
Study Setting Study Setting          
Region Region         0.37
Canada 303/1044 (29) 1.41 (0.96-2.07) 1.14 (0.77-1.67) 1.29 (0.88-1.89)
USA 44/131 (34) 1.56 (0.51-4.81) 1.43 (0.47-4.38) 3.43 (1.17-10.07)
Europe 16/43 (37) 0.86 (0.12-5.9) 2.40 (0.39-14.88) 0.89 (0.14-5.48)
Baseline Patient Characteristics Baseline Patient Characteristics Baseline Patient Characteristics        
Admission category Admission category         0.52
Surgical 59/255 (23) 2.16 (0.91-5.15) 1.94 (0.78-4.82) 1.58 (0.67-3.76)
Medical 304/963 (32) 1.28 (0.87-1.89) 1.08 (0.73-1.60) 1.43 (0.97-2.12)
Cancer patients Cancer patients         0.74
No 297/1048 (28) 1.48 (1.01-2.18) 1.15 (0.77-1.71) 1.42 (0.97-2.10)
Yes 66/170 (39) 1.05 (0.41-2.73) 1.43 (0.60-3.40) 1.38 (0.58-3.27)
Etiology of Shock Etiology of Shock         0.71
Cardiogenic 74/240 (31) 1.24 (0.56-2.79) 1.62 (0.75-3.51) 2.19 (1.03-4.67)
Septic 256/826 (31) 1.43 (0.93-2.19) 1.06 (0.69-1.63) 1.21 (0.79-1.86)
Other/Unkown/None 33/152 (22) 1.45 (0.46-4.57) 1.45 (0.43-4.86) 1.83 (0.60-5.78)
Vasopressors Vasopressors         0.37
lt15 mcg/min 162/595 (27) 1.58 (0.92-2.70) 1.66 (0.97-2.84) 1.50 (0.87-2.58)
gt15 mcg/min 201/623 (32) 1.32 (0.82-2.13) 0.92 (0.57-1.51) 1.39 (0.87-2.22)
Renal dysfunction Renal dysfunction         0.035
No 216/776 (28) 0.93 (0.59-1.46) 0.90 (0.58-1.40) 1.14 (0.74-1.77)
Yes 147/442 (33) 2.75 (1.50-5.03) 2.16 (1.15-4.07) 2.15 (1.17-3.94)
OR-odds ratio CI-confidence interval GLN-Glutamine AOX-antioxidants OR-odds ratio CI-confidence interval GLN-Glutamine AOX-antioxidants OR-odds ratio CI-confidence interval GLN-Glutamine AOX-antioxidants OR-odds ratio CI-confidence interval GLN-Glutamine AOX-antioxidants OR-odds ratio CI-confidence interval GLN-Glutamine AOX-antioxidants OR-odds ratio CI-confidence interval GLN-Glutamine AOX-antioxidants OR-odds ratio CI-confidence interval GLN-Glutamine AOX-antioxidants
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Additional Subgroup Analyses

• Age
• BMI
• Comorbidities
• Diabetes
• Number of organ failures

Subgroup analyses based on variable occurring
post randomization not valid
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Examination of Treatment Effect by Baseline Renal
Dysfunction and Post-Baseline Dialysis
Multivariable Subgroup Multivariable Subgroup OR (95 CI) Compared To Placebo Arm OR (95 CI) Compared To Placebo Arm OR (95 CI) Compared To Placebo Arm
Renal Dysfunction Ever On Dialysis deaths/n () GLN alone AOX alone GLNAOX
No No 158/634 (25) 1.1 (0.6-1.8) 1.1 (0.6-1.8) 1.3 (0.8-2.2)
No Yes 58/142 (41) 0.4 (0.2-1.2) 0.5 (0.2-1.3) 0.6 (0.3-1.6)
Yes No 76/240 (32) 3.9 (1.7-9.0) 3.3 (1.4-7.8) 1.6 (0.7-3.8)
Yes Yes 71/202 (35) 1.8 (0.7-4.4) 1.4 (0.6-3.5) 3.1 (1.2-7.6)
OR-odds ratio CI-confidence interval GLN-glutamine AOX-antioxidants OR-odds ratio CI-confidence interval GLN-glutamine AOX-antioxidants OR-odds ratio CI-confidence interval GLN-glutamine AOX-antioxidants OR-odds ratio CI-confidence interval GLN-glutamine AOX-antioxidants OR-odds ratio CI-confidence interval GLN-glutamine AOX-antioxidants
Cells in bold indicate treatment arm had significantly higher 28 day mortality than placebo at plt0.05. Cells in bold indicate treatment arm had significantly higher 28 day mortality than placebo at plt0.05. Cells in bold indicate treatment arm had significantly higher 28 day mortality than placebo at plt0.05. Cells in bold indicate treatment arm had significantly higher 28 day mortality than placebo at plt0.05. Cells in bold indicate treatment arm had significantly higher 28 day mortality than placebo at plt0.05. Cells in bold indicate treatment arm had significantly higher 28 day mortality than placebo at plt0.05.
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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.

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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

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• e

Experimental Diet enriched with Glutamine, AOX,
and Omega 3 FFAs
GLN-enriched EN
A van Zanten, unpublished data
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Experimental Diet enriched with Glutamine, AOX,
and Omega 3 FFAs
GLN-enriched EN
GLN-enriched EN
A van Zanten, unpublished data
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GLN-enriched EN
GLN-enriched EN
GLN-enriched EN
A van Zanten, unpublished data
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Future Trials Require Bedside Testing?
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Where does that leave Glutamine?
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Updated Meta-analysis of IV Glutamine (n28 RCTs)
Overall Mortality
Note Does not include EN GLN studies nor
REDOXS study
RR0.87 (0.75,1.02) P0.08
In press Critical Care
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Updated Meta-analysis of IV Glutamine (n28 RCTs)
Hospital Mortality
RR0.68 (0.51,0.89) P 0.005
In press Critical Care
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Updated Meta-analysis of IV Glutamine (n28 RCTs)
Influence of the number of study sites involved
in the trial
Hospital Mortality
In press Critical Care
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Updated Meta-analysis of IV Glutamine (n28 RCTs)
Infection
RR0.86 (0.73,1.03) P0.10
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Updated Meta-analysis of IV Glutamine (n28 RCTs)
ICU Length of Stay
Note Does not include EN GLN studies nor REDOXS
study
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Updated Meta-analysis of IV Glutamine (n28 RCTs)
Hospital Length of Stay
WMD-2.42 (-4.60, -0.24) P0.03
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• 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 (ISSgt24)
• Of treated patients, 39 had low plasma levels at
  END of treatment day 6 levels associated with
  worse outcomes

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Pre-specified subgroup in patients with low basal
levels of glutamine
Perez-Barcena ICM 2014
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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
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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
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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.

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Is the patient in shock or have multi-organ
failure, particularly renal failure?
Do not give any glutamine, neither EN or PN
No
Yes
Is EN possible?
Yes
No
Patient is PN dependent
Is the patient Burns? Trauma?
Yes
No
Give IV Glutamine 0.35 gm/kg/day as long as they
are on PN
Do not give glutamine
Give EN Glutamine 0.35-0.5 gm/kg/day as long as
they are on EN
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Questions?