Controversies in Nutrient-Specific Therapies: Effective or Ineffective?

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Controversies in Nutrient-Specific Therapies
Effective or Ineffective?

• 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 FAILUREThe 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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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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Post-hoc Secondary Analyses
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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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Adjusted Analysis
Imbalance in organ failures at baseline?
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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 1.4 (1.0-2.0, P 0.063), 1.2
  (0.8-1.7, P 0.31) and 1.4 (1.0-2.0, P0.049) 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 (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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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

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• e

Experimental Diet enriched with Glutamine, AOX,
and Omega 3 FFAs
EN glutamine associated with increased mortality?
A van Zanten, unpublished data
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GLN enriched
GLN enriched
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Where does that leave Glutamine?
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Updated Meta-analysis of IV Glutamine (n24 RCTs)
Overall Mortality
Note Does not include EN GLN studies nor
REDOXS study
RR0.88 (0.75,1.03) p0.10
Wischmeyer et al (under review)
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Updated Meta-analysis of IV Glutamine (n13 RCTs)
Hospital Mortality
RR0.68 (0.51,0.90) P 0.008
Note Does not include EN GLN studies nor
REDOXS study
Wischmeyer et al (under review)
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Updated Meta-analysis of IV Glutamine (n13 RCTs)
Influence of the number of study sites involved
in the trial
Hospital Mortality
Wischmeyer et al (under review)
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Updated Meta-analysis of IV Glutamine (n12 RCTs)
Infection
Note Does not include EN GLN studies nor REDOXS
study
RR0.86 (0.73,1.02) P0.10
Wischmeyer et al (under review)
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Updated Meta-analysis of IV Glutamine (n11 RCTs)
ICU Length of Stay
Note Does not include EN GLN studies nor REDOXS
study
WMD-1.91 (-4.10, -0.28) p0.09
Wischmeyer et al (under review)
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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) P0.02
Wischmeyer et al (under review)
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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.
• there 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 and
shock
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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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What does the updated meta-analyses say on
antioxidant supplementation in the critically
ill?
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Combined Antioxidants effect on mortality (n
23)
0.86 (0.75-0.99)
p 0.03
www.criticalcarenutrition.com
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Selenium supplementation and ICU infectious
complications, (n 8)
0.88(0.78-0.99)
www.criticalcarenutrition.com
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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

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Arginine

• 2009 Recommendation
• Based on 22 studies, we recommend arginine and
  other
• select nutrients not be used for critically ill
  patients

New RCTs 2
2013 No changes in recommendation
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Enteral Fish Oils
Product enhanced with fish oils borage oils
antioxidants
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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

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Timing of Feeding
Early Trophic (10 ml/hr)
Early Full Fast ramp up
S U P P L E M E N T
N-3 GLA Antioxidants (Module delivered as
bolus bid)
n 250 n 250
n 250 n 250
Control Standard EN (480 cal/ 20 g pro)
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OMEGA 60-Day Mortality
P0.05
bolus dilute effect? 50 pts underfed
(trophic) protein in placebo include but analyze
without

Rice et al JAMA Oct 2011
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• 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
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Clinical Outcomes
First multicentre study to use usual care in
control group.no effect on mortality
Grau-Carmona Clin Nutr 2011
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Fish Oils Effect on mortality (n 6)
INTERSEPT, Stapleton data not included
2009 RR 0.67, 95 CI 0.51, 0.97, p 0.003
Dhaliwal R et al NCP 2013 in press
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Fish oils effect on mortality removing bolus
RCT (n 5)
www.criticalcarenutrition.com
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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

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Questions?