Controversies in Nutrient-Specific Therapies: Effective or Ineffective? Daren K. Heyland MD...
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Transcript of Controversies in Nutrient-Specific Therapies: Effective or Ineffective? Daren K. Heyland MD...
Controversies in Nutrient-Specific Therapies: Effective or Ineffective?
Daren K. Heyland MD
Professor of MedicineQueen’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 studyDaren 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.
1200 ICU patientsEvidence of
Multi-organ failureR
glutamine
placebo
ConcealedStratified by site
R
R
antioxidants
placebo
Factorial 2x2 designDouble blind treatment
placebo
antioxidants
The REDOXS study
Mortality Outcomes
P=0.07
P=0.049
P=0.02
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 placebo P-values*Subgroup Deaths/n (%) GLN alone AOX alone GLN+AOX Overall
363/1218 (30%) 1.40 (0.98-2.00) 1.20 (0.84-1.72) 1.42 (1.00-2.03)Study Setting 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 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 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 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 0.37
<15 mcg/min 162/595 (27%) 1.58 (0.92-2.70) 1.66 (0.97-2.84) 1.50 (0.87-2.58)
>=15 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 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
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 (1.0-2.0, P =0.063), 1.2 (0.8-1.7, P =0.31) and 1.4 (1.0-2.0, 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 (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)
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
• eExperimental Diet enriched with Glutamine, AOX, and Omega 3 FFAs
A van Zanten, unpublished data
EN glutamine associated with increased mortality?
GLN enriched GLN enriched
Where does that leave Glutamine?
Updated Meta-analysis of IV Glutamine (n=24 RCTs)
OverallMortality
Note: Does not include EN GLN studies nor REDOXS study
RR=0.88(0.75,1.03)
p=0.10Wischmeyer 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= 0.008
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)
ICULength 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)HospitalLength 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 (0.75-0.99)
p= 0.03
www.criticalcarenutrition.com
0.88(0.78-0.99)
www.criticalcarenutrition.com
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 RecommendationBased on 22 studies, we recommend arginine and other
select nutrients not be used for critically ill patients
New RCTs = 2New RCTs = 2 2013: No changes in recommendation
Enteral Fish Oils*
*Product enhanced with fish oils +borage oils + antioxidants
Enteral Fish Oils**Product enhanced with fish oils +borage oils + antioxidants
2009 RecommendationBased on 5 studies, we recommend the use of
enteral formula with fish oils, borage oils, and
antioxidants in patients with ALI/ARDS
New RCTs = 4New RCTs = 4Rice 2011Grau-Carmona 2011Thiella 2011Elamin 2012+ Pontes Arruda 2011+ Stapleton 2011 (fish oil only)
Timing of FeedingTiming of Feeding
SSUUPPPPLLEEMMEENNTT
““Early Early Full”Full”Fast ramp upFast ramp up
““Early Early Trophic”Trophic”(10 ml/hr)(10 ml/hr)
N-3 + GLA +N-3 + GLA +AntioxidantsAntioxidants(Module delivered (Module delivered as as bolusbolus bid) bid)
ControlControlStandard ENStandard EN(480 cal/ 20 g pro)(480 cal/ 20 g pro)
n = 250 n = 250
n = 250 n = 250
NIH NHLBI
OMEGA: 60-Day MortalityOMEGA: 60-Day Mortality
P=0.05
26.6% 24.6% 16.3% 17.9%
0
5
10
15
20
25
30
OMEGA Observed
OMEGA Adjusted
Control Observed
Control Adjusted
FACTT Conservative
%
P=0.14P=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 = 0.003
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!
www.criticalcarenutrition.com
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?