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?