REDOX: A secondary analysis What did we learn? Daren K. Heyland MD Professor of Medicine Queen’s...

REDOX: A secondary analysisWhat did we learn?

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 study

Daren 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

The Research Protocol

• Adults (>18)• With 2 or more organ failures related to

their acute illness :– Requiring mechanically ventilation (P/F<300)– Clinical evidence of hypoperfusion defined by

need for vasopressor agents for more than 2 hour

– Renal dysfunction : Cr>171 or <500ml/24 hrs– platelet < 50

Inclusion Criteria

Optimizing the Dose of Glutamine Dipeptides and Antioxidants In Critically Ill Patients:

A Phase I dose finding study

• 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

Parenterally Enterally

Glutamine/day 0.35 gms/kg 30 gms

Antioxidantsper day

500 mcg Selenium

Vit C 1500 mgVit E 500 mg

B carotene 10 mgZinc 20 mgSe 300 ug

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

Pre-specified Sub-group AnalysisGlutamine vs. No Glutamine

Favours GLN OR Favours No GLN

0.5 0.7 0.9 1.5 2.0 3.0

Charlson co-morbidity index > 1

Charlson co-morbidity index 0-1

Age >=75

Age 65-74

Age 55-64

Age <55

Other admission diagnosis

Sepsis

APACHE II Score > median

APACHE II Score <= median

>2 organ failures on presentation

2 organ failures on presentation

All Patients p=0.049

p=0.47

p=0.05

p=0.10

p=0.31

p=0.11

p=0.33

p=0.07

p=0.55

p=0.05

p=0.57

p=0.10

p=0.22

p=0.48

p=0.82

p=0.3428 day mortality, OR with 95% CI)

Other Clinical Outcomes

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

Plasma Levels of Glutamine in Subset of Patients

P <0.001

Post-hoc Secondary Analyses

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 (n=187 vs. n=148 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

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 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, P=0.049). • 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)

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

• Age

• BMI

• Comorbidities

• Diabetes

• Number of organ failures

Additional Subgroup Analyses

Subgroup analyses based on variable occurring post randomization not valid

Examination of Treatment Effect by Baseline Renal Dysfunction and Post-Baseline Dialysis

Multivariable Subgroup OR (95% CI) Compared To Placebo Arm

Renal Dysfunction

Ever On Dialysis deaths/n (%) GLN alone AOX alone GLN+AOX

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

Cells in bold indicate treatment arm had significantly higher 28 day mortality than placebo at p<0.05.

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.

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

Where does that leave Glutamine?

Updated Meta-analysis of IV Glutamine (n=28 RCTs)

OverallMortality

Note: Does not include EN GLN studies nor REDOXS study

RR=0.87(0.75,1.02)

P=0.08

Study or Subgroup2.3.1 Patients on PN

GriffithsPowell-TuckWischmeyerXian-LiFuentes-Orozco 2004DechelotteTianSahinEstivarizFuentes-Orozco 2008Yang 2008Perez-Barcena 2008CaiLuoDuskaPerez-Barcena 2010AndrewsCekmanGrauWernermanZieglerSubtotal (95% CI)

Total eventsHeterogeneity: Tau² = 0.00; Chi² = 19.55, df = 19 (P = 0.42); I² = 3%Test for overall effect: Z = 1.93 (P = 0.05)

2.3.2 Patients on EN

PalmeseOzgultekinErogluSubtotal (95% CI)


Total (95% CI)

Total eventsHeterogeneity: Tau² = 0.00; Chi² = 19.99, df = 22 (P = 0.58); I² = 0%Test for overall effect: Z = 1.76 (P = 0.08)Test for subgroup differences: Chi² = 0.21, df = 1 (P = 0.65), I² = 0%

Events

1814

2022221213

17024

88398

15

195

612

1

19

214

Total

42831520175820203222251555111023

2501559

20575

1072

42202082

1154

Events

2520

5332566530

20002

806

131119

234

812

1

21

255

Total

42851621165620203122251555

91020

2521568

20875

1081

42202082

1163

Weight

12.6%6.2%1.1%0.3%0.8%0.6%1.0%1.1%0.5%1.0%0.5%0.3%8.3%

0.3%0.9%

37.9%1.6%3.9%2.9%6.5%

88.2%

2.5%9.0%0.3%

11.8%

100.0%

M-H, Random, 95% CI

0.72 [0.47, 1.11]0.72 [0.39, 1.32]0.43 [0.10, 1.88]0.15 [0.01, 2.73]0.63 [0.12, 3.28]0.97 [0.14, 6.62]0.40 [0.09, 1.83]0.33 [0.08, 1.46]0.16 [0.02, 1.26]0.40 [0.09, 1.85]0.33 [0.04, 2.99]

7.00 [0.39, 124.83]0.85 [0.50, 1.44]

Not estimable5.00 [0.27, 92.62]

1.74 [0.36, 8.51]1.11 [0.87, 1.42]0.50 [0.15, 1.64]0.80 [0.37, 1.73]0.74 [0.30, 1.80]0.79 [0.43, 1.43]0.84 [0.71, 1.00]

0.75 [0.28, 1.97]1.00 [0.60, 1.66]

1.00 [0.07, 14.90]0.94 [0.61, 1.47]

0.87 [0.75, 1.02]

Year

199719992001200420042006200620072008200820082008200820082008201020112011201120112012

200620082009

PN GLN Control Risk Ratio Risk RatioM-H, Random, 95% CI

0.1 0.2 0.5 1 2 5 10Favours PN GLN Favours control

In press Critical Care


Hospital Mortality

RR=0.68 (0.51,0.89)P= 0.005

Study or Subgroup

GriffithsPowell-TuckWischmeyerXian-LiFuentes-Orozco 2004DechelotteSahinPerez-Barcena 2008EstivarizLuoYang 2008Perez-Barcena 2010Ziegler

Total (95% CI)


Events

1814

2022231010

15

60

Total

42831520175820153211252375

436

Events

2520

5332606031

19

93

Total

428516211656201531

9252075

431

Weight

41.0%20.1%

3.4%0.9%2.8%2.0%3.5%0.9%1.8%

1.6%0.8%

21.2%

100.0%

M-H, Random, 95% CI

0.72 [0.47, 1.11]0.72 [0.39, 1.32]0.43 [0.10, 1.88]0.15 [0.01, 2.73]0.63 [0.12, 3.28]0.97 [0.14, 6.62]0.33 [0.08, 1.46]

7.00 [0.39, 124.83]0.16 [0.02, 1.26]

Not estimable0.33 [0.04, 2.99]0.29 [0.01, 6.78]0.79 [0.43, 1.43]

0.68 [0.51, 0.89]

Year

1997199920012004200420062007200820082008200820102012

PN GLN Control Risk Ratio Risk RatioM-H, Random, 95% CI

0.1 0.2 0.5 1 2 5 10Favours PN GLN Favours control



Hospital Mortality

Influence of the number of study sites involved in the trial

Study or Subgroup1.2.1 Single-center studies

GriffithsPowell-TuckWischmeyerFuentes-Orozco 2004Xian-LiSahinYang 2008EstivarizPerez-Barcena 2008LuoPerez-Barcena 2010Subtotal (95% CI)


1.2.2 Multi-center studies

DechelotteZieglerSubtotal (95% CI)


Total (95% CI)

Total eventsHeterogeneity: Tau² = 0.00; Chi² = 7.93, df = 11 (P = 0.72); I² = 0%Test for overall effect: Z = 2.79 (P = 0.005)Test for subgroup differences: Chi² = 0.46, df = 1 (P = 0.50), I² = 0%

Events

1814

220211300

43

215

17

60

Total

4283151720202532151123

303

5875

133

436

Events

2520

533636001

72

219

21

93

Total

428516162120253115

920

300

5675

131

431

Weight

41.0%20.1%

3.4%2.8%0.9%3.5%1.6%1.8%0.9%

0.8%76.7%

2.0%21.2%23.3%

100.0%

M-H, Random, 95% CI

0.72 [0.47, 1.11]0.72 [0.39, 1.32]0.43 [0.10, 1.88]0.63 [0.12, 3.28]0.15 [0.01, 2.73]0.33 [0.08, 1.46]0.33 [0.04, 2.99]0.16 [0.02, 1.26]

7.00 [0.39, 124.83]Not estimable

0.29 [0.01, 6.78]0.64 [0.47, 0.88]

0.97 [0.14, 6.62]0.79 [0.43, 1.43]0.80 [0.45, 1.42]

0.68 [0.51, 0.89]

Year

19971999200120042004200720082008200820082010

20062013

PN Glutamine Control Risk Ratio Risk RatioM-H, Random, 95% CI

0.01 0.1 1 10 100Favours PN Glutamine Favours control



Infection

RR=0.86 (0.73,1.03)P=0.10


GriffithsWischmeyerZhou 2004Fuentes-Orozco 2004DechelotteFuentes-Orozco 2008Perez-Barcena 2008GrauAndrewsZieglerSubtotal (95% CI)



PalmeseErogluSubtotal (95% CI)


Total (95% CI)

Total eventsHeterogeneity: Tau² = 0.03; Chi² = 19.86, df = 11 (P = 0.05); I² = 45%Test for overall effect: Z = 1.67 (P = 0.10)Test for subgroup differences: Chi² = 1.24, df = 1 (P = 0.27), I² = 19.1%

Events

28734

239

1124

13433

276

138

21

297

Total

4212151758221559

25075

565

422062

627

Events

2694

1232161331

13123

297

2110

31

328

Total

4214151656221568

25275

575

422062

637

Weight

12.5%5.7%1.6%3.1%

10.3%6.5%

11.1%9.9%

18.2%9.4%

88.3%

6.9%4.8%

11.7%

100.0%

M-H, Random, 95% CI

1.08 [0.78, 1.48]0.91 [0.49, 1.68]0.75 [0.20, 2.79]0.31 [0.13, 0.77]0.69 [0.47, 1.03]0.56 [0.32, 0.99]0.85 [0.59, 1.22]0.89 [0.60, 1.34]1.03 [0.87, 1.22]1.43 [0.94, 2.20]0.89 [0.74, 1.07]

0.62 [0.36, 1.07]0.80 [0.40, 1.60]0.68 [0.45, 1.05]

0.86 [0.73, 1.03]

Year

1997200120042004200620082008201120112012

20062009

PN Glutamine Control Risk Ratio Risk RatioM-H, Random, 95% CI

0.1 0.2 0.5 1 2 5 10Favours PN glutamine Favours control


ICULength of Stay

Note: Does not include EN GLN studies nor REDOXS study


Fuentes-Orozco 2004ZhangLuoPerez-Barcena 2008Fuentes-Orozco 2008EstivarizCaiCekmanSubtotal (95% CI)

Heterogeneity: Tau² = 22.29; Chi² = 101.60, df = 7 (P < 0.00001); I² = 93%Test for overall effect: Z = 1.42 (P = 0.16)


PalmeseOzgultekinErogluSubtotal (95% CI)

Heterogeneity: Tau² = 0.00; Chi² = 1.31, df = 2 (P = 0.52); I² = 0%Test for overall effect: Z = 2.11 (P = 0.03)

Total (95% CI)

Heterogeneity: Tau² = 10.25; Chi² = 103.50, df = 10 (P < 0.00001); I² = 90%Test for overall effect: Z = 2.11 (P = 0.03)Test for subgroup differences: Chi² = 0.68, df = 1 (P = 0.41), I² = 0%

Mean

7.211.73

7.622.9

1112

22.119.2

1211.8

14

SD

9.26.57

0.720.611.7

24.912

4.65.9

2

Total

1722111522325515

189

42202082

271

Mean

7.313.39

6.920.5

11.1423

23.827.4

1317.3

15

SD

4.55.08

0.916

7.416

5.112

3.416.4

2

Total

1622

91522315515

185

42202082

267

Weight

8.2%10.1%13.1%

2.4%7.2%

11.8%12.2%

4.6%69.6%

12.3%5.3%

12.7%30.4%

100.0%

IV, Random, 95% CI

-0.10 [-5.00, 4.80]-1.66 [-5.13, 1.81]0.70 [-0.02, 1.42]

2.40 [-10.80, 15.60]-0.14 [-5.93, 5.65]

-11.00 [-13.22, -8.78]-1.70 [-3.57, 0.17]

-8.20 [-16.79, 0.39]-2.70 [-6.43, 1.03]

-1.00 [-2.73, 0.73]-5.50 [-13.14, 2.14]

-1.00 [-2.24, 0.24]-1.08 [-2.08, -0.08]

-2.46 [-4.74, -0.18]

Year

20042007200820082008200820082011

200620082009

PN GLN Control Mean Difference Mean DifferenceIV, Random, 95% CI

-10 -5 0 5 10Favours PN GLN Favours control


HospitalLength of Stay

WMD=-2.42 (-4.60, -0.24) P=0.03

Study or Subgroup

Powell-TuckWischmeyerZhou 2004Fuentes-Orozco 2004Xian-LiSahinFuentes-Orozco 2008Perez-Barcena 2008Yang 2008EstivarizZiegler

Total (95% CI)

Heterogeneity: Tau² = 6.35; Chi² = 28.63, df = 10 (P = 0.001); I² = 65%Test for overall effect: Z = 2.18 (P = 0.03)

Mean

43.44042

16.525.314.2

30.1835.5

13.4820

25.1

SD

34.110

78.97.64.4

10.4233.61.42

225.6

Total

8312151720202215251575

319

Mean

48.94046

16.728.616.4

26.5942.9

15.1830

20.5

SD

38.49

6.67

6.93.9

13.328.81.14

615.5

Total

8514151621202215251275

320

Weight

3.3%6.0%9.9%8.8%

10.7%15.3%

6.4%0.9%

19.1%12.9%

6.8%

100.0%

IV, Random, 95% CI

-5.50 [-16.48, 5.48]0.00 [-7.36, 7.36]

-4.00 [-8.87, 0.87]-0.20 [-5.65, 5.25]-3.30 [-7.75, 1.15]-2.20 [-4.78, 0.38]3.59 [-3.47, 10.65]

-7.40 [-29.80, 15.00]-1.70 [-2.41, -0.99]

-10.00 [-13.54, -6.46]4.60 [-2.17, 11.37]

-2.42 [-4.60, -0.24]

Year

19992001200420042004200720082008200820082012

PN Glutamine Control Mean Difference Mean DifferenceIV, Random, 95% CI

-10 -5 0 5 10Favours PN Glutamine Favours control

• 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 (ISS>24)• Of treated patients, 39% had low plasma levels at END

of treatment – day 6 levels associated with worse outcomes

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’

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

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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REDOX: A secondary analysis What did we learn? Daren K. Heyland MD Professor of Medicine Queen’s...

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