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Redox
1. REDOX: A secondary analysis
What did we learn?
Can
a
dianCri
tical Care
TrialsG
roup
Daren K. Heyland MD
Professor of Medicine
Queen’s University, Kingston, ON Canada
On behalf of the REDOXS Study Investigators
2. 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.
3. 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 Medicine
Queen’s University, Kingston, ON Canada
On behalf of the REDOXS Study Investigators
N Engl J Med 2013;368:1489-97.
4. 1200 ICU patients
Evidence of
Multi-organ failure
R
glutamine
placebo
Concealed
Stratified by site
R
R
antioxidants
placebo
Factorial 2x2 design
Double blind treatment
placebo
antioxidants
The REDOXS study
5. 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
6. 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
Antioxidants
per day
500 mcg
Selenium
Vit C 1500 mg
Vit E 500 mg
B carotene 10 mg
Zinc 20 mg
Se 300 ug
8. Pre-specified Sub-group Analysis
Glutamine 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=0.34
28 day mortality, OR with 95% CI)
9. Other Clinical Outcomes
• No differences between groups
– SOFA
– Need for dialysis
– Duration of mechanical ventilation
– PODS
– infections
– ICU and Hospital LOS
12. 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
14. 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)
16. • Age
• BMI
• Comorbidities
• Diabetes
• Number of organ failures
Additional Subgroup Analyses
Subgroup analyses based on variable occurring
post randomization not valid
17. 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.
18. 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.
19. 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
25. Updated Meta-analysis of IV Glutamine
(n=28 RCTs)ICU
Length of Stay
Note: Does not include EN GLN studies nor REDOXS study
Study or Subgroup
2.4.1 Patients on PN
Fuentes-Orozco 2004
Zhang
Luo
Perez-Barcena 2008
Fuentes-Orozco 2008
Estivariz
Cai
Cekman
Subtotal (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)
2.4.2 Patients on EN
Palmese
Ozgultekin
Eroglu
Subtotal (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
7.2
11.73
7.6
22.9
11
12
22.1
19.2
12
11.8
14
SD
9.2
6.57
0.7
20.6
11.7
2
4.9
12
4.6
5.9
2
Total
17
22
11
15
22
32
55
15
189
42
20
20
82
271
Mean
7.3
13.39
6.9
20.5
11.14
23
23.8
27.4
13
17.3
15
SD
4.5
5.08
0.9
16
7.41
6
5.1
12
3.4
16.4
2
Total
16
22
9
15
22
31
55
15
185
42
20
20
82
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
2004
2007
2008
2008
2008
2008
2008
2011
2006
2008
2009
PN GLN Control Mean Difference Mean Difference
IV, Random, 95% CI
-10 -5 0 5 10
Favours PN GLN Favours control
26. Updated Meta-analysis of IV Glutamine
(n=28 RCTs)
Hospital
Length of
Stay
WMD=-2.42 (-4.60, -0.24)
P=0.03
Study or Subgroup
Powell-Tuck
Wischmeyer
Zhou 2004
Fuentes-Orozco 2004
Xian-Li
Sahin
Fuentes-Orozco 2008
Perez-Barcena 2008
Yang 2008
Estivariz
Ziegler
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
43.4
40
42
16.5
25.3
14.2
30.18
35.5
13.48
20
25.1
SD
34.1
10
7
8.9
7.6
4.4
10.42
33.6
1.42
2
25.6
Total
83
12
15
17
20
20
22
15
25
15
75
319
Mean
48.9
40
46
16.7
28.6
16.4
26.59
42.9
15.18
30
20.5
SD
38.4
9
6.6
7
6.9
3.9
13.3
28.8
1.14
6
15.5
Total
85
14
15
16
21
20
22
15
25
12
75
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
1999
2001
2004
2004
2004
2007
2008
2008
2008
2008
2012
PN Glutamine Control Mean Difference Mean Difference
IV, Random, 95% CI
-10 -5 0 5 10
Favours PN Glutamine Favours control
27. • 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
28. 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’
29. 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
30. 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.
Due to the two interim analysis, it was pre-specified that the significance level for the two primary comparisons was set at 4.4%. Rather than report the raw p-values (0.049 Glut and 0.48 AOX) and state that p&lt;0.044 is sig, I’ve reported the adjusted p-values so know 0.05 is sig. The adjusted p-values are simply the raw p-values multiplied by 0.05/0.044. Reporting the raw p-values and using a sig level of 0.044 or reporting the adjusted p-values and using a sig level of 0.05 are equivalent, but we felt that the latter approach may avoid miss-interpretation by those who assume that p&lt;0.05 implies pre-specified significance. No other p-values in this analysis are adjsuted. Note also that if neither treatment has any effect, the chance that either GLN or AOX would obtain a p-value &lt;0.05 by luck is about 10%.
Baseline median plasma glutamine and selenium levels were within normal limits in all patients (Supplementary Figure 2 and Table S5). Glutamine supplementation led to a statistically significant increase in plasma glutamine at both day 4 and day 7 of ICU stay (P &lt; 0.001) whereas antioxidant supplementation led to a significant increase in plasma selenium at day 4 and 7 of ICU stay (P &lt; 0.001).
Baseline median plasma glutamine and selenium levels were within normal limits in all patients (Supplementary Figure 2 and Table S5). Glutamine supplementation led to a statistically significant increase in plasma glutamine at both day 4 and day 7 of ICU stay (P &lt; 0.001) whereas antioxidant supplementation led to a significant increase in plasma selenium at day 4 and 7 of ICU stay (P &lt; 0.001).
