redox: a secondary analysis what did we learn? daren k. heyland md professor of medicine queen’s...
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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 eventsHeterogeneity: Tau² = 0.00; Chi² = 0.30, df = 2 (P = 0.86); I² = 0%Test for overall effect: Z = 0.27 (P = 0.79)
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
Updated Meta-analysis of IV Glutamine (n=28 RCTs)
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)
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)
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
In press Critical Care
Updated Meta-analysis of IV Glutamine (n=28 RCTs)
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)
Total eventsHeterogeneity: Tau² = 0.00; Chi² = 7.48, df = 9 (P = 0.59); I² = 0%Test for overall effect: Z = 2.77 (P = 0.006)
1.2.2 Multi-center studies
DechelotteZieglerSubtotal (95% CI)
Total eventsHeterogeneity: Tau² = 0.00; Chi² = 0.04, df = 1 (P = 0.84); I² = 0%Test for overall effect: Z = 0.75 (P = 0.45)
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
In press Critical Care
Updated Meta-analysis of IV Glutamine (n=28 RCTs)
Infection
RR=0.86 (0.73,1.03)P=0.10
Study or Subgroup2.1.1 Patients on PN
GriffithsWischmeyerZhou 2004Fuentes-Orozco 2004DechelotteFuentes-Orozco 2008Perez-Barcena 2008GrauAndrewsZieglerSubtotal (95% CI)
Total eventsHeterogeneity: Tau² = 0.04; Chi² = 17.37, df = 9 (P = 0.04); I² = 48%Test for overall effect: Z = 1.24 (P = 0.21)
2.1.2 Patients on EN
PalmeseErogluSubtotal (95% CI)
Total eventsHeterogeneity: Tau² = 0.00; Chi² = 0.33, df = 1 (P = 0.57); I² = 0%Test for overall effect: Z = 1.75 (P = 0.08)
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
Updated Meta-analysis of IV Glutamine (n=28 RCTs)
ICULength of Stay
Note: Does not include EN GLN studies nor REDOXS study
Study or Subgroup2.4.1 Patients on PN
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)
2.4.2 Patients on EN
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
Updated Meta-analysis of IV Glutamine (n=28 RCTs)
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.
Questions?