Transcript Periodic Report

Glutamine and Antioxidants
in the critically ill:
End of an Era?
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Daren K. Heyland MD
Professor of Medicine
Queen’s University, Kingston, ON Canada
On behalf of the REDOXS Study Investigators
up C an
Glutamine: Important Questions
• Is glutamine ‘conditionally essential’?
• Is glutamine safe?
– Mechanism of harm?
– Negative interactions between glutamine and
antioxidants
• What are the recommendations for
glutamine in 2015?
Glutamine: A conditionally
essential amino acid?
Glutamine levels drop:
- following extreme physical exercice
- after major surgery
- during critical illness
Low glutamine levels are associated with:
- immune dysfunction
- higer mortality in critically ill patients
Novak F, Heyland DK, A Avenell et al., Crit Care Med 2002
Oudemans-van Straaten HM, Bosman RJ, Treskes Met al., Intensive Car Med 2001
The “Oudemans-van Straaten-Study”
“high”
“low”
=> Low plasma glutamine at
ICU admission is related to
mortality.
Plasma Levels of Glutamine in
Subset of Patients
P <0.001
Heyland N Engl J Med 2013;368:1489-97.
Glutamine and glutathione at ICU admission
in relation to outcome
Rodas Clinical Science (2012) 122, 591–597
Future Trials Require Bedside Testing?
• 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)
• No effect in subgroup that had low levels of GLN at
baseline (n=60)
• Of treated patients, 39% had low plasma levels at
END of treatment – day 6 levels associated with
worse outcomes
Glutamine: Is it safe?
The REDOXS study
antioxidants
Factorial 2x2 design
Double blind treatment
1200 ICU patients
Evidence of
Multi-organ failure
glutamine
R
R
Concealed
Stratified by site
placebo
antioxidants
placebo
R
placebo
Heyland N Engl J Med 2013;368:1489-97.
The Research Protocol
Inclusion Criteria
• 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
Optimizing the Dose of Glutamine Dipeptides
and Antioxidants In Critically Ill Patients:
A Phase I dose finding study
Glutamine/day
Antioxidants
per day
Parenterally
Enterally
0.35 gms/kg
30 gms
500 mcg
Selenium
Vit C 1500 mg
Vit E 500 mg
B carotene 10 mg
Zinc 20 mg
Se 300 ug
• 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
Primary outcome of 28 day mortality using all
1218 evaluable patients (ITT)
Antioxidants (AOX)
Glutamine
(glut)
Yes
No
Glut OR conditioned
on AOX
Overall adjusted OR for glut
Yes
No
101/310 (32.6%)
97/301 (32.2%)
89/307 (29.0%)
AOX OR
conditioned on
Glut
1.02 (0.72, 1.43)
76/309 (25.3%)
Overall adjusted OR
of AOX
1.09 (0.86-1.40;
p=0.48*)
1.20 (0.84, 1.72)
1.18 (0.83-1.66)
1.40 (0.98-2.00)
1.28 (1.00-1.64; p=0.049*)
AOX by glut
interaction
p=0.49
OR=odds ratio. ORs are presented with 95% confidence intervals in parentheses. An OR>1 indicates increased
mortality with treatment.
All odds ratios adjust for presence of shock at baseline. Overall ORs also adjust for other treatment factor.
*To account for the two interim analyses, we pre-specified statistical significance of the final analysis at a two-sided
p<0.044 in our protocol. Thus, our primary outcome did not reach statistical significance for either intervention.
Mortality Outcomes
P=0.02
P=0.02
P=0.049
P=0.07
Note: all P values pertain to GLN vs No GLN;
no significant differences between AOX vs. No AOX
Other Clinical Outcomes
• No differences between groups
– SOFA
– Need for dialysis
– Duration of mechanical ventilation
– PODS
– infections
– ICU and Hospital LOS
Post-hoc Secondary Analyses
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)
JPEN May 2014
Selected Subgroup Analyses
Subgroup
Overall
Deaths/n (%)
363/1218 (30%)
OR (95% CI) compared to placebo
GLN alone
AOX alone
GLN+AOX
1.40 (0.98-2.00)
1.20 (0.84-1.72)
1.42 (1.00-2.03)
Study Setting
Region
Canada 303/1044 (29%)
1.41 (0.96-2.07)
USA
44/131 (34%)
1.56 (0.51-4.81)
Europe
16/43 (37%)
0.86 (0.12-5.9)
Baseline Patient Characteristics
Admission category
59/255 (23%)
Surgical
2.16 (0.91-5.15)
Medical 304/963 (32%)
1.28 (0.87-1.89)
Cancer patients
No 297/1048 (28%)
1.48 (1.01-2.18)
66/170 (39%)
Yes
1.05 (0.41-2.73)
Etiology of Shock
74/240 (31%)
Cardiogenic
1.24 (0.56-2.79)
Septic 256/826 (31%)
1.43 (0.93-2.19)
33/152 (22%)
Other/Unkown/None
1.45 (0.46-4.57)
Vasopressors
<15 mcg/min 162/595 (27%)
1.58 (0.92-2.70)
>=15 mcg/min 201/623 (32%)
1.32 (0.82-2.13)
Renal dysfunction
No 216/776 (28%)
0.93 (0.59-1.46)
Yes 147/442 (33%)
2.75 (1.50-5.03)
OR-odds ratio; CI-confidence interval; GLN-Glutamine; AOX-antioxidants
P-values*
0.37
1.14 (0.77-1.67)
1.43 (0.47-4.38)
2.40 (0.39-14.88)
1.29 (0.88-1.89)
3.43 (1.17-10.07)
0.89 (0.14-5.48)
0.52
1.94 (0.78-4.82)
1.08 (0.73-1.60)
1.58 (0.67-3.76)
1.43 (0.97-2.12)
0.74
1.15 (0.77-1.71)
1.43 (0.60-3.40)
1.42 (0.97-2.10)
1.38 (0.58-3.27)
0.71
1.62 (0.75-3.51)
1.06 (0.69-1.63)
1.45 (0.43-4.86)
2.19 (1.03-4.67)
1.21 (0.79-1.86)
1.83 (0.60-5.78)
0.37
1.66 (0.97-2.84)
0.92 (0.57-1.51)
1.50 (0.87-2.58)
1.39 (0.87-2.22)
0.035
0.90 (0.58-1.40)
2.16 (1.15-4.07)
1.14 (0.74-1.77)
2.15 (1.17-3.94)
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.
Metaplus Study
• 14 ICUs in the Netherlands, Germany, France, and
Belgium.
• 301 adult patients who were expected to be ventilated
and to require enteral nutrition (EN) for more than 72
hours
• Randomized to intervention feed
– High-protein EN enriched with 21 grams of glutamine, extra
antioxidants including an additional 275 mcg of selenium and an
additional 7.5 grams of fish oils, n = 152)
– or control (standard high-protein EN, n = 149).
• Feeds initiated within 48 hours of ICU admission and
continued for a maximum of 28 days
• Intention-to-treat analysis for total population as well as
predefined medical, surgical, and trauma
subpopulations.
Van Zanten JAMA 2014;312:514
Metaplus Study
• No statistically significant differences in the primary end point,
incidence of new infections
– 53% (95%CI, 44%-61%) in the enriched group vs 52% (95%CI,
44%-61%) in the control group (P = .96).
• No differences in secondary end points included mortality,
Sequential Organ Failure Assessment (SOFA) scores, mechanical
ventilation duration, ICU and hospital lengths of stay, and subtypes
of infections according to CDC definitions.
• Only positive finding was a higher 6-month mortality rate in the
medical subgroup: 54% (95%CI, 40%-67%) in the enriched group vs
35% (95%CI, 22%-49%) in the control group (P = .04).
• hazard ratio of 1.57 (95%CI, 1.03-2.39; P = .04) for 6-month
mortality adjusted for age and Acute Physiology and Chronic Health
Evaluation II score.
Van Zanten JAMA 2014;312:514
6 Month Survival Curves for
REDOXS and METAPLUS
Adjusted model, glutamine treated patients had higher
rate of death (HR 1.57, 95% CI 1.03, 2.39, p=0.04)
GLN-enriched EN
GLN-enriched EN
GLN-enriched EN
GLN-enriched EN
GLN-enriched EN
Key Question
• If we conclude that glutamine has potential
for harm, what impact does this have on
our clinical recommendations?
Updated Meta-analysis of IV Glutamine
(n=32 RCTs)
Overall
Mortality
RR=0.87
(0.75,1.01)
P=0.07)
Note:
Does not
include EN
GLN studies
nor REDOXS
study
Updated Meta-analysis of IV Glutamine
(n=32 RCTs)
Hospital
Mortality
RR=0.70 (0.53,0.92)
P= 0.01
Updated Meta-analysis of IV Glutamine
(n=32 RCTs)
Hospital
Mortality
Influence of the number of study sites involved in the trial
PN Glutamine
Control
Study or Subgroup
Events
Total Events Total Weight
1.2.1 Single-center studies
Griffiths
18
42
25
42 41.0%
Powell-Tuck
14
83
20
85 20.1%
Wischmeyer
2
15
5
16
3.4%
Fuentes-Orozco 2004
2
17
3
16
2.8%
Xian-Li
0
20
3
21
0.9%
Sahin
2
20
6
20
3.5%
Yang 2008
1
25
3
25
1.6%
Estivariz
1
32
6
31
1.8%
Perez-Barcena 2008
3
15
0
15
0.9%
Luo
0
11
0
9
Perez-Barcena 2010
0
23
1
20
0.8%
Subtotal (95% CI)
303
300 76.7%
Total events
43
72
Heterogeneity: 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
Dechelotte
2
58
2
56
2.0%
Ziegler
15
75
19
75 21.2%
Subtotal (95% CI)
133
131 23.3%
Total events
17
21
Heterogeneity: 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)
436
431 100.0%
Total events
60
93
Heterogeneity: 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%
Risk Ratio
M-H, Random, 95% CI Year
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]
Risk Ratio
M-H, Random, 95% CI
1997
1999
2001
2004
2004
2007
2008
2008
2008
2008
2010
0.97 [0.14, 6.62] 2006
0.79 [0.43, 1.43] 2013
0.80 [0.45, 1.42]
0.68 [0.51, 0.89]
0.01
0.1
1
10
100
Favours PN Glutamine Favours control
Updated Meta-analysis of IV Glutamine
(n=32 RCTs)
Hospital
Mortality
Influence of the type of glutamine used in the trials
Updated Meta-analysis of IV Glutamine
(n=32 RCTs)
Infection
RR=0.89 (0.77,1.03)
P=0.12
Updated Meta-analysis of IV Glutamine
(n=32 RCTs)
ICU Length of Stay
Note: Does not include EN GLN studies nor REDOXS study
Updated Meta-analysis of IV Glutamine
(n=32 RCTs)
Hospital Length of Stay
WMD=-2.56 (-4.71, -0.42)
P=0.02
Temporal trend of short-term mortality in
severely ill patients receiving
parenteral glutamine supplementation
All the beneficial treatment effect seen in older studies (before 2003)
Fadda Clinical Nutrition 32 (2013) 492–493
2015 Canadian Nutrition CPGs:
IV Glutamine
Draft Recommendation:
• When parenteral nutrition is prescribed to critically
ill patients, we recommend parenteral
supplementation with glutamine NOT be used*.
• There are insufficient data to generate
recommendations for intravenous glutamine in
critically ill patients receiving enteral nutrition, but
given the safety concerns we also recommend
intravenous glutamine NOT be used in enterally fed
critically ill patients.
*downgraded from ‘should be considered’
Updated Meta-analysis of EN Glutamine
(n=11 RCTs)
Mortality
No overall treatment effect or in trauma subset
but positive effect in burns (RR 0.19, 95% CI 0.06,0.67, p=0.01)
Updated Meta-analysis of EN Glutamine
(n=11 RCTs)
Infection
Few studies reported infection
No overall treatment effect or in trauma or burns subset
Updated Meta-analysis of EN Glutamine
(n=11 RCTs)
Hospital LOS
Positive effect driven by 3 studies in burn patients
2015 Canadian Nutrition CPGs:
EN Glutamine
Draft Conclusions:
1) Glutamine supplemented enteral nutrition may be associated
with a reduction in mortality and shorter hospital LOS in burn
patients, but inconclusive in other critically ill patients.
2) No overall effect in trauma patients
3) Concerns about safety of EN glutamine given METAPLUS study
Draft Recommendation:
We recommend enteral glutamine NOT be used in critically ill
patients*.
*downgraded from ‘should be considered in burn and trauma patients’
A RandomizEd trial of ENtERal
Glutamine to minimIZE thermal injury
EN glutamine
Double blind
treatment
2700 Burn
Injury patients
R
Concealed
Stratified by site
placebo
6 month
mortality
2015 Canadian Nutrition CPGs:
Combined IV+ EN Glutamine
Draft Recommendation:
• Based on one level 1 study (REDOXS) and 1 level 2
study, we strongly recommend that high dose
combined parenteral and enteral glutamine
supplementation NOT be used in critically ill patients
2015 Canadian Nutrition CPGs:
Supplemental Antioxidant Nutrients
Draft Recommendation:
• We recommend that high dose antioxidants,
specifically selenium, not be used in critically ill
patients*
*downgraded from ‘should be considered’
Questions?