selenium in sepsis a new magic bullet? daren k. heyland, md, frcpc, msc professor of medicine,...
TRANSCRIPT
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Selenium in SepsisA new magic bullet?
Daren K. Heyland, MD, FRCPC, MScProfessor of Medicine,
Queen’s University, Kingston, Ontario
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www.criticalcarenutrition.com
Updated January 2009
Summarizes 207 trials studying >20,000 patients
34 topics 17 recommendations
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Background
• Essential trace element for all mammalian species• Involved in a number of physiological processes• Incorporated into 25 different selenoproteins with activity
related to – T cell immunity
– Modulate inflammation
– Prevent lipid peroxidation
– Thyroid metabolism
• Deficiencies lead to submaximal expression of GSH-Px and other selenoproteins compromising cell function
Selenium
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Background
• Current dietary recommendations is between 55-75 ug/day (based on optimize G-Px)
• Found in various foods such as meats, nuts, breads, etc but is largely a function of soil composition.
• Some geographic areas are Selenium –poor (china, parts of US and Europe)
Selenium
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In Critical Illness, Low Levels of Se related to Severity of Illness
Manzanares ICM 2009;35:882
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In Critical Illness, Low Levels of Se related to Severity of Illness
Manzanares ICM 2009;35:882
Healthy Controls
ICU Patients
ICU+SIRS
ICU +MODS
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…and Correlate with GPx activity
Manzanares ICM 2009;35:882
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OFRCONSUMPTION
OFR
PRODUCTION
Depletion ofAntioxidant Enzymes
OFR Scavengers Vitamins/Cofactors
InfectionInflammation
Ischemia
OFR production > OFR consumption =Impaired- organ function- immune function- mtiochondrial function
Complications and Death
OXIDATIVESTRESS
Rationale for Antioxidants
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• Endogenous antioxidant defense mechanisms• Enzymes (superoxide dismutase, catalase,
glutathione perioxidase, glutathione reductase including their cofactors Zn and Selenium)
• Sulfhydryl group donors (glutathione)• Vitamins E, C, and B-carotene
Rationale for Antioxidants
Low endogenous levelsLipid peroxidation and inflammation
Organ failure
Mortality
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Oxidative Stress Connected to Organ Failure
Motoyama Crit Care Med 2003;31:1048
0
10
20
30
40
50
60
% increase in TBARS
With OrganFailureWithout OrganFailure
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• Non-survivors associated with :– Higher APACHE III scores – Higher degree of oxidative stress
• LPP • SH• TAC
– Higher levels of inflammation (NOx)– Higher levels of leukocyte activation
(myeloperoxidase, PMN elastase)
Rationale for Antioxidants
Alonso de Vega CCM 2002; 30: 1782
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• 21 patients with septic shock
• Exposed plasma from patients to naïve human umbilical vein endothelial cells and quantified degree of oxidative stress by a fluorescent probe (2,7,-dichorodihydrofluorescien diacetate)
Rationale for Antioxidants
Huet CCM 2007; 35: 821
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Rationale for Antioxidants
Huet CCM 2007; 35: 821
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Death
MetabolicShutdown
Survivors
•↓mt DNA•↓ ATP, ADP, NADPH•↓ Resp chain activity•Ultra structural changes
↓ mitochondrial activityProlonged
inflammation NO
Endocrineeffects
cytokine effect
Genetic down regulation
Tissue hypoxia
• preserved ATP•Recovery of mt DNA•Regeneration of mito proteins
Rationale for Antioxidants
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mtDna/nDNA Ratio by Day 28 Survival
0 5 10 15 20 250.0
0.5
1.0
1.5
2.0
Alive IndividualsExpired IndividualsAlive Reg lineExpired Reg Line
P=0.04
Day
mtD
na
/nD
NA
Ra
tio
Heyland JPEN 2007;31:109
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Mitochondrial Dysfunction is a Time-Dependent Phenonmenon
Hypoxia Accelerates Nitric Oxide Inhibition of Complex 1 Activity
Nitration of Complex 1 in Macrophages activated with LPS and IFN
21% O2 1% O2
Frost Am J Physio Regul Interg Comp Physio 2005;288:394
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mitochondria
Cell
Respiratorychain
nucleus
nDNA mtDNA
Mitochondrial Damage
ROS
RNS
LPS exposure leads to GSH depletion and oxidation of mtDNA within 6-24 hours
Levy Shock 2004;21:110 Suliman CV research 2004;279
Potentially Irreversible by 48 hours
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Effect of Antioxidants on Mitochondrial Function
Heyland JPEN 2007;31:109
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Smallest Randomized Trial of Selenium in Sepsis
Single center RCT double-blinded ITT analysis
40 patients with severe sepsis Mean APACHE II 18
Primary endpoint: need for RRT standard nutrition plus 474 ug x 3 days,
316 ug x 3 days; 31.6 ug thereafter vs 31.6 ug/day in control
Mishra Clinical Nutrition 2007;26:41-50
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Smallest Randomized Trial of Selenium in Sepsis
• Increased selenium levels
• Increased GSH-Px activity
• No difference in
• RRT (5 vs 7 patients)
• mortality (44% vs 50%)
• Other clinical outcomes
Mishra Clinical Nutrition 2007;26:41-50
*p=<0.006
* *
Effect on SOFA scores
•
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Randomized, Prospective Trial of AntioxidantSupplementation in Critically Ill Surgical
Patients
Nathens Ann Surg 2002;236:814
Surgical ICU patients, mostly trauma
770 randomized; 595 analysed
alpha-tocopherol 1,000 IU (20 mL) q8h per naso- or orogastric tube and 1,000 mg ascorbic acid IV q8h or placebo
Tendency to less pulmonary morbidity and shorter duration of vent days
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Influence of early antioxidant supplements on clinical evolution and organ function in critically ill cardiac surgery, major trauma and subarachnoid
hemorrhage patients.
0
50
100
150
200
250
0 1 2 3 4 5
CardiacTraumaSAH
CRP levels daily in the Control groups
Significant reduction with AOX in Cardiac and Trauma but not SAH
Berger Crit Care 2008
RCT 200 patients IV supplements for 5 days
after admission (Se 270 mcg, Zn 30 mg, Vit C 1.1 g, Vit B1 100 mg) with a double loading dose on days 1 and 2 (AOX group), or placebo.
No affect on clinical outcomes
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Largest Randomized Trial of Antioxidants
Multicenter RCT in Germany double-blinded non-ITT analysis
249 patients with severe sepsis
standard nutrition plus 1000 ug bolus followed by 1000 ug/day or placebo x14 days
0102030405060708090
100
28 day Mortality
SeleniumPlacebo
Greater treatment effect observed in those
patients with: •supra normal levels vs normal levels of selenium
•Higher APACHE III
•More than 3 organ failures Crit Care Med 2007;135:1
p=0.11
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o 16 RCTso Single nutrients (selenium) and combination
strategies (selenium, copper, zinc, Vit A, C, & E, and NAC)
o Administered various routes (IV/parenteral, enteral and oral)
o Patients:o Critically ill surgical, trauma, head injuredo SIRS, Pancreatitis, Pancreatic necrosiso Burnso Medical o Sepsis, Septic Shock
Supplementation with Antioxidants in the Critically Ill: A meta-analysis
Heyland Int Care Med 2005:31;327;updated on www.criticalcarenutrition.com
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Effect of Combined Antioxidant
Strategies in the Critically IllEffect on Mortality
Updated Jan 2009, see www.criticalcarenutrition.com
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Effect of Selenium-based Strategies
in the Critically IllEffect on Mortality
Updated Jan 2009, see www.criticalcarenutrition.com
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Biological Plausibility!
Inflammation/oxidative stress
Mitochondrial dysfunction
Organ dysfunction
Antioxidants
Antioxidants
Antioxidants
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Most Recent Trial of Selenium Supplementation in Sepsis
• Anti-inflammatory, anti-apoptotic effects of high dose Se
• Pilot RCT, double-blind, placebo controlled
• 60 patients with severe septic shock
Forceville Crit Care 2007:11:R73
4000 mcg followed by 1000mcg/day x 10 days
Placebo
No difference in pressor withdrawl, LOS, mortality
New organ failure: 32 vs 14%, p=0.09
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Toxicity dependent on dose and type of selenium
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REducing Deaths from OXidative Stress:
The REDOXS study
A multicenter randomized trial of glutamine and antioxidant
supplementation in critical illness
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The Research Protocol
In enterally fed, critically ill patients with a clinical evidence of acute multi organ dysfunction – What is the effect of glutamine
supplementation compared to placebo– What is the effect of antioxidant
supplementation compared to placebo
…on 28 day mortality?
The Question(s)
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1200 ICU patientsEvidence of
organ failureR
glutamine
placebo
ConcealedStratified by
site
R
R
antioxidants
placebo
Factorial 2x2 design
placebo
antioxidants Shock
REducing Deaths from OXidative Stress:
The REDOXS study
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Group Enteral Supplement Parenteral Supplement (Glutamine AOX) (Glutamine AOX)
A Glutamine + AOX + Glutamine + Selenium
B Placebo + AOX + Placebo + Selenium
C Glutamine + Placebo + Glutamine + Placebo
D Placebo + Placebo + Placebo + Placebo
Combined Entered and Parental Nutrients
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Optimal Dose?
• High vs Low dose: – observations of meta-analysis
• Providing experimental nutrients in addition to standard enteral diets
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Optimizing the Dose of Glutamine Dipeptides
and Antioxidants in Critically ill Patients:
A phase 1 dose finding study of glutamine and antioxidant
supplementation in critical illness
JPEN 2007;31:109
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The Research Protocol
In critically ill patients with a clinical evidence of hypoperfusion...
• What is the maximal tolerable dose (MTD) of glutamine dipeptides and antioxidants as judged by its effect on multiorgan dysfunction?
The Question
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The Research Protocol
• Single Center • Open-label • Dose-ranging study • Prospective controls
The Design
• Critically Ill patients in shock
Patients
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The Research ProtocolIntervention
GroupN Dose of Dipeptides (glutamine)
Parenterally*(gm/kg/day)
Enterally^(gm/day)
AOX
1 30 0 0 0
2 7 .5 (.35) 0 0
3 7 .5 (.35) 21 (15) ½ can
4 7 .5 (.35) 42 (30) full can (300 mcg
EN Selenium)
5 7 .5 (.35) 42 (30) full can + 500ug
IV Selenium
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The Research ProtocolOutcomes
•Primary: ∆SOFA• Secondary (groups 2-5);
• Plasma levels of Se, Zn , and vitamins• TBARS• Glutathione • Mitochondrial function (ratio)
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Control
N = 30
Group 2
N =7
Group 3
N= 7
Group 4
N= 7
Group 5
N=7
All
N=58
Age (Mean) 64.2 65.5 65.2 65.6 71.8 65.6
Female (%) 11 (37%) 2(29%) 1(14%) 2(29%) 3(43%) 19(33%)
APACHE II score (Mean) 23.2 25.1 22.1 21.9 20.6 22.8
Etiology of shock
Cardiogenic (%)
Septic (%)
Hypovolemic (%)
6 (86%)
1(14%)
3 (43%)
4 (57%)
3 (43%)
4 (57%)
1(14%)
5(71%)
1(14%)
13(46%)
14(50%)
1(4%)
ICU days (Median) 6.4 14.3 7.9 13.1 9.7 8.0
28 day mortality (%) 9(30%) 3(43%) 2(29%) 3(43%) 1(14%) 18(31%)
Baseline Characteristics
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4 vs 5: p=0.17
Total SOFA Score for Control Group
0 2 4 6 8 10 12 14 16 18 20 22 24 26 2802468
101214161820
Expired IndividualsIndividuals
Reg Line
P=<0.0001
Day
To
tal
So
fa S
co
re
Total SOFA Score for Group 2
0 2 4 6 8 10 12 14 16 18 20 22 24 26 2802468
101214161820
IndividualsExpired IndividualsReg Line
P=0.0897
Day
To
tal
So
fa S
co
re
Total SOFA Score for Group 3
0 2 4 6 8 10 12 14 16 18 20 22 24 26 2802468
101214161820
IndividualsExpired IndividualsReg Line
P= <0.0001
Day
To
tal
So
fa s
co
re
Total SOFA Score for Group 4
0 2 4 6 8 10 12 14 16 18 20 22 24 26 2802468
101214161820
Individuals
Expired Individuals
Reg Line
P= 0.0467
Day
To
tal
So
fa S
co
re
Total SOFA Score for Group 5
0 2 4 6 8 10 12 14 16 18 20 22 24 26 2802468
101214161820
IndividualsExpired IndividualsReg Line
P= 0.0005
Day
To
tal
So
fa S
co
re
Total SOFA Regression Lines
0 2 4 6 8 10 12 1402468
101214161820
ControlGroup 2Group 3
Group 4Group 5
P=0.1941
Day
To
tal
SO
FA
Sco
re
Effect on SOFA
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TBARS Group 2
0 5 10 15 20 250.000
0.025
0.050
0.075
0.100
0.125
0.150
0.175
Average SlopeExpired Individuals
P=0.82Individuals
Day
TB
AR
S
(nm
ol/
mg
pro
tein
)
TBARS Group 3
0 5 10 15 20 250.000
0.025
0.050
0.075
0.100
0.125
0.150
0.175Individuals
Expired IndividualsP=0.90
Average Slope
Day
TB
AR
S
(nm
ol/
mg
pro
tein
)
TBARS Group 4
0 5 10 15 20 250.000
0.025
0.050
0.075
0.100
0.125
0.150
0.175Individuals
Average SlopeExpired IndividualsP=0.11
Day
TB
AR
S
(nm
ol/
mg
pro
tein
)
TBARS Group 5
0 5 10 15 20 250.000
0.025
0.050
0.075
0.100
0.125
0.150
0.175
Average Slope
Expired Individuals
P=0.03Individuals
Day
TB
AR
S
(nm
ol/
mg
pro
tein
)
TBARS Average Slopes
0 2 4 6 8 10 12 140.000
0.025
0.050
0.075
0.100
0.125
0.150
0.175Group 2
Group 4Group 5
Group 3
P=0.25
Day
TB
AR
S
(nm
ol/
mg
pro
tein
)
Effect on TBARS
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GSH Group 2
0 5 10 15 20 250
200
400
600
800
1000
1200
1400
1600
Expired Individuals
P=0.03
Average Slope
Individuals
Day
GS
H (
Mo
l/L
)
GSH Group 3
0 5 10 15 20 250
200
400
600
800
1000
1200
1400
1600Individuals
Expired IndividualsP=0.14
Average Slope
Day
GS
H (
Mo
l/L
)
GSH Group 4
0 5 10 15 20 250
200
400
600
800
1000
1200
1400
1600Individuals
Expired IndividualsP=0.40
Average Slope
Day
GS
H (
Mo
l/L
)
GSH Group 5
0 5 10 15 20 250
200
400
600
800
1000
1200
1400
1600Individuals
Expired IndividualsP=0.61
Average Slope
Day
GS
H (
Mo
l/L
)
GSH Average Slopes
0 2 4 6 8 10 12 140
200
400
600
800
1000
1200
1400
1600P=0.61
Group 2
Group 3Group 4
Group 5
Day
GS
H (
Mo
l/L
)
Effect on Glutathione
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mtDna/nDNA Ratio Group 2
0 5 10 15 20 250.0
0.5
1.0
1.5
2.0
Expired Individuals
P=0.99
Average Slope
Individuals
Day
mtD
na
/nD
NA
Ra
tio
mtDna/nDNA Ratio Group 3
0 5 10 15 20 250.0
0.5
1.0
1.5
2.0Individuals
Expired Individuals
Average Slope
P=<0.0001
Day
mtD
na
/nD
NA
Ra
tio
mtDna/nDNA Ratio Group 4
0 5 10 15 20 250.0
0.5
1.0
1.5
2.0Individuals
Expired Individuals
Average Slope
P=0.90
Day
mtD
na
/nD
NA
Ra
tio
mtDna/nDNA Ratio Group 5
0 5 10 15 20 250.0
0.5
1.0
1.5
2.0Individuals
Expired Individuals
Average Slope
P=0.03
Day
mtD
na
/nD
NA
Ra
tio
mtDna/nDNA Average Slopes
0 2 4 6 8 10 12 140.0
0.5
1.0
1.5
2.0
Group 3
Group 4Group 5
P=0.001Group 2
Day
mtD
na
/nD
NA
Ra
tio
Effect on MITO RATIO
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Inferences
• 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
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REDOXS: A new paradigm!
• Nutrients dissociated from nutrition• Focus on single nutrient administration• Rigorous, large scale, multicenter trial
of nutrition related intervention powered to look at mortality
• sick homogenous population • Preceded by:
– standardization of nutrition support thru the development and implementation of CPGs
– a dosing optimizing study• Funded by CIHR
www.criticalcarenutrition.com
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Conclusions • “Insufficient data to put forward a
recommendation for Selenium alone”
• “Based on 3 level 1 and 13 level 2 studies, the use of supplemental combined vitamins and trace elements should be considered in critically ill patients.”
Canadian CPGs www.criticalcarenutrition.com
Optimal Dose: 500-1000 (800) mcg/day