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Selenium in SepsisA new magic bullet?
Daren K. Heyland, MD, FRCPC, MScProfessor of Medicine,
Queen’s University, Kingston, Ontario
www.criticalcarenutrition.com
Updated January 2009
Summarizes 207 trials studying >20,000 patients
34 topics 17 recommendations
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
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
In Critical Illness, Low Levels of Se related to Severity of Illness
Manzanares ICM 2009;35:882
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
…and Correlate with GPx activity
Manzanares ICM 2009;35:882
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
• 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
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
• 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
• 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
Rationale for Antioxidants
Huet CCM 2007; 35: 821
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
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
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
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
Effect of Antioxidants on Mitochondrial Function
Heyland JPEN 2007;31:109
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
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
•
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
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
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
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
Effect of Combined Antioxidant
Strategies in the Critically IllEffect on Mortality
Updated Jan 2009, see www.criticalcarenutrition.com
Effect of Selenium-based Strategies
in the Critically IllEffect on Mortality
Updated Jan 2009, see www.criticalcarenutrition.com
Biological Plausibility!
Inflammation/oxidative stress
Mitochondrial dysfunction
Organ dysfunction
Antioxidants
Antioxidants
Antioxidants
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
Toxicity dependent on dose and type of selenium
REducing Deaths from OXidative Stress:
The REDOXS study
A multicenter randomized trial of glutamine and antioxidant
supplementation in critical illness
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)
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
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
Optimal Dose?
• High vs Low dose: – observations of meta-analysis
• Providing experimental nutrients in addition to standard enteral diets
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
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
The Research Protocol
• Single Center • Open-label • Dose-ranging study • Prospective controls
The Design
• Critically Ill patients in shock
Patients
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
The Research ProtocolOutcomes
•Primary: ∆SOFA• Secondary (groups 2-5);
• Plasma levels of Se, Zn , and vitamins• TBARS• Glutathione • Mitochondrial function (ratio)
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
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
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
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
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
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
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
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
