Selenium in Sepsis A new magic bullet? Daren K. Heyland, MD, FRCPC, MSc Professor of Medicine,...

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