Selenium in sepsis a new magic bullet
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Selenium in Sepsis A new magic bullet?. Daren K. Heyland, MD, FRCPC, MSc. Professor of Medicine, Queen’s University, Kingston, Ontario. Updated January 2009 Summarizes 207 trials studying >20,000 patients 34 topics 17 recommendations. www.criticalcarenutrition.com. Background.

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Selenium in sepsis a new magic bullet

Selenium in SepsisA new magic bullet?

Daren K. Heyland, MD, FRCPC, MSc

Professor of Medicine,

Queen’s University, Kingston, Ontario


Selenium in sepsis a new magic bullet

  • Updated January 2009

  • Summarizes 207 trials studying >20,000 patients

  • 34 topics 17 recommendations

www.criticalcarenutrition.com


Background

Background

Selenium

  • 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


Background1

Background

Selenium

  • 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)


In critical illness low levels of se related to severity of illness

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 illness1

In Critical Illness, Low Levels of Se related to Severity of Illness

Healthy Controls

ICU Patients

ICU

+SIRS

ICU

+MODS

Manzanares ICM 2009;35:882


And correlate with gpx activity

…and Correlate with GPx activity

Manzanares ICM 2009;35:882


Selenium in sepsis a new magic bullet

Rationale for Antioxidants

Infection

InflammationIschemia

OFR

CONSUMPTION

OFR

PRODUCTION

Depletion of

Antioxidant Enzymes

OFR Scavengers

Vitamins/Cofactors

Impaired

- organ function

- immune function

- mtiochondrial function

OXIDATIVE

STRESS

OFR production > OFR consumption =

Complications and Death


Rationale for antioxidants

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

Low endogenous levels

  • Lipid peroxidation and inflammation

  • Organ failure

  • Mortality


Oxidative stress connected to organ failure

Oxidative Stress Connected to Organ Failure

Motoyama Crit Care Med 2003;31:1048


Rationale for antioxidants1

Rationale for Antioxidants

  • 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)

Alonso de Vega CCM 2002; 30: 1782


Rationale for antioxidants2

Rationale for Antioxidants

  • 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)

Huet CCM 2007; 35: 821


Rationale for antioxidants3

Rationale for Antioxidants

Huet CCM 2007; 35: 821


Rationale for antioxidants4

Rationale for Antioxidants

  • preserved ATP

  • Recovery of mt DNA

  • Regeneration of mito proteins

Genetic down regulation

Tissue hypoxia

Survivors

  • ↓mt DNA

  • ↓ ATP, ADP, NADPH

  • ↓ Resp chain activity

  • Ultra structural changes

cytokine effect

↓ mitochondrial activity

Prolonged inflammation

Metabolic

Shutdown

NO

Death

Endocrine

effects


Selenium in sepsis a new magic bullet

Heyland JPEN 2007;31:109


Mitochondrial dysfunction is a time dependent phenonmenon

Mitochondrial Dysfunction is a Time-Dependent Phenonmenon

Hypoxia Accelerates Nitric Oxide Inhibition of Complex 1 Activity

1% O2

21% O2

Nitration of Complex 1 in Macrophages activated with LPS and IFN

Frost Am J Physio Regul Interg Comp Physio 2005;288:394


Selenium in sepsis a new magic bullet

Mitochondrial Damage

mtDNA

Potentially Irreversible by 48 hours

Cell

mitochondria

Respiratory

chain

ROS

RNS

nDNA

nucleus

LPS exposure leads to GSH depletion and oxidation of mtDNA within 6-24 hours

Levy Shock 2004;21:110 Suliman CV research 2004;279


Selenium in sepsis a new magic bullet

Effect of Antioxidants on Mitochondrial Function

Heyland JPEN 2007;31:109


Smallest randomized trial of selenium in sepsis

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 sepsis1

Smallest Randomized Trial of Selenium in Sepsis

Effect on SOFA scores

  • Increased selenium levels

  • Increased GSH-Px activity

  • No difference in

    • RRT (5 vs 7 patients)

    • mortality (44% vs 50%)

    • Other clinical outcomes

*p=<0.006

*

*

Mishra Clinical Nutrition 2007;26:41-50


Randomized prospective trial of antioxidant supplementation in critically ill surgical patients

Randomized, Prospective Trial of AntioxidantSupplementation in Critically Ill Surgical Patients

  • 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

Nathens Ann Surg 2002;236:814


Selenium in sepsis a new magic bullet

Influence of early antioxidant supplements on clinical evolution and organ function in critically ill cardiac surgery, major trauma and subarachnoid hemorrhage patients.

  • 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

CRP levels daily in the Control groups

Significant reduction with AOX in Cardiac and Trauma but not SAH

Berger Crit Care 2008


Largest randomized trial of antioxidants

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

p=0.11

  • 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


Selenium in sepsis a new magic bullet

Supplementation with Antioxidants in the Critically Ill: A meta-analysis

  • 16 RCTs

  • Single nutrients (selenium) and combination strategies (selenium, copper, zinc, Vit A, C, & E, and NAC)

  • Administered various routes (IV/parenteral, enteral and oral)

  • Patients:

    • Critically ill surgical, trauma, head injured

    • SIRS, Pancreatitis, Pancreatic necrosis

    • Burns

    • Medical

    • Sepsis, Septic Shock

Heyland Int Care Med 2005:31;327;updated on www.criticalcarenutrition.com


Selenium in sepsis a new magic bullet

Effect of Combined Antioxidant Strategies in the Critically Ill

Effect on Mortality

Updated Jan 2009, see www.criticalcarenutrition.com


Selenium in sepsis a new magic bullet

Effect of Selenium-based Strategies

in the Critically Ill

Effect on Mortality

Updated Jan 2009, see www.criticalcarenutrition.com


Biological plausibility

Biological Plausibility!

Antioxidants

Antioxidants

Antioxidants

Inflammation/oxidative stress

Mitochondrial dysfunction

Organ dysfunction


Most recent trial of selenium supplementation in sepsis

R

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

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

Forceville Crit Care 2007:11:R73


Selenium in sepsis a new magic bullet

Toxicity dependent on dose and type of selenium


Re ducing d eaths from ox idative s tress the redoxs study

REducing Deaths from OXidative Stress:The REDOXS study

A multicenter randomized trial of glutamine and antioxidant supplementation in critical illness


The research protocol

The Research Protocol

The Question(s)

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?


Selenium in sepsis a new magic bullet

REducing Deaths from OXidative Stress:The REDOXS study

antioxidants

Factorial 2x2 design

glutamine

R

Concealed

Stratified by

1200 ICU patients

R

placebo

Evidence of

  • site

organ failure

antioxidants

  • Shock

R

placebo

placebo


Selenium in sepsis a new magic bullet

Combined Entered and Parental Nutrients

GroupEnteral Supplement Parenteral Supplement

(Glutamine AOX) (Glutamine AOX)

AGlutamine + AOX+Glutamine + Selenium

BPlacebo + AOX+Placebo + Selenium

CGlutamine + Placebo+Glutamine + Placebo

DPlacebo + Placebo+Placebo + Placebo


Optimal dose

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

Optimizing the Dose of Glutamine Dipeptidesand 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 protocol1

The Research Protocol

The Question

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?

Safety


The research protocol2

The Research Protocol

The Design

  • Single Center

  • Open-label

  • Dose-ranging study

  • Prospective controls

Patients

  • Critically Ill patients in shock


The research protocol3

The Research Protocol

Intervention


The research protocol4

The Research Protocol

Outcomes

  • Primary: ∆SOFA

  • Secondary (groups 2-5);

    • Plasma levels of Se, Zn , and vitamins

    • TBARS

    • Glutathione

    • Mitochondrial function (ratio)


Selenium in sepsis a new magic bullet

Baseline Characteristics


Selenium in sepsis a new magic bullet

Effect on SOFA

4 vs 5: p=0.17


Selenium in sepsis a new magic bullet

Effect on TBARS


Selenium in sepsis a new magic bullet

Effect on Glutathione


Selenium in sepsis a new magic bullet

Effect on MITO RATIO


Inferences

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


Redoxs a new paradigm

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

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.”

Optimal Dose: 500-1000 (800) mcg/day

Canadian CPGs www.criticalcarenutrition.com


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