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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

slide2

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 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

slide8

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

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

slide17

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

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

slide22

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

slide24

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

slide25

Effect of Combined Antioxidant Strategies in the Critically Ill

Effect on Mortality

Updated Jan 2009, see www.criticalcarenutrition.com

slide26

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

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?

slide32

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

slide33

Combined Entered and Parental Nutrients

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

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 protocol4
The Research Protocol

Outcomes

  • Primary: ∆SOFA
  • Secondary (groups 2-5);
    • Plasma levels of Se, Zn , and vitamins
    • TBARS
    • Glutathione
    • Mitochondrial function (ratio)
slide42

Effect on SOFA

4 vs 5: p=0.17

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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