Selenium in Sepsis A new magic bullet? Daren K. Heyland, MD

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Selenium in SepsisA new magic bullet?

• Daren K. Heyland, MD, FRCPC, MSc

Professor of Medicine, Queens University,
Kingston, Ontario
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• Updated January 2009
• Summarizes 207 trials studying gt20,000 patients
• 34 topics 17 recommendations

www.criticalcarenutrition.com
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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

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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)

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In Critical Illness, Low Levels of Se related to
Severity of Illness
Manzanares ICM 200935882
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In Critical Illness, Low Levels of Se related to
Severity of Illness
Manzanares ICM 200935882
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and Correlate with GPx activity
Manzanares ICM 200935882
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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 gt OFR consumption
Complications and Death
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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

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Oxidative Stress Connected to Organ Failure
Motoyama Crit Care Med 2003311048
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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
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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
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Rationale for Antioxidants
Huet CCM 2007 35 821
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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
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Heyland JPEN 200731109
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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
2005288394
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Mitochondrial Damage
Cell
mitochondria
Respiratory chain
ROS RNS
nDNA
nucleus
LPS exposure leads to GSH depletion and
oxidation of mtDNA within 6-24 hours
Levy Shock 200421110 Suliman CV research
2004279
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Effect of Antioxidants on Mitochondrial Function
Heyland JPEN 200731109
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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 20072641-50
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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 20072641-50
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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 2002236814
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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.

• 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
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Largest Randomized Trial of Antioxidants
p0.11

• 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

• 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 20071351
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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 200531327updated on
www.criticalcarenutrition.com
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Effect of Combined Antioxidant Strategies in the
Critically Ill
Effect on Mortality
Updated Jan 2009, see www.criticalcarenutrition.co
m
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Effect of Selenium-based Strategies in the
Critically Ill
Effect on Mortality
Updated Jan 2009, see www.criticalcarenutrition.co
m
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Biological Plausibility!
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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

4000 mcg followed by 1000mcg/day x 10 days
Placebo
No difference in pressor withdrawl, LOS,
mortality New organ failure 32 vs 14, p0.09
Forceville Crit Care 200711R73
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REducing Deaths from OXidative StressThe
REDOXS study

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

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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?

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REducing Deaths from OXidative StressThe
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
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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
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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 Dipeptidesand
Antioxidants in Critically ill Patients

• A phase 1 dose finding study of glutamine and
  antioxidant supplementation in critical illness

JPEN 200731109
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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
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The Research Protocol
The Design

• Single Center
• Open-label
• Dose-ranging study
• Prospective controls

Patients

• Critically Ill patients in shock

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The Research Protocol
Intervention
Group N Dose of Dipeptides (glutamine) Dose of Dipeptides (glutamine) 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 Protocol
Outcomes

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

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Baseline Characteristics
Control N 30 Group 2 N 7 Group 3 N 7 Group 4 N 7 Group 5 N7 All N58
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)
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Effect on SOFA
4 vs 5 p0.17
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Effect on TBARS
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Effect on Glutathione
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Effect on MITO RATIO
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Inferences
Parenterally Enterally
Glutamine/day 0.35 gms/kg 30 gms
Antioxidants per day 500 mcg Selenium Vit C 1500 mg Vit E 500 mg B carotene 10 mg Zinc 20 mg Se 300 ug

• 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
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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.

Optimal Dose 500-1000 (800) mcg/day
Canadian CPGs www.criticalcarenutrition.com