1. Selenium in Intensive Care (SIC): Results of a prospective randomized, placebo- controlled, multiple-center study in patients with severe systemic inflammatory response syndrome, sepsis, and septic shock* Matthias W. A. Angstwurm, MD; Lothar Engelmann, MD; Thomas Zimmermann, MD; Christian Lehmann, MD; Christoph H. Spes, MD; Peter Abel, MD; Richard Strauß, MD; Andreas Meier-Hellmann, MD; Rudolf Insel, MD; Joachim Radke, MD; Jürgen Schüttler, MD; Roland Gärtner, MD Internal medicine Division of pulmonology R2 이동영 Crit Care Med 2007 Vol. 35, No. 1

2. Introduction

3.  Mortality rate in patients with sepsis and septic shock: 28~50%  Challenge to reduce mortality  Intensive insulin Tx  Activated protein C  Hydrocortisone in adrenal insufficiency  Unsatisfactory results

4. cytokine activation oxidative stress free oxygen species  Selenium-dependent glutathione-peroxidases (GPx)  thioredoxin reductases : compound of redox system : activity regulated by availability of selenium Multiple organ failure reactive oxygen reactive nitrogen cell signaling, proliferation, apoptosis, and cell protection modulate

5.  severe oxidative stress: sepsis or septic shock  Required selenium ↑  low GPx activities  GPx-3 activities  negatively correlate: severity of disease  preterm infants- selenium supplementation- ↓ morbidity  Recently meta-analysis  selenium in critically ill patients reveal  mortality reduction  with high doses of sodium-selenite

6. Methods

7. Study design  Phase III, multiple-center, double-blind, randomized placebo-controlled trial  11 independent German intensive care units  Study group(Se1)  1mg sodium-selenite within 30 min iv  1mg during 24 hrs continuously for 14 days  Placebo group(Se0)  Normal saline  Additional selenium supplementation: 100 ug per day

8. Inclusion criteria  Age ≥18 yrs with APACHE III score ≥ 70 and two of the following criteria  Rectal BT ≥ 38°C or hypothermia ≤36°C  Heart rate ≥ 90 beats/min  Respiratory frequency ≥ 20 and PaCO2 ≤ 32mm Hg  Leukocytes ≥ 12,000/uL or ≤ 4 000/uL or ≥ 10% immature leukocytes  Decrease of platelet count 50% within the first 24 hrs or platelets ≤ 150,000/L at admission

9. End Points and Safety Criteria  Primary end point: 28 day mortality  Secondary end points were as follows  1. Time of survival after enrollment  2. Variable part of the APACHE III score percentage of change between day 1 and last visit  3. Logistic organ dysfunction system score at all visits or last available visit  4. Incidence of renal failure within the 28-day survey  5. Days of dialysis or CRRT  6. Incidence of cardiovascular failure defined as the demand for vasoactive drugs despite volume substitution  7. Number of days with vasopressor therapy

10.  8. Days of mechanical ventilation  9. Incidence of nosocomial pneumonia  10. Incidence of ARDS  11. Incidence of reinfection  12. Duration of stay (days) in the ICU  13. Analyses of subgroups

11. Results

12. Study population

14. Efficacy Estimated mean survival time 19.7 days in Se1 16.4 days in Se0 Absolutely mortality reduction 17.6% in Se1

15. Predefined Subgroup Analyses

16. Whole Blood Selenium and Mortality Se1Se0 APACHE III-27.6%-24.1% LOD Score-2.6-2.0 Duration15.112.7 Secondary End Points

17. No specific adverse effects a/w high-selenium supplements Tertiary end points

18. Discussion

19.  Per-protocol analysis  28-day mortality rate 14.3%, significantly lower: patients receiving adjuvant selenium treatment  140,000 sepsis-associated deaths/year in Germany ≈20,000/yr: prevented with this adjuvant therapy  Save 1050 Euros  Pts with septic shock: mortality rate 26.2% lower in Se1  Direct correlation  selenium conc. in whole blood and survival rate  This larger, multiple-centre trial confirm the efficacy of high dose sodium-selenite supplementation in patients with severe sepsis and septic shock

20.  Mechanisms: still unknown  At admission to the ICU selenium levels-below normal already, like acute phase reaction  Selenium blood levels: unreliable marker of intracellular selenium and selenoenzyme content  It is supposed High blood selenium supplies the organs with sufficient selenium to synthesize selenoenzymes.

21.  Septic shock a/w multiple organ failures and DIC  One hypothesis  Under selenium supplementation  selenoprotein P is rapidly generated  preventing endothelial cells from oxidative damage followed by a diminished activation of these cells  Administration of sodium-selenite  Reduce TNF α- induced intercellular adhesion molecule Selectin expression …in vitro

22.  In animal trials, selenium supplementation  reduce  oxidative stress, intranuclear nuclear factor-кB translocation, and cytokine formation as well as tissue damage  normalizes  all known selenoenzymes like intracellular GPx and thioredoxin reductase activities  reduce  hydrogen peroxide, lipid, and phospholipid hydroperoxides  dampen  the propagation of free radicals and reactive oxygen species  reduce  hydroperoxide intermediates in the cyclo-oxygenase and lipoxygenase pathways  diminish  the production of inflammatory prostaglandins and leukotrienes  modulate  the respiratory burst

23.  Endogenous glutathione reducing vascular hyporeactivity to exogenous NE due to its deactivation by superoxide and endothelial dysfunction in response to peroxynitrite and endotoxic shock  Depletion of glutathione also enhances the  Cytotoxic effects of hydrogen peroxide and free oxygen radicals in endothelial cells and smooth muscle cells in shock and, specifically, the peroxynitrite induced injury

24.  A low activity GPx in plasma, platelets, and leukocytes might contribute to  increased oxidative stress in several compartments  multiple organ failure  but might be prevented by selenium supplementation  High GPx activity regenerates the oxidized glutathione  Whether additional glutathione supplementation would augment the effect of selenium supplementation alone has to be established

25. CONCLUSION  This multiple-center trial shows that an adjuvant, high-dose selenium supplementation reduced the mortality rate in patients with severe sepsis and especially in septic shock.