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Selenium in Sepsis A new magic bullet?

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?

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  1. Selenium in SepsisA new magic bullet? Daren K. Heyland, MD, FRCPC, MSc Professor of Medicine, Queen’s University, Kingston, Ontario

  2. Updated January 2009 • Summarizes 207 trials studying >20,000 patients • 34 topics 17 recommendations www.criticalcarenutrition.com

  3. 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

  4. 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)

  5. In Critical Illness, Low Levels of Se related to Severity of Illness Manzanares ICM 2009;35:882

  6. 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

  7. …and Correlate with GPx activity Manzanares ICM 2009;35:882

  8. 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

  9. 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

  10. Oxidative Stress Connected to Organ Failure Motoyama Crit Care Med 2003;31:1048

  11. 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

  12. 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

  13. Rationale for Antioxidants Huet CCM 2007; 35: 821

  14. 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

  15. Heyland JPEN 2007;31:109

  16. 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

  17. 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

  18. Effect of Antioxidants on Mitochondrial Function Heyland JPEN 2007;31:109

  19. 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

  20. 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

  21. 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

  22. 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

  23. 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

  24. 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

  25. Effect of Combined Antioxidant Strategies in the Critically Ill Effect on Mortality Updated Jan 2009, see www.criticalcarenutrition.com

  26. Effect of Selenium-based Strategies in the Critically Ill Effect on Mortality Updated Jan 2009, see www.criticalcarenutrition.com

  27. Biological Plausibility! Antioxidants Antioxidants Antioxidants Inflammation/oxidative stress Mitochondrial dysfunction Organ dysfunction

  28. 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

  29. Toxicity dependent on dose and type of selenium

  30. REducing Deaths from OXidative Stress:The REDOXS study A multicenter randomized trial of glutamine and antioxidant supplementation in critical illness

  31. 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?

  32. 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

  33. 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

  34. Optimal Dose? • High vs Low dose: • observations of meta-analysis • Providing experimental nutrients in addition to standard enteral diets

  35. 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

  36. 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

  37. The Research Protocol The Design • Single Center • Open-label • Dose-ranging study • Prospective controls Patients • Critically Ill patients in shock

  38. The Research Protocol Intervention

  39. The Research Protocol Outcomes • Primary: ∆SOFA • Secondary (groups 2-5); • Plasma levels of Se, Zn , and vitamins • TBARS • Glutathione • Mitochondrial function (ratio)

  40. Baseline Characteristics

  41. Effect on SOFA 4 vs 5: p=0.17

  42. Effect on TBARS

  43. Effect on Glutathione

  44. Effect on MITO RATIO

  45. 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

  46. 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

  47. 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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