Journal Reading by Intern of NTU Hospital MD of FJ University 陳 永展

1. Systematic Review Antioxidant nutrients: a systematic review of trace elements and vitamins in the critically ill patient Journal Reading by Intern of NTU Hospital MD of FJ University 陳 永展

2. Journal profile • Daren K. Heyland , Rupinder Dhaliwal, Ulrich Suchner and Mette M. Berger • Intensive Care Med (2005) 31:327–337 • Department of Medicine, Queens University, Kingston, ONT, Canada • Kingston General Hospital, 76 Stuart Street, Kingston, ONT, K7L 2V7, Canada • Ludwig Maximilian University, Munich, Germany • Soins Intensifs de Chirurgie, CHUV, Lausanne, Switzerland

3. Introduction -- Attack • Oxidative stress is underlying pathophysiology of critical illness, esp. organ failure • Reactive oxygen species (ROS) and reactive nitrogen-oxygen species (RNOS) • Attack proteins, polysaccharides, nucleic acids, and polyunsaturated fatty acids  cellular damage and tissue dysfunction • Mitochondria dysfunction most critical • Trigger releasing of cytokine from immune cells, activate inflammation • Above increase generation of ROS • More tissue damage • SIRS, multiorgan dysfunction

4. Introduction – Against • Complex endogeneous defense system • Special enzyme: superoxide dismutase, catalase, glutathione peroxidase • Cofactor: Selenium, Zinc, Manganese, Iron • Sulfhydryl group donor (glutathione) • Vitamins (Vit. E, C, β-carotene ) • In critical illness, above decrease and lower activity • More severe trauma, SIRS, sepsis, the larger the depletion of antioxidant • Lower antioxidant, higher free radical generation

5. Let’s balance attack and against Exogenous supply of defined trace elements and vitamins would be helpful to regain balance between oxidants and antioxidants in critical illness

6. Method

7. Search strategy • 4 database: MEDLINE, EMBASE, CINAHL the Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews • 1980 to December 2003

8. Study selection criteria • Study design: randomized clinical trials • Population: critically ill adult patients receiving treatment with micronutrients (as opposed to prophylaxis) • Intervention: trace elements and/or vitamins vs. placebo (either via enteral, parenteral, or both) • Critically ill patients: care in ICU • Exclude studies of non-critically ill patients

9. Compare study

10. Analysis • Primary outcomes • Mortality (ICU and hospital) • Number of patients who developed infectious complications • Secondary outcome • Length of stay in hospital or ICU • p<0.05 to be statistically significant • p<0.20 as indicating a trend

11. Results

12. Study identification and selection • 44 articles searched out and 11 were eligible • Several authors examined the effects of single antioxidants • Most looked at selenium alone • One studied the effect of zinc supplementation • 3 studies the effects of vitamins A, C, E

15. Overall effect on mortality and infectious complications • 11 randomized controlled trials (n = 886) • Overall antioxidant had significant reduction in mortality (RR 0.65, 95% CI 0.44–0.97, p=0.03 ) • Antioxidant had no effect on infectious complication (RR 0.90, 95% CI 0.65–1.24, p=0.51 )

16. Fig. 1  Effect of antioxidants on mortality in critically ill patient

17. Subgroup analysis • Great variation • Type of antioxidants • Route of administration • Dosage • Effect of other combination nutrients • Determine which antioxidant strategies were more likely to affect clinical outcomes

18. Single vs. Combined antioxidants • Results of all studies using single antioxidant (n = 188) • Significant reduction in mortality (RR 0.52, 95% CI 0.27–0.98, p=0.04) • Results of combined nutrition • No effect on mortality (n=710, RR 0.87, 95% CI 0.47–1.62, p=0.67) • No effect on infectious complication (n=719, RR 0.85, 95% CI 0.60–1.23, p=0.39)

19. Fig. 3  Effect of single antioxidants on mortality

20. Parenteral/IV vs. Enteral route • Antioxidant supplied via parental/IV route in 8 of 11 studies (n = 266) • Significant reduction in mortality (RR 0.56, 95% CI 0.34–0.92, p=0.02) • No effects on infectious complication (n=78, RR 1.26, 95% CI 0.73–2.16, p=0.41) • Antioxidant supplied via an enteral formula in 1 of 11 studies • No meaning in mortality or infectious complication between groups (RR 1.13, 95% CI, 0.49–2.62, p=0.77) • Antioxidant supplied via combined routes in 2 of 11 studies

21. Fig. 4  Effect of parenteral antioxidants on mortality

22. Selenium vs. Nonselenium • 7 studies (n = 186) include Selenium as a component of antioxidant (alone or in combination with other antioxidant) • Trend toward lower mortality (RR 0.59, 95% CI 0.32, 1.08 p=0.09) • No effect on infectious complication (2 studies, n = 50, RR 0.78, 95%CI 0.49–1.26, p=0.3 ) • Nonselenium antioxidant (i.e., vitamins A, C, E and zinc; n=700) • No effect on mortality (RR 0.73, 95% CI 0.41, 1.29, p=0.3 ) • No effect on infectious complication (3 studies, n = 678, RR 1.10, 95% CI 0.60–2.04, p=0.8 )

23. Higher vs. Lower dose Selenium • Higher than median dose of Selenium (500–1000 µg/day, n=131) • Trend toward lower mortality (RR 0.52, 95% CI 0.24–1.14, p=0.10 ) • Lower than median dose of Selenium (<500 µg/day, n=55) • No effect on mortality (RR 1.47, 95% CI 0.20–10.78, p=0.7)

24. Fig. 5  Effect of selenium on mortality: dose response curve

25. Discussion

26. Will these antioxidants work? • Always low in plasma level of antioxidant • Markers for oxidative stress are often still high • However, the benefit of antioxidant is significant • Changes of markers cannot translate into clinical outcomes

27. Single antioxidant better than combined treatment? • Hypothesis: combined antioxidants provide better treatment effect than single micronutrient strategies • Se, glutathione, Vit. E & C function synergistically to regenerate water and fat-soluble antioxidants • Results of analysis do not confirm this hypothesis • Selenium supply (alone or in combination) w/ reduction in mortality than Zinc or other antioxidant • Multivitamin alone has no benefit

28. Reason for better result of single antioxidant • Selenium is cornerstone of antioxidant defense • Low selenium level in sepsis or shock • Correlation of the severity of SIRS and outcome with Selenium level • Mortality is 3 times higher in low plasma selenium level • Selenium is essential cofactor in glutathione enzymatic function and has favorable effects on cellular immune function • Selenium is component of selenoprotein which work as glutathione peroxidase  regenerate antioxidant system

29. The dose of Selenium • Selenium with beneficial mortality effect • 5-20 times the recommended parenteral intake • Recommended or standard dose based on requirement and metabolism in healthy • Little meaning in critically ill patient • However, at high dose, Vit. C & E, Selenium have some pro-oxidant property • More is not necessarily better • More research to determine the optimal dose

30. Routes of administration • Reduction in mortality was observed only by IV route • IV supply significant increase the plasma concentration of antioxidant level • Whole-body effect faster than enteral delivery • In acute disease, gut function is severely disturbed and delayed absorbed • However, enteral delivery may prove beneficial through prevention of local gut inflammatory response • Target of both routes appears complementary

31. Thanks for your attention

32. Conclusion • Trace element (Vitamins or Selenium) • Alone or in combination w/ other antioxidant • Safe • Reduction in morbidity in critically ill patient • Parenteral route w/ stronger impact on outcome than enteral route • All have no effect on infection control

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