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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
1
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
2
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
3
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 4
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
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Method
6
Search strategy
• 4 database: MEDLINE, EMBASE, CINAHL
the Cochrane Controlled Trials Register,
Cochrane Database of Systematic
Reviews
• 1980 to December 2003
7
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
8
Compare study
Single antioxidant Combined antioxidants
9
Analysis
• Primary outcomes
– Mortality (ICU and hospital)
– Number of patients who developed infectious
complications
• Secondary outcome
– Length of stay in hospital or ICU
11
Study identification and selection
12
13
14
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 )
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Fig. 1 Effect of antioxidants on mortality in critically ill patient
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Subgroup analysis
• Great variation
– Type of antioxidants
– Route of administration
– Dosage
– Effect of other combination nutrients
17
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)
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Higher vs. Lower dose Selenium
23
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Fig. 5 Effect of selenium on mortality: dose response curve
Discussion
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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
26
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
27
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
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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
29
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
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Comparison of outcome
With antioxidant use Without antioxidant use
勝
Single antioxidant Combined antioxidants
勝
Parenteral route Enteral route
勝
Selenium Nonselenium
勝 antioxidants
High- dose Selenium Low-dose Selenium
(>勝500 µg/day ) (< 500 µg/day )
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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
32
Thanks for your attention
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