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
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 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
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 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

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 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

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

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 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
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 Compare study
Single antioxidant Combined antioxidants

Parenteral route Enteral route

Selenium Nonselenium antioxidants

High- dose Selenium Low-dose Selenium

(> 500 µg/day ) (< 500 µg/day )

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 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
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Results

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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

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 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

• Determine which antioxidant strategies

were more likely to affect clinical outcomes

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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)
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Fig. 3 Effect of single antioxidants on mortality
 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
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Fig. 4 Effect of parenteral antioxidants on mortality
 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 )

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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)

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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

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 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
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 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
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 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

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Thanks for your attention
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