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Antioxidant micronutrients in the critically ill: a systematic review and meta-analysis

William Manzanares1, Rupinder Dhaliwal2, Xuran Jiang2, Lauren Murch2 and Daren K Heyland23*

Author Affiliations

1 Intensive Care Unit, Department of Critical Care Medicine, Universidad de la República, Hospital de Clínicas (University Hospital), Faculty of Medicine, Avda Italia s/n 14th Floor, Montevideo, 11600, Uruguay

2 Clinical Evaluation Research Unit, Kingston General Hospital, Angada 4, Kingston General Hospital, 76 Stuart Street, Kingston ON, K7L 2V7, Canada

3 Department of Medicine, Queen's University Kingston, Angada 4, Kingston General Hospital, 76 Stuart Street, Kingston, Ontario K7L 2V7, Canada

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Critical Care 2012, 16:R66  doi:10.1186/cc11316

Published: 25 April 2012



Critical illness is characterized by oxidative stress, which is a major promoter of systemic inflammation and organ failure due to excessive free radical production, depletion of antioxidant defenses, or both. We hypothesized that exogenous supplementation of trace elements and vitamins could restore antioxidant status, improving clinical outcomes.


We searched computerized databases, reference lists of pertinent articles and personal files from 1980 to 2011. We included randomized controlled trials (RCTs) conducted in critically ill adult patients that evaluated relevant clinical outcomes with antioxidant micronutrients (vitamins and trace elements) supplementation versus placebo.


A total of 21 RCTs met inclusion criteria. When the results of these studies were statistically aggregated (n = 20), combined antioxidants were associated with a significant reduction in mortality (risk ratio (RR) = 0.82, 95% confidence interval (CI) 0.72 to 0.93, P = 0.002); a significant reduction in duration of mechanical ventilation (weighed mean difference in days = -0.67, 95% CI -1.22 to -0.13, P = 0.02); a trend towards a reduction in infections (RR= 0.88, 95% CI 0.76 to 1.02, P = 0.08); and no overall effect on ICU or hospital length of stay (LOS). Furthermore, antioxidants were associated with a significant reduction in overall mortality among patients with higher risk of death (>10% mortality in control group) (RR 0.79, 95% CI 0.68 to 0.92, P = 0.003) whereas there was no significant effect observed for trials of patients with a lower mortality in the control group (RR = 1.14, 95% 0.72 to 1.82, P = 0.57). Trials using more than 500 μg per day of selenium showed a trend towards a lower mortality (RR = 0.80, 95% CI 0.63 to 1.02, P = 0.07) whereas trials using doses lower than 500 μg had no effect on mortality (RR 0.94, 95% CI 0.67 to 1.33, P = 0.75).


Supplementation with high dose trace elements and vitamins may improve outcomes of critically ill patients, particularly those at high risk of death.