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

Abstract

Introduction: 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.

Methods: 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.

Results: 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).

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

Figure 1

Effects of antioxidant strategies on mortality (n = 20). AOX, antioxidants; RR, risk ratio; 95% CI, 95% confidence intervals.

Figure 2

Effect of antioxidants on infections (n = 10). AOX, antioxidants; RR, risk ratio; 95% CI, 95% confidence intervals.

Figure 3

Effect of combined antioxidant therapy on ventilation days (n = 4). RR, risk ratio; 95% CI, 95% confidence intervals.

Figure 4

Effect of combined antioxidant by parenteral (n = 15) and enteral route on mortality (n = 4). AOX, antioxidants; EN: enteral nutrition; PN: parenteral nutrition; RR, risk ratio; 95% CI, 95% confidence intervals.

Figure 5

Effects of antioxidants supplementation on mortality according to high or low mortality in the control group. AOX, antioxidants; RR, risk ratio; 95% CI, 95% confidence intervals.

Figure 6

Results of subgroup analyses examining the effect of parenteral selenium supplementation on mortality. RR, risk ratio. P-values refer to the differences in the effects of selenium on mortality between subgroups.

Figure 7

Results of subgroup analyses examinating the effects of parenteral selenium supplementation on infections. RR, risk ratio. P-values refer to the differences in the effects of selenium on infectious complications between subgroups.