Antioxidant supplementation in critical illness: what do we know?

The inflammatory response and the proliferation of reactive oxygen species (ROS) affect the interaction, excretion, utilization, distribution, and storage of antioxidant vitamins and minerals.1 Decreased levels of selenium2–4 and vitamins A,5–8 C,5,6,9 and E5,6,8,10 occur during inflammation and are associated with increased mortality and morbidity.2,3,6 Is there a true deficiency or a redistribution of the affected nutrients? Will supplementation of antioxidants reduce inflammation and ROS activity, correct nutrient aberrations, and change clinical outcomes? What are the risks of toxicity and interactions? Is there a true deficiency or a redistribution of the affected nutrients? Critically ill patients showed a progressive decrease in serum selenium levels that was associated with hypoalbuminemia and urinary selenium losses.4 A study by Agarwal et al. showed that, although serum levels of vitamins A, C, and E were decreased after surgery, the levels returned to normal after 7 d.6 This suggests redistribution of micronutrients during inflammation rather than a true deficiency. However, nutrient deficiencies are more likely to occur with chronic inflammation, malnutrition, malabsorption, and liver disease. Therefore, if the inflammatory process is prolonged and micronutrients are not supplemented, a deficiency could occur. Will supplementation of antioxidants reduce inflammation and ROS activity, correct nutrient aberrations, and change clinical outcomes? Supplementation with standard vitamin and trace-element preparations has been ineffective at maintaining serum levels during critical illness.2,3,8 Studies that provided higher doses of vitamin E to patients with abdominal aortic aneurysm11 and hepatitis12 demonstrated a reduction in oxidative damage. However, patients with acute respiratory distress syndrome (ARDS) without enteral feeding or hemodynamic stability had no response to vitamin-E supplementation.13 Selenium-replacement therapy demonstrated normalization of serum selenium levels and a reduction in morbidity and mortality.3 Because the activities of vitamins and minerals are synergistic and complementary, several studies have given combinations of antioxidants.14–21 Supplementation of vitamins E and C, n-acetylcysteine (a glutathione precursor), and selenium resulted in increased survival in ARDS patients.14 Vitamins C and E plus allopurinol (an antioxidant) given before coronaryartery bypass surgery resulted in fewer perioperative infarcts and fewer ischemic electrocardiographic events in the treated groups.15 Infusion of vitamins A, C, and E plus a vitamin-B complex immediately before reperfusion of a transplanted kidney resulted in less peroxidative damage to the organ.17 Enteral nutrition formulas containing antioxidant enhancement are currently available.18–21 ARDS patients given a specialized formula had fewer days on the ventilator, shorter stays in the intensive care unit, and fewer new-organ failures than did those who received the standard formula.18 The optimal doses at which micronutrients will improve outcomes are not clearly defined. What are the risks of toxicity and interactions? b-carotene22 and vitamin C23 become prooxidants in certain circumstances. Supplementation of parenteral nutrition solutions above the content of standard vitamin and trace-element preparations raises issues of compatibility, cost, safety, and effectiveness. Fat-soluble vitamins become toxic when given in large doses. Does critical illness affect the level at which adverse effects and toxicity occur? Synergistic relationships exist among vitamins E and C, glutathione, and dietary fat. If supplemental vitamin E is given enterally, the diet must contain enough fat to stimulate the absorption of fat and fat-soluble vitamins. During inflammation, free iron is sequestered to reduce its effect on microorganism proliferation.24 Vitamin C, supplemented to enhance recycling of oxidized vitamin E,23,25 can promote free-iron availability23,26,27 and could contribute to increased risk of infection. The synthesis of glutathione, which reduces oxidation of vitamin E in the liver, requires cysteine and glutamine, both of which are reduced in critical illness. There are problems with stability and compatibility of cysteine and glutamine with enteral and parenteral formulas. Decreased selenium levels during critical illness are associated with impaired glutathione peroxidase activity.3,4 The interdependence and interactions of micronutrients complicate supplementation. Intriguing data are accumulating on the clinical effects of supplementing micronutrients in critically ill patients. However, study results are often based on small, specific populations and cannot be extrapolated to other patient groups. Keep in mind that an absolute deficiency is rare except with inborn errors of metabolism and long-term parenteral nutrition. It is important to supplement micronutrients cautiously. Nutrient interactions and risks of toxicity are not clearly identified in the critically ill. There is exciting potential for the use of micronutrients in the treatment of critical illness, but there are still too many unanswered questions to make definitive recommendations at this time.