Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients

Abstract

Objective: To determine the effectiveness of early, routine antioxidant supplementation using alpha-tocopherol and ascorbic acid in reducing the rate of pulmonary morbidity and organ dysfunction in critically ill surgical patients.

Summary background data: Oxidative stress has been associated with the development of the acute respiratory distress syndrome (ARDS) and organ failure through direct tissue injury and activation of genes integral to the inflammatory response. In addition, depletion of endogenous antioxidants has been associated with an increased risk of nosocomial infections. The authors postulated that antioxidant supplementation in critically ill surgical patients may reduce the incidence of ARDS, pneumonia, and organ dysfunction.

Methods: This randomized, prospective study was conducted to compare outcomes in patients receiving antioxidant supplementation (alpha-tocopherol and ascorbate) versus those receiving standard care. The primary endpoint for analysis was pulmonary morbidity (a composite measure of ARDS and nosocomial pneumonia). Secondary endpoints included the development of multiple organ failure, duration of mechanical ventilation, length of ICU stay, and mortality.

Results: Five hundred ninety-five patients were enrolled and analyzed, 91% of whom were victims of trauma. The relative risk of pulmonary morbidity was 0.81 (95% confidence interval 0.60-1.1) in patients receiving antioxidant supplementation. Multiple organ failure was significantly less likely to occur in patients receiving antioxidants than in patients receiving standard care, with a relative risk of 0.43 (95% confidence interval 0.19-0.96). Patients randomized to antioxidant supplementation also had a shorter duration of mechanical ventilation and length of ICU stay.

Conclusions: The early administration of antioxidant supplementation using alpha-tocopherol and ascorbic acid reduces the incidence of organ failure and shortens ICU length of stay in this cohort of critically ill surgical patients.

Figure 1. Kaplan-Meier estimates of the risk of pneumonia among 301 patients receiving antioxidant supplementation and 294 patients receiving standard care. There is some suggestion that antioxidant supplementation might be associated with a lower likelihood of pneumonia (P = .3 by the log-rank test). Solid line: no antioxidant supplementation; dashed line: antioxidant supplementation.

Figure 2. Kaplan-Meier estimates of the risk of ARDS among 301 patients receiving antioxidant supplementation and 294 patients receiving standard care. There is some suggestion that antioxidant supplementation might be associated with a lower likelihood of ARDS (P = .4 by the log-rank test). Solid line: no antioxidant supplementation; dashed line: antioxidant supplementation.

Figure 3. Kaplan-Meier estimates of the risk of pulmonary morbidity (ARDS or pneumonia) among 301 patients receiving antioxidant supplementation and 294 patients receiving standard care. There is a suggestion that antioxidant supplementation might be associated with a lower likelihood of pulmonary morbidity (P = .2 by the log-rank test). Solid line: no antioxidant supplementation; dashed line: antioxidant supplementation.

Figure 4. Kaplan-Meier estimates of the risk of multiple organ failure among 301 patients receiving antioxidant supplementation and 294 patients receiving standard care. Treatment with antioxidant supplementation was associated with a significant reduction in the risk of developing multiple organ failure (P = .04 by the log-rank test). Solid line: no antioxidant supplementation; dashed line: antioxidant supplementation.

Figure 5. Plasma concentrations of ascorbate in a subset of patients receiving antioxidant supplementation and those receiving standard care. Shaded area represents normal range for healthy individuals. Numbers in parentheses indicate number of patients available for sampling. Solid line: no antioxidant supplementation; dashed line: antioxidant supplementation.

Figure 6. Plasma concentrations of α-tocopherol in a subset of patients receiving antioxidant supplementation and those receiving standard care. Shaded area represents normal range for healthy individuals. Numbers in parentheses indicate number of patients available for sampling. Solid line: no antioxidant supplementation; dashed line: antioxidant supplementation.

Figure 7. Concentrations of alveolar lavage fluid F_2α isoprostanes on day 3 as a measure of oxidative stress in patients undergoing BAL in the antioxidant group (n = 9) and those receiving standard care (n = 9). Median values are demonstrated as a dashed line (P = .5, Wilcoxon rank-sum test).