The Beneficial Effects of Antioxidant Supplementation in Enteral Feeding in Critically Ill Patients: A Prospective, Randomized, Double-Blind, Placebo-Controlled TrialDepartment of Anesthesiology and Intensive Care, University of Eastern Piedmont, Novara, Italy; Coronary Care Unit, Pellegrini Hospital, Naples, Italy; Department of Medicine, University of Naples, Naples, Italy; Division of Clinical Pathology, II University of Naples, Naples, Italy; and the Department of Anesthesiology and Intensive Care, University of Catania, Catania, Italy
We investigated whether intervention with antioxidant vitamins C and E in
enteral feeding influenced oxidative stress and clinical outcome in critically
ill patients. Two-hundred sixteen patients expected to require at least 10
days of enteral feeding completed the study. One-hundred five patients
received enteral feeding supplemented with antioxidants, and 111 control
patients received an isocaloric formula. Plasma lipoperoxidation (by
thiobarbituric acid reactive substances [TBARS] and prostaglandin
F2 COMMENT: Previous studies have demonstrated an enhanced level of oxidative stress in critically ill patients. This can be attributed to increased production of reactive oxygen species and free radicals secondary to phagocytic cell activation, nitric oxide generation, and vascular ischemia/reperfusion injury. Oxidative stress can lead to lipoperoxidation and damage to cell membranes and DNA, subsequently resulting in cell death. Antioxidant defense systems, including vitamins E, C, and A, attempt to restore redox balance but may be overwhelmed during critical illness. The premise of this study was to examine the impact of antioxidant-supplemented enteral feeding on oxidative stress and 28-day clinical outcomes in critically ill patients.
This was a randomized, double-blind, placebo-controlled trial conducted
over a 5-year period involving adult medicosurgical, trauma, and coronary care
critically ill patients from 3 European medical centers. Study enrollment was
conducted within 48 hours of injury for trauma patients and within 72 hours of
ICU admission for nontrauma patients. Patients were excluded if they were
brain dead, had isolated or severe head injury (Glasgow Coma Scale score
Of the 224 patients enrolled, 216 patients completed the study protocol and were included in the analysis. The study population consisted predominantly of elderly men (68% men, mean age of 61 years), admitted for either trauma (40%) or cardiogenic shock (38.5%). The simplified acute physiology score and injury severity score (for trauma patients only) were similar between the AOX and control group: 18 vs 19 and 20 vs 19, respectively. In the AOX group, comparison of mean pretreatment and post-treatment oxidative stress variables revealed a significant reduction in plasma TBARS and isoprostane levels and a significant elevation of plasma vitamin E and LDL-bound vitamin E levels and time to LDL oxidation. No significant findings were demonstrated for the control group. Patients randomized to the AOX group had a significantly shorter mean duration of mechanical ventilation (6.2 vs 8.9 days, p = .05) and a greater number of ventilator-free days (15.7 vs 11.2 days, p = .01) despite a similar incidence of mechanical ventilation (79% vs 84%, p = NS). There was no significant difference in the incidence of infection, acute respiratory distress syndrome (ARDS), multiple-organ failure (MOF), or length of hospital stay. An absolute risk reduction of 21.8% in 28-day mortality was demonstrated in the AOX group (p < .05).
This study represents one of only a handful of prospective trials
evaluating antioxidant supplementation in critically ill patients. In contrast
to the current findings, a larger (n = 595) trial using higher doses of
vitamin E (3000 IU/day) and vitamin C (1000 mg/day) supplementation in a
predominantly young, male, trauma population demonstrated a significant
reduction in the development of MOF but failed to reduce 28-day
mortality.1 Other
previous studies in patients with acute lung injury or ARDS have also failed
to demonstrate a significant mortality benefit. Thus, the first question of
concern is why was a mortality benefit discovered in the current trial? This
is even more intriguing given that a recent meta-analysis demonstrated that
high-dose vitamin E supplementation ( Jeffrey J. Bruno, PharmD
Contributing Editor—Todd Canada, PharmD, BCNSP University of Texas MD Anderson, Houston, Texas
Nutrition in Clinical Practice, Vol. 20, No. 3,
363-364 (2005)
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isoprostane levels), low-density lipoprotein (LDL)
oxidizability, and LDL tocopherol content were determined at baseline and at
the end of the 10-day period. The clinical 28-day outcome was also assessed.
Plasma TBARS and isoprostanes were 5.33 ± 1.26 nM/mL and 312 ±
68 pg/mL, respectively, before treatment and 2.42 ± 0.61 nM/mL and 198
± 42 pg/mL after intervention (p < .01 for both
comparisons). Antioxidants improved LDL resistance to oxidative stress by
approximately 30% (the lag time before treatment was 87 ± 23 minutes
and was 118 ± 20 minutes after treatment; p < .04). There
was a significantly reduced 28-day mortality after antioxidant intervention
(45.7% in the antioxidant group and 67.5% in the regular-feeding group;
p < .05). Isoprostanes may provide a sensitive biochemical marker
for dose selection in studies involving antioxidants. 
6), or required anticoagulation with warfarin. Randomization occurred in a
1:1 fashion to either standard or antioxidant supplemented (AOX; vitamin C 500
mg/day and vitamin E 400 IU/day) enteral feeding. The standard formula
provided 1.3 kcal/mL, protein 70 g/L, free arginine 5 g/L, carbohydrate 130
g/L, lipid 45 g/L, vitamin E 10 IU, and ascorbic acid 50 mg. Daily caloric
needs were estimated through use of the Harris-Benedict equation, multiplied
by a correction factor of 1.3, 1.5, and 2 for low, moderate, and severe stress
levels, respectively. All patients were fed by nasogastric tube to achieve a
minimum of 75% of the calculated basal energy expenditure (BEE) within 48
hours of initiation of enteral feeding. The primary endpoint evaluated was the
impact of antioxidant supplementation on variables of oxidative stress,
including lipid peroxidation (thiobarbituric acid reactive substances [TBARS]
and prostaglandin F2
400 IU/day) may increase the risk of
mortality.
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