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University of Virginia Nutrition E-Journal Club
January 2005


Well, winter is here in the Shenandoah Valley.   We had very mild weather last week; it felt like Spring with temperatures in the 60’s during the day.  This week it has turned quite cold, and even though we were overdue for cold weather the rapid transition was a shock.  Theresa Fessler led the journal club this month; an article on antioxidant micronutrient supplementation in the ICU.

Crimi E, Liguori A, Condorelli M, Cioffi M, Astuto M, Bontempo P, Pignalosa O, Vietri MT, Molinari AM, Sica V, Della Corte F, Napoli C.  The beneficial effects of antioxidant supplementation in enteral feeding in critically ill patients: a prospective, randomized, double blind, placebo-controlled trial.  Anesth Analg 2004; 99: 857-863

Study Question:
Does supplementation with vitamins C and E during enteral feeding influence oxidative stress, antioxidant defenses, and 28 day clinical outcome in critically ill patients?

This was a randomized, double-blind trial of 224 critically ill adult patients from coronary care and medical-surgical units enrolled within 48 hours of trauma, or 72 hours from admission (for non-trauma patients).  All patients received nasogastric tube feedings during the 10 day study.  Patients were randomly assigned to receive either 500mg of vitamin C with 400  IU of Vitamin E (105 patients), or placebo (111 patients).

The primary end-point was measure of oxidative stress (malonydialdehyde-TBARS, PGF2a,  LDL tocopherol, and LDL oxidation.  Secondary end-points were infection, multi-organ failure, duration of ventilation, Vent-free days, 28 day outcome, and hospital length of stay.          

The short version of the results are that antioxidants improved LDL resistance to oxidative stress by about 30%.  The 28-day mortality was significantly reduced after antioxidant supplementation (45.7% vs 67.5%).  There was no significant reduction in incidence of organ failure, ARDS, or hospital length of stay.  The duration of mechanical ventilation, and the number of ventilator-free days was significantly improved in the antioxidant group. 

This study was randomized and double blind with a fairly large sample size, all patients were accounted for, the same enteral formula was used for all patients, with clearly defined endpoints with no significant differences in the baseline characteristics of the experimental and control groups. They also included the differences between experimental and control groups in both intention to treat and evaluable patients – and showed no significant differences.

Although individual pts were fed different calorie & protein levels based on stress level – the groups as a whole were treated the same, thus this is a good “picture” of actual clinical practice at some institutions.

This study confirms previous work that antioxidant supplements decrease oxidative markers in critically ill patients (1).  More importantly, it provides outcome data - significant improvement in mortality in this critically ill population.

However, without any significant change in organ failure, ARDS, or infectious complications, it is unclear why these patients had a mortality improvement.  Perhaps it can be considered that there was an improvement in pulmonary organ failure, as evidenced by the reduced ventilator requirements in the antioxidant group.  The improvements in pulmonary function are consistent with another study that we had reviewed (2) that reported decreased pulmonary morbidity (ARDS and pneumonia) with a combination of vitamin C and E.  A very recent meta-analysis reported favorably on antioxidant supplementation in critically ill patients – decreased overall morbidity without a significant change in infectious complications (3).

This is a well designed study, with very interesting findings, but there is no way to be sure if both micronutrients are necessary, or what is the optimal dose or form of antioxidants. The meta-analysis (3) describes positive outcomes with selenium supplementation.  Considering the  complementary physiologic action of vitamin E, vitamin C and selenium, there should be a study to determine if there are additional benefits of a combination of antioxidants.  This study is certainly not large enough to be sure that there is no potential for adverse reactions of some pharmaconutrients in some critically ill populations.  The immunonutrition studies should be the lesson that nutritional interventions in the critically ill population need to be treated with the same level of investigational rigor and repeatability as any other medical intervention.

Take home message: 
Outcome data is accumulating that antioxidant therapy may benefit critically ill patients.

Additional large trials to evaluate doses and combinations of antioxidant nutrients are required before routine use of supplemental antioxidants can be recommended.

1)     Preiser JC, Van Gossum A, Berre J, Vincent JL, Carpentier Y.  Enteral feeding with a solution enriched with antioxidant vitamins A, C, and E enhances the resistance to oxidative stress.  Crit Care Med. 2000 Dec;28(12):3828-32.

2)     Nathens AB, Neff MJ, Jurkovich GJ, Klotz P, Farver K, Ruzinski JT, Radella F, Garcia I, Maier RV.  Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients.  Ann Surg. 2002 Dec;236(6):814-22.

3)     Heyland DK, Dhaliwal R, Suchner U, Berger MM.  Antioxidant nutrients: a systematic review of trace elements and vitamins in the critically ill patient.  Intensive Care Med. 2004 Dec 17

"The aim of argument, or of discussion, should not be victory....but progress."

 -Joseph Joubert

Other News:

Check out the latest Practical Gastroenterology article:McCray S, Walker Sherrie, Parrish CR.  Much Ado about Refeeding.  Practical Gastroenterology  2004;XXVIII(12): 26.

Available at:http://www.healthsystem.virginia.edu/pub/digestive-health/nutrition.html

Joe Krenitsky MS, RD
Carol Parrish RD, MS

PS – Please feel free to send this on to friends and colleagues.
PPSS – See those of you who are attending ASPEN in Orlando!  JJ