Nutrition Support Blog: Antioxidants in Critical Illness?
May 7, 2013
Certain names are endowed with built-in marketing. The term probiotics literally means for life, and has the (misleading) inherent suggestion that they are always beneficial. Antioxidant is another name that implies benevolence. Oxidation is responsible for reactive oxygen species that contribute to everything from wrinkles to increased inflammation and cell injury in sepsis, so combating oxidation would appear desirable. There are numerous studies documenting that blood levels of antioxidants are decreased in conditions of illness or injury, and animal studies documenting the potential for antioxidant supplements to improve outcome (1-3). However, human studies that provide antioxidants with the goal of reducing disease incidence or improving outcomes in the ICU have not been universally positive. Vitamin E supplements do not decrease the incidence of cardiovascular disease, and high dose vitamin E supplements (> 400 iu/day) appear to increase all-cause mortality (3).
Recently, a large randomized multi-center study of antioxidants, glutamine or antioxidants and glutamine combined, in adult ICU patients (75% medical, 2/3 in septic shock) reported no benefit of antioxidants and a trend toward increased mortality from supplemental glutamine (4).
Why are the results of these randomized studies so different than what we expected? One possibility is that investigators provided the wrong dose, or the wrong form of nutrient antioxidants. The amounts of Cis and Trans configurations of beta-carotene can differ between typical diets and most supplements, and gamma-tocopherol is the primary form of vitamin E in food, but supplemental vitamin E is usually alpha-tocopherol.
Another possibility is that the timing of supplemental nutrients, or the patient selection may be a factor. Conceivably, reactive oxygen species may serve an important role in the response to injury or illness, and quenching them too early, or too thoroughly, may have unforeseen consequences. Large randomized studies are difficult and expensive to conduct, so it is not always feasible to test many different doses of nutrients. The temptation is to give very large doses to allow the best possible chance to see an effect. However, the effect of some supplemental nutrients, may follow a bell-shaped curve where low doses have a positive effect, but increasing doses may begin to have unexpected effects that negate the benefits. Most of us are familiar with the bell shaped curve of diminishing returns because we have experienced something similar when we increased our coffee intake beyond a certain point when studying or writing a paper. :)
The concept of providing antioxidant nutrients to critically ill patients is far from dead. While there are limitations and disadvantages to meta-analysis, a new systematic review of 12 studies of selenium supplementation in patients with sepsis syndrome suggested a significant reduction in mortality (5). Certainly, the results of available data emphasize the need for further large randomized studies before we provide supplemental nutrients to sick people. It is frustrating to have so much basic science and animal data suggesting potential benefits, but still not know how to use this knowledge to help our sickest patients. I hope future studies will be able to find a form, timing and doses of nutrient antioxidants that will benefit our patients….and perhaps, someday, even reduce wrinkles. Check out our May e-journal club in the next few weeks for more on the recent NEJM study – that will be the study critiqued at our next Nutrition Support Journal Club.
“A good catchword can obscure analysis for fifty years."
- Oliver Wendell Holmes
1. Andriantsitohaina R, Duluc L, García-Rodríguez JC, et al. Systems biology of antioxidants. Clin Sci (Lond). 2012;123(3):173-192.
2. Atli M, et al. The effects of selenium and vitamin E on lung tissue in rats with sepsis. Clin Invest Med. 2012;35(2):E48-54.
3. Saremi A, Arora R. Vitamin E and cardiovascular disease. Am J Ther. 2010;17(3):e56-65.
4. Heyland D, Muscedere J, Wischmeyer PE, et al. A randomized trial of glutamine and antioxidants in critically ill patients. N Engl J Med. 2013;368(16):1489-1497.
5. Alhazzani W, Jacobi J, Sindi A, et al. The Effect of Selenium Therapy on Mortality in Patients With Sepsis Syndrome: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Crit Care Med. 2013 Apr 12. [Epub ahead of print]