Micronutrients against oxidative stress - time for clinical recommendations?

Antioxidant micronutrient supplementation may be beneficial for critically ill patients. Often, cocktails of antioxidant micronutrients are used. Consequently, meta-analyses of available randomized controlled trials of antioxidant micronutrient supplementation are of particular interest. Because the majority of randomized controlled trials included in these meta-analyses use a combination of several antioxidant micronutrients, conclusions are difficult to draw. The scientific step to take now is to gain more knowledge about antioxidant mechanisms by coupling plasma concentrations to effects and outcomes.

Oxidative stress is the 'imbalance between oxidants and antioxidants leading to damage' [1]. Th is is suggested as pathogenesis in a wide range of conditions. Th e toxicity of a high concentration of oxygen in the inspiratory gas mixture of neonates as well as the toxic eff ects of some metal ions are examples in which the role of oxidative stress as pathogenesis is well established [2]. For the general infl ammatory reaction in critical illness resulting in multiple organ failure, oxidative stress is suggested to play a pivotal role, but the evidence for this hypothesis is not yet conclusive.
Several micronutrients have antioxidant properties; and, not uncommonly, defi ciency symptoms in the case of a shortage of micronutrients are connected to oxidative stress [3]. Although several nutrients other than micro nutrients also have antioxidant properties, a great deal of interest has focused on the role of antioxidant micronutrients. A number of trace elements and some vitamins are of particular interest: selenium, manganese, copper, zinc, and vitamins A, C, and E. Most often, several micronutrients are combined in what are commonly called antioxidant cocktails. Th ese are popular as food additives among healthy individuals as prevention against disease and also in critically ill patients.
Eff orts to use antioxidant micronutrients to treat sickness have, in general, not been particularly successful [4]. In critical illness, there are reports of statistical connections between low plasma levels of antioxidant micronutrients and unfavorable outcomes [5]. Th erefore, it is not farfetched to hypothesize that supplementation with antioxidant micronutrients may be benefi cial for critically ill patients. Consequently, two recent metaanalyses of available randomized controlled trials of antioxidant micronutrient supplementation are of particular interest [6,7].
Both meta-analyses aim to focus on only antioxidant micronutrients, disregarding trials in which micronutrients are combined with nutrients that have antioxidant properties and that are not micronutrients. Th is complexity of the antioxidant defense system is defi nitely a complicating factor because the possible eff ect of a single antioxidant in isolation may diff er from that in combination with other antioxidants. Th e eff ects may be additive or even synergistic. Another complicating factor is whether a low plasma concentration really is indicative of deple tion and an insuffi cient antioxidant defense in critical illness. Although it is well known that a general infl am mation is associated with a lowering of micronutrient plasma concentrations, the need for supplementation is not self-evident.
Because the majority of randomized con trolled trials included in the meta-analyses use a combi nation of several antioxidant micronutrients, conclusions are diffi cult to draw. Th e meta-analysis tool is useful as it helps to give a systematic overview, but the heterogeneity of antioxidant cocktails, protocols, and patient case mix also illustrates the diffi culty of making clinical recommendations. Th e three studies with the greatest impact in the Manzanares meta-analysis [6] illustrate this problem: one is a trial of selenium only [8], one is a trial of selenium and glutamine [9], and the third is a trial of vitamins C and E [10].

Abstract
Antioxidant micronutrient supplementation may be benefi cial for critically ill patients. Often, cocktails of antioxidant micronutrients are used. Consequently, meta-analyses of available randomized controlled trials of antioxidant micronutrient supplementation are of particular interest. Because the majority of randomized controlled trials included in these meta-analyses use a combination of several antioxidant micronutrients, conclusions are diffi cult to draw. The scientifi c step to take now is to gain more knowledge about antioxidant mechanisms by coupling plasma concentrations to eff ects and outcomes.
Both meta-analyses conclude that antioxidant micronutrients are of potential benefi t for critically ill patients and that larger prospective clinical trials are needed. It is easy to agree with the conclusion that supplementation with antioxidant micronutrients may be advantageous for critically ill patients. However, for any recommendation to change practice, it is necessary to scrutinize the safety of such supplementations. As the signal of an advantageous eff ect comes from a heterogeneous group of studies, conclusions regarding safety are particularly diffi cult to draw. Th is is further complicated by the diff erent cocktails that are used. Th e recommendation to start up more large prospective trials must be well thought out before they are launched. Th e present state of knowledge is compromised by the hetero geneity of cocktails and protocols of existing studies. Th e scientifi c step to take is to gain more knowledge of mechanisms before running ahead with new randomized controlled trials using new cocktails. Instead, the use of well-defi ned pharmacological principles coupling plasma concentrations (or even better concentrations at active sites if possible) to eff ects and then to outcomes should be recommended.
In summary, while waiting for a more scientifi c approach to the use of antioxidant micronutrients, the meta-analyses presented are very helpful in systemizing the evidence contained in randomized controlled clinical trials. Antioxidant micronutrient supplementation will be used in clinical practice, but safety should be the focus. New studies should focus on elucidating the eff ects of the diff erent components of antioxidant cocktails and linking eff ects to concentrations.