Can oxidative damage be treated nutritionally?

ARTICLE IN PRESS Clinical Nutrition (2005) 24, 172–183 http://intl.elsevierhealth.com/journals/clnu REVIEW Can oxidative damage be treated nutritionally? Mette M. Berger Surgical ICU, Soins Intensifs Chirurgicaux et Centre des Brûlés, CHUV – BH08.660, CH 1011 – Lausanne, Switzerland Received 13 October 2004; accepted 13 October 2004 KEYWORDS Supplement; Antioxidant; Selenium; Lipid peroxidation Summary Background & aims: Nutrition and dietary patterns have been shown to have direct impact on health of the population and of selected patient groups. The beneficial effects have been attributed to the reduction of oxidative damage caused by the normal or excessive free radical production. The papers aims at collecting evidence of successful supplementation strategies Methods: Review of the literature reporting on antioxidant supplementation trials in the general population and critically ill patients. Results: Antioxidant vitamin and trace element intakes have been shown to be particularly important in the prevention of cancer, cardiovascular diseases, age related ocular diseases and in aging. In animal models, targeted interventions have been associated with reduction of tissue destruction is brain and myocardium ischemia-reperfusion models. In the critically ill antioxidant supplements have resulted in reduction of organ failure and of infectious complications. Conclusions: Antioxidant micronutrients have beneficial effects in defined models and pathologies, in the general population and in critical illness: ongoing research encourages this supportive therapeutic approach. Further research is required to determined the optimal micronutrient combinations and the doses required according to timing of intervention. & 2004 Elsevier Ltd. All rights reserved. Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 Free radicals, inflammatory response and oxidative stress. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 Antioxidants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174 Tel.: +44 21 314 2095; fax: +41 21 314 1033. E-mail address: [email protected] (M.M. Berger). 0261-5614/$ - see front matter & 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.clnu.2004.10.003 ARTICLE IN PRESS Can oxidative damage be treated nutritionally? 173 Status of the general population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176 Intervention trials . . . . . . . . . . . . Experimental data . . . . . . . . . Animal data . . . . . . . . . . . . . Trials in the general population. Trials in critically ill patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176 176 177 177 178 Discussion and conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 Introduction The last 50 years have been characterised by the understanding of the impact of nutrition and dietary patterns on health.1 Oxidation of lipids, nucleic acids or proteins has been suggested to be involved in the aetiology of several chronic diseases including cancer, cardiovascular disease, cataract, age-related macular degeneration and aging in general. The ‘‘free radical theory of aging’’ proposed in 1957 by Harman2 has fostered a important body of research investigating the potential role of antioxidant nutrients in therapeutic or preventive strategies.3 In the critically ill patients, free radical-mediated damage has also generated a large body of research, and various antioxidant strategies have been proposed. Until very recently, the only mean of prolonging life span in laboratory animals was to restrict their calorie intake. A trial published in 2004 using nutritional antioxidants challenges this evidence: the life span of mice-fed diets enriched with a metabolite of curcuma vs. standard diets was prolonged 11.7% (84 days) by the supplementation: similarly in another series of mice-fed standard diets, the addition of green tea extracts to drinking water resulted in a 6.4% (52 days) prolongation of life span.4 Both antioxidant agents are know for their atherosclerosis preventing properties, pathology which is irrelevant in wild-type rodents, but is a killer in humans: supplementation with these agents can therefore be expected to be even more effective in humans. Beyond these specific results, these animal data demonstrate that AOX intervention strategies have a significant impact on a series of biological variables and on survival—is this form of supplementation to be considered as prevention or as a therapy? Individuals in the Mediterranean area have been shown to present with a lower risk of several important chronic diseases, including coronary heart disease and a number of types of cancer associated with nutritional traditions, such as breast, colon, and prostate cancer. The use of large amounts of vegetables and fruits in general and cooked tomatoes, together with olive oil, appears to account for this lower risk.5 Among the nutrients that have ‘‘disease preventive’’ properties, vitamins and trace elements have been shown to be the most active components. Beyond micronutrients, other nutrients such glutamine may also be considered as antioxidant especially in selected critically ill patients. Overall many substances can be considered antioxidant, including some drugs, but are beyond the scope of the present review which will concentrate on vitamins and trace elements, and consider their potential ‘‘therapeutic’’ value in treating oxidative damage. Free radicals, inflammatory response and oxidative stress Free radicals and their deleterious effects have been extensively reviewed.6–8 Briefly, free radicals are atoms or molecules containing one or more unpaired electrons: they are unstable and strive to restore parity. The oxygen-centred radicals which are produced under normal aerobic metabolism, are also called reactive oxygen species (ROS); they are mainly produced by leukocytes and by the respiratory mitochondrial chain; they are essential for cell signalling, and for bacterial defence. Another category of free radicals is derived from nitric oxide metabolism (NOS) and is the normal byproduct of endothelial metabolism. Four main pathways account for ROS production, especially in the critically ill: 1. The mitochondrial respiratory chain produces  O
2 as a by-product of the reaction of molecular oxygen with semi-ubiquinone. 2. The NADPH oxidase enzyme of neutrophils and macrophages is activated in cell stimulation and ARTICLE IN PRESS 174  can produce massive amounts of O
as a 2 microbiocidal mechanism. This pathway is probably predominant in the overproduction of ROS during severe sepsis. 3. The ubiquitous xanthine oxidase enzyme is activated during ischemia, and produces massive  amounts of O
during the reperfusion phase. 2 This pathway is probably activated during major cardiac and vascular surgery and during the transplantation of solid organs.9 4. Some metallic ions (iron, copper) are released during cell destruction/lysis and can amplify the oxidative stress, as cofactors of the conversion of hydrogen peroxide into hydroxyl. Under normal conditions daily about 1% of ROS escape the control of the endogenous AOX defences and contribute to peroxidative damage to surrounding tissues, and thereby to aging (Fig. 1). ROS can attack any biochemical component of the cell: if the body’s or cell’s capacity to neutralise ROS, then they will produce acute damage to vital proteins, lipids and DNA. In humans, unbalance between ROS production and endogenous AOX has been involved in the generation or worsening of more than a hundred pathologic conditions.10 Measuring the free radical activity in vivo, i.e. increased ROS and NOS production, is confronted with practical and analytical problems: we are left with the surrogate determinations of the end products of oxidation. In clinical settings the intensity of ‘‘oxidative stress’’ is determined by M.M. Berger the quantity of nucleic acid that is damaged with the Comet assay,11 the amount of end products of lipid peroxidation (the thiobarbituric acid reactive substances=TBARS, and recently the isoprostanes),12 or of protein oxidation. Free radicals cause a cascade of intracellular events resulting in liberation in cytoplasm of nuclear transcription factor kappa B (NFkB) from its inhibitory protein IkB;13 which permits its translocation into the nucleus, where it binds to DNA, enabling the initiation of the transcription process. NFkB controls the production of the acute phase mediators such as TNF-a; l’IL-2, and IL-2 receptors, which in turn activate NFkB; amplifying the inflammatory cascade. Selenium has been clearly shown to be able to down regulate NFkB and thereby to limit the extension of the inflammatory response.13,14 Another transcription factor called the activation protein 1 (AP-1) also appears to be regulated by the redox status of the cell, being activated by both oxidants and antioxidants depending on the intracellular condition: its role in the inflammatory response and in cancer promotion is less well understood, but is currently actively investigated.15 The systemic inflammatory response syndrome (SIRS) is the generic, standardised response to injury: it includes the production of free radicals, cytokines and other mediators in response to acute conditions such infections and sepsis, respiratory failure, pancreatitis, major trauma and burns as well as all ischemia/reperfusions conditions.16 A strong acute and persistent inflammatory response constitutes a serious risk factor for the development of organ dysfunction and failure in critically ill patients. The modulation of SIRS is therefore the aim of many trials in acute disease. Antioxidants Figure 1 Schematic diagram of the effect of the endogenous AOX status on the response to injury: an adequate status resulting from optimal intakes is associated with strong defences and potential repair capacity (1), while a deficient state does not permit confinement of oxidative damage (2) causing irreversible oxidative damage. Restoring the compromised AOX status can be achieved either by increased nutritional intakes or by delivering supplements. Antioxidants (AOX) are substances, which inhibit or delay oxidation of a substrate while present in minute amounts.17 Endogenous AOX defences are both non-enzymatic (e.g. uric acid, glutathione, bilirubin, thiols, albumin, and nutritional factors, including vitamins and phenols) and enzymatic (e.g. the superoxide dismutases, the glutathione peroxidases=GSHPx, and catalase). In the normal subject the endogenous antioxidant defences balance the ROS production, but for the abovementioned 1% daily leak. The most important source of AOX is provided by nutrition, many belonging to the phenol family (Table 1). The trace elements Cu, Se, Mn, and Zn are essential ARTICLE IN PRESS Can oxidative damage be treated nutritionally? Table 1 175 Origin of the most common nutritional AOX in food (non-exhaustive list). Components Compounds Food sources Vitamins Vitamin C (ascorbic acid) Vitamin E (tocopherols and tocotrienols) b-carotene and other carotenoids (lycopene, lutein, etc) Citrus fruit, berries, papaya Trace elements Copper Manganese Zinc Selenium Zoochemicals (animal origin) Glutathione coenzyme Q10 (Ubiquinone) Seed-like cereal grains, nuts and oils derived from plants Orange pigmented, and green leafy vegetables Tomato Oysters, nuts, dried legumes, cereals, potatoes, vegetables, meat Nuts, wheat germ, wheat bran, leafy green vegetables, beet tops, pineapple, and seeds Meat, liver, eggs, seafood Organ meats, seafood, grains and cereals, muscle meats and eggs, milk, fruit and vegetables* Meats, Whey protein Meats, especially meat organs, fish, oyster Phytochemicals (plant origin) Isoflavones (daidzein and genistein) Flavonoids Polyphenols Catechins * Soy Cranberries, peanuts, apples, chocolate, tea and red wine Cocoa, grapes, red wine, tea, onions, apples, Herbs, oregano, thyme Green tea, papaya Se enters the food chain through uptake by plants, and is hence soil dependent. components of the endogenous enzymatic AOX defences as part of the structure of AOX enzymes in the cytosol, in mitochondria, or in plasma: CuZn superoxide dismutase (SOD) and catalase (Cu, Fe), Mn-SOD, and the various types of glutathione peroxidases (GSHPx:Se). The SODs initiate the antioxidant process, transforming the superoxide anion into hydrogen peroxide: the later is metabolised by catalase, and further by the different types of GSHPx which neutralise the various peroxides at both intra- and extra-cellular levels. Nutritional antioxidants act through different mechanisms and in different compartments, but are mainly free radical scavengers: (1) they directly neutralise free radicals, (2) they reduce the peroxide concentrations and repair oxided membranes, (3) they quench iron to decrease ROS production, (4) via lipid metabolism, short-chain free fatty acids and cholesteryl esters neutralise ROS.18 The body’s antioxidant defence can be approximated by measuring AOX plasma levels (micronutrients, enzymes, other AOX), keeping in mind that the circulating compartment only reflects the flow between organs and tissues. The tissular levels of the various AOX remains limited to research protocols as tissue biopsies are required. The balance between oxidant and reducing forces is subtle.19 Trace elements with antioxidant properties such as copper and selenium,20 may become strongly pro-oxidant both in vivo and in vitro, as a consequence of their physical properties. This is also the case with vitamins A, C, E,21 which may become prooxidant under defined conditions. Iron is nearly always prooxidant. SIRS is associated with a redistribution on vitamins and trace elements from the circulating compartment to tissues and organs which are involved in protein synthesis and immune cell production: selenium, zinc are particularly affected,22 while copper and manganese tend to increase in plasma. The SIRS-related micronutrient redistribution mechanism has recently been understood. In an animal model, oxidative stress reflected by a decrease in the hepatic ratio of ARTICLE IN PRESS 176 glutathione (GSH) to oxidised glutathione (GSSG), increased the expression and the synthesis of metallothionein, which is the main zinc carrier protein. The liver metallothionein content increased rapidly in response to its mRNA expression: conversely the serum zinc concentrations decreased at 12 h in mirror image to the hepatic zinc concentrations.23 Under cytokine influence, Zn is hence moved from its reservoirs (muscle, skin, bone) towards organs and tissues with high cellular proliferation and intense protein synthesis such as thymus, bone medulla and liver tissues. This redistribution has recently been confirmed in a rat model of burns injury showing a biphasic increase of Zn and Cu in the liver, and an increase of Se in the kidney.24 Status of the general population An important part of the population is exposed to the risk of trace element and vitamin deficiency for multiple reasons including the changes in eating habits in Western countries, but also the lower food concentration of micronutrients caused by intensive agricultural techniques, compared to standards determined in the 1950s. Children, young women and elderly aged 65 years and up are most exposed.25 Indeed, more than 10 years ago, a French study showed of large-scale deficit in micronutrients (iron, selenium, zinc, vit. B1, B6, C, A and E) affecting 30–40% of the healthy population.25 This trial has since been confirmed by many other studies showing low plasma concentrations of a series of micronutrients, and particularly of selenium. Plasma selenium concentrations are decreasing progressively in the healthy European population since the 1980s, reflecting lower nutritional selenium intake due to decreased nutrient Se content.26,27 An interesting cohort study including 4419 individuals was carried out in the Reggio Emilia in Northern Italy, analysing the 7year temporal distribution of deaths due to coronary disease.28 Selenium in drinking water decreased from 7 mg/l to less than 1 mg/l: the cohort had been exposed for at least 5 years to the drinking water with higher selenium content, the risk for cardiovascular disease and for stroke was analysed to examine a possible relationship with changes in drinking water selenium. During the high selenium period deaths for coronary disease were 1 in males and 2 in females, and increased to 21 and 10, respectively, during the low selenium period:these findings are also consistent with the M.M. Berger hypothesis of a beneficial effect of selenium on coronary disease mortality. The mean plasma concentration in various European areas (40–85 mg/l) is 40% below the selenium concentration associated with a cancer prevention activity according to the American Nutritional Cancer Prevention Study29 or 30% below that required for maintenance of an optimal plasma GSHPx activity.27 Selenium appears as the key micronutrient in prevention of cardiovascular, infectious and neoplasic diseases. Intervention trials Efforts to fight nutrient deficiencies have centred on supplemental nutrient administration and on addition of selected nutrients to the food chain in the form of food fortification.1 Supplementation and fortification has been proposed in healthy individuals, with the aim of reducing their risk of future diseases such as cardiovascular diseases, diabetes, and cancer. Nevertheless, with our increasing understanding of the genetic heterogeneity of human nutrient requirements, it is likely that certain groups or even populations may benefit from higher intakes of certain nutrients. The latter concept is getting closer to the therapeutic modulation of nutrient intake. When considering to intervene, the action must be adapted to the target. It is important to distinguish between diseases that affect the general population on a ‘‘chronic mode’’ and those conditions which are hyper acute and potentially life threatening, as observed during critical illness. Two types of intervention strategies may be considered: (1) preventive, which consists in maintaining or restoring the normal antioxidant capacity of apparently healthy people, i.e. of the general population (i.e. fortification, fertilisation supplements, modification of food composition); and (2) ‘‘therapeutic’’, i.e. delivering antioxidant nutrient supplements in conditions caused or worsened by free radicals. The critically ill patient belongs to the later category. Experimental data Experimental conditions have helped understand the subtle balance existing between pro- and antioxidant activities of some micronutrients.19 It has been clearly demonstrated that antioxidant nutrients present in both the lipid and the aqueous compartments can remove free radicals generated in plasma. Their activity depends on the ARTICLE IN PRESS Can oxidative damage be treated nutritionally? localisation of the attacking radical species.30 This has recently been demonstrated in vitro by trials using very standardised conditions: (1) in plasma incubated with a hydrophilic radical generator (AAPH) consumption of antioxidant nutrients occurred in the following rate ascorbic acid 4 atocopherol 4 uric acid 4 lycopene 4 lutein 4 cryptoxanthin 4 b-carotene; (2) in plasma incubated with lipophylic free radical generator (MeOAMVN), a-tocopherol and carotenoids were depleted at similar rates. Antioxidants (selenium, vitamins C and E) have been shown to protect stored blood from lipid peroxidation.31 The prooxidant effects of selenium have been investigated on cultured vascular cells exposed to parenteral nutrition containing various forms and quantities of selenium:20 selenate and selenomethionine cause less ROS generation than selenite. Vitamin E can also become a prooxidant in isolated lipoprotein suspensions such as parenteral nutrition solutions in clinical conditions: lightinduced formation of triglyceride hydroperoxides can be prevented by covering the solution with aluminium foil or by modifying the ascorbic acid concentrations of the solution, showing the interactivity between the micronutrients.21 Agriculture-research has also brought some insights. The harnessing of solar energy by photosynthesis depends on a safety valve that effectively eliminates hazardous excess energy and prevents oxidative damage to the plant cells.32 A compound liable to do so in plants may also protect human cells. Improving plant resistance to stress may thus have the beneficial side effect of also improving the nutritional quality of vegetables in the human diet.32 Animal data Despite the fact that animal data, whatever the species, cannot be applied directly to humans, these experiments help in the understanding of the mechanisms. Many models of ischaemia-reperfusion, of trauma have been developed, and only some multiple investigations are listed hereafter: they all show that pre-emptive administration of antioxidant nutrients or enzymes is efficient in reducing secondary damage. In brain ischemia trace elements have been shown to limit oxidative damage: while zinc deficiency increases infarct size,33 selenium has been shown to protect the brain in models of focal cerebral ischemia,34 and atocopherol and ascorbic acid reduce lipid peroxidation.35 The extent of brain injury has been reduced in animal models by the use of CuZn-SOD.36 In a rat 177 model of myocardial ischemia, manganese has been shown to protect against mitochondrial lipid peroxidation.37 In a rat model designed to evaluate the effect of short-term, high-dose enteral supplementation of 3 different vitamin E derivatives on macrophage and monocyte short-term activation, degree of TNF suppression correlated directly with serum a-tocopherol levels whatever the type of vitamin E:monocyte and macrophage response to endotoxin was down modulated.38 A recent animal trial has analysed the impact of pre-injury deficiency on the severity of lipid peroxidation: it shows that depletion of selenium (demonstrated by low liver, renal and muscle concentrations of selenium) causes increased lipid peroxidation reflected by elevated TBARS.24 The same team has pushed one step further with a yet unpublished trial in burned rats: they show that in the same model of selenium depletion, selenium supplementation after injury can correct plasma concentrations of selenium and GSHPx, but only moderately decrease peroxidative damage caused by the burn.39 In summary, animal data suggest that antioxidants can limit extension of oxidative damage, when administered after the insult, but that the preventive effect is the most important: adequate pre-injury status is essential. Trials in the general population To achieve an impact on the general population, the question of supplementation must be raised at the Public Health level: this has been the case in specific settings. In Finland, the selenium deficit has been considered such an important problem: it has been solved by soil fertilisation in the 1980s.40–42 In China, the incidence of Keshan disease, a lethal dilative cardiomyopathy which is partly caused by selenium deficit and considered a Public Health issue, has been reduced by selenium fortification of salt.43 In France, based on the above-mentioned demonstration of significant micronutrient deficits,25 Hercberg et al. hypothesised that nutritional supplementation with AOX micronutrients would reduce freed radical related pathologies such as cancer and cardiovascular diseases and possibly impact on survival.44 A government supported supplementation trial was subsequently conducted including more than 13,000 subjects. Various conditions have been investigated ranging from pregnancy to cardiovascular diseases, age-related ocular diseases, and cancer. Pregnancy is a special physiologic condition during which ARTICLE IN PRESS 178 nutrition may prove therapeutic. Beyond the wellaccepted importance of iron and folate in prevention of anaemia and neural tube defects, vitamins E and C supplements are promising for preventing pre-eclampsia and preterm delivery and need further testing and vitamin A and b-carotene reduced maternal mortality.45 Cataract and other age-related ocular disorders are conditions, which are related to oxidative damage. The data of a large-scale supplementation trial including 4753 patients aged 55–81 years with a 6.5 years follow-up were recently published.46 The intervention consisted in AOX vitamins (vitamin C 500 mg, vitamin E 400 IU, b-carotene 15 mg), zinc (80 mg), AOX plus zinc or a placebo: the patients were stratified according to the severity of their ocular disease. The results show a 24% reduction in mortality (RR of death 0.76) in groups receiving high-dose zinc.46 The reduction of death was from causes other than cardiovascular or cancer deaths (the 2 later being unchanged). Selenium supplements were not included in the trial, but might be included in future trials. Antioxidants have been largely investigated in various types of cancer. Many nutritional AOX such as carotenoids (e.g. lycopene), retinoids (e.g. vitamin A), vitamin E, vitamin C, selenium, and polyphenols have been investigated in cancer trials. Selenium clearly has an outstanding place among these nutrients: its cancer preventing properties has been investigated for 2 decades. Indeed oxidative injury may induce gene mutation and promote carcinogenesis; ROS can modulate the apoptotic program, dysregulation of which has a role particularly in gastrointestinal cancer.47 In vitro studies have demonstrated significant and complex effects on prostate cancer cell proliferation, differentiation, and signalling related to the initiation, progression, and regression of the cancer.48 An American study enrolling 1312 patients suffering skin carcinomas randomised the patients to receive either 200 mg selenium per day for 4.5 years or a placebo: it showed a significant reduction of all type cancers (except for skin), as well as mortality reduction in the supplemented group.29 Since, many other trials have shown similar trends to cancer reduction. In males, low selenium concentrations are associated with an increase risk of prostate cancer,49 this risk decreases with plasma concentrations 4135 mg/l. In the Cancer Prevention Study II Nutrition Cohort, the authors examined the association between regular multivitamin use (four or more times per week) and colorectal cancer incidence among 145,260 men and women.50 Regular multivitamin users 10 years before enrolment were at similarly reduced risk M.M. Berger whether they were still regular multivitamin users at enrolment or had stopped. These results are consistent with the hypothesis that past, but not recent, multivitamin use may be associated with modestly reduced risk of colorectal cancer.50 In France, based on the previously mentioned demonstration of significant micronutrient deficits,25 Hercberg et al. hypothesised that nutritional supplementation with AOX micronutrients would reduce freed radical-related pathologies such as cancer and cardiovascular diseases and possibly impact on survival.44 A government supported supplementation trial ‘‘the SuViMax study’’ was conducted over a 8 year period including more than 13,000 subjects aged 45–60 years: it ended in 2003 in a randomised placebo-controlled supplementation trial. The intervention consisted in a daily supplements containing nutritional doses (1.2 times RDA) of b-carotene, vitamins C and E, selenium and zinc or a placebo: subjects were followed up for 7.2 years. The results are stunning with a 31% reduction of cancer risk in men and a 37% reduction of death risk [Hercberg S – 21 June 2003—www.suvimax. org]. But not all types of cancers nor all subjects are likely to benefit from supplementation. A trial oriented on lung cancer showed that supplements were only beneficial to selected parts of the population: selenium supplementation caused a significant decrease of cancer incidence among individuals with low baseline selenium concentrations.51 A recent meta-analysis could find no evidence of gastrointestinal cancer prevention by antioxidants, although there was doubt in favour of selenium.47 The above trials is only a limited selection of what can be found in the literature: while there are conflictual data, most trials tend to show that nutrition has an important preventive role. But among the health promoting nutritional factors, AOX vitamins and trace elements may only account for a part of the beneficial effects of fruits and vegetables. Nevertheless, selenium has a proven important role in preventing the damage caused by the normal daily ROS production on nuclear transcription factors and nucleic acids and hence on the control of the inflammatory response and cancer prevention. Trials in critically ill patients A series of critical illnesses are clearly either caused, worsened or maintained by increased ROS production. Critically ill patients, whatever the cause of their disease, are indeed characterised by increased ROS production along with depressed ARTICLE IN PRESS Can oxidative damage be treated nutritionally? circulating levels of nearly all AOX micronutrients. The cause of these low levels are many: SIRS as above mentioned is an important cause (redistribution of micronutrients from the circulating compartment), but acute losses through biological fluids (exudates,52 drains,53 effluents form continuous renal replacement,54 other digestive losses), dilution due to resuscitation fluids and insufficient intakes contribute heavily too. Critically ill patients on admission are no better than the general population: as previously mentioned a large proportion of patients has pre-illness deficient status: the animal data showing that pre-injury selenium deficiency is associated with increased baseline lipid peroxidation that cannot be regained by supplementation39 may well apply to humans. Before considering trace element and vitamin supplementation, a distinction should be made between the previous, and provision of immunomodulating diets. Various industrial feeding diets do contain the ‘‘immune-modulating substrates’’ (e.g. glutamine, arginine, omega-3 fatty acids, nucleotides) plus variable amounts of antioxidant micronutrients and have been investigated extensively during the last decade.55 The problem with these diets is that the micronutrient content is also strongly increased: it hence becomes difficult to know to which substance benefits or side effects should be attributed. Therefore these diets are not discussed in the present review. AOX research in the critically ill has focused mainly on five micronutrients: vitamins C and E, copper, selenium and zinc. Table 2 summarises the trials with prospective randomised design. In 42 critically ill patients with SIRS due to an infectious disease, selenium supplementation for 9 days was associated with a significant reduction of acute 3 9 renal failure ð21 patients vs: 21 ; P ¼ 0:035Þ; and a non-significant reduction of mortality.56 In major burns, copper, selenium and zinc supplements amounting 6–8 times RDA intakes were associated with reduced lipid peroxidation and reduction of infectious complications.57,58 In the same trial the interleukin-6 levels were lower in the supplemented patients after 24 h of trace element supplementation including 350 mg/day selenium.58 Further in burns, mega-doses of ascorbic acid provided during the first 24 h of major burns resuscitation reduced fluid requirements by about 30%59 by reducing alterations of capillary permeability. Providing selenium and vitamins C and E along with N-acetylcysteine or placebo to 18 trauma patients was associated with a decrease in infectious complications (8 vs. 18) and fewer organs dysfunctions (0 vs. 9).60 Another trial in 32 patients with major trauma using selenium in combination 179 with vitamin E, or placebo achieved a normalisation of thyroid function (triiodothyronine, and thyroxin concentrations particularly),61 with significant changes in antioxidant status in the supplemented patients.62 In severe brain injury, zinc supplements (20 mg for 2 weeks) were associated with improved neurological recovery.63 In all these trials the reinforcement of the AOX defences is the argued mechanism leading to the clinical and biological benefits. There are a series of less well-controlled trials, or studies with historical case control design, which show beneficial effects of AOX supplements. Overall these data show that delivering antioxidant micronutrients has very few side effects, and has potential clinical beneficial effects in critically ill. Discussion and conclusion For all the above-mentioned reasons my answer to the question ) can oxidative damage be treated nutritionally? * is yes. If one considers the cellular mechanisms, current knowledge clearly supports the role of AOX nutrients in the intracellular prevention AOX-related damage and of proximity damage propagation. AOX also appear to have defined pathology targets: some examples of AOX modulable conditions are ischemia-reperfusion, burns, renal failure, age-related ocular diseases, and some cancers. Moreover, the efficiency of supplementation is a question of timing. AOX nutrients cannot cure an installed disease, such as a gastrointestinal cancer: they may prevent its promotion. AOX cannot cure ischemia/reperfusion damage: they may limit its ongoing extension. Indeed to the slightly different question ‘‘can installed damage caused by ROS be treated by AOX nutrients?’’ the answer is therefore probably no. In acute conditions, the concept of a ‘‘therapeutic window’’ is essential:9 there appears to be an optimal early timing after the initial ROS production during which supplementation may still have a ‘‘preventive effect’’, i.e. a limitating effect if the supplement reaches target. In the critically ill, the response may well depend on the pre-disease antioxidant status. As shown by the rodent burn trial,24 the damage caused by an acute injury is likely to be more important in presence of preexisting selenium deficit, and cannot be completely counteracted by supplementation. This does by no means disqualify the attempt to restore the balance during acute disease: supplementation will 180 Table 2 Randomised studies evaluating antioxidant strategies in critically III patients (adapted from Heyland et al.66 Study Population Route Intervention Endpoint Berger et al.61,62 Trauma patients, surgical ICU N ¼ 32 IV AOX status Thyroid function Porter et al.60 Surgical ICU Penetrating trauma patients with injury severity score X25 N ¼ 18 General Surgical Trauma ICU N ¼ 770 Burns430% TBSA N ¼ 20 IV and EN IV Angstwurm et al.56 Patients with acute pancreatic necrosis N ¼ 17 Patients with SIRS, APACHE 415 and multi organ failure score 46 N ¼ 40 Patients with SIRS N ¼ 42 IV selenium supplementation (500 mg/day) vs. placebo (selenium group randomised further to two groups: (a) 500 mg selenium alone vs. (b) 500 mg selenium+150 mg a tocopherol+13 mg zinc) given slowly from day 1–5 after injury (all groups received EN) 50 mg selenium IV q 6 h+400 IU Vit E, 100 mg Vit. C q 8 h and 8 g of Nacetylcysteine (NAC) q 6 h from Day 0–7 via nasogastric or oral route vs. none a tocopherol 1000 IU q 8 h via naso or orogastric tube and ascorbic acid 1000 mg q 8 h via IV vs. standard care** IV copper (40.4 mmol), selenium (159 mg), zinc (406 mmol)+standard trace elements vs. standard trace elements (copper 20 mmol, selenium 32 mg, zinc 100 mmol) from day 0–8, all received early EN IV+selenium supplementation (500 mg/day) vs. PN without selenium supplementation 1000 mg Na-selenite as a bolus IV then 1000 mg Na-selenite/24 h as a continuous infusion over 28 days vs. standard Preiser et al.70 Mixed ICU N ¼ 51 EN Young et al.63 Severely head injured patients, ventilated N ¼ 68 IV then PO Maderazo et al.71y Blunt Trauma N ¼ 46 IV Berger et al.72 Burns 420% BSA N ¼ 17 IV Nathens et al.67 Berger et al.58 Zimmerman et al.69 IV IV IV PN with high-dose selenium from 24 h from admission for 9 days (535 mg  3 days, 285 mg  3 days and 155 mg  3 days and 35 mg thereafter) vs. low-dose selenium (35 mg/day for duration of study) Antioxidant rich formula via EN (133 mg/100 ml vit. A, 13 mg/100 ml Vit C & 4.9 mg/100 ml Vit E) vs. isonitrogenous, isocaloric standard formula (67 mg/100 ml vit. A, 5 mg/100 ml Vit C and 0.81 mg/100 ml Vit E) from day 0–7 12 mg elemental zinc via PN, then progressing to oral zinc from 0–15 days vs. 2.5 mg elemental zinc, then progressing to oral placebo 200 mg ascorbic acid, then m 500 mg+50 mg a tocopherol in 100 ml of D5W vs. 100 ml of D5W*. (experimental group divided into 2 groups, 200 mg ascorbic acid vs. 50 mg a tocopherol). Given as 2 h infusions from day 0–7 (all groups received enteral nutrition or po intake) 100 ml of copper (59 mmol)+selenium (380 mg)+zinc (574 mmol) vs. NaCl (0.9%) from admission for 14–21 days. Lethality Lethality Acute renal failure ICU Outcome Ex vivo LDL tolerance to oxidative stress Neurological outcome (Glasgow coma score at 28 days) Neutrophil locomotory Se and Zn tissue levels Infections M.M. Berger Selenium: 1 mg ¼ 0:0126 mmol: Abbreviations: IV intravenous; EN enteral nutrition; PO per os, LOS length of hospital stay. * Data from 1 study was reported in 2 articles.61,62 y Maderazo et al.71: Only data pertaining to the group receiving ascorbic acid+ a tocopherol vs. placebo presented here. Pneumonia Multiple organ failure Infections LOS ARTICLE IN PRESS Kuklinski et al.68 IV and EN Organ failure Infections Length of ICU stay ARTICLE IN PRESS Can oxidative damage be treated nutritionally? Table 3 Antioxidant nutrient dose ranges used in intervention trials. Micronutrient General population47 b-carotene Vitamin A Vitamin C Vitamin E 6–50 mg 1.5–15 mg 120–2000 mg 30–600 mg Selenium 100–230 mg Zinc 20–30 mg Critically ill16 — — 0.5–2 g (IV) 100–500 mg (enteral) 250–1000 mg (IV) 20–30 mg (IV) 181 people who consume less than 2000 kcal/day which is the cut off at which it is possible with normal food to get the lower RDAs: low-energy intakes are characteristic of elderly or subjects on slimming diets. The route is less obvious in the critically ill: depending on the target, i.e. achieving rapidly a systemic effect or aiming at a gut protective strategy, the AOX micronutrients should be delivered intravenously or enterally. The future antioxidant strategies will probably include a combination of the 2 routes in acute conditions. References only have less impact, as in only partly can counterbalance the acute condition. Which AOX nutrient is efficient? Selenium appears to be the most important both in the general population and in acute conditions: actual trials do not answer definitively on combinations. Many population-based trials have combined vitamins A, C and E with selenium and zinc. Considering the many different deficits observed in the population, this approach appear rational. In the critically ill, the same reasoning prevails: although selenium seems to be a must in the supplements, other AOX supplements appear justified as well. The doses that are required to achieve a therapeutic effect are not definitively determined (Table 3). The belief that if enough of an essential nutrient is good, then more is better is wide spread. With zinc this has been shown to be wrong:64 supplements using doses 450 mg/day have been associated with depressed immune response. Similarly, in vitro trials show that high doses of selenium, ascorbic acid and tocopherol are prooxidant. In the general population, doses slightly above the nutritional doses appear reasonably efficient as shown by the Suvimax trial: indeed prolonged high doses may have side effects as shown by epidemiological studies and case reports that indicate that chronic exposure to selenium compounds is associated with several adverse health effects.65 While the route of delivery is clearly oral in the general population, the optimal technique is yet not decided: the Chinese (fortification) and Finnish (fertilisation) interventions have both proven successful. These options are most efficient with minerals. But if the target is a defined group and not the entire population, there is clearly a place for oral supplements; this is even more true if does above the nutritional does are considered in groups at risk. Supplements may also be considered for 1. Caballero B. Fortification, supplementation, and nutrient balance. Eur J Clin Nutr 2003;57(Suppl 1):S76–8. 2. Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol 1957;12:257–65. 3. Mayne ST. Antioxidant nutrients and chronic disease: use of biomarkers of exposure and oxidative stress status in epidemiologic research. J Nutr 2003;133(Suppl 3):933S–40S. 4. Kitani K, Yokozawa T, Osawa T. Interventions in aging and age-associated pathologies by means of nutritional approaches. Ann NY Acad Sci 2004;1019:424–6. 5. Weisburger JH. Lycopene and tomato products in health promotion. Exp Biol Med 2002;227:924–7. 6. Cuzzocrea S, Riley DP, Caputi AP, Salvemini D. Antioxidant therapy: a new pharmacological approach of shock, inflammation, and ischemia/reperfusion injury. Pharmacol Rev 2001;53:135–59. 7. Goodyear-Bruch C, Pierce JD. Oxidative stress in critically ill patients. Am J Crit Care 2002;11:543–61. 8. Bulger E, Maier RV. Antioxidants in critical illness. Arch Surg 2001;136:1201–7. 9. Schiller HJ, Reilly PM, Bulkley GB. Antioxidant therapy. Crit Care Med 1993;21:S92–102. 10. Gutteridge JMC. Free radicals in disease processes— a compilation of cause and consequence—invited review. Free Radical Res Commun 1993;19:141–58. 11. Hartmann A, Agurell E, Beevers C, et al. Recommendations for conducting the in vivo alkaline Comet assay. Fourth international comet assay workshop. Mutagenesis 2003;18:45–51. 12. Sakamoto H, Corcoran TB, Laffey JG, Shorten GD. Isoprostanes—markers of ischemia reperfusion injury. Eur J Anaesthesiol 2002;19:550–9. 13. Flohé L, Brigelius-Flohé R, Saliou C, Traber MG, Packer L. Redox regulation of NF-kappa B activation. Free Radical Biol Med 1997;22:1115–26. 14. Kim IY, Stadtman TC. Inhibition of NF-kB DNA binding and nitric oxide induction in human T cells and lung adenocarcinoma cells by selenite treatment. Proc Natl Acad Sci USA 1997;94:12904–7. 15. Lambert JD, Yang CS. Mechanisms of cancer prevention by tea constituents. J Nutr 2003;133:3262S–7S. 16. Berger MM, Chioléro RL. Key vitamins and trace elements in the critically ill. In: Cynober L, Moore F, editors. Nutrition and critical care. Basel: Karger; 2003. p. 99–118. 17. Halliwell B, Gutteridge JMC. The antioxidants of human extracellular fluids. Arch Biochem Biophys 1990;280:1–8. 18. Parke DV. Nutritional antioxidants in disease prevention: mechanisms of action. In: Basu T, Temple N, Garg M, editors. ARTICLE IN PRESS 182 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. Antioxidants in human health and disease. New York: CABI Publisher; 1999. p. 1–13. Abuja PM. When might an antioxidant become a prooxidant? Acta Anaesthesiol Scand 1998;42(Suppl 112):229–30. Terada A, Yoshida M, et al. Active oxygen species generation and cellular damage by additives of parenteral preparation: selenium and sulfhydryl compounds. Nutrition 1999;15: 651–5. Neuzil J, Darlow BA, Inder TE, Sluis KB, Winterbourn CC, Stocker R. Oxidation of parenteral lipid emulsions by ambient and phototherapy lights: potential toxicity of routine parenteral feeding. J Pediatr 1995;126:785–90. Maehira F, Luyo GA, Miyagi I, et al. Alterations of serum selenium concentrations in the acute phase of pathological conditions. Clin Chim Acta 2002;316:137–46. Ding HQ, Zhou BJ, Liu L, Cheng S. Oxidative stress and metallothionein expression in the liver of rats with severe thermal injury. Burns 2002;28:215–21. Agay D, Anderson RD, Sandre C, et al. Alterations of antioxidant trace elements (Zn, Se, Cu) and related metaloenzymes in plasma and tissues following burn injury in rats. Burns 2005;31 in press. Hercberg S, Preziosi P, Galan P, Deheeger M, Papoz L, Dupin H. Apports nutritionnels d’un échantillon représentatif de la population du Val-de-Marne: III les apports en minéraux et vitamines. Rev Epidém Santé Publ 1991;39:245–61. Rayman MP. Dietary selenium: time to act. Br Med J 1997;314:387–8. Rayman MP. The importance of selenium to human health. Lancet 2000;356:233–41. Yeum KJ, Aldini G, Chung HY, Krinsky NI, Russell RM. The activities of antioxidant nutrients in human plasma depend on the localization of attacking radical species. J Nutr 2003;133:2688–91. Racek J, Herynkova R, Holecek V, Jerabek Z, Slama V. Influence of antioxidants on the quality of stored blood. Vox Sanguinis (Karger, Basel) 1997;72:16–9. Demmig-Adams B, Adams 3rd WW. Antioxidants in photosynthesis and human nutrition. Science 2002;298:2149–53. He Z, Matsumoto M, Cui L, et al. Zinc-deficiency increases infarct size following permanent middle cerebral artery occlusion in rats. Nutr Res 1997;17:305–16. Imai H, Masayasu H, Dewar D, Graham DI, Macrae IM. Ebselen protects both gray and white matter in a rodent model of focal cerebral ischemia. Stroke 2001;32: 2149–54. Bano S, Parihar MS. Reduction of lipid peroxidation in different brain regions by a combination of alpha-tocopherol and ascorbic acid. J Neural Transm 1997;104:1277–86. Mikawa S, Kinouchi H, Kamii H, et al. Attenuation of acute and chronic damage following traumatic brain injury in copper, zinc-superoxide dismutase transgenic mice. J Neurosurg 1996;85:885–91. Malecki EA, Greger JL. Manganese protects against heart mitochondrial lipid peroxidation in rats fed high levels of polyunsaturated fatty acids. J Nutr 1996;126:27–33. Bulger E, Helton WS, Clinton CM, Roque RP, Garcia I, Maier RV. Enteral vitamin E supplementation inhibits the cytokine response to endotoxin. Arch Surg 1997;132:1337–41. Agay D, Sandre C, Ducros V, et al. Kinetic evolution of oxidative stress and selenium status in plasma and tissues following burn injury in selenium deficient and selenium supplemented rats. J Trauma 2005;58 in press. Varo P, Alfthan G, Ekholm P, Aro A, Koivistoinen P. Selenium intake and serum selenium in Finland: effects of soil fertilization with selenium. Am J Clin Nutr 1988;48:324–9. M.M. Berger 39. Venäläinen ER, Hirvi T, Hirn J. Effect of selenium supplementation on the selenium content in muscle and liver of Finnish pigs and cattle. J Agric Food Chem 1997;45: 810–3. 40. Wang WC, Nanto V, Makela AL, Makela P. Effect of nationwide selenium supplementation in Finland on selenium status in children with juvenile rheumatoid arthritis. A ten-year follow-up study. Analyst 1995;120:955–8. 41. Yang FY, Lin ZH, Xing JR, et al. Se deficiency is a necessary but not sufficient factor required for the pathogenesis of Keshan disease. J Clin Biochem Nutr 1994;16:101–10. 42. Hercberg S, Preziosi P, Galan P, et al. ‘‘The SU.VI.MAX Study’’: a primary prevention trial using nutritional doses of antioxidant vitamins and minerals in cardiovascular diseases and cancers. Supplementation on vitamines et mineraux antioxydants. Food Chem Toxicol 1999;37:925–30. 43. Vinceti M, Rovesti S, Marchesi C, Bergomi M, Vivoli G. Changes in drinking water selenium and mortality for coronary disease in a residential cohort. Biol Trace Elem Res 1994;40:267–75. 44. Clark LC, Combs GF, Turnbull BW, et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin—a randomized controlled trial. JAMA 1996;276:1957–63. 45. Villar J, Merialdi M, Gulmezoglu AM, et al. Nutritional interventions during pregnancy for the prevention or treatment of maternal morbidity and preterm delivery: an overview of randomized controlled trials. J Nutr 2003;133 (5 Suppl 2):1606S–25S. 46. AREDS, Research, Group. Associations of mortality with occular disorders and an intervention of high-dose antioxidants and zinc in the age-related eye disease study. Arch Ophtalmol 2004;122:716–26. 47. Bjelakovic G, Nikolova D, Simonetti RG, Gluud C. Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis. Lancet 2004;364:1219–28. 48. Willis MS, Wians FH. The role of nutrition in preventing prostate cancer: a review of the proposed mechanism of action of various dietary substances. Clin Chim Acta 2003;330:57–83. 49. Vogt TM, Ziegler RG, Graubard BI, et al. Serum selenium and risk of prostate cancer in U.S. blacks and whites. Int J Cancer 2003;103:664–70. 50. Jacobs EJ, Connell CJ, Chao A, et al. Multivitamin use and colorectal cancer incidence in a US cohort: does timing matter? Am J Epidemiol 2003;158:621–8. 51. Reid ME, Duffield-Lillico AJ, Garland L, Turnbull BW, Clark LC, Marshall JR. Selenium supplementation and lung cancer incidence: an update of the nutritional prevention of cancer trial. Cancer Epidemiol Biomarkers Prev 2002;11:1285–91. 52. Berger MM, Cavadini C, Bart A, et al. Cutaneous zinc and copper losses in burns. Burns 1992;18:373–80. 53. Berger MM, Cavadini C, Chioléro R, Dirren H. Copper, selenium, and zinc status and balances after major trauma. J Trauma 1996;40:103–9. 54. Berger MM, Shenkin A, Revelly JP, et al. Copper, selenium, zinc and thiamine balances during continuous venovenous hemodiafiltration in critically ill patients. Am J Clin Nutr 2004;80:410–6. 55. Heyland DK, Novak F, Drover JW, Jain M, Su X, Suchner U. Should immunonutrition become routine in critically ill patients? a systematic review of the evidence. JAMA 2001;286:944–53. 56. Angstwurm MWA, Schottdorf J, Schopohl J, Gaertner R. Selenium replacement in patients with severe systemic ARTICLE IN PRESS Can oxidative damage be treated nutritionally? 57. 58. 59. 60. 61. 62. 63. 64. inflammatory response syndrome improves clinical outcome. Crit Care Med 1999;27:1807–13. Berger MM, Chioléro R. Relations between copper, zinc and selenium intakes and malondialdehyde excretion after major burns. Burns 1995;21:507–12. Berger MM, Spertini F, Shenkin A, et al. Trace element supplementation modulates pulmonary infection rates after major burns: a double blind, placebo controlled trial. Am J Clin Nutr 1998;68:365–71. Tanaka H, Matsuda T, Miyagantani Y, Yukioka T, Matsuda H, Shimazaki S. Reduction of resuscitation fluid volumes in severely burned patients using ascorbic acid administration. Arch Surg 2000;135:326–31. Porter JM, Ivatury RR, Azimuddin K, Swami R. Antioxidant therapy in the prevention of organ dysfunction syndrome and infectious complications after trauma: early results of a prospective randomized study. Am Surg 1999;65:478–83. Berger MM, Reymond MJ, Shenkin A, et al. Influence of selenium supplements on the post-traumatic alterations of the thyroid axis—a prospective placebo controlled trial. Intensive Care Med 2001;27:91–100. Berger MM, Baines M, Wardle CC, et al. Influence of early trace element and vitamin E supplements on the plasma antioxidant status after major trauma: a controlled trial. Nutr Res 2001;21:41–54. Young B, Ott L, Kasarskis E, et al. Zinc supplementation is associated with improved neurologic recovery rate and visceral protein levels of patients with severe closed head injury. J Neurotrauma 1996;13:25–34. Chandra RK, McBean LD. Zinc and immunity. Nutrition 1994;10:79–80. 183 65. Vinceti M, Wei ET, Malagoli C, Bergomi M, Vivoli G. Adverse health effects of selenium in humans. Rev Environ Health 2001;16:233–51. 66. Heyland DK, Dhaliwal R, Suchner U, Berger MM. Antioxidant nutrients: a systematic review of trace elements and vitamins in the critically ill. Intensive Care Med 2005;31 in press. 67. Nathens AB, Neff MJ, Jurkovich GJ, et al. Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients. Ann Surg 2002;236:814–22. 68. Kuklinski B, Buchner M, Schweder R, Nagel R. Akute Pancreatitis-eine ‘‘Free Radical Disease: letalitatssenkung durch Natriumselenit (Na2SeO3)-therapie. Z Gestamte Inn Med 1991;46:145–9. 69. Zimmermann T, Albrecht S, Kühne H, Vogelsang U, Grützmann R, Kopprasch S. Selensubstitution bei sepsispatienten—eine prospectiv randomizierte studie. Med Klin 1997;92(Suppl 3):3–4. 70. Preiser JC, Van Gossum A, Berré 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;28:3828–32. 71. Maderazo EG, Woronick CL, Hickingbotham N, Jacobs L, Bhagavan HN. A randomized trial of replacement antioxidant vitamin therapy for neutrophil locomotory dysfunction in blunt trauma. J Trauma 1991;31:1142–50. 72. Berger MM, Baines M, Wardle CA, Cayeux MC, Chiolero R, Shenkin A. Trace element supplements modulate tissue levels, antioxidant status and clinical course after major burns—preliminary results. Clin Nutr 2002;21 (Suppl):66.