The purpose of this evidence summary is to provide the best available information on the effect of anti-oxidants on mortality in patients with various diseases.

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Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases

Free radical oxidative stress has been implicated in the pathogenesis of a variety of human diseases. Natural antioxidant defences have been found to be defective in many of the same diseases. This has led to suggestions that oxidative damage and therefore disease progression may be retarded by supplementing natural antioxidant defences. Potential antioxidant therapy includes natural antioxidant enzymes and vitamins or synthetic agents with antioxidant activity. Diseases where antioxidant therapy may be beneficial include diabetes mellitus, reperfusion injury, inflammatory diseases and the prevention of chronic processes such as atherosclerosis and carcinogenesis. Further well controlled prospective clinical trials of antioxidants are required to establish the efficacy and tolerability of antioxidant therapy in the treatment of human diseases.

Prospects for the use of antioxidant therapies.

Critical illness is associated with the generation of oxygen free radicals and low endogenous antioxidant capacity leading to a condition of oxidative stress. We investigated whether supplementing critically ill patients with antioxidants, trace elements, and vitamins improves their survival. We searched four bibliographic databases from 1980 to 2003 and included studies that were randomized, reported clinically important endpoints in critically ill patients, and compared various trace elements and vitamins to placebo. Eleven articles met the inclusion criteria. When the results of all the trials were aggregated, overall antioxidants were associated with a significant reduction in mortality [Risk Ratio (RR) 0.65, 95% confidence intervals (CI) 0.44–0.97, p=0.03] but had no effect on infectious complications. Studies that utilized a single trace element were associated with a significant reduction in mortality [RR 0.52, 95% CI 0.27–0.98, p=0.04] whereas combined antioxidants had no effect. Studies using parenteral antioxidants were associated with a significant reduction in mortality [RR 0.56, 95% CI 0.34–0,92, p=0.02] whereas studies of enteral antioxidants were not. Selenium supplementation (alone and in combination with other antioxidants) may be associated with a reduction in mortality [RR 0.59, 95% CI 0.32–1.08, p=0.09] while nonselenium antioxidants had no effect on mortality. Trace elements and vitamins that support antioxidant function, particularly high-dose parenteral selenium either alone or in combination with other antioxidants, are safe and may be associated with a reduction in mortality in critically ill patients.

Antioxidant nutrients: a systematic review of trace elements and vitamins in the critically ill patient

BACKGROUND: Our previous systematic review has demonstrated that antioxidant supplements may increase mortality. We have now updated this review.OBJECTIVES: To assess the beneficial and harmful effects of antioxidant supplements for prevention of mortality in adults.METHODS:Search methods: We searched The Cochrane Library, Medline, Embase, Lilacs, the Science Citation Index Expanded, and Conference Proceedings Citation Index-Science to February 2011. We scanned bibliographies of relevant publications and asked pharmaceutical companies for additional trials. Selection criteria:We included all primary and secondary prevention randomized clinical trials on antioxidant supplements (beta-carotene, vitamin A, vitamin C, vitamin E, and selenium) versus placebo or no intervention. Data collection and analysis: Three authors extracted data. Random-effects and fixed-effect model meta-analyses were conducted. Risk of bias was considered in order to minimize the risk of systematic errors. Trial sequential analyses were conducted to minimize the risk of random errors. Random effects model meta-regression analyses were performed to assess sources of intertrial heterogeneity.MAIN RESULTS: Seventy-eight randomized trials with 296,707 participants were included. Fifty-six trials including 244,056 participants had low risk of bias. Twenty-six trials included 215,900 healthy participants. Fifty-two trials included 80,807 participants with various diseases in a stable phase. The mean age was 63 years (range 18 to 103 years). The mean proportion of women was 46%. Of the 78 trials, 46 used the parallel-group design, 30 the factorial design, and 2 the cross-over design. All antioxidants were administered orally, either alone or in combination with vitamins, minerals, or other interventions. The duration of supplementation varied from 28 days to 12 years (mean duration 3 years; median duration 2 years). Overall, the antioxidant supplements had no significant effect on mortality in a random-effects model meta-analysis (21,484 dead/183,749 (11.7%) versus 11,479 dead/112,958 (10.2%); 78 trials, relative risk (RR) 1.02, 95% confidence interval (CI) 0.98 to 1.05) but significantly increased mortality in a fixed-effect model (RR 1.03, 95% CI 1.01 to 1.05). Heterogeneity was low with an I2- of 12%. In meta-regression analysis, the risk of bias and type of antioxidant supplement were the only significant predictors of intertribal heterogeneity. Meta-regression analysis did not find a significant difference in the estimated intervention effect in the primary prevention and the secondary prevention trials. In the 56 trials with a low risk of bias, the antioxidant supplements significantly increased mortality (18,833 dead/146,320 (12.9%) versus 10,320 dead/97,736 (10.6%); RR 1.04, 95% CI 1.01 to 1.07). This effect was confirmed by trial sequential analysis. Excluding factorial trials with potential confounding showed that 38 trials with low risk of bias demonstrated a significant increase in mortality (2822 dead/26,903 (10.5%) versus 2473 dead/26,052 (9.5%); RR 1.10, 95% CI 1.05 to 1.15). In trials with low risk of bias, beta-carotene (13,202 dead/96,003 (13.8%) versus 8556 dead/ 77,003 (11.1%); 26 trials, RR 1.05, 95% CI 1.01 to 1.09) and vitamin E (11,689 dead/97,523 (12.0%) versus 7561 dead/73,721 (10.3%); 46 trials, RR 1.03, 95% CI 1.00 to 1.05) significantly increased mortality, whereas vitamin A (3444 dead/24,596 (14.0%) versus 2249 dead/16,548 (13.6%); 12 trials, RR 1.07, 95% CI 0.97 to 1.18), vitamin C (3637 dead/36,659 (9.9%) versus 2717 dead/ 29,283 (9.3%); 29 trials, RR 1.02, 95% CI 0.98 to 1.07), and selenium (2670 dead/39,779 (6.7%) versus 1468 dead/22,961 (6.4%); 17 trials, RR 0.97, 95% CI 0.91 to 1.03) did not significantly affect mortality. In univariate meta-regression analysis, the dose of vitamin A was significantly associated with increased mortality (RR 1.0006, 95% CI 1.0002 to 1.001, P = 0.002).AUTHORS' CONCLUSIONS: We found no evidence to support antioxidant supplements for primary or secondary prevention. Beta-carotene and vitamin E seem to increase mortality, and so may higher doses of vitamin A. Antioxidant supplements need to be considered as medicinal products and should undergo sufficient evaluation before marketing.

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The tripeptide thiol glutathione (GSH) has facile electron-donating capacity, linked to its sulfhydryl (—SH) group. Glutathione is an important water-phase antioxidant and essential cofactor for antioxidant enzymes; it provides protection also for the mitochondria against endogenous oxygen radicals. Its high electron-donating capacity combined with its high intracellular concentration endows GSH with great reducing power, which is used to regulate a complex thiol-exchange system (—SH —S-S—). This functions at all levels of cell activity, from the relatively simple (circulating cysteine/— SH thiols, ascorbate, other small molecules) to the most complex (cellular —SH proteins). Glutathione is homeostatically controlled, both inside the cell and outside. Enzyme systems synthesize it, utilize it, and regenerate it as per the gamma-glutamyl cycle. Glutathione is most concentrated in the liver (10 mM), where the “P450 Phase II” enzymes require it to convert fat-soluble substances into water-soluble GSH conjugates, in order to facilitate their excretion. While providing GSH for their specific needs, the liver parenchymal cells export GSH to the outside, where it serves as systemic source of —SH/reducing power. GSH depletion leads to cell death, and has been documented in many degenerative conditions. Mitochondrial GSH depletion may be the ultimate factor determining vulnerability to oxidant attack. Oral ascorbate helps conserve GSH; cysteine is not a safe oral supplement, and of all the oral GSH precursors probably the least flawed and most cost-effective is NAC (N-acetylcysteine). (Alt Med Rev 1997; 2(3):155-176)

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Glutathione: Systemic Protectant Against Oxidative and Free Radical Damage

Oxidant stress has been proposed as the initiating pathogenetic mechanism in pancreatitis, hence micronutrient antioxidant therapy has been assessed in patients with recurrent attacks and/or constant pancreatic pain. In a 20-week double-blind double-dummy crossover trial active treatment was given as two types of tablets providing daily doses of 600 micrograms organic selenium, 9000 IU beta carotene, 0.54 g vitamin C, 270 IU vitamin E and 2 g methionine. Of 28 patients enrolled, 20 adhered to the full protocol (idiopathic chronic 8, alcoholic chronic 7, idiopathic acute 5). Six patients had an attack whilst on placebo but none whilst on active treatment (P = 0.032). Analysis of visual analogue scoresheets to compare background pain in the 10-week period before entry and during each phase of the trial, using a 10-cm scale for each of 11 best descriptors, endorsed the beneficial effect of active treatment (placebo v baseline, P = 0.073; active v baseline, P less than 0.001; active v placebo, P = 0.049). The same trend emerged from analysis of pain-score diaries by conventional and time series methods. Micronutrient antioxidant therapy thus offers a new approach to the treatment of recurrent (non-gallstone) pancreatitis and/or pancreatic pain.

L. Nathan

Papers

Antioxidant therapy for recurrent pancreatitis: placebo-controlled trial

Placebo-Controlled Double-Blind Trial of Antioxidant Supplements in Patients with Recurrent Pancreatitis