Delayed increase of plasma selenoproteins and absence of side effect induced by infusion of pharmacological dose of sodium selenite in septic shock: Secondary analysis of a multicenter, randomized controlled trial.

BACKGROUND: In sepsis, neutrophil respiratory bursts participate in endothelium damage, the first step to multiple organ failure. In plasma two antioxidant selenoenzymes, which protect the endothelium, decrease: selenoprotein-P, and to a lesser extent glutathione peroxidase (GPX3). Sodium selenite (Na2SeO3) is a Se donor, but also an oxidant chemotherapy drug depending on its concentration. In a previous published study, Na2SeO3 continuous infusion in septic shock patients at a pharmacological dose of 4 mg1 Se/day on day-1, followed by a high nutritional dose of 1 mg Se/day during 9 days, showed no beneficial effect on weaning of catecholamine nor on survival. In this ancillary study, we report clinical and biological effects of such continuous infusion of Na2SeO3. METHODS: This was a multicenter, placebo-controlled, double-blind study on 60 patients. Na2SeO3 or placebo in continuous infusion as described above. Evolution with time of plasma Se, selenoprotein-P, GPX3, Organ dysfunction (sequential organ failure assessment SOFA scores, including PaO2/FiO2, for respiratory failure, and plasma lactate) and quality of life at 6 months (by SF36 scores) were analyzed using two-way (time, treatment) non-parametric repeated-measures analysis of variance (Friedman test). MAIN RESULTS: At baseline, plasma Se was about a quarter of reference values. From baseline to day-4 plasma Se, selenoprotein-P and GPX3 significantly increased by 3.9, 2.7 and 1.8 respectively in the Na2SeO3 group as compared with placebo and remained elevated by 2.3, 2.7 and 2.1 at day-14 respectively (p < 0.001). Na2SeO3 did not affect global and organ by organ SOFA Scores and plasma lactate concentration at day-1 and later up to day-14. The evolution of PaO2/FiO2 until day-14 was similar in the two groups. Quality of life in the surviving patients at 6 months was similar between the two groups. CONCLUSION: Continuous infusion of Na2SeO3 at 4 mg Se at day-1 seems to have neither beneficial nor toxic effect at day-1 or later and induces a late increase of selenoprotein-P at day-4. Preclinical studies are required to confirm the use of Na2SeO3 as a cytotoxic drug against neutrophils and protection of the endothelium by selenoprotein-P.

Selenocompounds and Sepsis-Redox Bypass Hypothesis: Part B-Selenocompounds in the Management of Early Sepsis.

Significance: Endothelial barrier damage, which is in part caused by excess production of reactive oxygen, halogen and nitrogen species (ROHNS), especially peroxynitrite (ONOO-), is a major event in early sepsis and, with leukocyte hyperactivation, part of the generalized dysregulated immune response to infection, which may even become a complex maladaptive state. Selenoenzymes have major antioxidant functions. Their synthesis is related to the need to limit deleterious oxidant redox cycling by small selenocompounds, which may be of therapeutic cytotoxic interest. Plasma selenoprotein-P is crucial for selenium transport from the liver to the tissues and for antioxidant endothelial protection, especially against ONOO-. Above micromolar concentrations, sodium selenite (Na2SeO3) becomes cytotoxic, with a lower cytotoxicity threshold in activated cells, which has led to cancer research. Recent Advances: Plasma selenium (<2% of total body selenium) is mainly contained in selenoprotein-P, and concentrations decrease rapidly in the early phase of sepsis, because of increased selenoprotein-P binding and downregulation of hepatic synthesis and excretion. At low concentrations, Na2SeO3 acts as a selenium donor, favoring selenoprotein-P synthesis in physiology, but probably not in the acute phase of sepsis. Critical Issues: The cytotoxic effects of Na2SeO3 against hyperactivated leukocytes, especially the most immature forms that liberate ROHNS, may be beneficial, but they may also be harmful for activated endothelial cells. Endothelial protection against ROHNS by selenoprotein-P may reduce Na2SeO3 toxicity, which is increased in sepsis. Future Direction: The combination of selenoprotein-P for endothelial protection and the cytotoxic effects of Na2SeO3 against hyperactivated leukocytes may be a promising intervention for early sepsis. Antioxid. Redox Signal. 37, 998-1029.

Elements of margin of safety, toxicity and action of sodium selenite in a lipopolysaccharide rat model.

PROJECT: Both septic shock and sodium selenite (Na2SeO3) lead to multiple organ failure through oxidation. Na2SeO3 has direct oxidant effects above the nutritional level and indirect anti-oxidant properties. In a lipopolysaccharide (LPS) rat model we assessed margin of safety, toxicity and beneficial effect of pentahydrate Na2SeO3 (5H2O·Na2SeO3) at oxidant doses. PROCEDURE: In a three-step study on 204 rats we: (i) observed toxic effects of Na2SeO3 injected intraperitoneously (IP) and determined its Minimum Dose Without Toxic effect (MDWT) 0.25-0.35 mg/kg selenium (Se) content; (ii) injected IP LPS at 70% lethal dose (LD) followed, or not, one hour later by IP Na2SeO3 at MDWT and (iii) by doses>MDWT. At 48 h, in survivors, we measured plasma creatinine, lactate, aspartate and alanine aminotransferase (AST, ALT), nitric oxide (NO) and Se concentrations. RESULTS: (i) Na2SeO3 alone did not increase NO and lactate. Encephalopathy appeared at 1mg Se/kg. Creatinine increased at 1-1.75 mg Se/kg, AST, ALT at 3-4.5 mg Se/kg, and the minimum LD was 3 mg Se/kg. (ii) Mortality after LPS was 37/50 (74%, [62-86%]) vs. 20/30 (67%, [50-84%]) when followed by Na2SeO3 at MDWT (p=0.483) with a decreased in NO (-31%, p=0.038) a trend for lactate decrease (-19%, p=0.068) and an increased Se in plasma of survivals. (iii) All rats died at doses ≥0.6 mg/kg (p<0.001). CONCLUSION: Mechanisms of LPS and Na2SeO3 toxicity differ (i.e. NO, lactate). In septic shock 5H2O·Na2SeO3 toxicity increased, margin of safety decrease, but IP administration of dose considered as oxidant of 5H2O·Na2SeO3 showed beneficial effects.

Critically elucidating the role of selenium.

PURPOSE OF REVIEW: To assess the current role of selenium supplementation in critically ill patients. RECENT FINDINGS: Studies consistently demonstrate decreased selenium concentration in plasma and whole blood in some critically ill patients, especially those with septic shock, and have suggested that persistent low concentrations may be associated with worse outcomes. However, clinical trials of selenium administration have not consistently or convincingly demonstrated improved outcomes. SUMMARY: Despite the low selenium content in the body (20-40 mg), selenoenzymes play an important role in antioxidant defense in humans. Selenium administration may be associated with improved outcomes, but further studies are needed to determine the precise mechanism of action. Studies are also needed to determine optimal dosing regimens, and to identify those patients in whom this approach is likely to be most effective. Currently, doses below the tolerable upper intake level (400 microg) may be used in supplementation. Higher doses (up to the level of no adverse effect, 800 microg) may be of interest and need to be studied further. The pro-oxidant effects of selenocompounds, especially sodium selenite, which vary depending on the compound, dose, and concentration, also need to be assessed further for their toxicity and potential therapeutic use in patients with septic shock.

Effects of high doses of selenium, as sodium selenite, in septic shock patients a placebo-controlled, randomized, double-blind, multi-center phase II study--selenium and sepsis.

Selenium has a double action. (i) Seleno-compounds, among them sodium selenite have a direct pro-oxidant action leading to acute toxicity but may be also beneficial as drug. (ii) Selenium is an essential anti-oxidant required for anti-oxidant seleno-enzymes. Septic shock is a common severe syndrome leading to endothelium damage and multiple organ failure, with increased data suggesting the principle role of oxidative stress. Selenoprotein P, main selenium constituent of the plasma, may decrease dramatically and specifically in septic shock patients and may be involved in the endothelium protection. A prospective, multi-center placebo-controlled, randomized, double-blind study in severe septic shock patients with documented infection has been preformed. Patients received, for 10 days, selenium as sodium selenite (4000 microg on the first day, 1000 microg/day on the 9 following days) or matching placebo using continuous intravenous infusion. Mortality rates did not significantly differ between groups at any time point. Adverse events rates were similar in the two groups. However, high-dose selenium administration has been associated with a tendency to decrease the mortality in septic shock animal and patients, especially when using a bolus administration, whereas studies using a continuous administration failed to find any benefit on mortality. The interest of the successive use of pro-oxidant action of seleno-compounds, followed by anti-oxidant action need to be the further studied in cellular and animal models, preceding new dose-effect phase II. The interest of the selenoprotein-P as a marker of septic shock and for endothelium protection needs also to be studied further.

Seleno-enzymes and seleno-compounds: the two faces of selenium.

Selenium protects cells and inhibits many inflammatory cell mechanisms through antioxidant seleno-enzymes. Immunity improvement is illustrated by the study of Berger and colleagues, with reduction of nosocomial pneumonia in burnt patients under multi-trace-element supplementation. As seleno-compounds (especially sodium selenite) are pro-oxidant, however, administration above 800 microg/day may be dangerous in septic shock. Paradoxically, direct reversible pro-oxidative effects of seleno-compounds may also be beneficial for reduction of inflammation (genomic action, apoptosis), and may even be bactericidal or virucidal. These facts need to be further examined, as well as the possible dramatic drop of plasma selenoprotein P in septic shock and its role in endothelium protection.