Abstract：
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).
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.
CONCLUSIONS: 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.
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.
CONCLUSIONS: 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.
摘要：
背景：在脓毒症中，中性粒细胞呼吸爆发参与内皮损伤，多器官衰竭的第一步。在血浆中两种抗氧化硒酶，保护内皮，减少：硒蛋白-P，和较小程度的谷胱甘肽过氧化物酶（GPX3）。亚硒酸钠（Na2SeO3）是硒供体，也是一种氧化剂化疗药物，取决于其浓度。在之前发表的一项研究中，感染性休克患者在第1天以4mg1Se/天的药理剂量连续输注Na2SeO3，然后在9天内以1mgSe/天的高营养剂量连续输注，对儿茶酚胺的断奶和存活率均无有益影响。在这项辅助研究中，我们报道了连续输注Na2SeO3的临床和生物学效应。方法：这是一个多中心，安慰剂对照,对60例患者进行双盲研究。如上所述连续输注的Na2SeO3或安慰剂。等离子体Se随时间的演化,硒蛋白-P，GPX3，器官功能障碍（序贯器官衰竭评估SOFA评分，包括PaO2/FiO2，用于呼吸衰竭，和血浆乳酸）和6个月时的生活质量（通过SF36评分）进行双向分析（时间，治疗)非参数重复测量方差分析(弗里德曼检验)。
结果：在基线时，血浆Se约为参考值的四分之一。从基线到第4天血浆硒，与安慰剂相比,在Na2SeO3组中硒蛋白-P和GPX3分别显著增加3.9、2.7和1.8,并且在第14天保持分别升高2.3、2.7和2.1(p<0.001)。在第1天和之后直到第14天，Na2SeO3不会影响整体和器官SOFA分数和血浆乳酸浓度。两组直到第14天的PaO2/FiO2的演变相似。两组患者在6个月时的生活质量相似。
结论：在第1天连续输注4mgSe的Na2SeO3似乎在第1天或更晚既没有益处也没有毒性作用，并在第4天诱导硒蛋白-P的晚期增加。需要进行临床前研究以确认使用Na2SeO3作为抗嗜中性粒细胞的细胞毒性药物以及硒蛋白P对内皮的保护。
结果：在基线时，血浆Se约为参考值的四分之一。从基线到第4天血浆硒，与安慰剂相比,在Na2SeO3组中硒蛋白-P和GPX3分别显著增加3.9、2.7和1.8,并且在第14天保持分别升高2.3、2.7和2.1(p<0.001)。在第1天和之后直到第14天，Na2SeO3不会影响整体和器官SOFA分数和血浆乳酸浓度。两组直到第14天的PaO2/FiO2的演变相似。两组患者在6个月时的生活质量相似。
结论：在第1天连续输注4mgSe的Na2SeO3似乎在第1天或更晚既没有益处也没有毒性作用，并在第4天诱导硒蛋白-P的晚期增加。需要进行临床前研究以确认使用Na2SeO3作为抗嗜中性粒细胞的细胞毒性药物以及硒蛋白P对内皮的保护。
