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Angstwurm 2007 Selenium improves sepsis recovery by 10% "The primary end point was 28-day mortality; secondary end points were survival time and clinical course of APACHE III and logistic organ dysfunction system scores. In addition, selenium levels in serum, whole blood, and urine as well as serum gluthation-peroxidase-3 activity were measured. From 249 patients included, 11 patients had to be excluded. The intention-to-treat analysis of the remaining 238 patients revealed a mortality rate of 50.0% in the placebo group and 39.7% in the selenium-treated group (p = .109; odds ratio, 0.66; confidence interval, 0.39–1.1). A further 49 patients had to be excluded before the final analysis because of severe violations of the study protocol. In the remaining 92 patients of the study group, the 28-day mortality rate was significantly reduced to 42.4% compared with 56.7% in 97 patients of the placebo group (p = .049, odds ratio, 0.56; confidence interval, 0.32–1.00). In predefined subgroup analyses, the mortality rate was significantly reduced in patients with septic shock with disseminated intravascular coagulation (n = 82, p = .018) as well as in the most critically ill patients with an APACHE III score ≥102 (>75% quartile, n = 54, p = .040) or in patients with more than three organ dysfunctions (n = 83, p = .039). Whole blood selenium concentrations and glutathione peroxidase-3 activity were within the upper normal range during selenium treatment, whereas they remained significantly low in the placebo group. There were no side effects observed due to high-dose sodium-selenite treatment." Barabutis 2017 Hydrocortisone and Ascorbic Acid Synergistically Prevent and Repair Lipopolysaccharide-Induced Pulmonary Endothelial Barrier Dysfunction. LPS alone induced profound hyperpermeability, as reflected in decreased values of transendothelial electrical resistance. vitC alone did not exhibit barrier enhancement properties nor did it affect the LPS-induced hyperpermeability. Similarly, HC alone exhibited only a minor barrier-enhancing and protective effect. Conversely, the combination of HC and vitC, either as before or after treatment, dramatically reversed the LPS-induced barrier dysfunction. The barrier-protective effects of HC and vitC were associated with reversal of LPS-induced p53 and phosphorylated cofilin downregulation and LPS-induced RhoA activation and myosin light chain phosphorylation. CONCLUSIONS: These data provide a novel mechanism of endothelial barrier protection and suggest one possible pathway that may contribute to the therapeutic effects of HC and vitC in patients with sepsis. Bodenstein 1984 Tocopherol improves Neonatal sepsis recovery by 10% Bodenstein reports on the anomaly if improved chances for surviving sepsis in neonates with the addition of Tocopherol tp an IV and wuestions the use of Polysorbate 60 as a preservative. Carr 2015 Ascorbate-dependent vasopressor synthesis: a rationale for vitamin C administration in severe sepsis and septic shock? Severe systemic inflammatory response to infection results in severe sepsis and septic shock, which are the leading causes of death in critically ill patients. Septic shock is characterised by refractory hypotension and is typically managed by fluid resuscitation and administration of catecholamine vasopressors such as norepinephrine. Vasopressin can also be administered to raise mean arterial pressure or decrease the norepinephrine dose. Endogenous norepinephrine and vasopressin are synthesised by the copper-containing enzymes dopamine β-hydroxylase and peptidylglycine α-amidating monooxygenase, respectively. Both of these enzymes require ascorbate as a cofactor for optimal activity. Patients with severe sepsis present with hypovitaminosis C, and pre-clinical and clinical studies have indicated that administration of high-dose ascorbate decreases the levels of pro-inflammatory biomarkers, attenuates organ dysfunction and improves haemodynamic parameters. It is conceivable that administration of ascorbate to septic patients with hypovitaminosis C could improve endogenous vasopressor synthesis and thus ameliorate the requirement for exogenously administered vasopressors. Ascorbate-dependent vasopressor synthesis represents a currently underexplored biochemical mechanism by which ascorbate could act as an adjuvant therapy for severe sepsis and septic shock. Comment in Adjuvant vitamin C treatment in sepsis-how many oranges a day keep (vasopressor-dependent) septic shock away? [J Thorac Dis. 2016]

Carr 2017 Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes. Abstract BACKGROUND: Vitamin C is an essential water-soluble nutrient which cannot be synthesised or stored by humans. It is a potent antioxidant with anti-inflammatory and immune-supportive roles. Previous research has indicated that vitamin C levels are depleted in critically ill patients. In this study we have assessed plasma vitamin C concentrations in critically ill patients relative to infection status (septic shock or non-septic) and level of inflammation (C-reactive protein concentrations). Vitamin C status was also assessed relative to daily enteral and parenteral intakes to determine if standard intensive care unit (ICU) nutritional support is adequate to meet the vitamin C needs of critically ill patients. METHODS: Forty-four critically ill patients (24 with septic shock, 17 non-septic, 3 uncategorised) were recruited from the Christchurch Hospital Intensive Care Unit. We measured concentrations of plasma vitamin C and a pro-inflammatory biomarker (C-reactive protein) daily over 4 days and calculated patients' daily vitamin C intake from the enteral or total parenteral nutrition they received. We compared plasma vitamin C and C-reactive protein concentrations between septic shock and non-septic patients over 4 days using a mixed effects statistical model, and we compared the vitamin C status of the critically ill patients with known vitamin C bioavailability data using a four-parameter log-logistic response model. RESULTS: Overall, the critically ill patients exhibited hypovitaminosis C (i.e., < 23 μmol/L), with a mean plasma vitamin C concentration of 17.8 ± 8.7 μmol/L; of these, one-third had vitamin C deficiency (i.e., < 11 μmol/L). Patients with hypovitaminosis C had elevated inflammation (C-reactive protein levels; P < 0.05). The patients with septic shock had lower vitamin C concentrations and higher C-reactive protein concentrations than the non-septic patients (P < 0.05). Nearly 40% of the septic shock patients were deficient in vitamin C, compared with 25% of the non-septic patients. These low vitamin C levels were apparent despite receiving recommended intakes via enteral and/or parenteral nutritional therapy (mean 125 mg/d). CONCLUSIONS: Critically ill patients have low vitamin C concentrations despite receiving standard ICU nutrition. Septic shock patients have significantly depleted vitamin C levels compared with non-septic patients, likely resulting from increased metabolism due to the enhanced inflammatory response observed in septic shock. KEYWORDS: C-reactive protein; Critical illness; Enteral nutrition; Hypovitaminosis C; Intensive care; Parenteral nutrition; Sepsis; Septic shock; Vitamin C Cole 2010 Oxidative stress causes reversible changes in mitochondrial permeability and structure " Electron microscopy revealed a loss of matrix density and disorganization of inner membrane cristae upon oxidative stress. Notably, the changes in permeability and in structure were rapidly reversed when the oxidative stress was relieved" Marik 2017 Ascorbate and Thiamine improve sepsis recovery by 7500% "The fall in serum and cellular levels occurs too rapidly to be explained by decreased gastrointestinal absorption or increased urinary losses. Indeed, in a guinea pig model, myocardial ascorbate was depleted within hours of endotoxin administration " Doctor—your septic patients have scurvy! "Scurvy is a disease of antiquity described in Egyptian Hieroglyphics and responsible for the deaths of thousands of sailors during the Renaissance. Today, clinicians consider scurvy a very rare disease seen only in patients with extreme dietary deficiencies. They would undoubtedly be shocked to learn that about 40% of the patients in their ICU with septic shock have serum levels of vitamin C supporting a diagnosis of scurvy (<11.3 u/mol/l). The remainder of their patients with sepsis are likely to have hypovitaminosis C (serum level < 23 u/mol/l). Half of their nonseptic ICU patients also have hypovitaminosis C. These are the findings recently reported by Carr et al. [1]. Surprisingly, these astonishing observations are not new. It has been known for over two decades that acute illness results in an acute deficiency of vitamin C with low serum and intracellular levels [2–4]. Low plasma concentrations of vitamin C are associated with more severe organ failure and increased risk of mortality [5]. The most likely explanation for the acute vitamin C deficiency (acute scurvy) in patients with sepsis (and other critical illnesses) is a consequence of metabolic consumption [1]. The fall in serum and cellular levels occurs too rapidly to be explained by decreased gastrointestinal absorption or increased urinary losses. Indeed, in a guinea pig model, myocardial ascorbate was depleted within hours of endotoxin administration [6]. Most clinicians are likewise unaware that primates and guinea pigs are the only mammals that are unable to synthesize vitamin C (in their livers) and that all other mammals increase the synthesis of vitamin C during stress (vitamin C is a true stress hormone). Anthropoid primates and guinea pigs have lost the ability to synthesize vitamin C due to mutations in the l-gulono-γ-lactone oxidase (GULO) gene which codes for the enzyme responsible for catalyzing the last step of vitamin C biosynthesis [7]. The inability to synthesize vitamin C may partly explain why humans and guinea pigs have an increased vulnerability to sepsis and to dying from sepsis [8]. The inability to generate vitamin C makes humans very susceptible to dysfunction in a variety of biochemical pathways that are vital for surviving a critical illness such as sepsis." NPR and Smithsoian Magazine, among others, reported on this at the time. They report how a doctor who only lost 1 out of 150 patients (a seventy five fold increased chance of survival) by using ascorbate (and thiamine). The medical industry, who loses 50-70% of sepsis patients responded by saying it will ignore it until proven by a double blind test. They really said that. They want to run a test guaranteed to kill patients before they stop killing patients, over something well understood in medical literature since the 1940s. You know who says doctors who say this are sane? Other doctors.