Biological Effects of Intravenous Vitamin C on Neutrophil Extracellular Traps and the Endothelial Glycocalyx in Patients with Sepsis-Induced ARDS.

(1) Background: The disease-modifying mechanisms of high-dose intravenous vitamin C (HDIVC) in sepsis induced acute respiratory distress syndrome (ARDS) is unclear. (2) Methods: We performed a post hoc study of plasma biomarkers from subjects enrolled in the randomized placebo-controlled trial CITRIS-ALI. We explored the effects of HDIVC on cell-free DNA (cfDNA) and syndecan-1, surrogates for neutrophil extracellular trap (NET) formation and degradation of the endothelial glycocalyx, respectively. (3) Results: In 167 study subjects, baseline cfDNA levels in HDIVC (84 subjects) and placebo (83 subjects) were 2.18 ng/µL (SD 4.20 ng/µL) and 2.65 ng/µL (SD 3.87 ng/µL), respectively, p = 0.45. At 48-h, the cfDNA reduction was 1.02 ng/µL greater in HDIVC than placebo, p = 0.05. Mean baseline syndecan-1 levels in HDIVC and placebo were 9.49 ng/mL (SD 5.57 ng/mL) and 10.83 ng/mL (SD 5.95 ng/mL), respectively, p = 0.14. At 48 h, placebo subjects exhibited a 1.53 ng/mL (95% CI, 0.96 to 2.11) increase in syndecan-1 vs. 0.75 ng/mL (95% CI, 0.21 to 1.29, p = 0.05), in HDIVC subjects. (4) Conclusions: HDIVC infusion attenuated cell-free DNA and syndecan-1, biomarkers associated with sepsis-induced ARDS. Improvement of these biomarkers suggests amelioration of NETosis and shedding of the vascular endothelial glycocalyx, respectively.

Any Role of High-Dose Vitamin C for Septic Shock in 2021?

While the use of vitamin C as a therapeutic agent has been investigated since the 1950s, there has been substantial recent interest in the role of vitamin C supplementation in critical illness and particularly, sepsis and septic shock. Humans cannot synthesize vitamin C and rely on exogenous intake to maintain a plasma concentration of approximately 70 to 80 µmol/L. Vitamin C, in healthy humans, is involved with antioxidant function, wound healing, endothelial function, and catecholamine synthesis. Its function in the human body informs the theoretical basis for why vitamin C supplementation may be beneficial in sepsis/septic shock.Critically ill patients can be vitamin C deficient due to low dietary intake, increased metabolic demands, inefficient recycling of vitamin C metabolites, and loss due to renal replacement therapy. Intravenous supplementation is required to achieve supraphysiologic serum levels of vitamin C. While some clinical studies of intravenous vitamin C supplementation in sepsis have shown improvements in secondary outcome measures, none of the randomized clinical trials have shown differences between vitamin C supplementation and standard of care and/or placebo in the primary outcome measures of the trials. There are some ongoing studies of high-dose vitamin C administration in patients with sepsis and coronavirus disease 2019; the majority of evidence so far does not support the routine supplementation of vitamin C in patients with sepsis or septic shock.

Preclinical trial of L-arginine monotherapy alone or with N-acetylcysteine in septic shock.

OBJECTIVE: L-arginine supplementation in sepsis is controversial. Septic shock has been alternatively viewed as an L-arginine-deficient state or as a syndrome caused by excess nitric oxide, an end-product of L-arginine metabolism. DESIGN: Randomized, placebo-controlled, and double-blinded (investigators, veterinarians, and pharmacists). SETTING: Laboratory. SUBJECTS: Purpose-bred, 1- to 2-yr-old, 10- to 12-kg beagles. INTERVENTIONS: The effects of parenteral L-arginine alone or in combination with N-acetylcysteine were compared with vehicle alone in a well-characterized canine model of Escherichia coli peritonitis. Two doses were studied that delivered approximately 1.5-fold (10 mg x kg(-1) x hr(-1)) and 15-fold (100 mg x kg(-1) x hr(-1)) the L-arginine dose typically administered with standard total parenteral nutrition. Animals in the low- and high-dose L-arginine arms were further randomized to receive vehicle alone or N-acetylcysteine (20 mg x kg(-1) x hr(-1)) as an antioxidant to prevent peroxynitrite formation. MEASUREMENTS AND MAIN RESULTS: The main measurements were hemodynamics, plasma arginine and ornithine, serum nitrate/nitrite, laboratory studies for organ injury, and survival. Both doses of L-arginine similarly increased mortality (p = .02), and worsened shock (p = .001 for reduced mean arterial pressure). These effects were associated with significant increases in plasma arginine (p = .0013) and ornithine (p = .0021). In addition, serum nitrate/nitrite (p = .02), liver enzymes (p = .08), and blood urea nitrogen/creatinine ratios (p = .001) rose, whereas arterial pH (p = .001) and bicarbonate levels (p = .001) fell. N-acetylcysteine did not significantly decrease any of the harmful effects of L-arginine. Thus, parenteral L-arginine monotherapy was markedly harmful in animals with septic shock. CONCLUSIONS: These findings suggest that supplemental parenteral L-arginine, at doses above standard dietary practices, should be avoided in critically ill patients with septic shock.

Prophylactic high-dose N(omega)-monomethyl-L-arginine prevents the late cardiac dysfunction associated with lethal tumor necrosis factor-alpha challenge in dogs.

We investigated nitric oxide (NO) as a possible cause of the cardiac dysfunction associated with high, lethal doses of tumor necrosis factor-alpha (TNF-alpha) in dogs. Eighty-seven awake, 2-year-old (10-12 kg), purpose-bred beagles were randomized to receive an infusion of saline or N-monomethyl-L-arginine (L-NMMA), a nonselective NO synthase (NOS) inhibitor, as a 40 mg kg bolus followed by a 40 mg kg(-1) h(-1) infusion for 3 to 6 h 3 h before (prophylactic) or 3 h after (therapeutic) challenge with TNF-alpha (60 microg kg(-1)) or vehicle. Serial radionuclide-heart scans and thermodilution pulmonary artery catheter hemodynamic measurements were performed. The effects of prophylactic L-NMMA on TNF-alpha-induced cardiac dysfunction as measured by decreases in mean left ventricular (LV) ejection fraction and downward and rightward shifts of LV function plots (peak systolic pressure versus end systolic volume index and LV stroke work index versus end diastolic volume index) were significantly different comparing early (3-6 h) and delayed (24 h) time points (P = 0.02). Prophylactic L-NMMA therapy did not appear to fully prevent early (3-6 h) TNF-alpha-induced cardiac dysfunction, but at 24 h, complete protection was seen. Therapeutic L-NMMA did not appear to fully protect the heart from TNF-alpha-induced early or delayed cardiac dysfunction (P = NS). Similarly, L-NMMA given prophylactically, but not therapeutically, blocked TNF-alpha-induced increases in exhaled NO flow rates and plasma nitrite and nitrate concentrations (both P = 0.02). These data suggest that TNF-alpha initiates two phases of cardiac injury: an early (3-6 h) phase that may be partially NO independent and a delayed (24 h) phase that is NO dependent. The delayed, more persistent dysfunction can be completely blocked by high doses of a nonselective NOS inhibitor administered before TNF-alpha.