Mechanism Of Metabolic Action Of Intravenous High-dose Vitamin C In Sepsis

Objective:To evaluate the efficacy of intravenous high-dose vitamin C in sepsis and to explore the possible metabolic mechanism of action in conjunction with metabolomic approaches.Methods:This study enrolled septic patients admitted to the Emergency Intensive Care Unit(EICU)of Sichuan Provincial People’s Hospital from 07/2022 to 01/2023.The enrolled patients were divided according to a randomisation protocol into an experimental group with intravenous vitamin C(3g,q12h for 72 to 96h)and a control group with the placebo(0.9%Na C1 or 5%GS).Primary outcome:28d,60d and 90d mortality.Secondary outcomes:duration of mechanical ventilation,duration of vasopressor use,duration of ICU stay,duration of hospital stay,change in SOFA score and APACHE II score after 96h,and safety assessment.Serum samples were also collected from patients at multiple time points for vitamin C assay and metabolomics analysis.Vitamin C was quantified by liquid chromatography tandem mass spectrometry.In addition,the metabolic pathways that may have had an impact were analysed by comparing the different metabolites between the two groups of patients at the corresponding time points using proton nuclear magnetic resonance(1H NMR)metabolomics.Results:Thirty septic patients were eventually enrolled(16 in the vitamin C group and 14 in the control group).The vitamin C level of the septic patients was significantly lower than normal subjects at the time of admission to the ICU[250.81(158.23,536.40)ng/m L vs 2759.81(2359.66,3030.86)ng/m L,p<0.001].After 72h of dosing,serum vitamin C levels in the vitamin C group were significantly higher than those in the control group and returned to normal levels.The 28d,60d and 90d mortality were00.00%,12.50%and 25.00%in the vitamin C group and 14.29%,28.57%and 28.57%in the control group,respectively,with no significant difference between the two groups.The duration of mechanical ventilation was significantly shorter in the vitamin C group[(5.83±1.72)d vs(13.4±8.53)d,P=0.026]and the APACHE II score decreased more significantly after 96h[(10.54±5.64)vs(5.75±4.31),P=0.009].The CD4~+T lymphocyte count was significantly higher in the vitamin C group on the fifth day after admission to the ICU(P=0.016).In addition,no significant adverse reactions were observed during the study.In this study,a total of 54 differential metabolites were screened,as well as five more significant metabolic pathways,namely histidine metabolism,β-alanine metabolism,arginine and proline metabolism,tryptophan metabolism,and glycerolipid metabolism.Conclusion:Intravenous high-dose vitamin C is safe and effective,it can correcte the early hypovitaminosis C state in septic patients,which in turn improves immune function,shortens the duration of mechanical ventilation and lowers the APACHE II score.Vitamin C may exert its therapeutic effects through metabolic pathways that regulate anti-inflammatory,antioxidant and immune functions.