Sepsis, a life-threatening organ dysfunction due to a dysregulated host response to infection, is a leading cause of morbidity and mortality worldwide. Decades of research have failed to identify any specific therapeutic targets outside of antibiotics, infectious source elimination, and supportive care. More recently, vitamin C has emerged as a potential therapeutic agent to treat sepsis. Vitamin C has been shown to be deficient in septic patients and the administration of high dose intravenous as opposed to oral vitamin C leads to markedly improved and elevated serum levels. Its physiologic role in sepsis includes attenuating oxidative stress and inflammation, improving vasopressor synthesis, enhancing immune cell function, improving endovascular function, and epigenetic immunologic modifications. Multiple clinical trials have demonstrated the safety of vitamin C and two recent studies have shown promising data on mortality improvement. Currently, larger randomized controlled studies are underway to validate these findings. With further study, vitamin C may become standard of care for the treatment of sepsis, but given its safety profile, current treatment can be justified with compassionate use.

Stored red blood cells (RBCs) undergo oxidative stress that induces deleterious metabolic, structural, biochemical, and molecular changes collectively referred to as “storage lesions”. We hypothesized that vitamin C (VitC, reduced or oxidized) would reduce red cell storage lesions, thus prolonging their storage duration. Whole-blood-derived, leuko-reduced, SAGM (saline-adenine-glucose-mannitol)-preserved RBC concentrates were equally divided into four pediatric storage bags and the following additions made: (1) saline (saline); (2) 0.3 mmol/L reduced VitC (Lo VitC); (3) 3 mmol/L reduced VitC (Hi VitC); or (4) 0.3 mmol/L oxidized VitC (dehydroascorbic acid, DHA) as final concentrations. Biochemical and rheological parameters were serially assessed at baseline (prior to supplementation) and Days 7, 21, 42, and 56 for RBC VitC concentration, pH, osmotic fragility by mechanical fragility index, and percent hemolysis, LDH release, glutathione depletion, RBC membrane integrity by scanning electron microscopy, and Western blot for β-spectrin. VitC exposure (reduced and oxidized) significantly increased RBC antioxidant status with varying dynamics and produced trends in reduction in osmotic fragility and increases in membrane integrity. Conclusion: VitC partially protects RBC from oxidative changes during storage. Combining VitC with other antioxidants has the potential to improve long-term storage of RBC.

The clinical outcome of allogeneic hematopoietic stem cell transplantation (SCT) may be influenced by the metabolic status of the recipient following conditioning, which in turn may enable risk stratification with respect to the development of transplant-associated complications such as graft vs. host disease (GVHD). To better understand the impact of the metabolic profile of transplant recipients on post-transplant alloreactivity, we investigated the metabolic signature of 14 patients undergoing myeloablative conditioning followed by either human leukocyte antigen (HLA)-matched related or unrelated donor SCT, or autologous SCT. Blood samples were taken following conditioning and prior to transplant on day 0 and the plasma was comprehensively characterized with respect to its lipidome and metabolome via liquid chromatography/mass spectrometry (LCMS) and gas chromatography/mass spectrometry (GCMS). A pro-inflammatory metabolic profile was observed in patients who eventually developed GVHD. Five potential pre-transplant biomarkers, 2-aminobutyric acid, 1-monopalmitin, diacylglycerols (DG 38:5, DG 38:6), and fatty acid FA 20:1 demonstrated high sensitivity and specificity towards predicting post-transplant GVHD. The resulting predictive model demonstrated an estimated predictive accuracy of risk stratification of 100%, with area under the curve of the ROC of 0.995. The likelihood ratio of 1-monopalmitin (infinity), DG 38:5 (6.0), and DG 38:6 (6.0) also demonstrated that a patient with a positive test result for these biomarkers following conditioning and prior to transplant will be at risk of developing GVHD. Collectively, the data suggest the possibility that pre-transplant metabolic signature may be used for risk stratification of SCT recipients with respect to development of alloreactivity.

Hematopoietic cell transplantation (HCT) conditioned using myeloablative conditioning (MAC) is complicated by end organ injury due to endothelial dysfunction and graft versus host disease. Mucositis and oxidant injury results in micronutrient deficiency. Ascorbic acid (AA) levels were measured in 15 patients undergoing HCT conditioned with MAC (11 allogeneic and 4 autologous HCT). Ascorbate levels declined post conditioning to 27.3 (±14.1) by day 0 (p <0.05 compared with baseline), reaching a nadir level of 21.5 (±13.8) on day 14 (p <0.05) post-transplant. Patients undergoing allogeneic HCT continued to have low AA levels to day 60 post transplant, whereas recipients of autologous HCT recovered plasma AA levels to normal. The role of AA in maintaining endothelial function and hematopoietic as well as T cell recovery is provided, developing the rationale for repletion of vitamin C following HCT.