INTRAVENOUS VITAMIN C SUPPLEMENTATION IN ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANT RECIPIENTS: SALUTARY IMPACT ON CLINICAL OUTCOMES.

Intravenous (IV) vitamin C improves organ function and reduces inflammation in sepsis, an inflammatory state like the post-hematopoietic stem cell transplant (SCT) milieu. The safety and efficacy of parenteral vitamin C after allogeneic hematopoietic stem cell transplant (HSCT) were evaluated in a phase I/II trial and clinical outcomes compared with a propensity score - matched historical control. Methods: Patients with advanced hematologic malignancies were enrolled in a phase 2 clinical trial, receiving IV vitamin C, 50mg/kg/d, divided into 3 doses given on days 1-14 after HSCT, followed by 500 mg bid oral from day 15 until 6 months post-SCT. Results: 55 patients received IV vitamin C: these include 10/10 HLA-MRD and MUD (n=48) and 9/10 HLA MUD recipients (n=7). All patients enrolled were deficient in vitamin C at day 0 and had restoration to normal levels for the remainder of the course. Vitamin C recipients had lower non-relapse mortality (11% vs. 25%, p-value = 0.07) and consequently, improved survival compared to historical controls (82% vs 62% p=0.06), with no attributable grade 3 and 4 toxicities to vitamin C. Patients with myeloid malignancies had improved survival (83% vs. 54%, p=0.02) and non-relapse mortality (NRM) (10% vs. 37%, p=0.009), as well as chronic GVHD, with similar relapse rates compared to controls. Conclusions: In patients undergoing allogeneic HSCT the administration of IV vitamin C is safe and reduces non-relapse mortality improving overall survival. Randomized trials are needed to confirm the utility of this easily available and inexpensive therapy.

Intravenous Vitamin C Supplementation in Allogeneic Hematopoietic Cell Transplant Recipients: Salutary Impact on Clinical Outcomes.

Intravenous (IV) vitamin C improves organ function and reduces inflammation in sepsis, an inflammatory state like the post-hematopoietic stem cell transplant (HCT) milieu. The safety and efficacy of parenteral vitamin C after allogeneic HCT were evaluated in a phase I/II trial. Clinical outcomes were compared with a propensity score - matched historical control. Methods: Patients with advanced hematologic malignancies received IV vitamin C, 50mg/kg/d, divided into 3 doses given on days 1-14 after HCT, followed by 500 mg bid oral from day 15 until 6 months post-SCT. Results: 55 patients received IV vitamin C. All patients were deficient in vitamin C at day 0. Vitamin C recipients had lower non-relapse mortality (NRM) (p = 0.07) and improved survival compared to historical controls (p=0.06), with no attributable grade 3 and 4 toxicities. Vitamin C recipients had similar relapse rate and acute graft versus host disease (GVHD) (p=0.35), but lower severe chronic GVHD (p=0.35). Patients with myeloid malignancies had improved survival (p=0.02) and NRM (p=0.009), as well as chronic GVHD, with similar relapse rates compared to controls. Conclusions: In patients undergoing allogeneic HCT the administration of IV vitamin C is safe and reduces non-relapse mortality and chronic GVHD improving overall survival.

Determining Intraosseous Needle Placement Using Point-of-Care Ultrasound in a Swine (Sus scrofa) Model.

OBJECTIVE: Intraosseous (IO) access is critical in resuscitation, providing rapid access when peripheral vascular attempts fail. Unfortunately, misplacement commonly occurs, leading to possible fluid extravasation and tissue necrosis. Current research exploring the utility of bedside ultrasound in confirming IO line placement is limited by small sample sizes of skeletally immature subjects or geriatric cadaveric models. The objective of this study was to investigate the potential value of ultrasound confirming IO needle placement in a live tissue model with bone densities approximated to the young adult medical or trauma patient. MATERIALS AND METHODS: In this randomized, blinded prospective study, IO devices were placed into the bilateral humeri of 36 sedated adult swine (N = 72) with bone densities approximating that of a 20-39-year-old adult. Of the 72 lines, 53 were randomized to the IO space ("correct") and 19 into the subcutaneous tissue ("incorrect"). Four emergency physicians with variable ultrasound experience and blinded to needle location independently assessed correct or incorrect needle placements based on the presence of an intramedullary "flare" on color power Doppler (CPD) during a saline flush. Participants adjusted the ultrasound beam trajectory and recorded assessments up to three times, totaling 204 separate observations. RESULTS: Overall, sensitivity for placement confirmation was 72% (95% CI: 64%-79%). Specificity was 79% (95% CI: 66%-89%). First assessment and final assessment results were similar. More experienced sonographers demonstrated greater success in identifying inaccurate placements with a specificity of 86% (95% CI: 63%-96%). CONCLUSION: Within the context of this study, point-of-care ultrasound with CPD did not reliably confirm IO line placement. However, more accurate assessments of functional and malpositioned catheters were noted in sonographers with greater than 4 years of experience. Future study into experienced sonographers' use of CPD to confirm IO catheter placement is needed.

Vitamin C epigenetically controls osteogenesis and bone mineralization.

Vitamin C deficiency disrupts the integrity of connective tissues including bone. For decades this function has been primarily attributed to Vitamin C as a cofactor for collagen maturation. Here, we demonstrate that Vitamin C epigenetically orchestrates osteogenic differentiation and function by modulating chromatin accessibility and priming transcriptional activity. Vitamin C regulates histone demethylation (H3K9me3 and H3K27me3) and promotes TET-mediated 5hmC DNA hydroxymethylation at promoters, enhancers and super-enhancers near bone-specific genes. This epigenetic circuit licenses osteoblastogenesis by permitting the expression of all major pro-osteogenic genes. Osteogenic cell differentiation is strictly and continuously dependent on Vitamin C, whereas Vitamin C is dispensable for adipogenesis. Importantly, deletion of 5hmC-writers, Tet1 and Tet2, in Vitamin C-sufficient murine bone causes severe skeletal defects which mimic bone phenotypes of Vitamin C-insufficient Gulo knockout mice, a model of Vitamin C deficiency and scurvy. Thus, Vitamin C's epigenetic functions are central to osteoblastogenesis and bone formation and may be leveraged to prevent common bone-degenerating conditions.

Development and validation of a GC-MS method for analysis of Dithiocarbamate Fungicide residues in the Spices Cardamom (Elettaria cardamomom) and black pepper (Piper nigrum).

Dithiocarbamates constitute an important class of broad-spectrum antifungal compounds used extensively in agriculture, including in the cultivation of spices. Maximum residue limits for these compounds have been enforced by several importing countries in international food trade. Validation of analytical methods for dithiocarbamates in spices have not been reported previously. A quick and sensitive method for estimation of total dithiocarbamates as carbon disulphide (CS2) using GC-MS in two major spices, viz. small cardamom (Elettaria cardamomom) and black pepper (Piper nigrum) was optimized and validated. Dithiocarbamate residues in these spice matrices were extracted and subjected to acid hydrolysis followed by reduction to CS2, which was then quantitatively absorbed into isooctane and analysed using GC-MS, employing selected ion monitoring and post-run mid-column backflush technique. For fortification levels from 0.1 to 1.0 mg kg- 1, recoveries obtained ranged from 75 to 98% in cardamom and 76-98% in black pepper, with intra-day precision (RSDr) < 12% and inter-day precision (RSDR) < 15% in all cases. Limit of Quantification of 0.05 mg kg- 1 was achieved in both spices. It was found that there was negligible interference in quantitative accuracy due to essential oils present in the two spices studied. Matrix effect was seen to be suppressive in the two spices studied, and sufficiently low to exclude the use of matrix-matched calibration in routine quantitative analysis. The optimized analytical method was found to be suitable for evaluation of compliance of real samples against the Codex maximum residue limits for cardamom and black pepper. Safety evaluation for human consumption, based on the incidence of Dithiocarbamate residues, was performed in real samples of cardamom and black pepper. This method offers the possibility of extending applicability to other spices also. Supplementary information: The online version contains supplementary material available at 10.1007/s13197-022-05462-9.

Synthesis and characterization of rhamnolipid based chitosan magnetic nanosorbents for the removal of acetaminophen from aqueous solution.

Biocatalytically synthesized mono-rhamnolipids are eco-friendly surfactants that exhibit strong industrial applications owing to their low toxicity and biodegradability as well as their efficient antimicrobial and surface tension reduction potential. In this present study, novel adsorbent chitosan encapsulated magnetic nanoparticles coated with rhamnolipids (Rh-cMNP) were prepared and used for the adsorption of the micropollutant acetaminophen. The SEM, FTIR, and VSM results showed that Rh-cMNP had abundant functional groups with a mesoporous feature and easy separation of the magnetic nanosorbent from the reaction mixture. The obtained nanosorbent was effectively used to remove acetaminophen, one of the most common persistent pharmaceutical pollutants in the environment. Optimization studies revealed the maximum removal of 96.7% acetaminophen with the ability of adsorption to be 96.3 mg/g at 60 min of contact time and process parameters of pH 5.0 and 303 K temperature. Langmuir isotherm was most favourable for the optimized data; kinetic studies obeyed pseudo-second-order whose feasibility and thermodynamic studies obtained spontaneity. Regeneration of used Rh-cMNP is performed with 0.1 N HCl/NaOH and observed to be consistent for eight adsorption-desorption cycles.

Understanding the factors affecting adsorption of pharmaceuticals on different adsorbents - A critical literature update.

Remediation of emerging pharmaceutically active compounds (PhACs) as micropollutants in wastewater is of foremost importance as they can cause extremely detrimental effects on life upon bioaccumulation and generation of drug-resistance microorganisms. Presently used physicochemical treatments, such as electrochemical oxidation, nanofiltration and reverse osmosis, are not feasible owing to high operating costs, incomplete removal of contaminants along with toxic by-products formation. Adsorption with the utilization of facile and efficient nanoparticulate adsorbents having distinctive properties of high surface area, excellent adsorption capacity, ability to undergo surface engineering and good regeneration displays great potential in this aspect along with the incorporation of nanotechnology for effective treatment. The application of such nanosorbents provides optimal performance under a wide range of physicochemical conditions, decreased secondary pollution with reduced mechanical stress along with excellent organic compound sequestration capacity, which in turn improves the quality of potable water in a sustainable way compared to current treatments. The present review intends to consolidate the range of factors that affect the process of adsorption of different PhACs on to various nanosorbents and also highlights the adsorption mechanism aiding in the retrieval.

Multi-residue method validation and safety evaluation of pesticide residues in seed spices cumin (Cuminum cyminum) and coriander (Coriandrum sativum) by gas chromatography tandem mass spectrometry (GC-MS/MS).

The manuscript reports comprehensive multi-residue determination of 215 pesticides in two commercially important Indian spices, Cumin (Cuminum cyminum) and Coriander (Coriandrum sativum) by GC-MS/MS analysis. The proposed method involved liquid-liquid extraction with acetonitrile, d-SPE clean-up and final reconstitution of extract in ethyl acetate. d-SPE clean-up with PSA and C18 minimized the matrix effects by 40 and 16%, respectively. Reconstitution of final extract reduced the non-volatile matrix co-extractives by 36-40%. The method was validated as per SANTE/12682/2019 and recoveries at 10, 25 and 50 µg kg-1 were within 70-120% with RSD ≤ 20%. A fit for purpose method LOQ of 10 µgkg-1 was achieved for 85% of analytes. The method was successfully applied for comprehensive screening of cumin and coriander market samples. The calculated TMDI for acute and chronic exposure assessment were less than calculated MPI in respective matrices and therefore did not cause any adverse effect to consumers.

Single Versus Double Anatomic Site Intraosseous Blood Transfusion in a Swine Model of Hemorrhagic Shock.

BACKGROUND: Blood transfusion via single site intraosseous access is a critical modality when caring for a trauma victim that lacks intravascular access. Flow rates and potential clinical complications when utilizing two sites of intraosseous access are not well known. MATERIALS AND METHODS: Anesthetized adult female Yorkshire swine (Sus scrofa; n = 48; 76.7 ± 1.75kg; range 66-90kg) were cannulated and then bled approximately 30% total blood volume. Swine were randomly assigned to treatment groups: single sited humerus, single sited sternum, dual sited humerus or dual sited humerus and sternum. Flow rates, hemolysis, physiologic measurements, biochemical variables, and pulmonary histologic inflammation and occlusion were contrasted between groups. RESULTS: Dual sited intraosseous transfusion flow rates (128ml/min, 95% CI 123-132) were double the flow rates of single sites (65ml/min, 95% CI 60-70), P < .0001.Single sited humeral flow rates were greater than sternal flow rates, with respective averages of 74ml/min and 55ml/min, though not reaching statistical significance (P < 0.17). There was no significant elevation of plasma free hemoglobin in any group after transfusion as compared to baseline (P = 0.7). Groups did not significantly differ in vitals or biochemical variables. Most pulmonary specimens had some intraparenchymal fat embolism, however no animals had evidence of occlusive intra-arterial fat embolism. CONCLUSIONS: Dual anatomic site, pressure bag driven, intraosseous blood transfusion approximately doubles flow rates without evidence of clinical complications or hemolysis. Further research using a survivability model is needed to characterize long-term complications from pressurized IO transfusions.

Laparoscopic D2 gastrectomy in advanced gastric cancer: Postoperative outcomes and long-term survival analysis.

INTRODUCTION: Data on laparoscopic treatment of operable gastric cancer from India is sparse. This study aims to document outcomes of laparoscopic D2 gastrectomy in an Indian population. MATERIALS AND METHODS: Data of patients who underwent laparoscopic D2 gastrectomy for operable advanced gastric cancer between February 2012 and January 2017 were collected from electronic hospital records supplemented by telephonic interviews and analyzed. Survival was evaluated using Kaplan-Meier survival analysis curves. RESULTS: In total 121 patients were included. Conversion to open gastrectomy was 5.7%. One hundred and fourteen patients (73 laparoscopic subtotal gastrectomy and 41 laparoscopic total gastrectomy) were included for analysis. D2 lymphadenectomy was done in all cases; mean number of dissected lymph nodes was 23.12 ± 9.14 (12-45). Major complications (Clavien-Dindo Grade III and IV) was seen in 6.1% of cases with reoperation rate of 3.5% (4/114). Stage 3 disease was seen in 60.6% cases and stage 2 disease in 32.5%. Follow-up data were available for 76.3% of patients with mean follow-up of 29.5 months. Overall survival across all stages was 38.7 months. Five-year disease-free survival and overall survival were 36.7% and 55.9% respectively, across all stages. CONCLUSION: Laparoscopic D2 gastrectomy is safe, feasible with similar postoperative complications and comparable survival outcomes across all stages when compared to available literature on open gastrectomy cases.

Efficacy of Hemostatic Gauzes in a Swine Model of Prolonged Field Care with Limb Movement.

INTRODUCTION: Prolonged field care for junctional wounds is challenging and involves limb movement to facilitate transport. No studies to date have explored the efficacy of gauze products to limit rebleeding in these scenarios. MATERIALS AND METHODS: We randomly assigned 48 swine to QuikClot Combat Gauze, ChitoGauze, NuStat Tactical, or Kerlix treatment groups (12 each) and then inflicted a severe groin injury by utilizing a modified Kheirabadi model of a 6-mm femoral artery punch followed by unrestricted bleeding for 60 seconds. We reassessed rebleed following limb movement at 30 minutes of stabilization and 4 hours after stabilization. RESULTS: Swine treated with Combat Gauze proved to have the lowest incidence of rebleeding, and conversely, NuStat Tactical had the highest incidence of rebleeding at wounds after limb movement. Importantly, rebleeds occurred at a rate of 25%-58% across all swine treatment groups at 30 minutes postinjury and 0%-42% at 270 minutes postinjury demonstrating that limb movements universally challenge hemostatic junctional wounds. CONCLUSIONS: Our findings highlight the difficulty of controlling hemorrhage from junctional wounds with hemostatic gauze in the context of prolonged field care and casualty transport. Our research can guide selection of hemorrhage control gauze when patients have prolonged field extraction or difficult transport. Our data demonstrates the frequency of junctional wound rebleeding after movement and thus the importance of frequent patient reassessment.

Performance study on adsorptive removal of acetaminophen from wastewater using silica microspheres: Kinetic and isotherm studies.

Owing to the global industrialization, a new generation of pharmaceutical pollutants with high toxicity and persistency have been detected. In the present study, silica microspheres, a promising adsorbent has been employed to investigate the extent of removal of prevalent therapeutic acetaminophen, an emerging micropollutant, from wastewater in isolated batch experiments. The BET surface area of the adsorbent was 105.46 m2/g with a pore size of 15 nm. Characterization of adsorbent by scanning electron microscopy analysis revealed the microparticulate nature with a 15 ± 5 µm particle size. Optimization of reaction parameters for enhanced assimilative removal of pollutants was performed and the highest adsorption of 96.7% of acetaminophen with an adsorption capacity of 89.0 mg/g was observed upon contact time of only 30 min. Mild process conditions of pH 5.0, 20 ppm of acetaminophen, temperature of 303 K, and 100 ppm sorbent concentration further aided in the removal process. Obtained data were best corresponded with the Freundlich isotherm (n = 2.685), indicating highly favorable adsorption. Acetaminophen adsorption kinetics obeyed the pseudo second order and feasible energetic changes were yielded through the thermodynamic analysis. Silica microspheres recovery carried out through a single-step desorption process had a 99.14% retrieval ability.

Vitamin C and inflammatory cytokine levels in elective total knee arthroplasty.

BACKGROUND: Vitamin C levels are decreased in arthritis patients and reduced levels following surgery may impair adequate healing. AIM: This study measured changes in vitamin C and inflammatory markers in patients undergoing total knee arthroplasty (TKA). METHODS: Venous blood samples were collected from 10 patients during the preoperative to postoperative period. Vitamin C, interleukin-1ß, interleukin-6 (IL-6), and C-reactive protein (CRP) levels were measured using various assays. RESULTS: No significant changes in vitamin C levels were measured. However, all participants had suboptimal preoperative vitamin C levels and 90% had suboptimal levels postoperatively. IL-6 and CRP levels significantly increased during the immediate postoerative period. CONCLUSION: There was a rise in inflammation following TKA while vitamin C levels did not significantly change during this short study period. Of note, every patient had suboptimal vitamin C levels prior to surgery and 90% continued with suboptimal levels two days postoperatively.

Intravenous and Intraosseous Blood Transfusion With Three Different Pediatric Pressure Transfusion Strategies in an Immature Swine (Sus scrofa) Model of Hemorrhagic Shock: A Pilot Study.

INTRODUCTION: Exsanguination remains the leading cause of preventable death in military conflicts, and pediatric casualties are common. Transfusion is crucial to preserve life, but vascular access is challenging in children, so intraosseous (IO) access is often required. However, the optimal transfusion method is unclear. There was therefore the need for feasibility testing of a model for contrasting the efficacy of blood infusion devices via intravenous (IV) and IO access in immature swine with bone densities similar to children. MATERIALS AND METHODS: Eighteen immature swine (21 ± 1 kg) were bled 31% of estimated blood volume and then received autologous blood delivered by pressure bag, push-pull (PP), or LifeFlow Rapid Infuser via IO (15-gauge IO needle placed in the humeral head) or IV (auricular 20-gauge), with monitoring for 60 minutes. RESULTS: Flow rates for LifeFlow (172 ± 28 mL/kg) were 4-fold higher than pressure bag (44 ± 13 mL/kg, P < 0.001) and 80% higher than PP (95 ± 28 mL/kg, P < 0.02). However, higher hemolysis was evident in the IV LifeFlow condition, with 6-fold more plasma-free hemoglobin than other conditions (P < 0.0001). CONCLUSIONS: IV LifeFlow conferred higher flows, but higher hemolysis in this pilot study demonstrates the feasibility of an immature swine model toward determining optimal methods for resuscitating children with hemorrhagic shock.

Comparison of thromboelastography versus conventional coagulation tests in simulated Crotalus atrox envenomation using human blood.

INTRODUCTION: Pit viper bites are a source of significant morbidity and mortality. Pit viper bites can cause venom-induced consumptive coagulopathy (VICC), typically evaluated with laboratory-based conventional coagulation tests (CCTs). However, CCTs require a laboratory and average 1 h to conduct. Thromboelastography (TEG) provides real-time, point-of-care tests of coagulation that are fast and require no separate laboratory facilities, which could be advantageous in both hospital and austere settings. However, the relative efficacy of TEG versus CCTs was unclear, particularly at low venom concentrations. Therefore, the objectives of this study were to test human blood with various concentrations of pit viper venom using CCTs and TEG to determine dose-dependent changes, lowest observed effect concentration (LOEC), and sensitivity to detecting samples out of normal diagnostic range. METHODS: Blood samples from 20 volunteers were mixed with varying concentrations of western diamond back rattlesnake (Crotalus atrox) venom based on the mouse LD50IV (none, 0.5%, 1%, 2%, 33%, 66%, and 100% LD50IV). Samples were split and assessed with both CCTs including prothrombin time (PT), international normalized ratio (INR), partial thromboplastin time (PTT), fibrinogen, and D-dimer, along with TEG measures of reaction time (R), kinetic time (K), rate of clot formation (α-angle), and clot strength (MA). Data were analyzed as dose-dependent concentration-based changes in raw values and in percent of samples exceeding diagnostic thresholds using ANOVA and nonparametric statistics at the p < .05 threshold. RESULTS: All evaluations showed significant concentration-dependent changes, and 100% of samples exceeded diagnostic thresholds at 33%LD50IV and above, save D-dimer. At 0.5%LD50IV, R, K, α-angle, PT, and INR were significantly different from controls, and at 1%LD50IV, mean values exceeded diagnostic thresholds for R, K, α-angle, MA, PT, and INR, but not for PTT, D-dimer, or fibrinogen. At 2%LD50IV, 100% of samples were out of normal range for K, α-angle, and PT. CONCLUSION: TEG is effective in coagulopathy evaluations of in vitro simulated pit viper envenomation. At low venom concentrations, TEG performed as well or better than the majority of CCTs. These findings provide empirical evidence supporting the use of TEG to rapidly and accurately evaluate VICC.

Safety of Pressurized Intraosseous Blood Infusion Strategies in a Swine Model of Hemorrhagic Shock.

BACKGROUND: Current guidelines support intraosseous access for trauma resuscitation when intravenous access is not readily available. However, safety of intraosseous blood transfusions with varying degrees of infusion pressure has not been previously characterized. MATERIALS AND METHODS: Adult female Yorkshire swine (Sus scrofa; n = 36; mean (M): 80 kg, 95% CI: 78-82 kg) were cannulated and then bled approximately 30% total blood volume. Swine were randomly assigned to proximal humerus intraosseous blood infusion with either Rapid Infuser, or Pressure Bag, or Push-Pull methods (n = 12 each). Flow rates, infusion pressures, vitals, biochemical variables, and pulmonary and renal tissue pathology were contrasted between groups. RESULTS: Flow rates were greater for the Push-Pull strategy than Pressure Bag (96.5 mL/min versus 72.6 mL/min, P = 0.02) or Rapid Infuser (96.5 mL/min versus 60 mL/min, P = 0.002) strategies. The pressures generated during the Push-Pull transfusion (3058 mmHg) were greater than the other strategies (≤360 mmHg). After the observation period, plasma-free hemoglobin levels were higher in the Push-Pull strategy than in the Rapid Infuser (40 mg/dL versus 12 mg/dL, P = 0.02) or Pressure Bag (40 mg/dL versus 12 mg/dL, P = 0.01). Groups did not significantly differ in vitals, biochemical variables, or tissue pathology. CONCLUSIONS: Push-Pull conferred the highest flow rates, but with higher infusion pressures and evidence of intravascular hemolysis. Rapid Infuser and Pressure Bag infusions had no increase from baseline in plasma-free hemoglobin. Pressure Bag infusion was noted to confer an advantage in flow rates over Rapid Infuser. Intraosseous blood transfusion with pressure bags can safely bridge toward central access in the early phases of trauma resuscitation.

Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial.

Importance: Experimental data suggest that intravenous vitamin C may attenuate inflammation and vascular injury associated with sepsis and acute respiratory distress syndrome (ARDS). Objective: To determine the effect of intravenous vitamin C infusion on organ failure scores and biological markers of inflammation and vascular injury in patients with sepsis and ARDS. Design, Setting, and Participants: The CITRIS-ALI trial was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 7 medical intensive care units in the United States, enrolling patients (N = 167) with sepsis and ARDS present for less than 24 hours. The study was conducted from September 2014 to November 2017, and final follow-up was January 2018. Interventions: Patients were randomly assigned to receive intravenous infusion of vitamin C (50 mg/kg in dextrose 5% in water, n = 84) or placebo (dextrose 5% in water only, n = 83) every 6 hours for 96 hours. Main Outcomes and Measures: The primary outcomes were change in organ failure as assessed by a modified Sequential Organ Failure Assessment score (range, 0-20, with higher scores indicating more dysfunction) from baseline to 96 hours, and plasma biomarkers of inflammation (C-reactive protein levels) and vascular injury (thrombomodulin levels) measured at 0, 48, 96, and 168 hours. Results: Among 167 randomized patients (mean [SD] age, 54.8 years [16.7]; 90 men [54%]), 103 (62%) completed the study to day 60. There were no significant differences between the vitamin C and placebo groups in the primary end points of change in mean modified Sequential Organ Failure Assessment score from baseline to 96 hours (from 9.8 to 6.8 in the vitamin C group [3 points] and from 10.3 to 6.8 in the placebo group [3.5 points]; difference, -0.10; 95% CI, -1.23 to 1.03; P = .86) or in C-reactive protein levels (54.1 vs 46.1 µg/mL; difference, 7.94 µg/mL; 95% CI, -8.2 to 24.11; P = .33) and thrombomodulin levels (14.5 vs 13.8 ng/mL; difference, 0.69 ng/mL; 95% CI, -2.8 to 4.2; P = .70) at 168 hours. Conclusions and Relevance: In this preliminary study of patients with sepsis and ARDS, a 96-hour infusion of vitamin C compared with placebo did not significantly improve organ dysfunction scores or alter markers of inflammation and vascular injury. Further research is needed to evaluate the potential role of vitamin C for other outcomes in sepsis and ARDS. Trial Registration: ClinicalTrials.gov Identifier: NCT02106975.

Temporal map of the pig polytrauma plasma proteome with fluid resuscitation and intravenous vitamin C treatment.

BACKGROUND: Fluid resuscitation plays a prominent role in stabilizing trauma patients with hemorrhagic shock yet there remains uncertainty with regard to optimal administration time, volume, and fluid composition (e.g., whole blood, component, colloids) leading to complications such as trauma-induced coagulopathies (TIC), acidosis, and poor oxygen transport. Synthetic fluids in combination with antioxidants (e.g., vitamin C) may resolve some of these problems. OBJECTIVES: We applied quantitative mass spectrometry-based proteomics [liquid chromatography-mass spectrometry (LC-MS/MS)] to map the effects of fluid resuscitation and intravenous vitamin C (VitC) in a pig model of polytrauma (hemorrhagic shock, tissue injury, liver reperfusion, hypothermia, and comminuted bone fracture). The goal was to determine the effects of VitC on plasma protein expression, with respect to changes associated with coagulation and trauma-induced coagulopathy (TIC). METHODS: Longitudinal blood samples were drawn from nine male Sinclair pigs at baseline, 2 h post trauma, and 0.25, 2, and 4 h post fluid resuscitation with 500 mL hydroxyethyl starch. Pigs were treated intravenously (N = 3/treatment group) with saline, 50 mg VitC/kg (Lo-VitC), or 200 mg VitC/kg (Hi-VitC) during fluid resuscitation. RESULTS: A total of 436 plasma proteins were quantified of which 136 changed following trauma and resuscitation; 34 were associated with coagulation, complement cascade, and glycolysis. Unexpectedly, Lo-VitC and Hi-VitC treatments stabilized ADAMTS13 levels by ~4-fold (P = .056) relative to saline and enhanced ADAMTS13/von Willebrand factor (VWF) cleavage efficiency based on LC-MS/MS evidence for the semitryptic VWF cleavage product (VWF1275-1286 ). CONCLUSIONS: This study provides the first comprehensive map of trauma-induced changes to the plasma proteome, especially with respect to proteins driving the development of TIC.

Reduced plasma ascorbic acid levels in recipients of myeloablative conditioning and hematopoietic cell transplantation.

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 four autologous HCT). Ascorbate levels declined postconditioning to 27.3 µMol/L (±14.1) by day 0 (P = .03 compared with pretransplant baseline), reaching a nadir level of 21.5 (±13.8) on day 14 (P = .003) post-transplant. Patients undergoing allogeneic HCT continued to have low AA levels to day 60 post-transplant. 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.