High-dose Intravenous Vitamin Research Articles

Intravenous vitamin C against acute respiratory distress syndrome: A narrative review

BackgroundThe use of intravenous vitamin C (IV-Vit-C) in the context of acute respiratory distress syndrome (ARDS) has been a topic of interest and research. ARDS is a severe and life-threatening form of respiratory failure that can be triggered by various factors, including infections, trauma, and inflammatory conditions. Some studies and clinical trials have explored the potential benefits of high-dose intravenous vitamin C in the treatment of ARDS, particularly in the context of severe respiratory illnesses such as those caused by viral infections. MethodsTwo literature reviews are performed by using the google scholar data base (scholar.google.com), one searching for “CITRIS-ALI”, and the other searching for “COVID-19 Vitamin C”, without any time restrictions, and selecting specific works, and citing or cited works, deemed appropriate. All the works included in the c19early.org data base are then indirectly considered through their statistical summary of improvements. ResultsMost of the studies support the use of IV-Vit-C against ARDS in general, including the COVID-19 induced ARDS. From the statistical analysis of 66 COVID-19 Vit-C studies, both IV and oral, there is a 18 % improvement in prophylaxis (RR 0.82 CI 0.69–0.97), a 37 % improvement in early treatment (RR 0.63, CI 0.41–0.98), and 21 % improvement in late treatment (RR 0.79, CI 0.70–0.88). Specific to this latter result are 39 studies of the 66. ConclusionsWhile IV-Vit-C was not a cure for COVID-19, it was a pragmatic but effectual means to reduce the COVID-19 mortality in cases of late infections and ARDS. IV and oral Vit-C may be considered one of the tools treating general ARDS.

Effect of high-dose intravenous vitamin C therapy on the prognosis in patients with moderately severe and severe acute pancreatitis: protocol of a prospective, randomized, double-blinded, placebo-controlled study.

Acute pancreatitis is a common gastrointestinal disease. The mortality of patients affected by severe acute pancreatitis (SAP) remains high. It is unclear whether high-dose intravenous vitamin C (HDIVC) therapy could improve the prognosis of these patients. The current prospective, randomized, double-blinded, placebo-controlled study will explore the effect of high-dose intravenous vitamin C therapy on the prognosis in patients with moderately severe and severe acute pancreatitis. A total of 418 participants with moderately severe and severe acute pancreatitis who meet the eligible criteria will be randomly assigned in a 1:1 ratio to receive treatment with HDIVC (200 mg/kg/24 h) or placebo (saline) for a period of 7 days. The primary outcome is 28-day mortality in these patients. The secondary outcomes include organ functions and interventions, laboratory tests, healthcare, and 90-day mortality. This protocol was approved by the institutional ethics board of the Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (Registration Number: 2019-90). The report of the study will be published in peer-reviewed journals and presented at conferences, both nationally and internationally. Chinese Clinical Trial Registry (ChiCTR1900022022). Version 1.5.

SERPINE1 and SERPINB7 as potential biomarkers for intravenous vitamin C treatment in non-small-cell lung cancer

High dose intravenous vitamin C (IVC) has been proposed as a pro-oxidant anticancer agent. However, there is a lack of biomarkers that are specific for this treatment. Here, we explored profiles of gene expression responding to IVC treatment in non-small cell lung cancer (NSCLC) cells as an effort for potential biomarker discovery. Genome-wide RNA-seq was performed in human NSCLC cell lines treated with pharmacological concentrations of vitamin C(VitC) for differential expression of genes. The identified genes were analyzed for correlations with patient prognosis using data from the Kaplan-Meier Plotter and the Human Protein Atlas databases. Further, tumor samples from a retrospective study of 153 NSCLC patients were analyzed with immunohistochemistry for expression of targeted genes, and patient prognosis was correlated to these genes. Two genes, namely SERPINE1 and SERPINB7 were found to be downregulated in NSCLC cells following VitC treatment. Combined patient data from the cohort analysis and online databases revealed that these 2 genes presented an unfavorable prognostic prediction of overall survival (OS) in NSCLC patients receiving standard of care. However, high expression level of these 2 genes were associated with prolonged OS in NSCLC patients receiving IVC in addition to standard of care. These data revealed that SERPINE1 and SERPINB7 have the potential to serve as predictive factors indicating favorable responses to IVC treatment in patients with NSCLC. Further validations are warranted.

Vitamin C in critical illness: end of the story or still a place?

Critical illness is associated with decreased micronutrient levels, including vitamin C, an essential antioxidant for systemic inflammation. This review discusses the most recent evidence of high-dose vitamin C monotherapy in critically ill adults. Three randomized-controlled trials (RCTs) were published in 2022. A pilot study including 40 patients with septic shock could not detect significant differences in outcome parameters after administering vitamin C. A multicenter study with 124 septic patients showed no significant difference in 28-day mortality, while vitamin C was associated with an increased risk of acute kidney dysfunction. The LOVIT trial, an international prospective RCT in 872 septic patients, revealed an increased risk of the composite endpoint persistent organ dysfunction plus death at day 28 in the high-dose vitamin C group. Six systematic reviews and meta-analyses (SRMA), including up to 4740 patients published before and 2 SRMA publications including these RCTs showed divergent results on clinical endpoints including mortality. The use of high-dose intravenous vitamin C cannot be recommended for the septic critically ill in clinical practice since the LOVIT trial. Further research is needed to evaluate its potential role in other critically ill patients.

High-dose intravenous versus low-dose oral vitamin C in burn care: potential protective effects in the severely burned: a retrospective cohort study.

The hospital burn database was used to obtain data on all patients with second-degree or deeper burns of 20% total-body-surface-area or greater. Fourteen patients were selected at random to receive a scheduled dose of 1250mg intravenous ascorbic acid every 6h for 72h. This was considered the high-dose group. During same period, 40 patients received scheduled 500mg oral ascorbic acid every 6h for 72h and this was considered the low-dose group. We gathered sociodemographic and clinical variables associated with ascorbic acid dosing. In our study, statistically significant variables were fluid requirements (p<0.001), hospital stay (p=0.011), length of time intubated on ventilator (p<0.001), colloids used (p=0.002), and total procedures required (p=0.014). Despite higher modified Baux predicted mortality in the high-dose group (10 patients vs. 24 patients, p=0.026) there was no noted significant association in days until the first infection and mortality rate (p=0.451 and 0.326, respectively). The calculated modified Baux predicted a higher mortality rate with the higher dosing group, yet this study did not find a mortality difference between the groups. We speculate that high-dose intravenous ascorbic acid may have protective effects in burn resuscitation. This finding may support some previous studies that found that high-dose ascorbic acid may improve clinical outcomes.

Multiple Bone Metastatic Invasion with Clinical Implications due to Ductal Mammary Carcinoma – Case report and Short Literature Review

Multidisciplinary approach of clinical cases in rehabilitations units can be very complex and divers. Method: We present a case of a woman 30 years old, whose oncological histo-ry begins 9 years ago, when the diagnosis of invasive ductal mammary infiltrating ca-nelular carcinoma grade I was made and treated by tumorectomy (lumpectomy). The pa-tient refused oncological treatment at that time and resorted to alternative medicine dur-ing a period of 7 years: diet without sugar and animal products; regular vitamin B17 treatments; almond kernel cure; high-dose intravenous vitamin C treatment for; intrave-nous ozone therapy; apitherapy with bee venom; oral administration of cannabis oil dur-ing the past four years until now; physical therapy. Results: The evolution is marked by the appearance of multiple bone metastatic lesions. The most worst clinical consequence was a hyperalgesic cervicobrachial neuralgia, due to multiple C6-T3 lytic lesions diag-nosed 2 years ago and C7 compression (close to spinal cord injury), situation which had as medical approach two surgeries interventions, radiotherapy and chemotherapy. Con-clusions: The rehabilitation program was adapted to every stage of clinical evolution and was marked by many complications. All the steps were made for functional improvement and for increase the quality of life.

Evaluation of Response to High-Dose Intravenous Vitamin K Administration.

Essential to the coagulation pathway, vitamin K (phytonadione) is used to correct clotting factor deficiencies and for reversal of warfarin-induced bleeding. In practice, high-dose intravenous (IV) vitamin K is often used, despite limited evidence supporting repeated dosing. This study sought to characterize differences in responders and nonresponders to high-dose vitamin K to guide dosing strategies. This was a case-control study of hospitalized adults who received vitamin K 10 mg IV daily for 3 days. Cases were represented by patients who responded to the first dose of IV vitamin K and controls were nonresponders. The primary outcome was change in international normalized ratio (INR) over time with subsequent vitamin K doses. Secondary outcomes included factors associated with response to vitamin K and incidence of safety events. The Cleveland Clinic Institutional Review Board approved this study. There were 497 patients included, and 182 were responders. Most patients had underlying cirrhosis (91.5%). In responders, the INR decreased from 1.89 at baseline (95% CI = [1.74-2.04]) to 1.40 on day 3 (95% CI = [1.30-1.50]). In nonresponders, the INR decreased from 1.97 (95% CI = [1.83-2.13]) to 1.85 ([1.72-1.99]). Factors associated with response included lower body weight, absence of cirrhosis, and lower bilirubin. There was a low incidence of safety events observed. In this study of mainly patients with cirrhosis, the overall adjusted decrease in INR over 3 days was 0.3, which may have minimal clinical impact. Additional studies are needed to identify populations who may benefit from repeated daily doses of high-dose IV vitamin K.

Intravenous high dose vitamin C and ozonated saline effective treatment for Covid -19: The Evolution of Local Standard of Care

An effective protocol for COVID-19 treatment was started at an internal medicine clinic in Gulf Breeze, FL and began with a local group of physicians using best practices from review of all the literature including the Sars CoV-1 at the turn of this century. There are limited studies on the early outpatient treatment of COVID-19 using intravenous-ozonated saline. The purpose of this report is to describe our experience.

High dose intravenous vitamin C for lyme disease: a safety and tolerability study with an exploratory assessment of treatment efficacy.

Lyme disease is the most common vector-borne disease in the United States with an estimated 476,000 new cases per year. Delays in diagnosis and treatment are common and there is a lack of consensus on the antibiotic therapy protocols to ensure successful outcomes. Much of this discord is due to the observation that more than 50 percent of people treated with conventional antibiotic protocols, which have changed little in the last 30 years, report persistent and/or recurring symptoms within 6 months of completing treatment. Labeled as chronic Lyme or post-treatment Lyme disease, it is a syndrome that afflicts more than 2 million people in the United States and can have a devastating impact on both quality of life and socioeconomic capacity. Despite these known treatment failures, the research community has lacked the funding necessary to advance our understanding of this syndrome or to explore innovative options to improve success. In this regard, complementary and alternative therapies, which are generally not patentable and have little potential for producing large economic gain, are generally disregarded in favor of new designer drugs or old reworked protocols. Intravenous vitamin C is one such example that has research validated effectiveness for a wide range of clinical conditions ranging from infection to cancer care. Achieving serum levels much higher than could be obtained orally, high dose intravenous vitamin C has the capacity to generate a concentration of intracellular peroxide that exerts both cytotoxic and immune stimulating effects. Unfortunately, these high doses of intravenous vitamin C have never been evaluated to establish safety and tolerability in Lyme positive patients. This study’s primary aim is to examine this question with the unique additions of DMSO and calcium EDTA into the formula to enhance tissue penetration and address biofilm formation respectively, both of which are known barriers to antibiotic success. The secondary aim of the study is to determine whether subjects gain relief from Lyme-associated symptoms by tracking changes in both the PROMIS-29 and the Horowitz-Lyme-MSIDS questionnaires. The exploratory objective is to assess changes in Lyme specific labs including the standard immunoblot and the T-cell based Elispot as well as the CD57+ lymphocyte immune marker. Administered at a 75-gram dose twice weekly over 12 weeks, high dose intravenous vitamin C was shown to be both well tolerated and safe. The secondary and exploratory aims of the study provide insight into the potential efficacy of this protocol, as both subjective measures of symptom severity and objective assessment of Lyme biomarkers showed marked improvement. Ultimately, this study paves the way for future research using high dose intravenous vitamin C in Lyme patents either as a stand-alone treatment or in synergy with other therapies. It is this author’s hope that employing an integrative medical approach such as this will eventually see chronic Lyme disease as a rare rather than common occurrence.

High-Dose Intravenous Ascorbate in Sepsis, a Pro-Oxidant Enhanced Microbicidal Activity and the Effect on Neutrophil Functions.

Vitamin C (ascorbic acid), a water-soluble essential vitamin, is well-known as an antioxidant and an essential substrate for several neutrophil functions. Because of (i) the importance of neutrophils in microbial control and (ii) the relatively low vitamin C level in neutrophils and in plasma during stress, vitamin C has been studied in sepsis (a life-threatening organ dysfunction from severe infection). Surprisingly, the supraphysiologic blood level of vitamin C (higher than 5 mM) after the high-dose intravenous vitamin C (HDIVC) for 4 days possibly induces the pro-oxidant effect in the extracellular space. As such, HDIVC demonstrates beneficial effects in sepsis which might be due to the impacts on an enhanced microbicidal activity through the improved activity indirectly via enhanced neutrophil functions and directly from the extracellular pro-oxidant effect on the organismal membrane. The concentration-related vitamin C properties are also observed in the neutrophil extracellular traps (NETs) formation as ascorbate inhibits NETs at 1 mM (or less) but facilitates NETs at 5 mM (or higher) concentration. The longer duration of HDIVC administration might be harmful in sepsis because NETs and pro-oxidants are partly responsible for sepsis-induced injuries, despite the possible microbicidal benefit. Despite the negative results in several randomized control trials, the short course HDIVC might be interesting to use in some selected groups, such as against anti-biotic resistant organisms. More studies on the proper use of vitamin C, a low-cost and widely available drug, in sepsis are warranted.

Intravenous high dose vitamin C and selected antiviral drugs in hospitalized COVID-19 patients: a descriptive cohort study.

There is lack of universal agreement on the management of COVID-19. Intravenous high dose vitamin C (HDVC), remdesivir (RDV), and favipiravir (FPV) have been suggested as part of the treatment regimens and only RDV is approved by the Food and Drug Administration (FDA) so far. There is no study in Lebanon that addresses the descriptive cohort of HDVC and antiviral therapy amongst COVID-19 inpatients. Our goal was to highlight such a cohort. A retrospective electronic chart review of COVID-19 inpatients was done over a period of 10 months (August 2020 to April 2021). Comparative data analysis was performed between HDVC and non-HDVC (NHDVC) groups, and RDV and FPV groups. Among HDVC patients, 70.1% (p = 0.035) and 67.2% (p = 0.008) had dyspnea and desaturation respectively. Patients on HDVC were less likely to remain in hospital for more than 20 days (p = 0.003). HDVC patients were more likely to be on oxygen therapy with 74.7% (p = 0.002). RDV patients were more likely to be on other COVID-19-related medications during hospitalization including the use of tofacitinib, baricitinib, tocilizumab, and anticoagulation as recommended in the guidelines. Statistical significance was noted for the status on discharge as 90.1% of the patients that received RDV were discharged after clinical improvement, compared to the 74.2% of the FPV patients. Further research is needed to establish local guidelines for the treatment of COVID-19. A significant role of HDVC and FPV might resurface if randomized control trials are conducted.

Ascorbic Acid in Combination with Chemotherapeutic Agents for Cancer

Cancer accounts for nearly one-quarter of deaths in the United States. The life expectancy after standard treatment for these patients is dismal. New treatment modalities should be considered and evaluated. Ascorbic Acid (AA, Vitamin C) is a relatively low cost and safe nutrient even when given at very high doses (intravenous) that could be a very relevant co-adjuvant in cancer treatment. In vitro and in vivo studies have shown benefit of using high dose intravenous vitamin C as adjuvant therapy in cancer patients. There is significant supporting evidence of the benefits of the use vitamin C with chemotherapy.

The effect of high-dose vitamin C on renal functions in COVID–19 patients

Background: With its important properties, Vitamin C has been used in several diseases and sepsis. COVID-19 may cause sepsis, and therefore high dose Vitamin C has been integrated to the treatment protocols.Concerning the potential risk of oxalate nephropaty related with the use of long term or high dose Vitamin C, we retrospectively evaluated the COVID-19 patients treated with the high dose intravenous Vitamin C, in terms of kidney dysfunction. Material and Method: Critically ill COVID-19 patients who were given Vitamin C 45-50 gr/day/5 days (Group C, n=21), and the ones who did not (Group NC, n=22) along with the hydroxychloroquine- favipiravir treatment were compared in terms of developing renal dysfunction within the 15 days of ICU stay. Results: There were no difference in the development of renal dysfunction between the groups with and without Vitamin C treatment (p&gt;0.05). But when the patients who had KDIGO stage 1 kidney damage on admission, and had worsening renal dysfunction during ICU stay were excluded, patients groups were more similar and the development of the renal failure was significantly more in Vitamin C group(p&lt;0.05). Conclusion: We conclude that when administering high dose parenteral Vitamin C, kidney functions should be carefully assessed.

The Variable Nature of Vitamin C-Does It Help When Dealing with Coronavirus?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still spreading worldwide. For this reason, new treatment methods are constantly being researched. Consequently, new and already-known preparations are being investigated to potentially reduce the severe course of coronavirus disease 2019 (COVID-19). SARS-CoV-2 infection induces the production of pro-inflammatory cytokines and acute serum biomarkers in the host organism. In addition to antiviral drugs, there are other substances being used in the treatment of COVID-19, e.g., those with antioxidant properties, such as vitamin C (VC). Exciting aspects of the use of VC in antiviral therapy are its antioxidant and pro-oxidative abilities. In this review, we summarized both the positive effects of using VC in treating infections caused by SARS-CoV-2 in the light of the available research. We have tried to answer the question as to whether the use of high doses of VC brings the expected benefits in the treatment of COVID-19 and whether such treatment is the correct therapeutic choice. Each case requires individual assessment to determine whether the positives outweigh the negatives, especially in the light of populational studies concerning the genetic differentiation of genes encoding the solute carriers responsible forVC adsorption. Few data are available on the influence of VC on the course of SARS-CoV-2 infection. Deducing from already-published data, high-dose intravenous vitamin C (HDIVC) does not significantly lower the mortality or length of hospitalization. However, some data prove, among other things, its impact on the serum levels of inflammatory markers. Finally, the non-positive effect of VC administration is mainly neutral, but the negative effect is that it can result in urinary stones or nephropathies.

High Dose Intravenous Ascorbic Acid (Vitamin C) and Glutathione as Integrative Therapy in a Patient with Diffuse Large B-Cell Lymphoma: Case Report

Diffuse Large B-Cell Lymphoma is the most common Non-Hodgkin’s Lymphoma. Given its prevalence, there is an interest in studying the treatments available and how these can be improved. The standard treatment is a chemotherapeutic regimen known as R-CHOP. The goal of this paper is to inform of an integrative approach to R-CHOP, implementing high dose intravenous Vitamin C (AA) with glutathione (GSH). In the case presented herein, the patient attained complete remission with a minimal toxicity profile and an excellent performance status. These results present a possible viable approach for patients suffering of Diffuse Large B-Cell Lymphoma. In this paper, we also briefly review the literature available on the aforementioned treatment.

IV ASCORBATE REDUCTION OF ARDS MORTALITY IS CONTINGENT AND DOSE-DEPENDENT WITH THE DEGREE OF HYPEROXIC SUPPORT

TYPE: Late Breaking Abstract TOPIC: Critical Care PURPOSE: Several randomized trials have failed to demonstrate a mortality benefit of high-dose intravenous ascorbate (vitamin C) in patients with sepsis. Recent ex-vivo human lung experiments have revealed that ascorbate acts directly on lung endothelium in hyperoxic conditions. We hypothesized that similar effects may have occurred in CITRIS-ALI trial patients, a double-blind randomized controlled trial of high-dose intravenous vitamin C in patients with ARDS. METHODS: CITRIS-ALI patients were classified, post-hoc, into three groups: Low, moderate, and severe hyperoxia based upon FiO2 < 50%, 50-80%, and ≥ 80% respectively. Logistic regression analysis was applied to evaluate the statistical interactions between hyperoxic groups and 28-day mortality and marginal analysis was performed. RESULTS: Severe hyperoxia support significantly interacted with vitamin C administration instead of placebo (p<0.001). Patients with mild hyperoxia had mortality 30% (95% CI 13.6–46.4%) and 42.4% (95% CI 25.6–59.3) for placebo and vitamin C arms respectively, p=0.3. Moderate hyperoxia groups exhibited mortality of 41.4% (95% CI 23.5 – 59.3%) and 26.7% (95% CI10.8–42.5) for placebo and vitamin C arms, p=0.2. The highest degree of hyperoxia group had mortality 74% (95% CI 56–92%) and 14.3% (95% CI 0–29.3%) for placebo and vitamin C arms, p<0.001. CONCLUSIONS: These findings suggest that high-dose intravenous vitamin C reduction of ARDS mortality is significantly linked to the degree of hyperoxia required for support, being most significant in patients who require the highest levels of hyperoxia. CLINICAL IMPLICATIONS: These findings explain the heterogeneity of outcomes in vitamin C sepsis trials in contrast to CITRIS-ALI and could guide the design of future clinical trials. DISCLOSURE: Nothing to declare. KEYWORD: Hyperoxia

SO-17 A randomized, open-label, multicenter, phase III study of high-dose vitamin C plus FOLFOX +/- bevacizumab versus FOLFOX +/- bevacizumab as first-line treatment in patients with unresectable metastatic colorectal cancer

Previous studies showed that intravenously high dose vitamin C probably have anti-cancer effect. Preclinical study found that high dose vitamin C selectively killed human colorectal cancer cells harboring KRAS or BRAF mutations. Our phase I dose-escalation and expansion study has shown that high dose (up to 1.5g/kg) intravenous vitamin C with FOLFOX or FOLFIRI is well tolerated in patients with colorectal or gastric cancer. This is a randomized, open-label, phase III study, enrolled patients with unresectable metastatic colorectal cancer (mCRC), normal G6PD status and no prior treatment. Patients with mCRC were randomized 1:1 into one of two groups. Patients in the control group were treated with FOLFOX with or without bevacizumab every 2 weeks. Patients in the experimental group were treated with vitamin C intravenously (1.5g/kg/day, d1-3) plus FOLFOX with or without bevacizumab every 2 weeks. Randomization was stratified by the location of primary site (left- or right-sided) and treatment with bevacizumab (with or without). The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), objective response rate, assessment of treatment-related adverse events (TRAEs), and PFS and OS in RAS or BRAF mutant patients. Between July 2017 and December 2019, 442 patients were randomized 1:1 into the control group (chemotherapy only) and the experimental group (chemotherapy plus high-dose vitamin C) respectively. After a median follow-up of 24.5 months (95% confidence interval [CI], 23.4 to 27.2 months), chemotherapy plus high dose vitamin C was not superior to chemotherapy only group in terms of PFS (8.6 vs 8.3 months; hazard ratio [HR] = 0.86, 95% confidence interval [CI], 0.70-1.05, P = 0.1). An overall response, as evaluated with Response Evaluation Criteria in Solid Tumors version 1.1, was observed in 44.3% of the patients in the experimental group and 42.1% in the control group. In the prespecified subgroup analysis, patients with RAS mutation (HR = 0.67, 95%CI, 0.50-0.91) showed significantly improved PFS in the experimental group than in the control group. Patients with RAS mutation showed longer PFS in the experimental group than in the control group (9.2 vs 7.8 months, P = 0.01). TRAEs of grade 3 or higher occurred in 33.5% of the patients in the experimental group, as compared with 30.3% in the control group. High-dose vitamin C plus FOLFOX with or without bevacizumab failed to show superior PFS than FOLFOX with or without bevacizumab in patients with mCRC as first-line treatment, but showed some benefit in patients with RAS mutation.

Lessening Organ Dysfunction With Vitamin C (LOVIT) Trial: Statistical Analysis Plan

BackgroundThe LOVIT (Lessening Organ Dysfunction with Vitamin C) trial is a blinded multicenter randomized clinical trial comparing high-dose intravenous vitamin C to placebo in patients admitted to the intensive care unit with proven or suspected infection as the main diagnosis and receiving a vasopressor.ObjectiveWe aim to describe a prespecified statistical analysis plan (SAP) for the LOVIT trial prior to unblinding and locking of the trial database.MethodsThe SAP was designed by the LOVIT principal investigators and statisticians, and approved by the steering committee and coinvestigators. The SAP defines the primary and secondary outcomes, and describes the planned primary, secondary, and subgroup analyses.ResultsThe SAP includes a draft participant flow diagram, tables, and planned figures. The primary outcome is a composite of mortality and persistent organ dysfunction (receipt of mechanical ventilation, vasopressors, or new renal replacement therapy) at 28 days, where day 1 is the day of randomization. All analyses will use a frequentist statistical framework. The analysis of the primary outcome will estimate the risk ratio and 95% CI in a generalized linear mixed model with binomial distribution and log link, with site as a random effect. We will perform a secondary analysis adjusting for prespecified baseline clinical variables. Subgroup analyses will include age, sex, frailty, severity of illness, Sepsis-3 definition of septic shock, baseline ascorbic acid level, and COVID-19 status.ConclusionsWe have developed an SAP for the LOVIT trial and will adhere to it in the analysis phase.International Registered Report Identifier (IRRID)DERR1-10.2196/36261

Oxidative Stress and Hyper-Inflammation as Major Drivers of Severe COVID-19 and Long COVID: Implications for the Benefit of High-Dose Intravenous Vitamin C.

Oxidative stress is a pivotal point in the pathophysiology of COVID-19 and presumably also in Long-COVID. Inflammation and oxidative stress are mutually reinforcing each other, thus contributing to the systemic hyperinflammatory state and coagulopathy which are cardinal pathological mechanisms of severe stages. COVID-19 patients, like other critically ill patients e.g. with pneumonia, very often show severe deficiency of the antioxidant vitamin C. So far, it has not been investigated how long this deficiency lasts or whether patients with long COVID symptoms also suffer from deficiencies. A vitamin C deficit has serious pathological consequences because vitamin C is one of the most effective antioxidants, but also co-factor of many enzymatic processes that affect the immune and nervous system, blood circulation and energy metabolism. Because of its anti-oxidative, anti-inflammatory, endothelial-restoring, and immunomodulatory effects the supportive intravenous (iv) use of supraphysiological doses has been investigated so far in 12 controlled or observational studies with altogether 1578 inpatients with COVID-19. In these studies an improved oxygenation, a decrease in inflammatory markers and a faster recovery were observed. In addition, early treatment with iv high dose vitamin C seems to reduce the risks of severe courses of the disease such as pneumonia and also mortality. Persistent inflammation, thrombosis and a dysregulated immune response (auto-immune phenomena and/or persistent viral load) seem to be major contributors to Long-COVID. Oxidative stress and inflammation are involved in the development and progression of fatigue and neuro-psychiatric symptoms in various diseases by disrupting tissue (e.g. autoantibodies), blood flow (e.g. immune thrombosis) and neurotransmitter metabolism (e.g. excitotoxicity). In oncological diseases, other viral infections and autoimmune diseases, which are often associated with fatigue, cognitive disorders, pain and depression similar to Long-COVID, iv high dose vitamin C was shown to significantly relieve these symptoms. Supportive iv vitamin C in acute COVID-19 might therefore reduce the risk of severe courses and also the development of Long-COVID.

The Result of Vitamin C Treatment of Patients with Cancer: Conditions Influencing the Effectiveness.

Vitamin C (ascorbic acid, AA) is a weak sugar acid structurally related to glucose. All known physiological and biochemical functions of AA are due to its action as an electron donor. Ascorbate readily undergoes pH-dependent autoxidation creating hydrogen peroxide (H2O2). In vitro evidence suggests that vitamin C functions at low concentrations as an antioxidant while high concentration is pro-oxidant. Thus, both characters of AA might be translated into clinical benefits. In vitro obtained results and murine experiments consequently prove the cytotoxic effect of AA on cancer cells, but current clinical evidence for high-dose intravenous (i.v.) vitamin C’s therapeutic effect is ambiguous. The difference might be caused by the missing knowledge of AA’s actions. In the literature, there are many publications regarding vitamin C and cancer. Review papers of systematic analysis of human interventional and observational studies assessing i.v. AA for cancer patients’ use helps the overview of the extensive literature. Based on the results of four review articles and the Cancer Information Summary of the National Cancer Institute’s results, we analyzed 20 publications related to high-dose intravenous vitamin C therapy (HAAT). The analyzed results indicate that HAAT might be a useful cancer-treating tool in certain circumstances. The AA’s cytotoxic effect is hypoxia-induced factor dependent. It impacts only the anoxic cells, using the Warburg metabolism. It prevents tumor growth. Accordingly, discontinuation of treatment leads to repeated expansion of the tumor. We believe that the clinical use of HAAT in cancer treatment should be reassessed. The accumulation of more study results on HAAT is desperately needed.