Randomized Clinical Trial of Antioxidant Therapy Patients with Septic Shock and Organ Dysfunction in the ICU: SOFA Score Reduction by Improvement of the Enzymatic and Non-Enzymatic Antioxidant System.

BACKGROUND AND AIM: Here, we assess the effect of adjuvant antioxidant therapies in septic shock patients with organ dysfunction and their effect on the enzymatic and non-enzymatic antioxidant systems. METHODS: Randomized clinical trial run between 2018 and 2022. One hundred and thirty-one patients with septic shock were included in five groups with 25, 27, 24, 26 and 29 patients each. Group 1 received vitamin C (Vit C), Group 2 vitamin E (Vit E), Group 3 n-acetylcysteine (NAC), Group 4 melatonin (MT) and group 5 no treatment. All antioxidants were administered orally or through a nasogastric tube for 5 days as an adjuvant to standard therapy. RESULTS: All patients had multiple organ failure (MOF) and low Vit C levels. Vit C therapy decreased CRP, PCT and NO3-/NO2- but increased Vit C levels. The SOFA score decreased with MT in 75%, Vit C 63% and NAC 50% vs. controls 33% (p = 0.0001, p = 0.03 and p = 0.001 respectively). MT diminished lipid peroxidation (LPO) (p = 0.01) and improved total antioxidant capacity (TAC) (p = 0.04). Vit E increased thiol levels (p = 0.02) and tended to decrease LPO (p = 0.06). Selenium levels were decreased in the control group (p = 0.04). CONCLUSIONS: Antioxidants used as an adjuvant therapy in the standard treatment of septic shock decrease MOF and oxidative stress markers. They increase the TAC and thiols, and maintain selenium levels.

Thiamine pharmaconutrition in sepsis: Monotherapy, combined therapy, or neither? Current evidence on safety and efficacy.

Sepsis is a life-threatening condition characterized by multiorgan dysfunction due to an exaggerated host response to infection associated with a homeostatic failure. In sepsis, different interventions, aimed at improving clinical outcomes, have been tested over the past decades. Among these most recent strategies, intravenous high-dose micronutrients (vitamins and/or trace elements) have been investigated. According to current knowledge, sepsis is characterized by low thiamine levels, which are associated with illness severity, hyperlactatemia, and poor clinical outcomes. However, caution is needed about the clinical interpretation of thiamine blood concentration in critically ill patients, and the inflammatory status, based on C-reactive protein levels, should always be measured. In sepsis, parenteral thiamine has been administered as monotherapy or in combination with vitamin C and corticosteroids. Nevertheless, most of those trials failed to report clinical benefits with high-dose thiamine. The purpose of this review is to summarize the biological properties of thiamine and to examine current knowledge regarding the safety and efficacy of high-dose thiamine as pharmaconutrition strategy when administering singly or in combination with other micronutrients in critically ill adult patients with sepsis or septic shock. Our examination of the most up-to-date evidence concludes that Recommended Daily Allowance supplementation is relatively safe for thiamine-deficient patients. However, current evidence does not support pharmaconutrition with high-dose thiamine as a single therapy or as combination therapy aimed at improving clinical outcomes in critically ill septic patients. The best nutrient combination still needs to be determined, based on the antioxidant micronutrient network and the multiple interactions among different vitamins and trace elements. In addition, a better understanding of the pharmacokinetic and pharmacodynamic profiles of intravenous thiamine is needed. Future well-designed and powered clinical trials are urgently warranted before any specific recommendations can be made regarding supplementation in the critical care setting.

Effects of l-Arginine Plus Vitamin C Supplementation on l-Arginine Metabolism in Adults with Long COVID: Secondary Analysis of a Randomized Clinical Trial.

Altered l-arginine metabolism has been described in patients with COVID-19 and has been associated with immune and vascular dysfunction. In the present investigation, we determined the serum concentrations of l-arginine, citrulline, ornithine, monomethyl-l-arginine (MMA), and symmetric and asymmetric dimethylarginine (SDMA, ADMA) in adults with long COVID at baseline and after 28-days of l-arginine plus vitamin C or placebo supplementation enrolled in a randomized clinical trial, compared with a group of adults without previous history of SARS-CoV-2-infection. l-arginine-derived markers of nitric oxide (NO) bioavailability (i.e., l-arginine/ADMA, l-arginine/citrulline+ornithine, and l-arginine/ornithine) were also assayed. Partial least squares discriminant analysis (PLS-DA) models were built to characterize systemic l-arginine metabolism and assess the effects of the supplementation. PLS-DA allowed discrimination of participants with long COVID from healthy controls with 80.2 ± 3.0% accuracy. Lower markers of NO bioavailability were found in participants with long COVID. After 28 days of l-arginine plus vitamin C supplementation, serum l-arginine concentrations and l-arginine/ADMA increased significantly compared with placebo. This supplement may therefore be proposed as a remedy to increase NO bioavailability in people with long COVID.

Hmong microbiome ANd Gout, Obesity, Vitamin C (HMANGO-C): A phase II clinical study protocol.

BACKGROUND: Hmong men in Minnesota exhibit a high prevalence of gout and hyperuricemia. Although evidence of vitamin C's effectiveness as a treatment for gout is mixed, analysis of therapeutic benefit based on an individual's multiomic signature may identify predictive markers of treatment success. OBJECTIVES: The primary objective of the Hmong Microbiome ANd Gout, Obesity, Vitamin C (HMANGO-C) study was to assess the effectiveness of vitamin C on serum urate in Hmong adults with and without gout/hyperuricemia. The secondary objectives were to assess if 1) vitamin C impacts the taxonomic and functional patterns of microbiota; 2) taxonomic and functional patterns of microbiota impact vitamin C's urate-lowering effects; 3) genetic variations impact vitamin C's urate-lowering effects; 4) differential microbial biomarkers exist for patients with or without gout; and 5) there is an association between obesity, gut microbiota and gout/hyperuricemia. METHODS: This prospective open-labelled clinical trial was guided by community-based participatory research principles and conducted under research safety restrictions for SARS-CoV-2. We aimed to enroll a convenient sample of 180 Hmong adults (120 with gout/hyperuricemia and 60 without gout/hyperuricemia) who provided medical, demographic, dietary and anthropometric information. Participants took vitamin C 500mg twice daily for 8 weeks and provided pre-and post- samples of blood and urine for urate measurements as well as stool samples for gut microbiome. Salivary DNA was also collected for genetic markers relevant to uric acid disposition. EXPECTED RESULTS: We expected to quantify the impact of vitamin C on serum urate in Hmong adults with and without gout/hyperuricemia. The outcome will enhance our understanding of how gut microbiome and genomic variants impact the urate-lowering of vitamin C and associations between obesity, gut microbiota and gout/hyperuricemia. Ultimately, findings may improve our understanding of the causes and potential interventions that could be used to address health disparities in the prevalence and management of gout in this underserved population. TRIAL REGISTRATION: ClinicalTrials.gov NCT04938024 (first posted: 06/24/2021).

Impact of Zinc, Vitamins C and D on Disease Prognosis among Patients with COVID-19 in Bangladesh: A Cross-Sectional Study.

Vitamin C, (ascorbic acid), vitamin D (cholecalciferol) and zinc (zinc sulfate monohydrate) supplements are important in immunity against coronavirus disease-2019 (COVID-19). However, a limited number of studies have been conducted on the association of vitamins and supplements with the reduced risks of COVID-19 infection. This study aims to evaluate the association of vitamins and supplements as treatment options to reduce the severity of COVID-19. Data were collected from 962 participants from 13 December 2020 to 4 February 2021. The presence of COVID-19 was confirmed by qRT-PCR. The Chi-square test and multivariate regression analyses were conducted. The ratio of uptake of vitamin C:vitamin D:zinc was 1:1:0.95. Uptake of vitamin C, vitamin D and zinc were significantly associated with the reduced risk of infection and severity of COVID-19 (OR: 0.006 (95% CI: 0.03-0.11) (p = 0.004)) and (OR: 0.03 (95% CI: 0.01-0.22) (p = 0.005)). The tendency of taking supplements was associated with the presence of infection of COVID-19 (p = 0.001), age (p = 0.02), sex (p = 0.05) and residence (p = 0.04). The duration of supplementation and medication was significantly associated with reduced hospitalization (p = 0.0001). Vitamins C, D and zinc were not significantly (p = 0.9) associated with a reduced risk of severity when taken through the diet. Hospitalization (p = 0.000001) and access to health facilities (p = 0.0097) were significantly associated with the survival period of the participants. Participants with better access to health facilities recovered early (OR: 6.21, 95% CI 1.56-24.7). This study will add knowledge in the field of treatment of COVID-19 by using vitamins and zinc supplements.

Effects of l-Arginine Plus Vitamin C Supplementation on Physical Performance, Endothelial Function, and Persistent Fatigue in Adults with Long COVID: A Single-Blind Randomized Controlled Trial.

Long COVID, a condition characterized by symptom and/or sign persistence following an acute COVID-19 episode, is associated with reduced physical performance and endothelial dysfunction. Supplementation of l-arginine may improve endothelial and muscle function by stimulating nitric oxide synthesis. A single-blind randomized, placebo-controlled trial was conducted in adults aged between 20 and 60 years with persistent fatigue attending a post-acute COVID-19 outpatient clinic. Participants were randomized 1:1 to receive twice-daily orally either a combination of 1.66 g l-arginine plus 500 mg liposomal vitamin C or a placebo for 28 days. The primary outcome was the distance walked on the 6 min walk test. Secondary outcomes were handgrip strength, flow-mediated dilation, and fatigue persistence. Fifty participants were randomized to receive either l-arginine plus vitamin C or a placebo. Forty-six participants (median (interquartile range) age 51 (14), 30 [65%] women), 23 per group, received the intervention to which they were allocated and completed the study. At 28 days, l-arginine plus vitamin C increased the 6 min walk distance (+30 (40.5) m; placebo: +0 (75) m, p = 0.001) and induced a greater improvement in handgrip strength (+3.4 (7.5) kg) compared with the placebo (+1 (6.6) kg, p = 0.03). The flow-mediated dilation was greater in the active group than in the placebo (14.3% (7.3) vs. 9.4% (5.8), p = 0.03). At 28 days, fatigue was reported by two participants in the active group (8.7%) and 21 in the placebo group (80.1%; p < 0.0001). l-arginine plus vitamin C supplementation improved walking performance, muscle strength, endothelial function, and fatigue in adults with long COVID. This supplement may, therefore, be considered to restore physical performance and relieve persistent symptoms in this patient population.

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

INTRODUCTION: 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. METHODOLOGY: 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. RESULTS: 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. CONCLUSIONS: 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.

Vitamin C Supplementation for the Treatment of COVID-19: A Systematic Review and Meta-Analysis.

Since the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, caused by the severe respiratory syndrome coronavirus 2 (SARS-CoV-2), millions of people have died, and the medical system has faced significant difficulties. Our purpose was to perform a meta-analysis to estimate the effect of vitamin C on in-hospital mortality and the ICU or hospital length of stay for patients diagnosed with COVID-19. We conducted a systematic review with meta-analysis in the following databases: PubMed, Web of Science, Scopus and Cochrane Central Register of Controlled Trials. We included studies that evaluated the effect of vitamin C supplementation, compared with standard treatment in COVID-19 patients who are ≥18 y of age. Nineteen trials were included in the meta-analysis. In-hospital mortality with and without vitamin C supplementation was 24.1% vs. 33.9% (OR = 0.59; 95%CI: 0.37 to 0.95; p = 0.03), respectively. Sub-analysis showed that, in randomized clinical trials, in-hospital mortality varied and amounted to 23.9% vs. 35.8% (OR = 0.44; 95%CI: 0.25 to 0.76; p = 0.003), respectively. In the non-randomized trials, in-hospital mortality was 24.2% vs. 33.5% (OR = 0.72; 95%CI: 0.38 to 1.39; p = 0.33), respectively. The ICU length of stay was longer in patients treated with vitamin C vs. standard therapy, 11.1 (7.3) vs. 8.3 (4.7) days (MD = 1.91; 95%CI: 0.89 to 2.93; p < 0.001), respectively. Acute kidney injury in patients treated with and without vitamin C varied and amounted to 27.8% vs. 45.0% (OR = 0.56; 95%CI: 0.40 to 0.78; p < 0.001), respectively. There were no differences in the frequency of other adverse events among patients' treatment with and without vitamin C (all p > 0.05). The use of vitamin C reduces hospital mortality. The length of stay in the ICU is longer among patients treated with vitamin C. In terms of patient safety, vitamin C has an acceptable profile. Low doses of vitamin C are effective and safe. Despite some evidence of the usefulness of vitamin C in modifying the course of COVID-19, it is too early to modify guidelines and recommendations. Further studies, in particular randomized clinical trials, are necessary.

Effect of Vitamin C Supplements on Respiratory Tract Infections: A Systematic Review and Meta-Analysis.

BACKGROUND: Respiratory tract infections are a primary cause of illness and mortality over the world. OBJECTIVE: This study was aimed to investigate the effectiveness of vitamin C supplementation in preventing and treating respiratory tract infections. METHODS: We used the Cochrane, PubMed, and MEDLINE Ovid databases to conduct our search. The inclusion criteria were placebo-controlled trials. Random effects meta-analyses were performed to measure the pooled effects of vitamin C supplementation on the incidence, severity, and duration of respiratory illness. RESULTS: We found ten studies that met our inclusion criteria out of a total of 2758. The pooled risk ratio (RR) of developing respiratory illness when taking vitamin C regularly across the study period was 0.94 (with a 95% confidence interval of 0.87 to 1.01) which found that supplementing with vitamin C lowers the occurrence of illness. This effect, however, was statistically insignificant (P= 0.09). This study showed that vitamin C supplementation had no consistent effect on the severity of respiratory illness (SMD 0.14, 95% CI -0.02 to 0.30: I2 = 22%, P=0.09). However, our study revealed that vitamin C group had a considerably shorter duration of respiratory infection (SMD -0.36, 95% CI -0.62 to -0.09, P = 0.01). CONCLUSION: Benefits of normal vitamin C supplementation for reducing the duration of respiratory tract illness were supported by our meta-analysis findings. Since few trials have examined the effects of therapeutic supplementation, further research is needed in this area.

Combining L-Arginine with vitamin C improves long-COVID symptoms: The LINCOLN Survey.

INTRODUCTION: Recent evidence suggests that oxidative stress and endothelial dysfunction play critical roles in the pathophysiology of COVID-19 and Long-COVID. We hypothesized that a supplementation combining L-Arginine (to improve endothelial function) and Vitamin C (to reduce oxidation) could have favorable effects on Long-COVID symptoms. METHODS: We designed a survey (LINCOLN: L-Arginine and Vitamin C improves Long-COVID), assessing several symptoms that have been associated with Long-COVID to be administered nationwide to COVID-19 survivors; the survey also included effort perception, measured using the Borg scale. Patients receiving the survey were divided in two groups, with a 2:1 ratio: the first group included patients that received L-Arginine + Vitamin C, whereas the second group received a multivitamin combination (alternative treatment). RESULTS: 1390 patients successfully completed the survey. Following a 30-day treatment in both groups, the survey revealed that patients in the L-Arginine + Vitamin C treatment arm had significantly lower scores compared to patients who had received the multivitamin combination. There were no other significant differences between the two groups. When examining effort perception, we observed a significantly lower value (p < 0.0001) in patients receiving L-Arginine + Vitamin C compared to the alternative-treatment arm. CONCLUSIONS: Our survey indicates that the supplementation with L-Arginine + Vitamin C has beneficial effects in Long-COVID, in terms of attenuating its typical symptoms and improving effort perception.

Update on vitamin C administration in critical illness.

PURPOSE OF REVIEW: Several studies have recently explored the effects of intravenous vitamin C in sepsis. We aimed to summarize their findings to provide perspectives for future research. RECENT FINDINGS: Sepsis trials examined 6 g/day of intravenous vitamin C with or without the thiamine and/or hydrocortisone compared with placebo or hydrocortisone. Network meta-analysis reported that intravenous vitamin C, thiamine, hydrocortisone, or combinations of these drugs was not proven to reduce long-term mortality. However, the component network meta-analysis suggested an association of high-dose (>6 g/day) and very-high dose vitamin C (>12 g/day) and decreased mortality but with low certainty. The preclinical investigations have, however, advanced to much higher doses of intravenous vitamin C therapy since a scoping review on harm reported that mega-doses of intravenous vitamin C (50-100 g/day) had been administered without any conclusive adverse effects. In a Gram-negative sheep model, renal tissue hypoperfusion was reversed, followed by improvements in kidney function when a mega-dose of vitamin C (150 g/day equivalent) was administered. SUMMARY: The effect of intravenous vitamin C in critically ill patients has yet to be determined and might be dose-dependent. Clinical studies of very high or mega doses of vitamin C are justified by preclinical data.

A Pilot of a Randomized Control Trial of Melatonin and Vitamin C for Mild-to-Moderate COVID-19.

This study aimed to help determine the effect of dietary supplements on symptom course and quality of life in patients with mild-to-moderate COVID-19 infection. DESIGN: We modified the Wisconsin Upper Respiratory Symptom Survey (WURSS) to conduct a 3 arm, parallel, randomized, double-blind, placebo-controlled trial, enrolling patients with mild-to-moderate symptoms of COVID-19 infection. Patients took placebo (n = 34), vitamin C 1000 mg (n = 32), or melatonin 10 mg (n = 32) orally for 14 days. OUTCOMES: Ninety Eight (98 out of 104 recruited; mean age = 52 years) patients completed the study. Outcomes were calculated as differences from baseline scores on each of 2 WURSS-derived surveys and analyzed using a spline regression analysis. Regarding symptom progression, those patients taking placebo and vitamin C progressed at the same rate. When compared with those taking placebo (coefficient = -1.09 (95% confidence interval [CI] = -1.39 to -0.8) the group taking melatonin had a faster resolution of symptoms (coefficient = -0.63 [95% CI -1.02 to -0.21] P = .003). By day 14 all 3 groups had reached plateau.Quality-of-life impact analysis demonstrated that the group taking vitamin C improved at the same rate as the group taking placebo (coefficient = -0.71 (95% CI = -1.11 to -0.3)). The group taking melatonin (coefficient = -1.16 (95% CI = -1.75 to - 0.57) P < .005) had a faster improvement in quality-of-life. By day 14 all 3 groups had reached plateau. CONCLUSION: Vitamin C 1000 mg once daily has no effect on disease progression. Melatonin 10 mg daily may have a statistically significant effect but it is unclear if this represents a clinically significant benefit to those with mild-to-moderate symptoms of COVID-19 infection. Further study is warranted.

Vitamin C and its therapeutic potential in the management of COVID19.

COVID19 has emerged as one of the worst pandemics in the history of mankind. Several vaccines have been approved by different government agencies worldwide, but data on their efficacy and safety are limited, and distribution remains a massive challenge. As per WHO, personal immunity is vital for protection against COVID19. Earlier, Vitamin C-mediated pathways have been shown to play critical role in boosting immunity attributed to its antioxidant properties. Recently, the involvement of such pathways in protection against COVID19 has been suggested. The controlled doses of Vitamin C administered through intravenous (IV) injections are being studied for determining its role in the prognosis of COVID19. In this article, we have discussed the potential role of Vitamin C in the management in COVID19 patients and presented recent clinical trials data. Additionally, we have elaborated the possibility of administering Vitamin C through inhalers in order to achieve local high concentration and the challenges of such approach.

Vitamins C and D and COVID-19 Susceptibility, Severity and Progression: An Evidence Based Systematic Review.

Background and Objectives: Starting in early December 2019, the novel Coronavirus Disease (COVID-19) from infection with COVID-19 has caused a global pandemic. Many aspects of its pathogenesis and related clinical consequences are still unclear. Early diagnosis and dynamic monitoring of prognostic factors are essential to improve the ability to manage COVID-19 infection. This study aimed to provide an account of the role played by vitamins C and D on the onset, progression and severity of COVID-19. Clinical features and infection-related risk factors are also briefly discussed. Material and Methods: In March 2022, the main online databases were accessed. All the articles that investigate the possible role of vitamins C and D on COVID-19 susceptibility, severity and progression were considered. Results: The current evidence on vitamin C and D supplementation in patients with COVID-19 infection is inconsistent and controversial. In some studies, vitamins were used as coadjuvant of a formal experimental therapy, while in others as main treatment. Ethnicity and hospital setting (inpatient/outpatient) were also variable. Moreover, there was no consensus between studies in administration protocol: high heterogeneity in dosage, administration, and duration of the treatment were evident. Finally, some studies administered vitamins pre- and/or during COVID infection, in patients with different risk factors and infection severity. Conclusions: While waiting to develop a targeted, safe and effective therapy, it is important to investigate individual predisposition and proper disease management. Concluding, available data on the use of nutraceuticals in COVID-19 are inconsistent. However, there is a lack of evidence-based guidelines which recommend vitamin C and D supplementation in patients with COVID-19, and results from high quality randomised controlled trials (RCTs) are inconsistent. Current investigations so far are mostly observational, and include a relatively small sample size which can lead to biased results. Large-scale multicentre studies are therefore needed.