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Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis: The VICTAS Randomized Clinical Trial.
Sevransky, JE, Rothman, RE, Hager, DN, Bernard, GR, Brown, SM, Buchman, TG, Busse, LW, Coopersmith, CM, DeWilde, C, Ely, EW, et al
JAMA. 2021;(8):742-750
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Abstract
IMPORTANCE Sepsis is a common syndrome with substantial morbidity and mortality. A combination of vitamin C, thiamine, and corticosteroids has been proposed as a potential treatment for patients with sepsis. OBJECTIVE To determine whether a combination of vitamin C, thiamine, and hydrocortisone every 6 hours increases ventilator- and vasopressor-free days compared with placebo in patients with sepsis. DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, double-blind, adaptive-sample-size, placebo-controlled trial conducted in adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction. Participants were enrolled in the emergency departments or intensive care units at 43 hospitals in the United States between August 2018 and July 2019. After enrollment of 501 participants, funding was withheld, leading to an administrative termination of the trial. All study-related follow-up was completed by January 2020. INTERVENTIONS Participants were randomized to receive intravenous vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) every 6 hours (n = 252) or matching placebo (n = 249) for 96 hours or until discharge from the intensive care unit or death. Participants could be treated with open-label corticosteroids by the clinical team, with study hydrocortisone or matching placebo withheld if the total daily dose was greater or equal to the equivalent of 200 mg of hydrocortisone. MAIN OUTCOMES AND MEASURES The primary outcome was the number of consecutive ventilator- and vasopressor-free days in the first 30 days following the day of randomization. The key secondary outcome was 30-day mortality. RESULTS Among 501 participants randomized (median age, 62 [interquartile range {IQR}, 50-70] years; 46% female; 30% Black; median Acute Physiology and Chronic Health Evaluation II score, 27 [IQR, 20.8-33.0]; median Sequential Organ Failure Assessment score, 9 [IQR, 7-12]), all completed the trial. Open-label corticosteroids were prescribed to 33% and 32% of the intervention and control groups, respectively. Ventilator- and vasopressor-free days were a median of 25 days (IQR, 0-29 days) in the intervention group and 26 days (IQR, 0-28 days) in the placebo group, with a median difference of -1 day (95% CI, -4 to 2 days; P = .85). Thirty-day mortality was 22% in the intervention group and 24% in the placebo group. CONCLUSIONS AND RELEVANCE Among critically ill patients with sepsis, treatment with vitamin C, thiamine, and hydrocortisone, compared with placebo, did not significantly increase ventilator- and vasopressor-free days within 30 days. However, the trial was terminated early for administrative reasons and may have been underpowered to detect a clinically important difference. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03509350.
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Ascorbic acid as an adjunctive therapy in critically ill patients with COVID-19: a propensity score matched study.
Al Sulaiman, K, Aljuhani, O, Saleh, KB, Badreldin, HA, Al Harthi, A, Alenazi, M, Alharbi, A, Algarni, R, Al Harbi, S, Alhammad, AM, et al
Scientific reports. 2021;(1):17648
Abstract
Ascorbic acid represents an appealing option for clinicians to utilize in the context of the global COVID-19 pandemic due to its proposed clinical efficacy, relative safety, and low cost. The aim of this study was to evaluate the efficacy and safety of using ascorbic acid in supplemental doses as adjunctive therapy for patients critically ill with COVID-19. This was a two-center, non-interventional, retrospective cohort study. All critically ill adult patients admitted to ICU with a confirmed COVID-19 diagnosis between March 1st and December 31st, 2020, were included in the final analysis. The study was conducted at two large governmental tertiary hospitals in Saudi Arabia. The purpose was to investigate the clinical outcomes of low-dose ascorbic acid as adjunctive therapy in COVID-19 after propensity score matching using baseline severity scores, systematic use of corticosteroids, and study centers. A number of 739 patients were included in this study, among whom 296 patients were included after propensity score matching. There was no association between the administration of ascorbic acid and in-hospital mortality or the 30-day mortality [OR (95% CI) 0.77 (0.47, 1.23), p value = 0.27 and OR (95% CI) 0.73 (0.43, 1.20), p value = 0.21, respectively]. Using ascorbic acid was associated with a lower incidence of thrombosis compared with the non-ascorbic-acid group [6.1% vs. 13% respectively; OR (95% CI) 0.42 (0.184, 0.937), p value = 0.03]. Low dose of ascorbic acid as an adjunctive therapy in COVID-19 critically ill patients was not associated with mortality benefits, but it was associated with a lower incidence of thrombosis. Further studies are required to confirm these findings.
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Effect of High-Dose Zinc and Ascorbic Acid Supplementation vs Usual Care on Symptom Length and Reduction Among Ambulatory Patients With SARS-CoV-2 Infection: The COVID A to Z Randomized Clinical Trial.
Thomas, S, Patel, D, Bittel, B, Wolski, K, Wang, Q, Kumar, A, Il'Giovine, ZJ, Mehra, R, McWilliams, C, Nissen, SE, et al
JAMA network open. 2021;(2):e210369
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Abstract
IMPORTANCE There is limited evidence regarding early treatment of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection to mitigate symptom progression. OBJECTIVE To examine whether high-dose zinc and/or high-dose ascorbic acid reduce the severity or duration of symptoms compared with usual care among ambulatory patients with SARS-CoV-2 infection. DESIGN, SETTING, AND PARTICIPANTS This multicenter, single health system randomized clinical factorial open-label trial enrolled 214 adult patients with a diagnosis of SARS-CoV-2 infection confirmed with a polymerase chain reaction assay who received outpatient care in sites in Ohio and Florida. The trial was conducted from April 27, 2020, to October 14, 2020. INTERVENTION Patients were randomized in a 1:1:1:1 allocation ratio to receive either 10 days of zinc gluconate (50 mg), ascorbic acid (8000 mg), both agents, or standard of care. OUTCOMES The primary end point was the number of days required to reach a 50% reduction in symptoms, including severity of fever, cough, shortness of breath, and fatigue (rated on a 4-point scale for each symptom). Secondary end points included days required to reach a total symptom severity score of 0, cumulative severity score at day 5, hospitalizations, deaths, adjunctive prescribed medications, and adverse effects of the study supplements. RESULTS A total of 214 patients were randomized, with a mean (SD) age of 45.2 (14.6) years and 132 (61.7%) women. The study was stopped for a low conditional power for benefit with no significant difference among the 4 groups for the primary end point. Patients who received usual care without supplementation achieved a 50% reduction in symptoms at a mean (SD) of 6.7 (4.4) days compared with 5.5 (3.7) days for the ascorbic acid group, 5.9 (4.9) days for the zinc gluconate group, and 5.5 (3.4) days for the group receiving both (overall P = .45). There was no significant difference in secondary outcomes among the treatment groups. CONCLUSIONS AND RELEVANCE In this randomized clinical trial of ambulatory patients diagnosed with SARS-CoV-2 infection, treatment with high-dose zinc gluconate, ascorbic acid, or a combination of the 2 supplements did not significantly decrease the duration of symptoms compared with standard of care. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04342728.
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The safety and efficacy of 2% vitamin C solution spray for relief of mucosal irritation caused by Lugol chromoendoscopy: a multicenter, randomized, double-blind, parallel trial.
Jin, D, Wang, J, Zhan, Q, Huang, K, Wang, H, Zhang, G, Xu, Y, Yao, J, Sun, R, Huang, Q, et al
Gastrointestinal endoscopy. 2020;(3):554-564
Abstract
BACKGROUND AND AIMS Lugol chromoendoscopy facilitates endoscopic visualization of esophageal dysplasia and carcinoma. Vitamin C solution (VCS) can theoretically neutralize free iodine, which causes mucosal irritation. The aim was to assess the safety and efficacy of VCS for relieving adverse symptoms caused by Lugol iodine staining. METHODS Two hundred forty eligible patients were randomized to receive 20 mL of normal saline solution (NS), 5% sodium thiosulfate solution (STS), or 2% VCS after spraying 10 mL of 2% Lugol iodine solution on the mid-distal esophagus. The primary endpoints were statistically significant reductions in acute and late adverse symptom severity scores. The secondary endpoint was the discoloration effect on esophageal brown iodine-stained mucosa. RESULTS Spraying both VCS and STS similarly decreased the severity scores of acute (NS vs VCS = 2.58 vs 1.61, P = .040; VCS vs STS = 1.61 vs 1.89, P > .999) and late (NS vs VCS = 1.70 vs 0.91, P = .002; VCS vs STS = 0.91 vs 1.38; P = .212) adverse symptoms after Lugol chromoendoscopy compared with spraying NS. Compared with STS spray, VCS spray alleviated acute acid regurgitation or heartburn (33% vs 15%, P = .017) and late retrosternal discomfort or pain (21% vs 9%, P = .027). Moreover, compared with spraying NS, spraying VCS quickly discolored the iodine-stained mucosa, with a better decolorization score (2.26 vs 3.56, P = .000), and the effects of fading iodine dye were similar between VCS and STS (3.56 vs 3.59, P = .908). CONCLUSIONS VCS can reduce mucosal irritation symptoms induced by Lugol chromoendoscopy and can be routinely recommended. (Chinese Clinical Trial Registry number: ChiCTR1900022000.).
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Plasma Cortisol, Aldosterone, and Ascorbic Acid Concentrations in Patients with Septic Shock Do Not Predict Treatment Effect of Hydrocortisone on Mortality. A Nested Cohort Study.
Cohen, J, Bellomo, R, Billot, L, Burrell, LM, Evans, DM, Finfer, S, Hammond, NE, Li, Q, Liu, D, McArthur, C, et al
American journal of respiratory and critical care medicine. 2020;(5):700-707
Abstract
Rationale: Whether biomarkers can identify subgroups of patients with septic shock with differential treatment responses to hydrocortisone is unknown.Objectives: To determine if there is heterogeneity in effect for hydrocortisone on mortality, shock resolution, and other clinical outcomes based on baseline cortisol, aldosterone, and ascorbic acid concentrations.Methods: From May 2014 to April 2017, we obtained serum samples from 529 patients with septic shock from 22 ICUs in Australia and New Zealand.Measurements and Main Results: There were no significant interactions between the association with 90-day mortality and treatment with either hydrocortisone or placebo for total cortisol (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.02-1.16 vs. OR, 1.07; 95% CI, 1.00-1.13; P = 0.70), free cortisol (OR, 1.20; 95% CI, 1.04-1.38 vs. OR, 1.16; 95% CI, 1.02-1.32; P = 0.75), aldosterone (OR, 1.01; 95% CI, 0.97-1.05 vs. OR, 1.01; 95% CI, 0.98-1.04; P = 0.99), or ascorbic acid (OR, 1.11; 95% CI, 0.89-1.39 vs. OR, 1.05; 95% CI, 0.91-1.22; P = 0.70), respectively. Similar results were observed for the association with shock resolution. Elevated free cortisol was significantly associated with 90-day mortality (OR, 1.13; 95% CI, 1.00-1.27; P = 0.04), but total cortisol, aldosterone, and ascorbic acid were not.Conclusions: In patients with septic shock, there was no heterogeneity in effect of adjunctive hydrocortisone on mortality, shock resolution, or other clinical outcomes based on cortisol, aldosterone, and ascorbic acid concentrations. Plasma aldosterone and ascorbic acid concentrations are not associated with outcome.
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A longitudinal study of pre-pregnancy antioxidant levels and subsequent perinatal outcomes in black and white women: The CARDIA Study.
Harville, EW, Lewis, CE, Catov, JM, Jacobs, DR, Gross, MD, Gunderson, EP
PloS one. 2020;(2):e0229002
Abstract
BACKGROUND Although protective associations between dietary antioxidants and pregnancy outcomes have been reported, randomized controlled trials of supplementation have been almost uniformly negative. A possible explanation is that supplementation during pregnancy may be too late to have a beneficial effect. Therefore, we examined the relationship between antioxidant levels prior to pregnancy and birth outcomes. METHODS AND FINDINGS Serum carotenoids and tocopherols were assayed in fasting specimens at 1985-86 (baseline) and 1992-1993 (year 7) from 1,215 participants in Coronary Artery Risk Development in Young Adults (CARDIA) study. An interviewer-administered quantitative food-frequency questionnaire assessed dietary intake of antioxidants. Pregnancy outcome was self-reported at exams every 2 to 5 years. Linear and logistic regression modeling was used to assess relationships of low birthweight (LBW; <2,500 g), continuous infant birthweight, preterm birth (PTB; <37 weeks) and length of gestation with antioxidant levels adjusted for confounders, as well as interactions with age and race. RESULTS In adjusted models, lycopene was associated with higher odds of LBW (adjusted odds ratio for top quartile, 2.15, 95% confidence interval 1.14, 3.92) and shorter gestational age (adjusted beta coefficient -0.50 weeks). Dietary intake of antioxidants was associated with lower birthweight, while supplement use of vitamin C was associated with higher gestational age (0.41 weeks, 0.01, 0.81). CONCLUSIONS Higher preconception antioxidant levels are not associated with better birth outcomes.
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Update to the Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) protocol: statistical analysis plan for a prospective, multicenter, double-blind, adaptive sample size, randomized, placebo-controlled, clinical trial.
Lindsell, CJ, McGlothlin, A, Nwosu, S, Rice, TW, Hall, A, Bernard, GR, Busse, LW, Ely, EW, Fowler, AA, Gaieski, DF, et al
Trials. 2019;(1):670
Abstract
BACKGROUND Observational research suggests that combined therapy with Vitamin C, thiamine and hydrocortisone may reduce mortality in patients with septic shock. METHODS AND DESIGN The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) trial is a multicenter, double-blind, adaptive sample size, randomized, placebo-controlled trial designed to test the efficacy of combination therapy with vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) given every 6 h for up to 16 doses in patients with respiratory or circulatory dysfunction (or both) resulting from sepsis. The primary outcome is ventilator- and vasopressor-free days with mortality as the key secondary outcome. Recruitment began in August 2018 and is ongoing; 501 participants have been enrolled to date, with a planned maximum sample size of 2000. The Data and Safety Monitoring Board reviewed interim results at N = 200, 300, 400 and 500, and has recommended continuing recruitment. The next interim analysis will occur when N = 1000. This update presents the statistical analysis plan. Specifically, we provide definitions for key treatment and outcome variables, and for intent-to-treat, per-protocol, and safety analysis datasets. We describe the planned descriptive analyses, the main analysis of the primary end point, our approach to secondary and exploratory analyses, and handling of missing data. Our goal is to provide enough detail that our approach could be replicated by an independent study group, thereby enhancing the transparency of the study. TRIAL REGISTRATION ClinicalTrials.gov, NCT03509350. Registered on 26 April 2018.
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Adverse Maternal and Neonatal Outcomes in Indicated Compared with Spontaneous Preterm Birth in Healthy Nulliparas: A Secondary Analysis of a Randomized Trial.
Tita, AT, Doherty, L, Roberts, JM, Myatt, L, Leveno, KJ, Varner, MW, Wapner, RJ, Thorp, JM, Mercer, BM, Peaceman, A, et al
American journal of perinatology. 2018;(7):624-631
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OBJECTIVE To compare the risks of adverse maternal and neonatal outcomes associated with spontaneous (SPTB) versus indicated preterm births (IPTB). METHODS A secondary analysis of a multicenter trial of vitamin C and E supplementation in healthy low-risk nulliparous women. Outcomes were compared between women with SPTB (due to spontaneous membrane rupture or labor) and those with IPTB (due to medical or obstetric complications). A primary maternal composite outcome included: death, pulmonary edema, blood transfusion, adult respiratory distress syndrome (RDS), cerebrovascular accident, acute tubular necrosis, disseminated intravascular coagulopathy, or liver rupture. A neonatal composite outcome included: neonatal death, RDS, grades III or IV intraventricular hemorrhage (IVH), sepsis, necrotizing enterocolitis (NEC), or retinopathy of prematurity. RESULTS Of 9,867 women, 10.4% (N = 1,038) were PTBs; 32.7% (n = 340) IPTBs and 67.3% (n = 698) SPTBs. Compared with SPTB, the composite maternal outcome was more frequent in IPTB-4.4% versus 0.9% (adjusted odds ratio [aOR], 4.0; 95% confidence interval [CI], 1.4-11.8), as were blood transfusion and prolonged hospital stay (3.2 and 3.7 times, respectively). The frequency of composite neonatal outcome was higher in IPTBs (aOR, 1.8; 95% CI, 1.1-3.0), as were RDS (1.7 times), small for gestational age (SGA) < 5th percentile (7.9 times), and neonatal intensive care unit (NICU) admission (1.8 times). CONCLUSION Adverse maternal and neonatal outcomes were significantly more likely with IPTB than with SPTB.
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Intravenous vitamin C in the treatment of allergies: an interim subgroup analysis of a long-term observational study.
Vollbracht, C, Raithel, M, Krick, B, Kraft, K, Hagel, AF
The Journal of international medical research. 2018;(9):3640-3655
Abstract
UNLABELLED Objective Oxidative stress appears to be a key factor in the pathogenesis of allergic diseases and a potential therapeutic target in allergy treatment. Allergic diseases are reportedly associated with reduced plasma levels of ascorbate, which is a key physiological antioxidant. Ascorbate prevents excessive inflammation without reducing the defensive capacity of the immune system. Methods An interim analysis of a multicenter, prospective, observational study was conducted to investigate the change in disease-specific and nonspecific symptoms (fatigue, sleep disorders, depression, and lack of mental concentration) during adjuvant treatment with intravenous vitamin C (Pascorbin®; Pascoe, Giessen, Germany) in 71 patients with allergy-related respiratory or cutaneous indications. Results Between the start and end of treatment, the mean sum score of three disease-specific symptoms decreased significantly by 4.71 points and that of four nonspecific symptoms decreased significantly by 4.84 points. More than 50% of patients took no other allergy-related medication besides vitamin C. Conclusions Our observations suggest that treatment with intravenous high-dose vitamin C reduces allergy-related symptoms. Our observations form a basis for planning a randomized controlled clinical trial to obtain more definitive evidence of the clinical relevance of our findings. We also obtained evidence of ascorbate deficiency in allergy-related diseases. TRIAL REGISTRATION Clinical Trials NCT02422901.
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[Vitamin C+sodium bicarbonate versus sodium bicarbonate alone in preventing contrast-induced nephropathy].
Laroussi, L, Triki, M, Ibn Elhaj, Z, Ben Halima, A, Boukhris, M, Ben Amara, W, Keskes, H, Kraiem, S, Lahidheb, D, Marrakchi, S, et al
Annales de cardiologie et d'angeiologie. 2017;(4):190-196
Abstract
INTRODUCTION Contrast-induced nephropathy (CIN) is a common and severe complication in interventional cardiology. OBJECTIVE The aim of our study was to compare the incidence of contrast-induced nephropathy in two accelerated hydration protocols: the first one by the serum bicarbonate and the second combining the serum bicarbonate and oral vitamin C. METHODS This is a multicenter prospective, randomized study conducted between October 2012 and May 2013, including 160 patients. RESULTS The mean age of our study population was 60.8±9.3 years (36-83 years). The two study groups were comparable in terms of cardiovascular risk factors, concomitant medication, and baseline serum creatinine. The CIN incidence was 6.3% in the vitamin C group and 10% in the control group (P=0.38). No significant difference was observed in terms of CIN incidence between the different subgroups analyzed. CONCLUSION According to our study, ascorbic acid administered orally as part of an accelerated hydration protocol does not reduce the incidence of CIN.