Fig. The data we collected also suggest that our protocol impacts the pathophysiology of sepsis, thereby limiting organ failure, reducing vasopressor requirements, and reducing the mortality from sepsis.. Of these, 82 patients were excluded; the intention-to-treat (ITT) analysis included all the 426 patients. J Res Pharm Pract. Kahn SA, Lentz CW. Addressing vitamin C deficiency in patients receiving renal replacement therapy is complicated. 2). Qi-Hong Chen, Email: moc.361@76536015081. Yang R, Huang J, Zhao Y, Wang J, Niu D, Ye E, Yue S, Hou X, Cui L, Wu J. }); jQuery(function($) { Moreover, our patients severity of organ failure is also corroborated by the significantly greater incidence of mechanical ventilation (72%) and the need for RRT (37%), compared with the patients included in the trial of Marik et al. Tanaka H, Matsuda T, Miyagantani Y, et al. HHS Vulnerability Disclosure, Help Urinary loss of thiamine is increased by low doses of furosemide in healthy volunteers. 8600 Rockville Pike Vitamin therapy in sepsis | Pediatric Research - Nature Bethesda, MD 20894, Web Policies In the safety population, the most common serious adverse events were severe hypernatremia (>160mmol/L) (occurring in 9 patients in the intervention group and 4 patients in the placebo group, P=0.16) and fluid overload (occurring in 7 and 5 patients, respectively, P=0.56). These data do not support routine use of this combination therapy for adult patients with septic shock. 4, 13 Vitamin C is a co-substrate for the biosynthesis of endogenous vasopressors (e.g., norepinephrine), cortisol, and vasopressin.12 Endothelial function and microcirculatory flow are preserved through vitamin Cs promotion of collagen synthesis and its effect on tightening the junctions between endothelial and epithelial cells.14 Vitamin C also has immune effects including regulation of macrophage bactericidal activity and inhibition of the activation of the transcription protein nuclear factor-B, thereby downregulating the production of proinflammatory mediators (e.g., tumor necrosis factor alpha).15, 16 Finally, vitamin C prevents sepsis-induced immunosuppression likely by reducing apoptosis of lymphocytes and monocytes.4, 12, 17. Our results suggest that the early use of intravenous vitamin C, together with corticosteroids and thiamine, are effective in preventing progressive organ dysfunction, including acute kidney injury, and in reducing the mortality of patients with severe sepsis and septic shock. Scurvy, the most well-known disease caused by severe and long-term vitamin C deficiency is manifested by swollen and bleeding gums, poor wound closure, easy bruising, hair and tooth loss, joint pain and swelling.15 These symptoms appear to be related to impaired collagen biosynthesis leading to the weakening of blood vessels, connective tissue, and bone. Molecular basis for the deficiency in humans of gulonolactone oxidase, a key enzyme for ascorbic acid biosynthesis. 2023 Jan 17;2023:2629262. doi: 10.1155/2023/2629262. This study was approved by the Human Research Ethics Committee of Northern Jiangsu People's Hospital (2019KY-145) and was conducted in accordance with the Declaration of Helsinki and relevant clinical research regulations in China. Based on the experimental and emerging clinical data, 49, 51 vitamin C pharmacokinetic modeling and the package insert 40, and dramatic recovery of three patients with fulminant sepsis at a university medical center, Marik et al described their experience with the vitamin C, thiamine and hydrocortisone (VCTS) regimen in 47 patients with severe . Hazard ratio for mortality is 1.07; 95% CI 0.791.46. He J, Zheng G, Qian X, Sheng H, Chen B, Zhao B, Chen E, Mao E, Bian X. The type of infection sites is maybe not a key determinant for the effectiveness of combination therapy. JAMA. There are several clinical studies that have investigated the use of vitamin C alone or VCTS in patients with sepsis and septic shock or are ongoing. jQuery(function($) { Based on experimental and emerging clinical data, as well as personal experience, Paul E. Marik MD, FCCP, FCCM, and colleagues conducted a studypublished in Chestto confirm the effectiveness of combination IV vitamin C, hydrocortisone, and thiamine in treating septic patients. The site is secure. Vitamin C plays a vital role in human physiology. jQuery(function($) { sharing sensitive information, make sure youre on a federal Recent studies have generated keen interest in the use of vitamin C, thiamine, and corticosteroids (VCTS) to treat sepsis. Fourthly, very few patients were lost to follow-up, thus minimizing attrition bias. Putzu A, Daems AM, Lopez-Delgado JC, et al. Iglesias J, Vassallo AV, Patel VV, Sullivan JB, Cavanaugh J, Elbaga Y. It is worth pointing out that Marik et al. Every factor in subgroup analyses was analyzed with rates of the primary endpoint by testing the treatment by factor interaction with the use of Cox models. The inclusion criteria of our research were restricted in patients with septic shock, a deteriorative subset of sepsis, while the research of Marik et al. Like vitamin C, thiamine is renally excreted.23, Thiamine, specifically the TPP form, is an important cofactor for enzymes utilized in multiple biochemical reactions for carbohydrate metabolism and energy production. Keywords: Hydrocortisone; ICU; Sepsis; Septic shock; Thiamine; Veteran; Vitamin C. Published by Elsevier Inc. Ascorbic acid, corticosteroids, and thiamine in sepsis: a review of the biologic rationale and the present state of clinical evaluation. Moreover, we performed the sensitivity analyses of 72-h SOFA scores to model worst-possible and best-possible scenarios: (1) The worst-possible SOFA score (score of 24) was imputed for those participants who discharged within 72h; (2) only those patients who survive 72 h were included (Additional file 1: Tables S1 and S2). ; Medical Respiratory Intensive Care Unit Nursing: Phase 1 safety trial of intravenous ascorbic acid in patients with severe sepsis. }); FOIA http://journal.chestnet.org/article/S0012-3692(16)62564-3/fulltext. Vitamin C alleviates LPS-induced myocardial injury by inhibiting pyroptosis via the ROS-AKT/mTOR signalling pathway. $(".mega-back-deepdives").removeClass("mega-toggle-on"); There are positive anecdotal . Jaffe RM, Kasten B, Young DS, MacLowry JD. The Difference Between an IV and a Vitamin Shot - IV Revival Marik P. Vitamin S (steroids) and vitamin C for the treatment of severe sepsis and septic shock! Clipboard, Search History, and several other advanced features are temporarily unavailable. Septic shock, a subset of sepsis, is characterized by circulatory and cellular/metabolic abnormalities that are associated with a higher risk of mortality [3]. Trial registration ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT03872011","term_id":"NCT03872011"}}NCT03872011, registration date: March 12, 2019. Front Pharmacol. When the patients were diagnosed as septic shock, they were primarily treated with aggressive fluid challenge, adequate antibiotics, and vasoactive agents, according to Surviving Sepsis Campaign guidelines [3]. 2022 Oct 7;2022:1192902. doi: 10.1155/2022/1192902. 2017;6:1229-1238. While patients treated with the vitamin C protocol were weaned off vasopressors an average of 18.3 hours after starting treatment, those in the control group had an average length of vasopressor use of 54.9 hours. Dr. Marik and colleagues found a hospital mortality rate of 8.5% in the treatment group, compared with a rate of 40.4% in the control group. Repetitive bolus application of hydrocortisone compared with a continuous infusion likely results in higher peak serum and intracellular concentrations with greater binding to the glucocorticoid receptor and subsequently greater therapeutic effects [29]. Vitamin C and Thiamine for Sepsis and Septic Shock - PubMed }); jQuery(function($) { $('.mega-back-button-specialties').on('click', function(e) { The study was approved by the Human Research Ethics Committee of Northern Jiangsu People's Hospital (2019KY-145) and was registered at clinicaltrial.gov ({"type":"clinical-trial","attrs":{"text":"NCT03872011","term_id":"NCT03872011"}}NCT03872011). There is no established upper limit for the total daily dose. 8 Citations 3 Altmetric Metrics Abstract Vitamins are essential micronutrients with key roles in many biological pathways relevant to sepsis. In the ITT population, the primary outcome of 90-day mortality was 40.4% (86/213) and 39.0% (83/213) in the intervention and the placebo groups, respectively, and was not significantly different (P=0.77) (Table (Table3).3). Thiamine as a renal protective agent in septic shock. Therefore, it is possible to rule out the effect of time delay in the combination therapy application on the mortality of septic shock. Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, Weiss YG, Benbenishty J, Kalenka A, Forst H, et al. Conclusions: Randomized, double-blind, placebo-controlled trial of thiamine as a metabolic resuscitator in septic shock: a pilot study. government site. Whole blood samples contain thiamine diphosphate (TPP), the biologically active form and is the current specimen of choice. Rui-Qiang Zheng, Email: moc.361@11412725931. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Treating Sepsis with Vitamin C, Thiamine, and Hydrocortisone: Exploring In critically ill patients, variations in timing, dose, and administration route of vitamin C plays a role because direct radical scavenging depends on plasma concentrations > 175 mg/L (1,000 mmol/L).39 Oral regimens cannot increase plasma concentrations to normal levels because transported-mediated enteral uptake is rate-limited and possibly impaired in critical illness.40 Thus, intravenous administration is the preferred route in critical illness where levels of vitamin C must be acutely raised.41, 42, It has been suggested that due to increased metabolic demands in critically ill patients with sepsis, restoring low levels of plasma vitamin C (i.e., < 23 mol/L) may require approximately 6 g/day, a 30-fold higher total daily dose than healthy subjects.18 However, the details of the optimal dosing approach are still being studied. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of - CHEST Thus, a negative study could be consistent with an ineffective therapy or dosing regimen. The combination of hydrocortisone, vitamin C, and thiamine might show synergetic effect in ameliorating the systemic inflammatory response, preventing progressive organ dysfunction and reducing mortality of the septic shock patients [18]. Mohamed, Z. U. et al. Throughout the study, patients, investigators, clinical staff, and research staff remained blinded to the allocated therapy, with the exception of designated nurses who were responsible for the preparation of both study drug and placebo. Moreover, there is no uniformity of practice regarding the specimen type [plasma (or serum), leukocytes and urine] analyzed by the reference laboratories. Thus, thiamine results too are not available for daily practice and the decision to treat a patient prophylactically or to make a presumptive or definitive diagnosis of thiamine deficiency is commonly based on clinical judgment. Human adrenal glands secrete vitamin C in response to adrenocorticotrophic hormone. Humans, unlike most animals, are unable to synthesize vitamin C due to the absence of functional L-gulonolactone oxidase, an enzyme required for the final conversion of glucose to ascorbic acid.7 Hence, humans depend on dietary sources of vitamin C. Failure to generate vitamin C makes humans very susceptible to dysfunction in various vitamin C dependent biochemical pathways necessary for surviving a critical illness.8, Ascorbic acid and dehydroascorbic acid (DHAA or oxidized vitamin C), components of fruits and vegetables or marketed as vitamin supplements, are the primary dietary sources of vitamin C for humans. In addition, there were no significant differences in shock reversal, or vasopressor-free days between the groups. [22] enrolled patients with sepsis and septic shock. Before $('mega-back-specialties').on('click', function(e) { Based on the experimental and emerging clinical data,49, 51 vitamin C pharmacokinetic modeling and the package insert40, and dramatic recovery of three patients with fulminant sepsis at a university medical center, Marik et al described their experience with the vitamin C, thiamine and hydrocortisone (VCTS) regimen in 47 patients with severe sepsis and septic shock in 2017.5 Vitamin C was administered at 1500 mg IV every 6 h (6 g/day), thiamine 200 mg IV every 12 h and hydrocortisone 50 mg IV every 6 h). Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, et al. The difference of our study from other studies should be considered when interpreting the discrepancies in efficacy of combination therapy. Additional studies are On the contrary, the falsely high testing results were also reported in devices adopting glucose dehydrogenase pyrroloquinoline quinone (GDH-PQQ) method [31, 33]. Both ascorbic acid and DHAA are absorbed from the lumen of the intestine and renal tubules by enterocytes and renal epithelial cells, respectively, and then circulate in the blood and enter all body cells (Figure 1A).9 Vitamin C is also secreted into the gastric juice, cerebrospinal fluid, and aqueous humor, all of which have higher concentrations than those in plasma. Therefore, we performed this randomized controlled clinical trial to evaluate the efficacy of early administration of hydrocortisone, vitamin C, and thiamine combination therapy for patients with diagnosis of septic shock within 12h. This study was a single-center, double-blind RCT conducted in a 45-bed intensive care unit (ICU) of Northern Jiangsu People's Hospital in Yangzhou, China. The specific reasons for exclusion are shown in Fig. Ascor (ascorbic acid injection) for intravenous use. Vitamin C levels become abnormally low within 24 hours of acute injury, critical illness, multiple organ failure and sepsis, and is related to the patients severity of illness.1, 4, 12, 18 Animal studies have demonstrated that the decrease in vitamin C levels is associated with a fall in intracellular levels. Such trials are currently being planned in the United States and worldwide. This differs from the results of the ACTS study [9], which observed a longer shock-free days in the intervention group. Thiamine deficiency in critically ill patients with sepsis. J Crit Care. These funding sources had no role in the design of this study, its execution, analyses, interpretation of the data, or decision to submit results. Arch Surg. XG conceived and designed the experiments, provided study supervision and critically revised the manuscript for important intellectual content, and had full access to all the data in the study. 2020 Jul;158(1):164-173. doi: 10.1016/j.chest.2020.02.049. Unpeeling the evidence for the Banana Bag: Evidence-based recommendations for the management of alcohol-associated vitamin and electrolyte deficiencies in the ICU. In the post hoc subgroup analysis, the 90-day mortality of the all subgroups was not significantly different between the intervention and placebo groups (P>0.05 for all comparisons) (Additional file 1: Fig. Additional secondary outcomes included shock reversal rate; time to shock reversal; 72-h delta SOFA score; ICU-free days, vasopressor-free days and ventilator support-free days up to day 28 (patients who died before day 28 were assigned zero free days); ICU length of stay (LOS) and hospital LOS. Both groups had similar characteristics, such as LOS prior to randomization, time from diagnosis of septic shock to randomization, time from randomization to the first study drug administration, time from randomization to the first antibiotic administration, proportion of antibiotic administration before randomization, appropriateness of antimicrobials, open-label corticosteroid administration, amount of fluid administered before vasopressor, need for ventilator support, and need for RRT (P>0.05). Background: Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Sepsis and Thiamine for prevention and treatment of WernickeKorsakoff syndrome in people who abuse alcohol. The remaining authors have no conflicts to disclose. 72-h Delta Sequential Organ Failure Assessment (SOFA) score was calculated by subtracting the SOFA score at 72 h from the corresponding value at enrollment (SOFA score=initial SOFA score at enrollmentSOFA score after 72h). If the patient discharged within 72h after being enrolled in the study, the SOFA score at discharge was used for the analysis. Vitamin C: a concentration-function approach yields pharmacology and therapeutic discoveries. Similarly, deficiencies of both vitamins have been treated empirically, with or without measuring levels, and with variable dosing regimens. Zabet M, Mohammadi M, Ramezani M, et al. Global, regional, and national sepsis incidence and mortality, 19902017: analysis for the Global Burden of Disease Study. APACHE-acute physiology and chronic health evaluation: a physiologically based classification system. Mayo Medical Laboratories: Ascorbic acid (Vitamin C), Plasma. Obi J, Pastores SM, Ramanathan LV, Yang J, Halpern NA. document.getElementById( "ak_js_1" ).setAttribute( "value", ( new Date() ).getTime() ); document.getElementById( "ak_js_2" ).setAttribute( "value", ( new Date() ).getTime() ); The content of this site is intended for healthcare professionals. Angus DC, van der Poll T. Severe sepsis and septic shock. Among adult patients with septic shock, early use of hydrocortisone, vitamin C, and thiamine combination therapy compared with placebo did not confer survival benefits. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intriguingly, the current study revealed a phenomenon of blood glucose measurement interference, in consistent with previous studies [3032]. Some of these relevant biological mechanisms include. At the 24-month follow-up, 12 months after the 1-year-intervention, survival and measures of mental and physical health were collected by telephone interviews. and transmitted securely. Recruited patients were randomized 1:1 to receive intervention (hydrocortisone 200mg daily, vitamin C 2g every 6h, and thiamine 200mg every 12h) or placebo (0.9% saline) for 5days or until ICU discharge. Disclosures: Drs. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Attaluri P, Castillo A, Edriss H, Nugent K. Thiamine deficiency: an important consideration in critically ill patients. Critical Illness-Related Corticosteroid Insufficiency (CIRCI): A Narrative Review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM). However, early use of combination treatment in our study did not result in survival benefits. Oftentimes a common antioxidant featured in an anti-aging IV is Glutathione.
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