ascorbic-acid and Shock--Septic

Topics: Ascorbic Acid; Drug Therapy, Combination; Humans; Hydrocortisone; Sepsis; Shock, Septic; Thiamine

Elevated lactate levels at 24 h are highly predictive of in-hospital mortality in adults with septic shock. Thiamin is closely involved in carbohydrate metabolism, and in thiamin-deficient states, increased lactic acid levels can be found, exacerbated by critical illness. This integrative literature review focused on the relationship between supplemental thiamin, lactate clearance, and impact on mortality in sepsis.. A search in PubMed, Embase, and CINAHL was conducted for literature published between January 2016 and January 2021. We included observational studies and clinical trials with ≥10 participants. We excluded studies involving pediatric (<18 years old) populations, animal studies, case studies, dropout rate of >20%, nonhospitalized patients, or patients receiving comfort measures only.. A total of 48 full-text articles were assessed for eligibility, with 15 evaluated for this integrative review. Included were five retrospective, two prospective observational, and eight randomized controlled trials. In almost all retrospective studies, thiamin administration was associated with decreased mortality, and in observational studies, with decreased lactate and improved clinical outcomes. In clinical trials, thiamin with or without vitamin C/hydrocortisone did not impact clinical outcomes or mortality. However, four trials testing intravenous thiamin 200-500 mg two to three times daily for up to 3 days reported improved lactate clearance.. Thiamin supplementation may improve lactate clearance when administered in the first 24 h. Those deficient in thiamin may benefit more from supplementation. The combination of thiamin, vitamin C, and/or hydrocortisone may not be advantageous. Lactate reduction in response to thiamin needs further rigorous research.

Topics: Ascorbic Acid; Humans; Hydrocortisone; Lactic Acid; Observational Studies as Topic; Retrospective Studies; Sepsis; Shock, Septic; Thiamine; Vitamins

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.

Topics: Adult; Ascorbic Acid; Critical Illness; Humans; Micronutrients; Sepsis; Shock, Septic; Thiamine; Trace Elements; Vitamins

To update a meta-analysis of randomized controlled trials (RCTs) and further explore the outcome of IV vitamin C (IVVC) administration in sepsis or septic shock patients.. This study is a meta-analysis of RCTs. The RCTs of vitamin C therapy in sepsis or septic shock were searched in PubMed, EMBASE and Clinical Trials.gov from inception to January 16, 2023. We registered the protocol with PROSPERO (CRD42022354875). The primary outcome was delta Sequential Organ Failure Assessment (SOFA) score at 72-96 h. Two reviewers independently assessed RCTs according to eligibility criteria: (1) study type: RCT; (2) patient population: patients ≥ 18 years with sepsis or septic shock; (3) intervention: IVVC at any doses as monotherapy or combined with thiamine or and hydrocortisone compared with standard of care, no intervention or placebo (defined as control group); (4) the RCT described short-term mortality or SOFA score. Then, two authors independently extracted related information from RCTs.. Eighteen RCTs (n = 3364 patients) were identified in this meta-analysis. There were significant effects in the delta SOFA score from baseline to 72-96 h (MD, - 0.62; 95% CI, - 1.00 to - 0.25; p = 0.001) and the duration of vasopressor use (MD, - 15.07; 95% CI, - 21.59 to - 8.55; p < 0.00001) with IVVC therapy. Treatment with IVVC was not shown to improve short-term mortality (OR, 0.89; 95% CI, 0.77 to 1.04; p = 0.14); nevertheless, dose at 25-100 mg/kg/d subgroup associated with a significant reduction in short-term mortality (OR, 0.80; 95% CI, 0.65 to 0.97; p = 0.03). An increase adverse event was observed in IVVC therapy (OR, 1.98; 95% CI, 1.06 to 3.68; p = 0.03).. In this meta-analysis, IVVC in sepsis or septic shock patients significantly improved delta SOFA score and reduced the duration of vasopressor use, whereas it was not associated with reduction in short-term mortality and had higher adverse events.

Topics: Ascorbic Acid; Humans; Randomized Controlled Trials as Topic; Sepsis; Shock, Septic; Vasoconstrictor Agents; Vitamins

This study explored the efficacy of hydrocortisone combined with vitamin C and thiamine (HVT) in the treatment of sepsis/septic shock.. PubMed, EMBASE and Web of Science were searched (establishment of the database to October 31, 2022). The meta-analysis included randomized controlled trials (RCTs); comparing the efficacy of HVT regimen and placebo in the treatment of sepsis/septic shock. The Cochrane Handbook for Systematic Reviews of Interventions was used to assess the risk of bias. The Review Manager 5.4 software was used for meta-analysis, and the relative risk (RR), mean difference (MD) and 95% confidence intervals (CI) were then determined. Trial sequential analysis (TSA) was then conducted.. Eight RCTs with 1,572 patients were identified. Meta-analysis showed that HVT regimen did not reduce all-cause (RR=0.96, 95% CI: 0.83 - 1.11, P=0.60), hospital (RR=1.03, 95% CI: 0.83 - 1.27, P=0.80) or intensive care unit (ICU) mortalities (RR=1.05, 95% CI: 0.86 - 1.28, P=0.65). Furthermore, there was no significant difference in the change of sequential organ failure assessment score, length of ICU stay, length of hospital stay, duration of the use of vasopressors, incidence of acute kidney injury and ventilator-free days between HVT and control groups. TSA showed that more trials are needed to confirm the results.. HVT regimen did not reduce the mortality of patients with sepsis/septic shock and was not associated with a significant improvement in outcomes. The TSA result showed that more RCTs with high quality and large sample sizes are needed to further confirm the results.

Topics: Ascorbic Acid; Humans; Hydrocortisone; Intensive Care Units; Sepsis; Shock, Septic; Thiamine

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.

Topics: Adult; Antioxidants; Ascorbic Acid; Critical Illness; Humans; Multicenter Studies as Topic; Shock, Septic; Vitamins

Vitamin C has been used as an adjuvant in the treatment of sepsis and septic shock; however, its role remains controversial. This study aimed to assess the effectiveness of intravenous high-dose vitamin C in sepsis and septic shock patients by meta-analysis.. The PubMed, Embase, and Cochrane Library electronic databases were searched to identify relevant studies. The primary outcome was defined as the short-term all-cause mortality rate. Secondary outcomes included duration of vasoactive drug use, intensive care unit length of stay, sequential organ failure assessment scores up to 96 hours after treatment and 90-day mortality. Review Manager version 5.4 was used to perform the meta-analysis. Relative risk and mean differences (MD) with 95% confidence intervals were determined using fixed- or random-effects models.. Eight randomized controlled trials (RCTs) comprising 1394 patients were eligible for assessment. Overall, the pooled results showed that high-dose vitamin C decreased short-term all-cause mortality in patients with sepsis, but no significant differences were observed in patients with septic shock. Additionally, high-dose vitamin C was associated with decreased duration of vasoactive drug use in patients with sepsis, but not in patients with septic shock. However, it did not significantly affect the duration of intensive care unit stay in RCTs of patients with sepsis and septic shock. Additionally, it did not significantly affect sequential organ failure assessment scores 96 hours post-treatment or 90-day mortality.. These results suggest that intravenous high-dose vitamin C may improve outcomes in patients with sepsis, but do not benefit patients with septic shock. Further RCTs and other studies should be conducted to determine whether vitamin C should be recommended as an adjunctive sepsis treatment.

Topics: Antineoplastic Agents; Ascorbic Acid; Humans; Intensive Care Units; Randomized Controlled Trials as Topic; Sepsis; Shock, Septic

We aimed to compare the effects of vitamin C, glucocorticoids, vitamin B1, combinations of these drugs, and placebo or usual care on longer-term mortality in adults with sepsis or septic shock. MEDLINE, Embase, CENTRAL, ClinicalTrials.gov and WHO-ICTRP were searched. The final search was carried out on September 3rd, 2021. Multiple reviewers independently selected randomized controlled trials (RCTs) comparing very-high-dose vitamin C (≥ 12 g/day), high-dose vitamin C (< 12, ≥ 6 g/day), vitamin C (< 6 g/day), glucocorticoid (< 400 mg/day of hydrocortisone), vitamin B1, combinations of these drugs, and placebo/usual care. We performed random-effects network meta-analysis and, where applicable, a random-effects component network meta-analysis. We used the Confidence in Network Meta-Analysis framework to assess the degree of treatment effect certainty. The primary outcome was longer-term mortality (90-days to 1-year). Secondary outcomes were severity of organ dysfunction over 72 h, time to cessation of vasopressor therapy, and length of stay in intensive care unit (ICU). Forty-three RCTs (10,257 patients) were eligible. There were no significant differences in longer-term mortality between treatments and placebo/usual care or between treatments (10 RCTs, 7,096 patients, moderate to very-low-certainty). We did not find any evidence that vitamin C or B1 affect organ dysfunction or ICU length of stay. Adding glucocorticoid to other treatments shortened duration of vasopressor therapy (incremental mean difference, - 29.8 h [95% CI - 44.1 to - 15.5]) and ICU stay (incremental mean difference, - 1.3 days [95% CI - 2.2 to - 0.3]). Metabolic resuscitation with vitamin C, glucocorticoids, vitamin B1, or combinations of these drugs was not significantly associated with a decrease in longer-term mortality.

Topics: Adult; Ascorbic Acid; Glucocorticoids; Humans; Network Meta-Analysis; Sepsis; Shock, Septic; Thiamine

Sepsis is a condition characterized by life-threatening organ dysfunction caused by a dysregulated host response to infection. The emergency department (ED) serves as a crucial entry point for patients presenting with sepsis. Given the heterogeneous presentation and high mortality rate associated with sepsis and septic shock, several clinical controversies have emerged in the management of sepsis. These include the use of novel therapeutic agents like angiotensin II, hydrocortisone, ascorbic acid, thiamine ("HAT") therapy, and levosimendan, Additionally, controversies with current treatments in vasopressor dosing, and the use of and balanced or unbalanced crystalloid are crucial to consider. The purpose of this review is to discuss clinical controversies in the management of septic patients, including the use of novel medications and dosing strategies, to assist providers in appropriately determining what treatment strategy is best suited for patients.

Topics: Angiotensin II; Ascorbic Acid; Crystalloid Solutions; Disease Management; Drug Therapy, Combination; Emergency Service, Hospital; Humans; Hydrocortisone; Randomized Controlled Trials as Topic; Sepsis; Shock, Septic; Simendan; Thiamine

Vitamin C deficiency is common in sepsis patients and is related to disease severity. At present, sepsis still has a high incidence and fatality rate. In sepsis, the body may develop microcirculation disorders and even develop organ failure. Exogenous vitamin C supplementation may be one of the effective adjuvant treatment measures for sepsis, which can not only improve the microcirculation of the body, but also affect the prognosis of patients by participating in the synthesis of norepinephrine, improving peripheral vascular resistance and increasing perfusion pressure. The efficacy and safety of vitamin C adjuvant therapy for septic shock are inconsistent in many studies, so it is very important to systematically evaluate the adjuvant effect of intravenous vitamin C in the treatment of septic shock.. Literature search of PubMed, EMBASE, The Cochrane Library, Web of Science, Wanfang, China Biology Medicine (CBM), and China National Knowledge Infrastructure (CNKI) electronic databases for vitamin C data since August 2021 for the treatment of patients with sepsis and septic shock. After screening, data extraction and quality evaluation were performed according to inclusion criteria, and meta-analysis was conducted using RevMan 5.3.. The final 13 studies comprised 6 cohort studies and 7 randomized controlled trials (RCTs), with a total of 1,423 patients enrolled. Meta-analysis showed no significant effect of intravenous vitamin C on reducing in-hospital mortality rate [odds ratio (OR) =0.91, 95% confidence interval (CI): 0.76-1.08, P=0.27], intensive care unit (ICU) mortality rate (OR =0.84, 95% CI: 0.69-1.01, P=0.07), ICU stay (OR =0.88, 95% CI: 0.72-1.08, P=0.23) or total stay (OR =0.91, 95% CI: 0.68-1.21, P=0.51) in sepsis patients, nor did it improve the 72-h sequential organ failure assessment (72-h SOFA) score (OR =0.95, 95% CI: 0.77-1.18, P=0.66).. Intravenous vitamin C showed no efficacy in the treatment of sepsis.

Topics: Ascorbic Acid; Humans; Sepsis; Shock, Septic; Treatment Outcome; Vitamins

To evaluate current evidence on the utility of hydrocortisone, ascorbic acid, and thiamine (HAT) therapy for the management of septic shock.. The following keyword search terms were utilized in PubMed to identify relevant articles: ascorbic acid, thiamine, hydrocortisone, shock, and critical care. Articles relevant to HAT therapy in patients with septic shock were selected. Retrospective cohorts and randomized controlled trials were included in this review; case reports/series were excluded. Data from included studies illustrating the use of HAT therapy for the management of sepsis and septic shock, including data on time to HAT therapy initiation, severity of illness at baseline, duration of vasopressor therapy, progression of organ failure, and mortality, were evaluated.. The utilization of HAT therapy for the management of sepsis and septic shock remains controversial. Hemodynamic benefits have been shown to be most pronounced when HAT therapy is initiated earlier. Future studies directed at earlier initiation may be necessary to confirm this theory.

Topics: Ascorbic Acid; Drug Therapy, Combination; Humans; Hydrocortisone; Retrospective Studies; Sepsis; Shock, Septic; Thiamine

to critically appraise and synthesize the evidence on the effects of vitamin C-based regimens for patients with sepsis or septic shock.. a broad search was performed on May 2021 to identify randomized clinical trials (RCTs) assessing vitamin C-based regimens as adjuvant therapy for adults with sepsis or septic shock. We used the Cochrane Risk of Bias table to assess the methodological quality of the included RCTs and the GRADE approach to evaluate the evidence certainty.. We included 20 RCTs (2124 participants). Evidence from low to very low certainty showed that vitamin C compared to placebo may reduce all-cause mortality up to 28 days (relative risk [RR] 0.60, 95% confidence interval (CI) 0.45 to 0.80, 4 RCTs, 335 participants). Considering the other comparisons (vitamin C alone or combined with thiamine and/or hydrocortisone, compared to placebo, standard care or hydrocortisone), there were a little to no difference or very uncertain evidence for adverse events, SOFA score, ICU length of stay, acute kidney injury, mechanical ventilation- and vasoactive drugs-free days up to 28 days.. Further RCTs with higher methodological quality, an increased number of participants and assessing clinically relevant outcomes are needed to provide better decision-making guidance.. CRD42021251786.

Topics: Adult; Ascorbic Acid; Humans; Hydrocortisone; Randomized Controlled Trials as Topic; Sepsis; Shock, Septic

Septic and vasoplegic shock are common types of vasodilatory shock (VS) with high mortality. After fluid resuscitation and the use of catecholamine-mediated vasopressors (CMV), vasopressin, angiotensin II, methylene blue (MB), and hydroxocobalamin can be added to maintain blood pressure.. VS treatment utilizes a phased approach with secondary vasopressors added to vasopressor agents to maintain an acceptable mean arterial pressure (MAP). This review covers additional vasopressors and adjunctive therapies used when fluid and catecholamine-mediated vasopressors fail to maintain target MAP.. Evidence supporting additional vasopressor agents in catecholamine-resistant VS is limited to case reports, series, and a few randomized control trials (RCTs) to guide recommendations. Vasopressin is the most common agent added next when MAPs are not adequately supported with CMV. VS patients failing fluids and vasopressors with cardiomyopathy may have cardiotonic agents such as dobutamine or milrinone added before or after vasopressin. Angiotensin II, another class of vasopressor, is used in VS to maintain adequate MAP. MB and/or hydroxocobalamin, vitamin C, thiamine, and corticosteroids are adjunctive therapies used in refractory VS. More RCTs are needed to confirm the utility of these drugs, at what doses, which combinations and in what order they should be given.

Topics: Angiotensin II; Ascorbic Acid; Cardiotonic Agents; Catecholamines; Cytomegalovirus Infections; Dobutamine; Humans; Hydroxocobalamin; Methylene Blue; Milrinone; Shock; Shock, Septic; Thiamine; Vasoconstrictor Agents; Vasopressins

To investigate the clinical efficacy of vitamin C-containing therapy for patients with sepsis.. PubMed, Embase, Cochrane Library, and ClinicalTrials.gov were searched from inception to July 27, 2022. Only randomized controlled trials (RCTs) comparing vitamin C-containing therapy and placebo or alternative treatment for patients with sepsis were included, and the primary outcome was all-cause mortality.. Sixteen RCTs involving a total of 2985 patients were included in this meta-analysis. Overall, no significant difference in 28-day mortality was observed between the study group, who received vitamin C-containing treatment, and the control group (odds ratio [OR], 0.87; 95% confidence interval [CI]: 0.71-1.08; P = .20). In subgroup analysis of eight RCTs focusing on patients with septic shock, there was no significant difference in 28-day mortality between the study and control groups (OR, 1.09; 95% CI: 0.89-1.34; P = .41). In addition, no significant difference was observed between the study and control groups in intensive care unit-mortality (OR, 1.03; 95% CI: 0.84-1.25; P = .81), in-hospital mortality (OR, 1.06; 95% CI: 0.85-1.13; P = .60), and 90-day mortality (OR, 1.23; 95% CI: 0.75-2.02; P = .40).. The results of this systematic review and meta-analysis indicated that adjunctive vitamin C-containing therapy did not help improve the clinical outcomes of patients with sepsis/septic shock. Our findings do not support the additional use of vitamin C for septic patients.

Topics: Ascorbic Acid; Humans; Randomized Controlled Trials as Topic; Sepsis; Shock, Septic; Vitamins

There is a conflicting body of evidence regarding the benefit of vitamin C, thiamine, and hydrocortisone in combination as an adjunctive therapy for sepsis with or without septic shock. We aimed to assess the efficacy of this treatment among predefined populations.. A literature review of major electronic databases was performed to include randomized controlled trials (RCTs) evaluating vitamin C, thiamine, and hydrocortisone in the treatment of patients with sepsis with or without septic shock in comparison to the control group.. Seven studies met our inclusion criteria, and 6 studies were included in the final analysis totaling 839 patients (mean age 64.2 ± 18; SOFA score 8.7 ± 3.3; 46.6% female). There was no significant difference between both groups in long term mortality (Risk Ratio (RR) 1.05; 95% CI 0.85-1.30; P = 0.64), ICU mortality (RR 1.03; 95% CI 0.73-1.44; P = 0.87), or incidence of acute kidney injury (RR 1.05; 95% CI 0.80-1.37; P = 0.75). Furthermore, there was no significant difference in hospital length of stay, ICU length of stay, and ICU free days on day 28 between the intervention and control groups. There was, however, a significant difference in the reduction of SOFA score on day 3 from baseline (MD -0.92; 95% CI -1.43 to -.41; P < 0.05). In a trial sequential analysis for mortality outcomes, our results are inconclusive for excluding lack of benefit of this therapy.. Among patients with sepsis with or without septic shock, treatment with vitamin C, thiamine, and hydrocortisone was not associated with a significant reduction in mortality, incidence of AKI, hospital and ICU length of stay, or ICU free days on day 28. There was a significant reduction of SOFA score on day 3 post-randomization. Further studies with a larger number of patients are needed to provide further evidence on the efficacy or lack of efficacy of this treatment.

Topics: Aged; Aged, 80 and over; Ascorbic Acid; Female; Humans; Hydrocortisone; Male; Middle Aged; Randomized Controlled Trials as Topic; Sepsis; Shock, Septic; Thiamine

Sepsis and septic shock are severe medical conditions that can damage multiple organs with a higher risk of mortality. Recently, the combination of hydrocortisone, ascorbic acid and thiamine (HAT) was hypothesized to work synergistically to reverse septic shock and reduce mortality.. To ascertain the efficacy of HAT therapy and compare whether HAT therapy is more beneficial compared to the standard of care in sepsis and septic shock patients.. PubMed, Clinicaltrials.gov, Scopus, Web of Science, Cochrane and Embase are databases that were used to identify trials that conducted a study of the combination of HAT in sepsis or septic shock.. There were 134 articles identified through a database search and 16 from other sources, which were subsequently reduced to 11 trials (six randomized trials and five non-randomized trials) that were deemed appropriate for inclusion in this review. Most of the outcomes from these studies focused on mortality, the need for renal replacement therapy, duration of vasopressor use, changes in Sequential Organ Failure Assessment score, procalcitonin clearance and lengths of intensive care unit stay.. Due to inconsistent results from clinical studies, the benefits of HAT therapy cannot be confirmed at this point in sepsis and septic shock. Currently, there are at least 20 randomized controlled trials testing HAT in various combinations and dosages in patients with severe sepsis and septic shock. The results of these studies are required before definitive conclusions can be made regarding the impact of this novel treatment strategy on the morbidity and mortality of patients with sepsis.

Topics: Ascorbic Acid; Humans; Hydrocortisone; Sepsis; Shock, Septic; Thiamine

This study aims to assess the effect of HAT therapy on patients with sepsis and septic shock.. We searched PubMed, Embase, and Cochrane Library for studies on HAT therapy published up to November 11, 2020. The primary outcome was the duration of vasopressor use. Secondary outcomes were change of Sequential Organ Failure Assessment (SOFA) score within 72 h; death within intensive care unit (ICU), hospital, and 28 or 30 days; length of stay in ICU and hospital; rate of procalcitonin (PCT) clearance and incidence of adverse events. We also used trial sequential analysis (TSA) to assess the reliability of the available evidence.. Six randomized controlled trials (RCTs) and seven observational studies enrolling 1,559 patients were included (762 were treated with HAT, and 797 were treated with hydrocortisone alone, standard care or placebo). HAT therapy was associated with significant reductions in duration of vasopressor use (mean differences [MD], -14.68, [95% CI, -24.28 to -5.08], P = 0.003) in RCTs, but not in observational studies (MD, 11.21 [95% CI, -44.93 to 67.35], P = 0.70). HAT therapy was associated with less organ dysfunction at 72 h both in RCTs (MD, -0.86 [95% CI, -1.32 to -0.40], P < 0.001) and observational studies (MD, -2.65 [95% CI, -5.29 to -0.01], P = 0.05). HAT therapy was associated with lower hospital mortality and higher PCT clearance in observational studies. Similar results for the primary outcome were found in the sensitivity analysis. TSA results suggested more trials to reach the required information size.. Among patients with sepsis and septic shock, a combination therapy of hydrocortisone, ascorbic acid, and thiamine, compared with placebo, could reduce the duration of vasopressor use and SOFA scores during the first 72 h.. PROSPERO registration ID for this study is CRD42020170648 (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=170648).

Topics: Ascorbic Acid; Humans; Hydrocortisone; Sepsis; Shock, Septic; Thiamine

Supplementation of vitamin C in septic patients remains controversial despite eight large clinical trials published only in 2020. We aimed to evaluate the evidence on potential effects of vitamin C treatment on mortality in adult septic patients.. Data search included PubMed, Web of Science, and the Cochrane Library. A meta-analysis of eligible peer-reviewed studies was performed in accordance with the PRISMA statement. Only studies with valid classifications of sepsis and intravenous vitamin C treatment (alone or combined with hydrocortisone/thiamine) were included.. A total of 17 studies including 3133 patients fulfilled the predefined criteria and were analyzed. Pooled analysis indicated no mortality reduction in patients treated with vitamin C when compared to reference (risk difference - 0.05 [95% CI - 0.11 to - 0.01]; p = 0.08; p for Cochran Q = 0.002; I. Although vitamin C administration did not reduce pooled mortality, patients may profit if vitamin C is administered over 3 to 4 days. Consequently, further research is needed to identify patient subgroups that might benefit from intravenous supplementation of vitamin C.

Topics: Administration, Intravenous; Antioxidants; Ascorbic Acid; Humans; Mortality; Shock, Septic

Septic shock is a leading cause of death and morbidity worldwide. The cornerstones of management include prompt identification of sepsis, early initiation of antibiotic therapy, adequate fluid resuscitation and organ support. Over the past two decades, there have been considerable improvements in our understanding of the pathophysiology of sepsis and the host response, including regulation of inflammation, endothelial disruption and impaired immunity. This has offered opportunities for innovative adjunctive treatments such as vitamin C, corticosteroids and beta-blockers. Some of these approaches have shown promising results in early phase trials in humans, while others, such as corticosteroids, have been tested in large, international, multicentre randomised controlled trials. Contemporary guidelines make a weak recommendation for the use of corticosteroids to reduce mortality in sepsis and septic shock. Vitamin C, despite showing initial promise in observational studies, has so far not been shown to be clinically effective in randomised trials. Beta-blocker therapy may have beneficial cardiac and non-cardiac effects in septic shock, but there is currently insufficient evidence to recommend their use for this condition. The results of ongoing randomised trials are awaited. Crucial to reducing heterogeneity in the trials of new sepsis treatments will be the concept of enrichment, which refers to the purposive selection of patients with clinical and biological characteristics that are likely to be responsive to the intervention being tested.

Topics: Adrenal Cortex Hormones; Adrenergic beta-Antagonists; Anti-Bacterial Agents; Ascorbic Acid; Combined Modality Therapy; Fluid Therapy; Humans; Shock, Septic

Thiamine and vitamin C have been increasingly used in patients with sepsis or septic shock because of their potential for improving metabolism and reducing mortality.. We aim to determine if thiamine combined vitamin C can reduce mortality in patients with sepsis or septic shock.. We comprehensively searched the PubMed, Embase, Cochrane Library, and Web of Science databases from their inception dates through 1 January 2021. Literature works evaluating the efficacy of thiamine combined vitamin C in patients with sepsis or septic shock were considered.. Two reviewers extracted data and assessed study quality. A meta-analysis was performed to calculate an odds ratio (OR), 95% confidence intervals (CIs), and P values for in-hospital mortality (primary outcome). Secondary outcomes included duration of ICU stay, duration of hospital stay, duration of vasopressor use, and change in sequential organ failure assessment (SOFA) scores.. Seven randomized controlled trials were identified, encompassing a total of 868 patients. There was no statistical difference between groups for in-hospital mortality (OR: 1.11; 95% CI [0.79-1.56]; P = 0.55). Other than improving SOFA score during the first 72 h after enrollment and duration of vasopressor use, we found no other significant associations.. Despite widespread enthusiasm for thiamine combined with vitamin C for sepsis and septic shock, we only found an association with reduced SOFA score and time of vasopressor use. There was no association with in-hospital mortality.

Topics: Ascorbic Acid; Humans; Sepsis; Shock, Septic; Thiamine; Vitamins

Sepsis remains a leading cause of death in the critically ill. The combination of thiamine, vitamin C, and hydrocortisone has recently emerged as a potential adjunctive therapy and supportive care for patients with sepsis and septic shock.. Several randomized and observational controlled trials evaluated the role of vitamin C in sepsis and septic shock. However, there are variabilities in the findings of these studies that led to a substantial global debate on incorporating vitamin C therapy in clinical practice.. A PubMed and Embase English language literature search through April 2021 was performed using the following terms: ascorbic acid, vitamin C, corticosteroid, hydrocortisone, thiamine, HAT, sepsis, and shock. Citations, including controlled trials, observational studies, review articles, guidelines, and consensus statements, were reviewed. The risk of bias for each clinical study was systematically evaluated. Relevant clinical data focusing on efficacy, safety, and special considerations regarding the use of vitamin C with and without thiamine and hydrocortisone in sepsis and septic shock were narratively summarized.. The most commonly used vitamin C dosing in sepsis and septic shock is 1.5 g every 6 hours with and without thiamine and hydrocortisone. Current literature is limited because of heterogeneity in vitamin C regimen used, initiation time, and duration of treatment. This limitation led to variability in outcomes evaluated. Vitamin C decreases proinflammatory mediators and slows the progression of endothelial injury in severe sepsis. There is an inconsistency between randomized controlled trials and observational controlled trials regarding mortality, resolution in organ failure, hospital and intensive care unit length of stay findings with the use of vitamin C in septic shock. Vitamin C seems to be safe in comparison with placebo.. Future studies with consistent end points, initiation time with an emphasis on early initiation, and standard vitamin C dosing regimen are needed to determine the overall benefit of vitamin C in sepsis.

Topics: Ascorbic Acid; Drug Therapy, Combination; Humans; Sepsis; Shock, Septic; Vitamins

To assess the effect from individual component in combinations of steroid, ascorbic acid, and thiamine on outcomes in adults with sepsis and septic shock with component network meta-analysis (NMA). We searched PubMed, EMBASE, and the Cochrane Library Central Register of Controlled Trials from 1980 to March 2021 for randomized controlled trials (RCT) that studied the use of glucocorticoid, fludrocortisone, ascorbic acid, and thiamine in patients with sepsis and septic shock. Citations screening, study selection, data extraction, and risk of bias assessment were independently performed by two authors. The primary outcome was short-term mortality. Secondary outcomes were longer-term mortality, time to resolution of shock and duration of mechanical ventilation. Thirty-three RCTs including 9898 patients presented on short-term mortality. In additive component NMA, patients on ascorbic acid alone (RR 0.74, 95% CI 0.57-0.97) or the combination of glucocorticoid and fludrocortisone (RR 0.89, 95% CI 0.80-0.99) had lower short-term mortality, but only the latter was associated with improved long-term mortality (RR 0.89, 95% CI 0.82-0.98). The use of glucocorticoid or the combination of glucocorticoid, ascorbic acid and thiamine hastened resolution of shock. Component NMA showed glucocorticoid (MD - 0.96, 95% CI - 1.61 to - 0.30) but not ascorbic acid or thiamine shortened the time to resolution of shock. Glucocorticoid shortened the duration of mechanical ventilation (MD - 1.48, 95% CI - 2.43 to - 0.52). In adults with sepsis and septic shock, the combination of glucocorticoid and fludrocortisone improved short-term and longer-term mortality. Glucocorticoid shortened the time to resolution of shock and duration of mechanical ventilation. There was no strong evidence supporting the routine use of thiamine and ascorbic acid, but they were associated with minimal adverse effects.

Topics: Ascorbic Acid; Drug Therapy, Combination; Female; Fludrocortisone; Glucocorticoids; Humans; Male; Randomized Controlled Trials as Topic; Respiration, Artificial; Sepsis; Shock, Septic; Thiamine; Time Factors; Treatment Outcome

The role of vitamin C in sepsis is still controversial, we aimed to systematically review the efficacy of intravenous vitamin C supplementation in the treatment of sepsis.. MEDLINE, EmBase, Web of Science, WanFang Data and CNKI were comprehensively searched to collect randomized controlled trails (RCTs) of vitamin C supplementation for patients with sepsis or sepsis shock from January 2000 to March 2021. Two researchers independently screened the literature, extracted the data and accessed the risk of bias in the included studies; meta-analysis was then performed by using Revman 5.4 software.. A total of 10 RCTs involving 1400 participants were included. The results of meta-analysis showed that intravenous vitamin C supplementation can improve SOFA (ΔSOFA) within 72 h [RR = 1.32,95% CI(0.80,1.85), P < 0.0001] of septic patients. There were no difference on short term mortality (28-30d)[RR = 0.83,95% CI(0.65,1.05), P = 0.11], long term mortality (90d) [RR = 1.16,95% CI(0.82,1.66), P = 0.40], hospital LOS[RR = 0.15,95% CI(-0.73,1.03), P = 0.55], ventilator-free days[RR = 0.09,95% CI(-0.24,0.42), P = 0.60], ICU-LOS[RR = 0.22,95% CI(-0.13,0.57), P = 0.22], between two groups. The results of Subgroup analysis showed that intravenous vitamin C alone can reduce the risk of short term mortality (28-30d) [RR = 0.61,95% CI(0.47,0.79), P = 0.0002]of sepsis patients.. Based on current RCTs, our work indicated that mono-intravenous vitamin C therapy may reduce short-term mortality of sepsis patients, and it may protect organ functions. Due to the limitation of the quantity and quality of included studies, the above conclusions need to be verified by more large scale and high quality randomized control trials.

Topics: Administration, Intravenous; Ascorbic Acid; Humans; Organ Dysfunction Scores; Randomized Controlled Trials as Topic; Sepsis; Shock, Septic

The definition of sepsis continues to be as dynamic as the management strategies used to treat this. Sepsis-3 has replaced the earlier systemic inflammatory response syndrome (SIRS)-based diagnoses with the rapid Sequential Organ Failure Assessment (SOFA) score assisting in predicting overall prognosis with regards to mortality. Surgeons have an important role in ensuring adequate source control while recognizing the threat of carbapenem-resistance in gram-negative organisms. Rapid diagnostic tests are being used increasingly for the early identification of multi-drug-resistant organisms (MDROs), with a key emphasis on the multidisciplinary alert of results. Novel, higher generation antibiotic agents have been developed for resistance in ESKCAPE (

Topics: Acinetobacter baumannii; Acinetobacter Infections; Angiotensin II; Anti-Bacterial Agents; Antioxidants; Ascorbic Acid; Carbapenem-Resistant Enterobacteriaceae; Drug Resistance, Multiple, Bacterial; Duration of Therapy; Enterobacteriaceae Infections; Enterococcus faecium; Enzyme Inhibitors; Gram-Positive Bacterial Infections; Humans; Klebsiella Infections; Klebsiella pneumoniae; Machine Learning; Methicillin-Resistant Staphylococcus aureus; Methylene Blue; Organ Dysfunction Scores; Patient Care Bundles; Postoperative Complications; Practice Guidelines as Topic; Procalcitonin; Pseudomonas aeruginosa; Pseudomonas Infections; Sepsis; Shock, Septic; Staphylococcal Infections; Thiamine; Vancomycin-Resistant Enterococci; Vasoconstrictor Agents; Vitamin B Complex

The administration of ascorbic acid (vitamin C) alone or in combination with thiamine (vitamin B1) and corticosteroids (VCTS) has recently been hypothesized to improve hemodynamics, end-organ function, and may even increase survival in critically ill patients. 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. Some of these studies have demonstrated its safety and potential benefit in septic patients. However, many questions remain regarding the optimal dosing regimens and plasma concentrations, timing of administration, and adverse effects of vitamin C and thiamine. These questions exist because the bulk of research regarding the efficacy of vitamin C alone or in combination with thiamine and corticosteroids in sepsis is limited to a few randomized controlled trials, retrospective before-and-after studies, and case reports. Thus, although the underlying rationale and mechanistic pathways of vitamin C and thiamine in sepsis have been well described, the clinical impact of the VCTS regimen is complex and remains to be determined. This review aims to explore the current evidence and potential benefits and adverse effects of the VCTS regimen for the treatment of sepsis.

Topics: Adrenal Cortex Hormones; Ascorbic Acid; Ascorbic Acid Deficiency; Clinical Protocols; Critical Illness; Dietary Supplements; Hemodynamics; Humans; Hydrocortisone; Intestines; Patient Safety; Randomized Controlled Trials as Topic; Retrospective Studies; Sepsis; Shock, Septic; Thiamine; Vitamins

Sepsis and septic shock are significant health issues in the United States. Novel treatment options focusing on mitigating the dysregulated host response while reducing the need for vasopressor support are needed. This review discusses ascorbic acid, thiamine, and steroids as monotherapy and in combination for the treatment of sepsis and septic shock.. The results of clinical studies using ascorbic acid, thiamine, and steroids as monotherapy or in combination are reviewed. High doses of IV ascorbic acid improved organ failure evidenced by changes in SOFA scores, declining CRP and PCT levels, and reduced vasopressor use. Thiamine initiation improved lactate levels in thiamine deficient patients in one study and demonstrated quicker lactate clearance and lower 28-day mortality in another study. Steroid studies demonstrated greatest benefit when initiating hydrocortisone and fludrocortisone early in septic shock. Combination therapy with ascorbic acid, thiamine and steroids reduced hospital mortality and vasopressor use in sepsis and septic shock in a small single-center study.. Initial studies in patients with sepsis and septic shock demonstrated beneficial effects of ascorbic acid, thiamine, and steroids as monotherapy or in combination without safety concerns. However, the efficacy and safety of these therapies warrant further validation in larger clinical studies.

Topics: Ascorbic Acid; Humans; Sepsis; Shock, Septic; Thiamine; Vitamins

The current review discusses the supplemental use of vitamin C as an adjunct in the management of sepsis and septic shock.. The antioxidant properties of vitamin C are touted to be useful in modulating the inflammatory response, decreasing vasopressor requirements, and improving resuscitation. Current resuscitation practices are focused on addressing the hemodynamic instability and ensuring adequate oxygen delivery to tissues. The conceptual framework of the use of vitamin C during a resuscitation is to modulate in a beneficial fashion the inflammatory response to sepsis while concomitantly resuscitating and treating the infection. While there is promising animal and burn-related data on improved fluid resuscitation with the use of vitamin C as an adjunct, the most recent meta-analyses of the available data fail to show a survival benefit in sepsis, and concerns regarding nephrotoxicity remain.. Although there are large number of animal studies, only a few small prospective and retrospective studies in humans address the use of vitamin C to treat sepsis. Further research in a controlled and randomized fashion is needed to determine if vitamin C is effective in this role. While there is a promise of ascorbate's addition to the sepsis bundle as an adjunct to resuscitation, the evidence is not conclusive.

Topics: Antioxidants; Ascorbic Acid; Humans; Prospective Studies; Resuscitation; Retrospective Studies; Sepsis; Shock, Septic; Treatment Outcome

The overarching goals of early sepsis management include early recognition, appropriate antibiotic therapy and source control, maintenance of hemodynamic stability, and supportive care of organ dysfunction. Despite increasing awareness of the global burden of sepsis, and general agreement on the goals of management, there is ongoing controversy regarding the implementation of specific treatment strategies to optimize patient outcomes. This article will address five current points of controversy in the management of sepsis and septic shock. These include optimal timing of antibiotics in patients with potential sepsis, the role of glucocorticoids in septic shock, vitamin C as a novel therapy for sepsis, the ideal intravenous fluid for resuscitation, and the optimal balance of fluid resuscitation and vasopressor administration in septic shock. For each of these topics, we review relevant literature, discuss areas of controversy, and present our current approach to management.

Topics: Animals; Anti-Bacterial Agents; Ascorbic Acid; Fluid Therapy; Glucocorticoids; Humans; Resuscitation; Sepsis; Shock, Septic

Sepsis is a life-threatening medical condition, affecting approximately 26 million people worldwide every year. The disease is a continuum, marked by dysregulated inflammation and hemodynamic instability leading to shock, multi-system organ dysfunction, and death. Over the past decades, there has been a focus on the early identification and treatment of sepsis primarily with bundled and goal directed therapy. Despite these advances, morbidity and mortality has remained high, prompting investigation into novel therapies. Vitamin C is a water-soluble vitamin that plays a role in mediating inflammation through antioxidant activities and is also important in the synthesis of cortisol, catecholamines, and vasopressin, which are key mediators in the disease process. Emerging evidence provides cursory data in support of the administration of vitamin C in addition to standard therapy to ameliorate the effects of inflammation and improve hemodynamic stability in patients with sepsis and septic shock; however, further evidence is needed to support this practice. This review discusses the physiologic role of vitamin C as well as the recent literature and evidence for the use of vitamin C in patients presenting with sepsis.

Topics: Ascorbic Acid; Critical Care; Humans; Shock, Septic

Sepsis is defined as the dysregulated host response to an infection resulting in life-threatening organ dysfunction. The metabolic demand from inefficiencies in anaerobic metabolism, mitochondrial and cellular dysfunction, increased cellular turnover, and free-radical damage result in the increased focus of micronutrients in sepsis as they play a pivotal role in these processes. In the present review, we will evaluate the potential role of micronutrients in sepsis, specifically, thiamine, l-carnitine, vitamin C, Se and vitamin D. Each micronutrient will be reviewed in a similar fashion, discussing its major role in normal physiology, suspected role in sepsis, use as a biomarker, discussion of the major basic science and human studies, and conclusion statement. Based on the current available data, we conclude that thiamine may be considered in all septic patients at risk for thiamine deficiency and l-carnitine and vitamin C to those in septic shock. Clinical trials are currently underway which may provide greater insight into the role of micronutrients in sepsis and validate standard utilisation.

Topics: Ascorbic Acid; Carnitine; Deficiency Diseases; Dietary Supplements; Humans; Micronutrients; Nutritional Status; Selenium; Sepsis; Shock, Septic; Thiamine; Thiamine Deficiency; Vitamin D

Topics: Ascorbic Acid; Cyanosis; Daucus carota; Diagnosis, Differential; Dyspnea; Emergency Treatment; Humans; Infant; Male; Methemoglobinemia; Nitrites; Severity of Illness Index; Shock, Septic; Tunisia

In severe sepsis and septic shock the severe impairment of the microcirculation is one of the main reasons for tissue hypoxia, multiple organ failure and death. Fast resuscitation of the microvascular blood flow to improve the reduced functional capillary density is necessary. Based scientific evidence, an early haemodynamic stabilisation directed by predefined haemodynamic and metabolic goals and the application of activated protein C (rhAPC) according to the guidelines could be recommended. The specific effects of dobutamine and rhAPC on the microcirculation as well as the effects selective inhibitors of iNOS or vasodilators may be therapeutic options in the future.

Topics: Ascorbic Acid; Dobutamine; Germany; Humans; Microcirculation; Practice Guidelines as Topic; Practice Patterns, Physicians'; Sepsis; Shock, Septic; Vasculitis; Vasodilator Agents

This review presents the rationale for the therapeutic use of antioxidants in treating critically ill patients; it is not a systematic review of the clinical evidence that has been assessed recently by others. Clinical and nonclinical evidence is presented to support the notion that natural antioxidants are of therapeutic value in treating cardiovascular shock. Oxidative stress is a major promoter and mediator of the systemic inflammatory response. The microcirculation is particularly susceptible to oxidative stress that causes hemodynamic instability, leading to multiple organ failure due to systemic inflammatory response syndrome. Vitamin C is the antioxidant used experimentally to demonstrate oxidative stress as a key pathophysiologic factor in septic shock. Pharmacologic studies reveal that vitamin C (as ascorbate), at supraphysiologic doses, significantly affects the bioavailability of nitric oxide during acute inflammation, including inhibiting nitric oxide synthetase induction. Parenteral high-dose vitamin C inhibits endotoxin-induced endothelial dysfunction and vasohyporeactivity in humans and reverses sepsis-induced suppression of microcirculatory control in rodents. In severe burn injury, in both animals and patients, parenteral high-dose vitamin C significantly reduces resuscitation fluid volumes. Therefore, a significant body of pharmacologic evidence and sound preliminary clinical evidence supports the biological feasibility of using the exemplary antioxidant, vitamin C, in the treatment of the critically ill.

Topics: Animals; Antioxidants; Ascorbic Acid; Critical Illness; Dose-Response Relationship, Drug; Endothelium, Vascular; Humans; Microcirculation; Multiple Organ Failure; Oxidative Stress; Shock, Septic; Systemic Inflammatory Response Syndrome; Vasodilation; Vitamins; Wounds and Injuries

Septic shock is a serious problem in critically ill and surgical patients throughout the world. It is a systemic inflammatory response caused by excessive secretion of proinflammatory mediators, such as tumor necrosis factor-alpha, mainly induced by endotoxin, a major component of the Gram-negative bacterial outer membrane. Experimental evidence suggests that reactive oxygen species (ROS) may be important mediators of cellular injury during endotoxemia, either as a result of macromolecular damage or by interfering with extracellular and intracellular regulatory processes. In addition, nitric oxide is thought to play a key role in the pathogenesis of sepsis. This review begins with a brief overview of the toxic effects of endotoxin at organism level, paying particular attention to cardiovascular damage. It continues by analysing the mechanism by which endotoxin is recognized by specific cells of the immune system, which then respond to bacterial infection and the pathway leading to nuclear factor-kappaB activation and proinflammatory gene transcription. With regard to this process, the review focuses on the involvement of reactive oxygen and nitrogen species. Lastly, the protective role of antioxidants against endotoxin toxicity and their potential clinical use is discussed.

Topics: Animals; Antioxidants; Ascorbic Acid; Cardiovascular System; Cytokines; Humans; Lipopolysaccharides; Mice; Mice, Knockout; Mice, Transgenic; NF-kappa B; Reactive Nitrogen Species; Reactive Oxygen Species; Shock, Septic; Signal Transduction; Vitamin E

Purpose: The aim of the study is to evaluate the effect of combined hydrocortisone, vitamin C, and thiamine (triple therapy) on the mortality of patients with septic shock. Methods : This multicenter, open-label, two-arm parallel-group, randomized controlled trial was conducted in four intensive care units in Qatar. Adult patients diagnosed with septic shock requiring norepinephrine at a rate of ≥0.1 μg/kg/min for ≥6 h were randomized to a triple therapy group or a control group. The primary outcome was in-hospital mortality at 60 days or at discharge, whichever occurred first. Secondary outcomes included time to death, change in Sequential Organ Failure Assessment (SOFA) score at 72 h of randomization, intensive care unit length of stay, hospital length of stay, and vasopressor duration. Results: A total of 106 patients (53 in each group) were enrolled in this study. The study was terminated early because of a lack of funding. The median baseline SOFA score was 10 (interquartile range, 8-12). The primary outcomes were similar between the two groups (triple therapy, 28.3% vs. control, 35.8%; P = 0.41). Vasopressor duration among the survivors was similar between the two groups (triple therapy, 50 h vs. control, 58 h; P = 0.44). Other secondary and safety endpoints were similar between the two groups. Conclusion: Triple therapy did not improve in-hospital mortality at 60 days in critically ill patients with septic shock or reduce the vasopressor duration or SOFA score at 72 h. Trial Registration:ClinicalTrials.gov identifier: NCT03380507. Registered on December 21, 2017.

Topics: Adult; Ascorbic Acid; Humans; Hydrocortisone; Shock, Septic; Thiamine; Vasoconstrictor Agents; Vitamins

To investigate the effects of hydrocortisone combined with vitamin C and vitamin B1 versus hydrocortisone on sublingual microcirculation in septic shock patients.. This pilot study enrolled septic shock patients admitted to the ICU of a tertiary teaching hospital from February 2019 to January 2020. We randomly assigned the enrolled patients to the treatment group (hydrocortisone combined with vitamin C and vitamin B1 added to standard care) and the control group (hydrocortisone alone added to standard care) in a 1 : 1 ratio. The primary outcome was perfused small vascular density (sPVD) monitored by a sublingual microcirculation imaging system at 24 hours after treatment.. Twelve patients in the treatment group and ten in the control group completed the study. The baseline characteristics were comparable between the groups. No statistically significant difference was found in the sPVD between the groups at baseline. The sPVD in the treatment group was significantly higher than that in the control group at 4 hours after treatment (mean difference, 7.042; 95% CI, 2.227-11.857; P = 0.009) and 24 hours after treatment (mean difference, 7.075; 95% CI, 2.390-11.759; P = 0.008).. Compared with hydrocortisone, hydrocortisone combined with vitamin C and vitamin B1 significantly improves microcirculation in septic shock patients.

Topics: Ascorbic Acid; Humans; Hydrocortisone; Microcirculation; Pilot Projects; Shock, Septic; Thiamine

Topics: Ascorbic Acid; Double-Blind Method; Humans; Pilot Projects; Shock, Septic; Thiamine

Previous studies indicate supplemental vitamin C improves microcirculation and reduces glycocalyx shedding in septic animals. Our randomized, double-blind, placebo-controlled trial aimed to investigate whether a high dose of intravenous ascorbic acid (AA) might improve microcirculation and affect glycocalyx in septic patients. In our study, 23 septic patients were supplemented with a high dose (50 mg/kg every 6 h) of intravenous AA or placebo for 96 h. Sublingual microcirculation was examined using a handheld Cytocam-incident dark field (IDF) video microscope. A sidestream dark field video microscope (SDF), connected to the GlycoCheck software (GlycoCheck ICU®; Maastricht University Medical Center, Maastricht, the Netherlands), was employed to observe glycocalyx. We found a significantly higher proportion of perfused small vessels (PPV) 6 h after the beginning of the trial in the experimental group compared with placebo. As an indicator of glycocalyx thickness, the perfused boundary region was lower in capillaries of the 5-9 μm diameter in the AA group than placebo after the first dose of AA. Our data suggest that high-dose parenteral AA tends to improve microcirculation and glycocalyx in the early period of septic shock. The study was retrospectively registered in the clinicaltrials.gov database on 26/02/2021 (registration number NCT04773717).

Topics: Ascorbic Acid; Glycocalyx; Humans; Microcirculation; Sepsis; Shock, Septic

Mega-dose sodium ascorbate (NaAscorbate) appears beneficial in experimental sepsis. However, its physiological effects in patients with septic shock are unknown.. We conducted a pilot, single-dose, double-blind, randomized controlled trial. We enrolled patients with septic shock within 24 h of diagnosis. We randomly assigned them to receive a single mega-dose of NaAscorbate (30 g over 1 h followed by 30 g over 5 h) or placebo (vehicle). The primary outcome was the total 24 h urine output (UO) from the beginning of the study treatment. Secondary outcomes included the time course of the progressive cumulative UO, vasopressor dose, and sequential organ failure assessment (SOFA) score.. We enrolled 30 patients (15 patients in each arm). The mean (95% confidence interval) total 24-h UO was 2056 (1520-2593) ml with placebo and 2948 (2181-3715) ml with NaAscorbate (mean difference 891.5, 95% confidence interval [- 2.1 to 1785.2], P = 0.051). Moreover, the progressive cumulative UO was greater over time on linear mixed modelling with NaAscorbate (P < 0.001). Vasopressor dose and SOFA score changes over time showed faster reductions with NaAscorbate (P < 0.001 and P = 0.042). The sodium level, however, increased more over time with NaAscorbate (P < 0.001). There was no statistical difference in other clinical outcomes.. In patients with septic shock, mega-dose NaAscorbate did not significantly increase cumulative 24-h UO. However, it induced a significantly greater increase in UO and a greater reduction in vasopressor dose and SOFA score over time. One episode of hypernatremia and one of hemolysis were observed in the NaAscorbate group. These findings support further cautious investigation of this novel intervention. Trial registration Australian New Zealand Clinical Trial Registry (ACTRN12620000651987), Date registered June/5/2020.

Topics: Ascorbic Acid; Australia; Double-Blind Method; Humans; Sepsis; Shock, Septic; Vasoconstrictor Agents

We evaluated the effects of vitamin C and thiamine administration on biomarkers in patients with septic shock.. This was a post-hoc analysis of the Ascorbic Acid and Thiamine Effect in Septic Shock (ATESS) trial, a multicenter, double-blind, randomized controlled trial. Patients were randomized to either a treatment group (intravenous vitamin C and thiamine for 48 h) or a control group. Interleukin (IL)-6, IL-10, angiopoietin-II (AP2), and S100β were assessed at baseline and at 72 h. The primary outcomes were the biomarker levels at 72 h, and the secondary outcome was reduction rate.. Forty-five patients were assigned to the treatment group and 52 were assigned to the control group. Baseline biomarker levels and at 72 h were not significantly different between the treatment and the placebo groups. The reduction rates were not significantly different between the two groups. These outcome variables showed fair diagnostic accuracy for predicting 28-day mortality according to the area under the receiver operating characteristic curve.. Vitamin C and thiamine administration during the early phase of septic shock did not significantly change prognostic biomarker levels of IL-6, IL-10, AP2, and S100β.. NCT, ClinicalTrials.gov NCT03756220, ATESS. Registered 28 November 2018, https://clinicaltrials.gov/ct2/show/NCT03756220.

Topics: Aged; Angiopoietin-2; Ascorbic Acid; Biomarkers; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Interleukin-10; Interleukin-6; Male; Middle Aged; S100 Calcium Binding Protein beta Subunit; Shock, Septic; Thiamine; Vitamins

To determine whether IV vitamin C therapy reduces 28-day mortality in patients with septic shock.. Multicenter, double-blinded, randomized controlled trial.. One academic medical ICU and four community ICUs.. Of 167 adult patients within 24 hours of vasopressor initiation for septic shock, 126 consented to participation, and 124 received study drug and were included in analysis.. IV vitamin C (10 mg/mL in normal saline) administered as a 1,000-mg bolus over 30 minutes followed by continuous infusion of 250 mg/hr for 96 hours or placebo of equal volumes of normal saline.. Of 124 subjects receiving study drug and included in analysis, 60 received vitamin C and 64 placebo. The primary outcome of all-cause 28-day mortality (vitamin C, 26.7%; placebo, 40.6%; p = 0.10) was lower in the vitamin C arm but did not reach statistical significance. Initiation of renal replacement therapy was higher in the vitamin C arm (vitamin C, 16.7%; placebo, 3.3%; p = 0.015), as was volume of fluid administration within 6 hours of study drug initiation (vitamin C, 1.07 L; placebo, 0.76 L; p = 0.03). There were no statistically significant differences in other secondary outcomes. In post hoc subgroup analysis, there was a decrease in 28-day mortality in the vitamin C arm among patients requiring positive-pressure ventilation at the time of enrollment (vitamin C, 36.3%; placebo, 60.0%; p = 0.05). This trial is registered at clinicaltrials.gov under identifier NCT03338569.. Vitamin C monotherapy failed to significantly reduce mortality in septic shock patients as hypothesized. Our findings do not support its routine clinical use for this purpose.

Topics: Adult; Ascorbic Acid; Double-Blind Method; Humans; Saline Solution; Shock, Septic; Vasoconstrictor Agents; Vitamins

Intravenous vitamin C administration in septic shock may have a sparing effect on vasopressor requirements, and vitamin C's enzyme cofactor functions provide a mechanistic rationale. Our study aimed to determine the effect of intravenous vitamin C administration on vasopressor requirements and other outcomes in patients with septic shock.. This was a double-blind, randomised placebo-controlled trial in 40 patients with septic shock who were randomised (1:1) to receive intravenous vitamin C (at a dose of 25 mg/kg of body weight every 6 h) or placebo (intravenous 5% dextrose) for up to 96 h, or until death or discharge. The primary outcome was intravenous vasopressor requirements (dose and duration), and secondary outcomes included Sequential Organ Failure Assessment (SOFA) scores, intensive care unit (ICU) and hospital length of stay, and mortality. In addition, blood samples were collected to determine vitamin C kinetics and inflammatory marker concentrations.. Median plasma vitamin C concentrations were deficient at baseline (9.2 [4.4, 12] µmol/L) and increased to 408 (227, 560) µmol/L following 72 h of intervention. The mean duration of intravenous vasopressor infusion in the vitamin C group was 48 (95% CI 35-62) hours and in the placebo group was 54 (95% CI 41-62) hours (p = 0.52). The dose of vasopressor delivered over time was comparable between the two groups, as were SOFA scores (p > 0.05). The median ICU length of stay in the intervention group was 3.8 (2.2, 9.8) days versus 7.1 (3.1, 20) days in the placebo group (p = 0.12). The median hospital length of stay for the vitamin C group was 18 (11, 35) days versus 22 (10, 52) days for the placebo group (p = 0.65). Mortality was comparable between the two groups (p > 0.05). Of the inflammatory markers, neutrophil counts were elevated in the vitamin C group relative to placebo by 72 h (p = 0.01). C-reactive protein and myeloperoxidase concentrations were elevated at baseline, however, the two groups were comparable over time (p > 0.05).. Our pilot study indicated that intravenous vitamin C did not provide significant decreases in the mean dose or duration of vasopressor infusion. Further research that takes into account the potential impact of intervention timing, dose and duration, and location of trial, may provide more definitive evidence.. ACTRN12617001184369 (11/8/2017).

Topics: Ascorbic Acid; Double-Blind Method; Humans; Organ Dysfunction Scores; Pilot Projects; Shock, Septic; Vitamins

The global burden of sepsis is overwhelming and novel therapeutic agents is the need of the hour. The present study was designed to understand the role of Malondialdehyde as a marker of the oxidative stress in sepsis, as well as the effect of supplementation of Vitamin C and Thiamine in patients of sepsis.. 80 patients of sepsis were randomly divided into 4 groups of 20 each. Twenty age-sex matched healthy volunteers were chosen as controls. The first group received Vitamin C, the second group received Thiamine, the third group received both and the fourth group received neither. Vitamin C (2g 8 hourly) and Thiamine (200 mg 12 hourly) were given intravenously for five days. The outcome was recorded in terms of mortality in the various groups as well as by the improvement in SOFA scores (ΔSOFA). The serum levels of Vitamin C, Thiamine and Malondialdehyde were estimated.. Among the 80 patients, 17 (21%) were in septic shock. The mortality rate was 10% overall, and 47% among patients of septic shock. No additional mortality benefit was observed in the groups supplemented with Vitamin C and Thiamine. However, the ΔSOFA score in patients who received both Vitamin C and Thiamine was significantly higher as compared to the other groups. The mean malondialdehyde level was higher in patients of sepsis (1.81±1.18 µmol/l) as compared with healthy controls (0.78 ± 0.36 µmol/l). The Vitamin C level and Thiamine level (estimated indirectly by TPP effect), at presentation were 5.14±4.19 ng/ml and 52.99±28.45 % in patients of sepsis, which was significantly lower than that in healthy controls, in whom the levels were 14.64±5.51 ng/ml and 27.55±13.67% respectively.. Vitamin C and Thiamine supplementation is a cost-effective approach with a good safety profile. Additional studies including a larger population is required to study the mortality benefits and reaffirm our findings.

Topics: Ascorbic Acid; Dietary Supplements; Humans; Malondialdehyde; Sepsis; Shock, Septic; Thiamine; Vitamins

The combination therapy of hydrocortisone, vitamin C, and thiamine has been proposed as a potential treatment in patients with sepsis and septic shock. However, subsequent trials have reported conflicting results in relation to survival outcomes. Hence, we performed this randomized controlled trial (RCT) to evaluate the efficacy and safety of early combination therapy among adult patients with septic shock.. This single-center, double-blind RCT enrolled adult patients with diagnosis of septic shock within 12 h from Northern Jiangsu People's Hospital between February 2019 and June 2021. Recruited patients were randomized 1:1 to receive intervention (hydrocortisone 200 mg daily, vitamin C 2 g every 6 h, and thiamine 200 mg every 12 h) or placebo (0.9% saline) for 5 days or until ICU discharge. The primary endpoint was 90-day mortality. The secondary endpoints included mortality at day 28, ICU discharge, and hospital discharge; shock reversal; 72-h Delta SOFA score; ICU-free days, vasopressor-free days, and ventilator support -free days up to day 28; ICU length of stay (LOS) and hospital LOS.. Among 426 patients randomized, a total of 408 patients with septic shock were included in the per-protocol (PP) analysis, of which 203 were assigned to the intervention group and 205 to the placebo group. In the PP population, the primary outcome of 90-day mortality was 39.9% (81/203) and 39.0% (80/205) in the intervention and the placebo groups, respectively, and was not significantly different (P = 0.86). There was no significant difference between two groups in 28-day mortality (36.5% vs. 36.1%, P = 0.94) or the ICU mortality (31.5% vs. 28.8%, P = 0.55) and hospital mortality (34.5% vs. 33.2%, P = 0.78). No other secondary outcomes showed significant differences between two groups, including shock reversal, vasopressor-free days, and ICU LOS. Intention-to-treat analysis included all the 426 patients and confirmed these results (all P > 0.05).. Among adult patients with septic shock, early use of hydrocortisone, vitamin C, and thiamine combination therapy compared with placebo did not confer survival benefits. Trial registration ClinicalTrials.gov: NCT03872011 , registration date: March 12, 2019.

Topics: Adult; Ascorbic Acid; Drug Therapy, Combination; Humans; Hydrocortisone; Saline Solution; Shock, Septic; Thiamine; Vasoconstrictor Agents; Vitamins

It is unclear whether vitamin C, hydrocortisone, and thiamine are more effective than hydrocortisone alone in expediting resolution of septic shock.. To determine whether the combination of vitamin C, hydrocortisone, and thiamine, compared with hydrocortisone alone, improves the duration of time alive and free of vasopressor administration in patients with septic shock.. Multicenter, open-label, randomized clinical trial conducted in 10 intensive care units in Australia, New Zealand, and Brazil that recruited 216 patients fulfilling the Sepsis-3 definition of septic shock. The first patient was enrolled on May 8, 2018, and the last on July 9, 2019. The final date of follow-up was October 6, 2019.. Patients were randomized to the intervention group (n = 109), consisting of intravenous vitamin C (1.5 g every 6 hours), hydrocortisone (50 mg every 6 hours), and thiamine (200 mg every 12 hours), or to the control group (n = 107), consisting of intravenous hydrocortisone (50 mg every 6 hours) alone until shock resolution or up to 10 days.. The primary trial outcome was duration of time alive and free of vasopressor administration up to day 7. Ten secondary outcomes were prespecified, including 90-day mortality.. Among 216 patients who were randomized, 211 provided consent and completed the primary outcome measurement (mean age, 61.7 years [SD, 15.0]; 133 men [63%]). Time alive and vasopressor free up to day 7 was 122.1 hours (interquartile range [IQR], 76.3-145.4 hours) in the intervention group and 124.6 hours (IQR, 82.1-147.0 hours) in the control group; the median of all paired differences was -0.6 hours (95% CI, -8.3 to 7.2 hours; P = .83). Of 10 prespecified secondary outcomes, 9 showed no statistically significant difference. Ninety-day mortality was 30/105 (28.6%) in the intervention group and 25/102 (24.5%) in the control group (hazard ratio, 1.18; 95% CI, 0.69-2.00). No serious adverse events were reported.. In patients with septic shock, treatment with intravenous vitamin C, hydrocortisone, and thiamine, compared with intravenous hydrocortisone alone, did not significantly improve the duration of time alive and free of vasopressor administration over 7 days. The finding suggests that treatment with intravenous vitamin C, hydrocortisone, and thiamine does not lead to a more rapid resolution of septic shock compared with intravenous hydrocortisone alone.. ClinicalTrials.gov Identifier: NCT03333278.

Topics: Administration, Intravenous; Aged; Anti-Inflammatory Agents; Ascorbic Acid; Drug Therapy, Combination; Female; Hospital Mortality; Humans; Hydrocortisone; Male; Middle Aged; Shock, Septic; Thiamine; Vasoconstrictor Agents; Vitamins

Topics: Aged; Aldosterone; Anti-Inflammatory Agents; Ascorbic Acid; Australia; Biomarkers; Female; Follow-Up Studies; Humans; Hydrocortisone; Male; Middle Aged; New Zealand; Retrospective Studies; Severity of Illness Index; Shock, Septic; Survival Rate; Treatment Outcome

To evaluate the effects of early combination therapy with intravenous vitamin C and thiamine on recovery from organ failure in patients with septic shock.. The ascorbic acid and thiamine effect in septic shock (ATESS) trial was a multi-centre, double-blind, randomized, controlled trial conducted in four academic emergency departments, enrolling adult patients with septic shock from December 2018 through January 2020. Patients were randomly assigned in a 1:1 ratio to either the treatment group [intravenous vitamin C (50 mg/kg, maximum single dose 3 g) and thiamine (200 mg) administration every 12 h for a total of 48 h] or the placebo group (identical volume of 0.9% saline with the same protocol). The primary outcome was Δ Sequential Organ Failure Assessment (SOFA) score (SOFA score at enrolment-SOFA score after 72 h). Eighteen secondary outcomes were predefined, including shock reversal and 28-day mortality.. A total of 111 patients were enrolled, of which 53 were assigned to the treatment group and 58 were assigned to the placebo group. There was no significant difference in ΔSOFA scores between the treatment group and the placebo group [3, interquartile range (IQR) - 1 to 5 vs. 3, IQR 0-4, respectively, p = 0.96]. Predefined secondary outcomes were also not significantly different between the groups.. In this study, vitamin C and thiamine administration in the early phase of septic shock did not improve organ function compared with placebo, despite improvements in vitamin C and thiamine levels.

Topics: Adult; Ascorbic Acid; Humans; Organ Dysfunction Scores; Shock, Septic; Thiamine; Vitamins

The combination of ascorbic acid, corticosteroids, and thiamine has been identified as a potential therapy for septic shock.. To determine whether the combination of ascorbic acid, corticosteroids, and thiamine attenuates organ injury in patients with septic shock.. Randomized, blinded, multicenter clinical trial of ascorbic acid, corticosteroids, and thiamine vs placebo for adult patients with septic shock. Two hundred five patients were enrolled between February 9, 2018, and October 27, 2019, at 14 centers in the United States. Follow-up continued until November 26, 2019.. Patients were randomly assigned to receive parenteral ascorbic acid (1500 mg), hydrocortisone (50 mg), and thiamine (100 mg) every 6 hours for 4 days (n = 103) or placebo in matching volumes at the same time points (n = 102).. The primary outcome was change in the Sequential Organ Failure Assessment (SOFA) score (range, 0-24; 0 = best) between enrollment and 72 hours. Key secondary outcomes included kidney failure and 30-day mortality. Patients who received at least 1 dose of study drug were included in analyses.. Among 205 randomized patients (mean age, 68 [SD, 15] years; 90 [44%] women), 200 (98%) received at least 1 dose of study drug, completed the trial, and were included in the analyses (101 with intervention and 99 with placebo group). Overall, there was no statistically significant interaction between time and treatment group with regard to SOFA score over the 72 hours after enrollment (mean SOFA score change from 9.1 to 4.4 [-4.7] points with intervention vs 9.2 to 5.1 [-4.1] points with placebo; adjusted mean difference, -0.8; 95% CI, -1.7 to 0.2; P = .12 for interaction). There was no statistically significant difference in the incidence of kidney failure (31.7% with intervention vs 27.3% with placebo; adjusted risk difference, 0.03; 95% CI, -0.1 to 0.2; P = .58) or in 30-day mortality (34.7% vs 29.3%, respectively; hazard ratio, 1.3; 95% CI, 0.8-2.2; P = .26). The most common serious adverse events were hyperglycemia (12 patients with intervention and 7 patients with placebo), hypernatremia (11 and 7 patients, respectively), and new hospital-acquired infection (13 and 12 patients, respectively).. In patients with septic shock, the combination of ascorbic acid, corticosteroids, and thiamine, compared with placebo, did not result in a statistically significant reduction in SOFA score during the first 72 hours after enrollment. These data do not support routine use of this combination therapy for patients with septic shock.. ClinicalTrials.gov Identifier: NCT03389555.

Topics: Adrenal Cortex Hormones; Adult; Aged; Ascorbic Acid; Cross Infection; Drug Therapy, Combination; Female; Humans; Hyperglycemia; Hypernatremia; Male; Middle Aged; Multiple Organ Failure; Organ Dysfunction Scores; Proportional Hazards Models; Shock, Septic; Thiamine; Treatment Failure

Topics: Antioxidants; Ascorbic Acid; Humans; Lipid Peroxidation; Shock, Septic; Vitamin E

To study vitamin C pharmacokinetics in septic shock.. Prospective pharmacokinetic study.. Two intensive care units.. Twenty-one patients with septic shock enrolled in a randomised trial of high dose vitamin C therapy in septic shock.. Patients received 1.5 g intravenous vitamin C every 6 hours. Plasma samples were obtained before and at 1, 4 and 6 hours after drug administration, and vitamin C concentrations were measured by high performance liquid chromatography.. Clearance, volume of distribution, and half-life were calculated using noncompartmental analysis. Data are presented as median (interquartile range [IQR]).. Of the 11 participants who had plasma collected before any intravenous vitamin C administration, two (18%) were deficient (concentrations < 11 μmol/L) and three (27%) had hypovitaminosis C (concentrations between 11 and 23 μmol/L), with a median concentration 28 μmol/L (IQR, 11-44 μmol/L). Volume of distribution was 23.3 L (IQR, 21.9-27.8 L), clearance 5.2 L/h (IQR, 3.3-5.4 L/h), and half-life 4.3 h (IQR, 2.6-7.5 h). For the participants who had received at least one dose of intravenous vitamin C before sampling, T0 concentration was 258 μmol/L (IQR, 162- 301 μmol/L). Pharmacokinetic parameters for subsequent doses were a median volume of distribution 39.9 L (IQR, 31.4-44.4 L), clearance 3.6 L/h (IQR, 2.6-6.5 L/h), and half-life 6.9 h (IQR, 5.7-8.5 h).. Intravenous vitamin C (1.5 g every 6 hours) corrects vitamin C deficiency and hypovitaminosis C and provides an appropriate dosing schedule to achieve and maintain normal or elevated vitamin C levels in septic shock.

Topics: Administration, Intravenous; Ascorbic Acid; Ascorbic Acid Deficiency; Biomarkers; Chromatography, High Pressure Liquid; Critical Illness; Dose-Response Relationship, Drug; Humans; Prospective Studies; Shock, Septic; Vitamins

Septic shock is a common and highly morbid condition. To date, there is no specific therapy proven to attenuate organ injury in septic shock. Recent studies have suggested a role for the combination of ascorbic acid, corticosteroids and thiamine, although randomised data are lacking.. The Ascorbic Acid, Corticosteroids, and Thiamine in Sepsis trial is a multi-centre, double-blind, randomised, placebo-controlled clinical trial that aims to determine the impact of ascorbic acid, corticosteroids and thiamine versus placebo on organ injury and mortality in patients with septic shock. Patients are randomised to receive 1500 mg of ascorbic acid, 100 mg of thiamine and 50 mg of hydrocortisone parenterally versus matching placebo every 6 hours for 4 days. Clinical and laboratory data are collected at the time of study enrolment, at 24, 72 and 120 hours. The primary end-point for the trial is change in the Sequential Organ Failure Assessment score between enrolment and 72 hours. Additional key secondary outcomes include the incidence of renal failure and 30-day mortality.. The study was approved by the international review board of each participating study site. Study findings will be disseminated through peer-reviewed publications and conference presentations.. The trial is registered on clinicaltrials.gov (NCT03389555). It was posted on 3 January 2018.

Topics: Ascorbic Acid; Double-Blind Method; Drug Combinations; Glucocorticoids; Humans; Hydrocortisone; Multicenter Studies as Topic; Prospective Studies; Randomized Controlled Trials as Topic; Shock, Septic; Thiamine

Septic shock is associated with poor outcomes. Vitamin C (ascorbic acid) is a cellular antioxidant and has anti-inflammatory properties. Whether the combination therapy of vitamin C, thiamine and hydrocortisone reduces vasopressor dependency in septic shock is unclear.. To describe the protocol and statistical analysis plan of a multicentre, open-label, prospective, phase 2 randomised clinical trial evaluating the effects of vitamin C, thiamine and hydrocortisone when compared with hydrocortisone monotherapy on the duration of vasopressor administration in critically ill patients with septic shock.. VITAMINS is a multicentre cardiovascular efficacy trial in adult patients with septic shock. Randomisation occurs via a secure website with stratification by site, and allocation concealment is maintained throughout the trial. The primary outcome is the duration of time alive and free of vasopressor administration at Day 7. Secondary outcomes include feasibility endpoints and some patientcentred outcomes. All analyses will be conducted on an intention-to-treat basis.. The VITAMINS trial will determine whether combination therapy of vitamin C, thiamine and hydrocortisone when compared with hydrocortisone increases vasopressor-free hours in critically ill patients with septic shock. The conduct of this study will provide important information on the feasibility of studying this intervention in a phase 3 trial.. ClinicalTrials.gov, identification No. NCT03333278.

Topics: Adult; Ascorbic Acid; Drug Therapy, Combination; Female; Hospital Mortality; Humans; Hydrocortisone; Intensive Care Units; Male; Prospective Studies; Shock, Septic; Thiamine; Treatment Outcome; Vasoconstrictor Agents; Vitamins

Septic shock is a life-threatening condition with underlying circulatory and cellular/metabolic abnormalities. Vitamin C and thiamine are potential candidates for adjunctive therapy; they are expected to improve outcomes based on recent experimental and clinical research. The aim of the Ascorbic Acid and Thiamine Effect in Septic Shock (ATESS) trial is to evaluate the effects of early combination therapy with intravenous vitamin C and thiamine on recovery from organ failure in patients with septic shock.. This study is a randomized, double-blind, placebo-controlled, multicentre trial in adult patients with septic shock recruited from six emergency departments in South Korea. Patients will be randomly allocated into the treatment or control group (1:1 ratio), and we will recruit 116 septic shock patients (58 per group). For the treatment group, vitamin C (50 mg/kg) and thiamine (200 mg) will be mixed in 50 ml of 0.9% saline and administered intravenously every 12 h for a total of 48 h. For the placebo group, an identical volume of 0.9% saline will be administered in the same manner. The primary outcome is the delta Sequential Organ Failure Assessment (SOFA) score (ΔSOFA = initial SOFA at enrolment - follow-up SOFA after 72 h).. This trial will provide valuable evidence about the effectiveness of vitamin C and thiamine therapy for septic shock. If effective, this therapy might improve survival and become one of the main therapeutic adjuncts for patients with septic shock.. ClinicalTrials.gov, NCT03756220 . Registered on 5 December 2018.

Topics: Adult; Aged; Aged, 80 and over; Ascorbic Acid; Double-Blind Method; Drug Combinations; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Republic of Korea; Shock, Septic; Thiamine; Time Factors; Treatment Outcome; Vitamin B Complex; Young Adult

Enteral diets enriched with eicosapentaenoic acid (EPA), gamma-linolenic acid (GLA), and antioxidants have previously been shown to improve outcomes in patients with acute respiratory distress syndrome. Several studies using animal models of sepsis demonstrate that enteral nutrition enriched with omega-3 fatty acids reduces mortality rate. This study investigated whether an enteral diet enriched with EPA, GLA, and antioxidant vitamins can improve outcomes and reduce 28-day all-cause mortality in patients with severe sepsis or septic shock requiring mechanical ventilation.. Prospective, double-blind, placebo-controlled, randomized trial.. Three different intensive care units of a tertiary hospital in Brazil.. The study enrolled 165 patients.. Patients were randomized to be continuously tube-fed with either a diet enriched with EPA, GLA, and elevated antioxidants or an isonitrogenous and isocaloric control diet, delivered at a constant rate to achieve a minimum of 75% of basal energy expenditure x 1.3 during a minimum of 4 days.. Patients were monitored for 28 days. Patients who were fed with the study diet experienced a significant reduction in mortality rate compared with patients fed with the control diet, the absolute mortality reduction amounting to 19.4% (p = .037). The group who received the study diet also experienced significant improvements in oxygenation status, more ventilator-free days (13.4 +/- 1.2 vs. 5.8 +/- 1.0, p < .001), more intensive care unit (ICU)-free days (10.8 +/- 1.1 vs. 4.6 +/- 0.9, p < .001), and a lesser development of new organ dysfunctions (p < .001).. In patients with severe sepsis or septic shock and requiring mechanical ventilation and tolerating enteral nutrition, a diet enriched with EPA, GLA, and elevated antioxidants contributed to better ICU and hospital outcomes and was associated with lower mortality rates.

Topics: Aged; Antioxidants; Ascorbic Acid; Brazil; Double-Blind Method; Eicosapentaenoic Acid; Enteral Nutrition; Female; gamma-Linolenic Acid; Humans; Intensive Care Units; Length of Stay; Male; Middle Aged; Multiple Organ Failure; Prospective Studies; Pulmonary Gas Exchange; Respiration, Artificial; Respiratory Distress Syndrome; Sepsis; Shock, Septic; Vitamin E

Oxidative stress is implicated in septic shock. We investigated the effect of intravenous antioxidant therapy on antioxidant status, lipid peroxidation, hemodynamics and nitrite in patients with septic shock. Thirty patients randomly received either antioxidants (n-acetylcysteine 150 mg/kg for 30 min then 20 mg/kg/h plus bolus doses of 1 g ascorbic acid and 400 mg alpha-tocopherol) or 5% dextrose. Basal vitamin C was low and redox-reactive iron was elevated in all patients. In the 16 patients receiving antioxidants, vitamin C increased (p = .0002) but total antioxidant capacity was unaffected. Lipid peroxides were elevated in all patients but did not increase further in the patients receiving antioxidants. Plasma total nitrite also increased (p = .007) in the antioxidant group. Heart rate increased in patients receiving antioxidants at 60 min (p = .018) and 120 min (p = .004). Cardiac index also increased at 60 min (p = .007) and 120 min (p = .05). Systemic vascular resistance index decreased at 120 min in the antioxidant treated patients (p = .003). The effect of antioxidants on hemodynamic variables has not previously been reported. Antioxidant administration may be a useful adjunct to conventional approaches in the management of septic shock.

Topics: Acetylcysteine; Adult; Aged; Aged, 80 and over; Antioxidants; Ascorbic Acid; Drug Therapy, Combination; Free Radicals; Hemodynamics; Humans; Injections, Intravenous; Lipid Peroxides; Male; Middle Aged; Nitrites; Oxidation-Reduction; Shock, Septic; Vitamin E

This study aimed to evaluate whether early vitamin C and thiamine administration was associated with a lower 28-day and in-hospital mortality in surgical critically ill patients with refractory septic shock.. We performed a retrospective before-and-after study on patients with refractory septic shock. According to local protocol, hydrocortisone is initiated in case of refractory septic shock. In January 2017, the protocol was changed and vitamin C and thiamine were included. Patients who were admitted in 2015-2016 and 2017-2018 were included in the control and treatment groups, respectively. The primary end point was 28-day and in-hospital mortality. Secondary end points were ICU mortality, ICU and hospital length of stay, duration of vasopressors and mechanical ventilation, use of renal replacement therapy (RRT), and the modification in serum procalcitonin and SOFA score during the first 72 h.. A total of 120 patients were included (58 in the treatment group and 62 in the control group). Log-rank test in Kaplan-Meier curves showed lower 28-day and in-hospital mortality over time in the treatment group (p=0.021 and p=0.035, respectively) but it not reached statistical significance in ICU mortality over time (p=0.100). The need of RRT was less frequent in treatment group (17.2% vs. 37.1%, p=0.024). There were no differences in other secondary outcomes.. Intravenous vitamin C and thiamine administration in surgical patients with refractory septic shock may be associated with a lower 28-day and in-hospital mortality. Further prospective studies are needed in refractory septic shock.

Topics: Ascorbic Acid; Critical Illness; Humans; Intensive Care Units; Retrospective Studies; Sepsis; Shock, Septic; Thiamine

Topics: Ascorbic Acid; Humans; Shock, Septic; Vitamins

Topics: Ascorbic Acid; Humans; Pilot Projects; Shock, Septic; Thiamine; Vitamin A; Vitamin K; Vitamins

Previous randomized trials of vitamin C, hydrocortisone, and thiamine on sepsis were limited by short-term vitamin C administration, heterogeneous populations, and the failure to evaluate each component's effect. The purpose of this study was to determine whether vitamin C alone for ≥ 5 days or in combination with corticosteroids and/or thiamine was associated with decreased mortality across the sepsis population and subpopulation.. Nationwide population-based study conducted using the Korean National Health Insurance Service database. A total of 384,282 adult patients with sepsis who were admitted to the intensive care unit were enrolled from January 2017 to December 2019. The primary outcome was hospital mortality, while the key secondary outcome was 90-day mortality.. The mean [standard deviation] age was 69.0 [15.4] years; 57% were male; and 36,327 (9%) and 347,955 did and did not receive vitamin C, respectively. After propensity score matching, each group involved 36,327 patients. The hospital mortality was lower by - 0.9% in the treatment group (17.1% vs 18.0%; 95% confidence interval, - 1.3 to - 0.5%; p < 0.001), a significant but extremely small difference. However, mortality decreased greater in patients who received vitamin C for ≥ 5 days (vs 1-2 or 3-4 days) (15.8% vs 18.8% vs 18.3%; p < 0.001). Further, vitamin C was associated with a lower hospital mortality in patients with older age, multiple comorbidities, pneumonia, genitourinary infection, septic shock, and mechanical ventilation. Consistent findings were found for 90-day mortality. Moreover, vitamin C alone or in combination with thiamine was significantly associated with decreased hospital mortality.. Intravenous vitamin C of ≥ 5 days was significantly associated with decreased hospital and 90-day mortality in sepsis patients. Vitamin C combined with corticosteroids and/or thiamine in specific sepsis subgroups warrants further study.

Topics: Adolescent; Adult; Aged; Ascorbic Acid; Cohort Studies; Drug Therapy, Combination; Hospital Mortality; Humans; Male; Sepsis; Shock, Septic; Thiamine

Vitamin C has potential protective effects through antioxidant and anti-inflammatory properties. However, the effect of vitamin C supplementation on microvascular function and peripheral tissue perfusion in human sepsis remains unknown. We aimed to determine vitamin C effect on microvascular endothelial dysfunction and peripheral tissue perfusion in septic shock patients.. Patients with septic shock were prospectively included after initial resuscitation. Bedside peripheral tissue perfusion and skin microvascular reactivity in response to acetylcholine iontophoresis in the forearm area were measured before and 1 h after intravenous vitamin C supplementation (40 mg/kg). Norepinephrine dose was not modified during the studied period.. We included 30 patients with septic shock. SOFA score was 11 [8-14], SAPS II was 66 [54-79], and in-hospital mortality was 33%. Half of these patients had vitamin C deficiency at inclusion. Vitamin C supplementation strongly improved microvascular reactivity (AUC 2263 [430-4246] vs 5362 [1744-10585] UI, p = 0.0004). In addition, vitamin C supplementation improved mottling score (p = 0.06), finger-tip (p = 0.0003) and knee capillary refill time (3.7 [2.6-5.5] vs 2.9 [1.9-4.7] s, p < 0.0001), as well as and central-to-periphery temperature gradient (6.1 [4.9-7.4] vs 4.6 [3.4-7.0] °C, p < 0.0001). The beneficial effects of vitamin C were observed both in patients with or without vitamin C deficiency.. In septic shock patients being resuscitated, vitamin C supplementation improved peripheral tissue perfusion and microvascular reactivity whatever plasma levels of vitamin C. ClinicalTrials.gov Identifier: NCT04778605 registered 26 January 2021.

Topics: Ascorbic Acid; Humans; Microcirculation; Perfusion; Resuscitation; Shock, Septic

Topics: Ascorbic Acid; Humans; Randomized Controlled Trials as Topic; Shock, Septic; Vitamins

Topics: Ascorbic Acid; Humans; Nutrition Therapy; Sepsis; Shock, Septic

Topics: Ascorbic Acid; Humans; Sepsis; Shock, Septic; Vitamins

While the use of vitamin C as a therapeutic agent has been investigated since the 1950s, there has been substantial recent interest in the role of vitamin C supplementation in critical illness and particularly, sepsis and septic shock. Humans cannot synthesize vitamin C and rely on exogenous intake to maintain a plasma concentration of approximately 70 to 80 μmol/L. Vitamin C, in healthy humans, is involved with antioxidant function, wound healing, endothelial function, and catecholamine synthesis. Its function in the human body informs the theoretical basis for why vitamin C supplementation may be beneficial in sepsis/septic shock.Critically ill patients can be vitamin C deficient due to low dietary intake, increased metabolic demands, inefficient recycling of vitamin C metabolites, and loss due to renal replacement therapy. Intravenous supplementation is required to achieve supraphysiologic serum levels of vitamin C. While some clinical studies of intravenous vitamin C supplementation in sepsis have shown improvements in secondary outcome measures, none of the randomized clinical trials have shown differences between vitamin C supplementation and standard of care and/or placebo in the primary outcome measures of the trials. There are some ongoing studies of high-dose vitamin C administration in patients with sepsis and coronavirus disease 2019; the majority of evidence so far does not support the routine supplementation of vitamin C in patients with sepsis or septic shock.

Topics: Animals; Antioxidants; Ascorbic Acid; Ascorbic Acid Deficiency; Clinical Trials as Topic; Critical Illness; Dose-Response Relationship, Drug; Glucocorticoids; Humans; Inflammation Mediators; Shock, Septic; Vasoconstrictor Agents; Vitamins

Sepsis is a potentially life-threatening condition characterized by a deregulated body's response to infection causing injury to its own tissues and organs. Sepsis is the primary cause of death from infection. If not recognized and treated timely, it can evolve within minutes/hours to septic shock. Sepsis is associated with an acute deficiency of Vitamin C. Despite the proof-of-concept of the benefit of administering Vitamin C in patients with sepsis or septic shock, Vitamin C administration is not yet current practice.. To investigate the potential benefit of early administration of high doses of Vitamin C in addition to standard of care in patients with sepsis or septic shock.. This phase 3b multi-center trial is conducted in 8 hospitals throughout Belgium. In total 300 patients will be randomly assigned to one of two groups in a 1:1 allocation ratio. The intervention group will receive 1.5 g Vitamin C 4 times a day during 4 days, started within 6 hours after admission. The primary outcome is the average post-baseline patient SOFA score.. This trial will determine whether the early administration of Vitamin C in patients with sepsis or septic shock can lead to a more rapid solution of shock and less deterioration from sepsis to septic shock, hereby reducing morbidity and mortality as well as the length of hospital stay in this patient population.. The C-EASIE trial has been registered on the ClinicalTrials.gov website on 10 February 2021 with registration number NCT04747795.. UZ Leuven (sponsor's reference S63213).

Topics: Ascorbic Acid; Emergency Service, Hospital; Length of Stay; Shock, Septic

Topics: Adrenal Cortex Hormones; Ascorbic Acid; Humans; Hydrocortisone; Sepsis; Shock, Septic; Thiamine

Topics: Ascorbic Acid; Critical Illness; Fruit; Humans; Life Support Care; Shock, Septic

Topics: Ascorbic Acid; COVID-19; Humans; SARS-CoV-2; Shock, Septic; Vitamins

Preliminary data have produced conflicting results regarding whether initial vitamin C levels in patients with severe sepsis correlate with mortality outcomes. We hypothesized that low plasma ascorbic acid or thiamine levels in severe sepsis patients admitted from the Emergency Department (ED) to the Intensive Care Unit (ICU) would be associated with increased mortality and an increased incidence of shock. Retrospective analysis of a prospective database of severe sepsis patients admitted to the ICU at an urban, academic medical center. Ascorbic acid and thiamine levels were analyzed in relation to survivors vs. non-survivors and shock vs. non-shock patients. 235 patients were included; mean age, 59.4 years ± 16.8 years; male, 128 (54.5%); in-hospital mortality, 16.6% (39/235); mean APACHE3 score, 61.8 ± 22.8; mean ascorbic acid level (reference range 0.40-2.10 mg/dL), 0.23 mg/dL (95% CI 0.07-4.02); and the mean thiamine level (reference range 14.6-29.5 nmol/L), 6.0 nmol/L (95% CI 4.0-9.5). When survivors were compared to non-survivors, survivors were more likely to be male (57.7% [113/196] vs. 38.5% [15/39]) and have lower APACHE3 scores (58.2 ± 22.6 vs. 79.9 ± 16.0). For the total cohort of 235 patients, there was no statistically significant relationship between a patient's initial ascorbic acid or thiamine level and either survival or development of shock. In this analysis of early plasma samples from patients with severe sepsis admitted from the ED to the ICU, we found that mean ascorbic acid and thiamine levels were lower than normal range but that there was no relationship between these levels and outcomes, including 28 day mortality and development of shock.

Topics: Ascorbic Acid; Female; Hospital Mortality; Hospitalization; Humans; Intensive Care Units; Male; Middle Aged; Retrospective Studies; Sepsis; Shock, Septic; Thiamine

Sepsis and septic shock are medical emergencies resulting in significant morbidity and mortality. Intravenous (IV) vitamin C, thiamine, and hydrocortisone have shown promise in reducing hospital mortality. The Memphis Veterans Affairs Medical Center (VAMC) similarly implemented this regimen, called the vitamin C protocol, for patients presenting in sepsis or septic shock in the intensive care unit (ICU).. This retrospective study in Veteran ICU patients with sepsis or septic shock compared outcomes of patients treated with IV vitamin C, thiamine, and hydrocortisone (treatment) with those who received IV hydrocortisone alone (control). Data was propensity matched to ensure comparability at baseline. The Sequential Organ Failure Assessment (SOFA) score was calculated at day of diagnosis (day 0) and daily for 3 subsequent days. 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.. Hospital mortality, the primary outcome, did not differ significantly between groups. Secondary outcomes including ICU, 28-day, and 60-day mortality were also not different, nor were vasopressor duration or hospital length of stay. However, ICU length of stay was significantly reduced in the treatment group compared to control (7.1 vs 15.6 days, respectively, P = 0.04).. Although no significant mortality benefit was observed, the vitamin C protocol was not associated with patient harm. In this Veteran population, there was reduced ICU length of stay, suggesting possible benefit. Though further investigation is warranted, utilization of IV vitamin C, thiamine, and hydrocortisone in patients with sepsis or septic shock may be a treatment option worth considering.

Topics: Aged; Ascorbic Acid; Clinical Protocols; Critical Care; Female; Humans; Hydrocortisone; Infusions, Intravenous; Male; Retrospective Studies; Sepsis; Shock, Septic; Thiamine

Topics: Adolescent; Ascorbic Acid; Child; Child, Preschool; Drug Combinations; Female; Humans; Hydrocortisone; Male; Propensity Score; Retrospective Studies; Shock, Septic; Thiamine

Topics: Ascorbic Acid; Humans; Hydrocortisone; Sepsis; Shock, Septic; Thiamine; Vitamins

Whether hydrocortisone, vitamin C, and thiamine treatment can reduce the mortality of patients with sepsis is controversial.. To evaluate the efficacy and safety of hydrocortisone, vitamin C, and thiamine combination treatment for patients with sepsis or septic shock (HYVCTTSSS).. This single-blind, randomized controlled trial evaluated treatment with hydrocortisone (50 mg every 6 h for 7 days), vitamin C (1.5 g every 6 h for 4 days), and thiamine (200 mg every 12 h for 4 days) vs placebo (normal saline) in patients with sepsis. The intention-to-treat analysis was used. Primary outcome was 28-day all-cause mortality, and secondary outcomes were organ protection, procalcitonin reduction, and adverse events related to hydrocortisone, vitamin C, and thiamine.. Eighty patients were randomized to receive combination treatment (n = 40) or normal saline (n = 40). No difference in 28-day all-cause mortality was observed (27.5% vs 35%, respectively; P = .47); however, treatment was associated with a significant improvement of 72-h change in Sequential Organ Failure Assessment score (P = .02). In adverse events analysis, the treatment group exhibited more incidents of hypernatremia (P = .005). In prespecified subgroup analysis, patients of the treatment subgroup diagnosed with sepsis within 48 h showed lower mortality than those in the control subgroup (P = .02). The study was terminated after the midterm analysis.. Among patients with sepsis or septic shock, the combination of hydrocortisone, vitamin C, and thiamine did not reduce mortality compared with placebo.. ClinicalTrials.gov; No.: NCT03258684; URL: www.clinicaltrials.gov.

Topics: Adult; Aged; Anti-Inflammatory Agents; Ascorbic Acid; Critical Care; Drug Therapy, Combination; Female; Humans; Hydrocortisone; Male; Middle Aged; Organ Dysfunction Scores; Shock, Septic; Single-Blind Method; Survival Rate; Thiamine; Vitamins

Topics: Adrenal Cortex Hormones; Ascorbic Acid; Controlled Before-After Studies; Humans; Hydrocortisone; Retrospective Studies; Sepsis; Shock, Septic; Thiamine; Vitamins

Topics: Ascorbic Acid; Humans; Hydrocortisone; Shock, Septic; Thiamine; Vitamins

Topics: Ascorbic Acid; Humans; Hydrocortisone; Shock, Septic; Thiamine; Vitamins

Triple therapy with steroids, vitamin C and thiamine has been recently proposed as a safe and beneficial in patients with sepsis. In 2017, we added the use of intravenous vitamin C and thiamine in septic shock patients receiving low dose hydrocortisone because poorly responsive to vasopressors. Aim of this study is to verify whether triple therapy rather than steroids alone can improve outcome in patients with refractory shock.. In this before-after retrospective analysis, we compared septic shock patients admitted to our intensive care unit (ICU) who received triple therapy from June 2017 to November 2019 to septic shock patients who received only hydrocortisone from January 2015 to June 2017. Patients of the two study periods were matched 1:1 using a propensity score model.. A final cohort of 56 patients treated with triple therapy were matched to 56 patients treated only with steroids. Triple therapy reduced the length of mechanical ventilation (p = 0,01) and showed a trend in lowering the 30-day and hospital mortality compared to therapy with only hydrocortisone.. Although with significant limitations, our experience indicated that triple therapy seems to provide an improvement of clinical outcomes in patients with refractory septic shock.

Topics: Administration, Intravenous; Adult; Aged; Anti-Inflammatory Agents; Ascorbic Acid; Case-Control Studies; Drug Therapy, Combination; Female; Hospital Mortality; Humans; Hydrocortisone; Intensive Care Units; Male; Middle Aged; Propensity Score; Retrospective Studies; Sepsis; Shock, Septic; Thiamine; Treatment Outcome; Vasoconstrictor Agents; Vitamin B Complex; Vitamins

Topics: Ascorbic Acid; Citrus sinensis; Fruit; Glucocorticoids; Humans; Sepsis; Shock, Septic; Thiamine

Topics: Anti-Inflammatory Agents; Ascorbic Acid; Humans; Hydrocortisone; Shock, Septic; Thiamine

Topics: Aged; Aged, 80 and over; Anti-Inflammatory Agents; Ascorbic Acid; Cohort Studies; Drug Therapy, Combination; Evidence-Based Medicine; Female; Hospital Mortality; Humans; Hydrocortisone; Male; Middle Aged; Observational Studies as Topic; Practice Patterns, Physicians'; Retrospective Studies; Shock, Septic; Thiamine; Vitamin B Complex; Vitamins

Topics: Adult; Ascorbic Acid; Critical Illness; Humans; Hydrocortisone; Patients; Shock, Septic; Thiamine

Topics: Aldosterone; Ascorbic Acid; Biomarkers; Cohort Studies; Dust; Humans; Hydrocortisone; Shock, Septic

Methemoglobinemia is a rare disorder of the blood in which there is an increase in methemoglobin, which occurs when hemoglobin is present in the oxidized form. Methemoglobin impairs hemoglobin's ability to transport oxygen, produces functional anemia, and leads to tissue hypoxia. We report the successful management of a case of refractory hypoxia due to acutely acquired methemoglobinemia in a patient undergoing treatment for coronavirus disease 2019 (COVID-19) pneumonia. The cause of methemoglobinemia in this patient remains unknown. Hypoxia and methemoglobinemia did not respond to methylene blue and required administration of packed red blood cell transfusions.

Topics: Acute Kidney Injury; Aged; Antibodies, Monoclonal, Humanized; Antioxidants; Ascorbic Acid; Betacoronavirus; Coronavirus Infections; Corynebacterium; Corynebacterium Infections; COVID-19; Cytokine Release Syndrome; Enzyme Inhibitors; Erythrocyte Transfusion; Hematinics; Humans; Hydroxocobalamin; Hydroxychloroquine; Hypoxia; Male; Methemoglobinemia; Methylene Blue; Pandemics; Pneumonia, Bacterial; Pneumonia, Viral; Renal Replacement Therapy; Respiratory Insufficiency; SARS-CoV-2; Shock, Septic

Sepsis has high incidence and mortality rates, particularly in the intensive care unit (ICU). Corticosteroids may improve outcomes, and vitamin C may add benefit. We aimed to assess whether vitamin C and corticosteroids improved outcomes compared with corticosteroids alone.. This historical cohort study (11 December 2016 to 21 February 2018) was conducted in the ICU of a quaternary referral hospital. Patients with an ICU admission diagnosis of sepsis or septic shock who received vitamin C and hydrocortisone within 72 hr were compared with those who received only hydrocortisone. All patients received standard sepsis care including source control, antibiotics, and fluid resuscitation. Most patients received thiamine as standard ICU care. The primary outcome was hospital mortality. Secondary outcomes included ICU mortality, ventilator-free days, vasopressor-free days, dialysis use, and duration of ICU admission.. One hundred and forty-four patients were included in the study. The mean (standard deviation [SD]) age was 64 (15) yr; 39% were female; and the mean (SD) Acute Physiology And Chronic Health Evaluation IV score was 89 (30). Eighty-eight patients did not receive vitamin C and 52 received vitamin C. There was no observed difference in hospital mortality between the non-vitamin C (36%) and vitamin C (39%) groups (adjusted odds ratio for hospital death, 0.52; 95% confidence interval, 0.20 to 1.34; P = 0.18). There were no statistically significant differences in any secondary outcomes.. In this small observational study of ICU patients with septic shock, the addition of vitamin C to hydrocortisone therapy did significantly affect hospital mortality or other measures of mortality or organ dysfunction.. RéSUMé: OBJECTIF: Le sepsis comporte une incidence et des taux de mortalité élevés, particulièrement à l’unité de soins intensifs (USI). Les corticostéroïdes pourraient améliorer les pronostics, et la vitamine C pourrait être bénéfique. Notre objectif était d’évaluer si la vitamine C et les corticostéroïdes amélioraient les devenirs par rapport à un traitement de corticostéroïdes seulement. MéTHODE: Cette étude de cohorte historique (réalisée entre le 11 décembre 2016 et le 21 février 2018) a été réalisée à l’USI d’un hôpital quaternaire. Les patients ayant un diagnostic de sepsis ou de choc septique lors de leur admission à l’USI et ayant reçu de la vitamine C et de l’hydrocortisone dans les premières 72 heures ont été comparés à ceux n’ayant reçu que de l’hydrocortisone. Tous les patients ont reçu des soins standard pour le sepsis, soit un contrôle de la source de l’infection, un traitement antibiotique et une réanimation liquidienne. La plupart des patients ont reçu de la thiamine, un traitement standard à l’USI. Le critère d’évaluation principal était la mortalité hospitalière. Les critères d’évaluation secondaires comprenaient la mortalité à l’USI, les jours sans respirateur, les jours sans vasopresseurs, le recours à la dialyse et la durée de séjour à l’USI. RéSULTATS: Cent quarante-quatre patients ont été inclus dans notre étude. L’âge moyen (écart type [ÉT]) était de 64 (15) ans; 39 % étaient de sexe féminin; et le score APACHE IV moyen (ÉT) de 89 (30). Quatre-vingt-huit patients n’ont pas reçu de vitamine C et 52 en ont reçu. Aucune différence n’a été observée en matière de mortalité hospitalière entre les groupes sans vitamine C (36 %) ou avec vitamine C (39 %) (rapport de cotes ajusté pour la mortalité hospitalière, 0,52; intervalle de confiance 95 %, 0,20 à 1,34; P = 0,18). Il n’y a eu aucune différence statistiquement significative en ce qui touchait aux critères d’évaluation secondaires. CONCLUSION: Dans cette petite étude observationnelle portant sur des patients de l’USI en choc septique, l’ajout de vitamine C à un traitement d’hydrocortisone n’a pas eu d’impact significatif sur la mortalité hospitalière ou les autres mesures de mortalité ou d’atteintes organiques.

Topics: Ascorbic Acid; Cohort Studies; Female; Hospital Mortality; Humans; Hydrocortisone; Intensive Care Units; Male; Sepsis; Shock, Septic; Vitamins

Topics: Ascorbic Acid; Humans; Sepsis; Shock, Septic; Thiamine; Vitamins

We aimed to study the use of ascorbic acid, thiamine, and steroids (ATS) in patients with septic shock (SS).. Data on 62 patients with SS were collected from Acute Physiologic and Chronic Health Evaluation (APACHE) Outcome database and medical records. The ATS group received full doses of intravenous (IV) ATS (ascorbic acid [1.5 g every 6 hours for 4 days], hydrocortisone [50 mg every 6 hours for 7 days], and thiamine [200 mg every 12 hours for 4 days]). Data included age, gender, APACHE III, acute physiologic score (APS), mechanical ventilation (MV), lactic acid (LA), serum creatinine (Cr), duration of vasopressors (VP, days, median: interquartile ranges [IQR]: [Q1, Q3]), MV-free days (median: IQR [Q1-Q3]), percentage of patients requiring renal replacement therapy (RRT) for acute kidney injury (AKI), and mortality. Propensity analysis was used to match patients on age, gender, MV, APACHE III, APS, LA, and Cr.. The ATS group had longer duration of VP (4.5: 4.0-6.0 vs 2.0: 1.0-2.0,. The use of IV ascorbic acid, thiamine, and hydrocortisone might be beneficial in patients with SS.

Topics: Ascorbic Acid; Humans; Hydrocortisone; Intensive Care Units; Retrospective Studies; Sepsis; Shock, Septic; Thiamine

Topics: Anti-Inflammatory Agents; Antioxidants; Ascorbic Acid; Humans; Hydrocortisone; Shock, Septic; Treatment Outcome; Vasoconstrictor Agents

Topics: Ascorbic Acid; Controlled Before-After Studies; Critical Illness; Humans; Hydrocortisone; Retrospective Studies; Sepsis; Shock, Septic; Thiamine

Topics: Ascorbic Acid; Controlled Before-After Studies; Humans; Hydrocortisone; Retrospective Studies; Sepsis; Shock, Septic; Thiamine

Topics: Ascorbic Acid; Controlled Before-After Studies; Humans; Hydrocortisone; Retrospective Studies; Sepsis; Shock, Septic; Thiamine

Two recent publications by Sheikh and Horner and Teng et al. reviewed studies on incorporating vitamin C to treat septic patients; however, a meta-analysis was not offered in either report. This commentary extends both reviews by integrating a meta-analysis and sharing aggregated results. Pooled analyses demonstrated a marked reduction in mortality and duration of vasopressor administration in the group with the use of vitamin C.

Topics: Ascorbic Acid; Humans; Sepsis; Shock, Septic; Vasoconstrictor Agents; Vitamins

Topics: Ascorbic Acid; Controlled Before-After Studies; Humans; Hydrocortisone; Retrospective Studies; Sepsis; Shock, Septic; Thiamine

Topics: Ascorbic Acid; Controlled Before-After Studies; Humans; Hydrocortisone; Retrospective Studies; Sepsis; Shock, Septic; Thiamine

Topics: Ascorbic Acid; Controlled Before-After Studies; Humans; Hydrocortisone; Retrospective Studies; Sepsis; Shock, Septic; Thiamine

Topics: Ascorbic Acid; Controlled Before-After Studies; Humans; Hydrocortisone; Retrospective Studies; Sepsis; Shock, Septic; Thiamine

Topics: Ascorbic Acid; Controlled Before-After Studies; Humans; Hydrocortisone; Retrospective Studies; Sepsis; Shock, Septic; Thiamine

Topics: Ascorbic Acid; Controlled Before-After Studies; Humans; Hydrocortisone; Retrospective Studies; Sepsis; Shock, Septic; Thiamine

Topics: Ascorbic Acid; Controlled Before-After Studies; Humans; Hydrocortisone; Retrospective Studies; Sepsis; Shock, Septic; Thiamine

Topics: Ascorbic Acid; Controlled Before-After Studies; Humans; Hydrocortisone; Retrospective Studies; Sepsis; Shock, Septic; Thiamine

Vitamin C is an essential water-soluble nutrient which cannot be synthesised or stored by humans. It is a potent antioxidant with anti-inflammatory and immune-supportive roles. Previous research has indicated that vitamin C levels are depleted in critically ill patients. In this study we have assessed plasma vitamin C concentrations in critically ill patients relative to infection status (septic shock or non-septic) and level of inflammation (C-reactive protein concentrations). Vitamin C status was also assessed relative to daily enteral and parenteral intakes to determine if standard intensive care unit (ICU) nutritional support is adequate to meet the vitamin C needs of critically ill patients.. Forty-four critically ill patients (24 with septic shock, 17 non-septic, 3 uncategorised) were recruited from the Christchurch Hospital Intensive Care Unit. We measured concentrations of plasma vitamin C and a pro-inflammatory biomarker (C-reactive protein) daily over 4 days and calculated patients' daily vitamin C intake from the enteral or total parenteral nutrition they received. We compared plasma vitamin C and C-reactive protein concentrations between septic shock and non-septic patients over 4 days using a mixed effects statistical model, and we compared the vitamin C status of the critically ill patients with known vitamin C bioavailability data using a four-parameter log-logistic response model.. Overall, the critically ill patients exhibited hypovitaminosis C (i.e., < 23 μmol/L), with a mean plasma vitamin C concentration of 17.8 ± 8.7 μmol/L; of these, one-third had vitamin C deficiency (i.e., < 11 μmol/L). Patients with hypovitaminosis C had elevated inflammation (C-reactive protein levels; P < 0.05). The patients with septic shock had lower vitamin C concentrations and higher C-reactive protein concentrations than the non-septic patients (P < 0.05). Nearly 40% of the septic shock patients were deficient in vitamin C, compared with 25% of the non-septic patients. These low vitamin C levels were apparent despite receiving recommended intakes via enteral and/or parenteral nutritional therapy (mean 125 mg/d).. Critically ill patients have low vitamin C concentrations despite receiving standard ICU nutrition. Septic shock patients have significantly depleted vitamin C levels compared with non-septic patients, likely resulting from increased metabolism due to the enhanced inflammatory response observed in septic shock.

Topics: Aged; Ascorbic Acid; Ascorbic Acid Deficiency; Biomarkers; C-Reactive Protein; Critical Illness; Enteral Nutrition; Female; Humans; Intensive Care Units; Male; Middle Aged; New Zealand; Nutritional Requirements; Organ Dysfunction Scores; Parenteral Nutrition; Shock, Septic

The global burden of sepsis is estimated as 15 to 19 million cases annually, with a mortality rate approaching 60% in low-income countries.. In this retrospective before-after clinical study, we compared the outcome and clinical course of consecutive septic patients treated with intravenous vitamin C, hydrocortisone, and thiamine during a 7-month period (treatment group) with a control group treated in our ICU during the preceding 7 months. The primary outcome was hospital survival. A propensity score was generated to adjust the primary outcome.. There were 47 patients in both treatment and control groups, with no significant differences in baseline characteristics between the two groups. The hospital mortality was 8.5% (4 of 47) in the treatment group compared with 40.4% (19 of 47) in the control group (P < .001). The propensity adjusted odds of mortality in the patients treated with the vitamin C protocol was 0.13 (95% CI, 0.04-0.48; P = .002). The Sepsis-Related Organ Failure Assessment score decreased in all patients in the treatment group, with none developing progressive organ failure. All patients in the treatment group were weaned off vasopressors, a mean of 18.3 ± 9.8 h after starting treatment with the vitamin C protocol. The mean duration of vasopressor use was 54.9 ± 28.4 h in the control group (P < .001).. 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. Additional studies are required to confirm these preliminary findings.

Topics: Acute Kidney Injury; Administration, Intravenous; Adult; Aged; Anti-Inflammatory Agents; Antioxidants; Ascorbic Acid; Controlled Before-After Studies; Drug Therapy, Combination; Female; Hospital Mortality; Humans; Hydrocortisone; Intensive Care Units; Male; Middle Aged; Retrospective Studies; Sepsis; Shock, Septic; Thiamine; Treatment Outcome; Vasoconstrictor Agents; Vitamin B Complex

Topics: Ascorbic Acid; Humans; Intensive Care Units; Sepsis; Shock, Septic; Vitamins

Severe systemic inflammatory response to infection results in severe sepsis and septic shock, which are the leading causes of death in critically ill patients. Septic shock is characterised by refractory hypotension and is typically managed by fluid resuscitation and administration of catecholamine vasopressors such as norepinephrine. Vasopressin can also be administered to raise mean arterial pressure or decrease the norepinephrine dose. Endogenous norepinephrine and vasopressin are synthesised by the copper-containing enzymes dopamine β-hydroxylase and peptidylglycine α-amidating monooxygenase, respectively. Both of these enzymes require ascorbate as a cofactor for optimal activity. Patients with severe sepsis present with hypovitaminosis C, and pre-clinical and clinical studies have indicated that administration of high-dose ascorbate decreases the levels of pro-inflammatory biomarkers, attenuates organ dysfunction and improves haemodynamic parameters. It is conceivable that administration of ascorbate to septic patients with hypovitaminosis C could improve endogenous vasopressor synthesis and thus ameliorate the requirement for exogenously administered vasopressors. Ascorbate-dependent vasopressor synthesis represents a currently underexplored biochemical mechanism by which ascorbate could act as an adjuvant therapy for severe sepsis and septic shock.

Topics: Arginine Vasopressin; Ascorbic Acid; Hemodynamics; Humans; Norepinephrine; Sepsis; Shock, Septic; Vasoconstrictor Agents; Vasopressins

The aim of this study was to determine the effects of enrofloxacin (ENR), flunixin meglumine (FM) and dexamethasone (DEX) on antioxidant status and organ damage markers in experimentally-induced endotoxemia. Rats were divided into three groups. To induce endotoxemia, lipopolysaccharide (LPS) was injected into all groups, including the positive control. The two other groups received the following drugs (simultaneously with LPS): ENR + FM + low-dose DEX and ENR + FM + high-dose DEX. After the treatments, blood samples were collected at 0, 1, 2, 4, 6, 8, 12, 24 and 48 h. Oxidative stress parameters were determined by ELISA, while serum organ damage markers were measured by autoanalyser. LSP increased (p < 0.05) malondialdehyde, 13,14-dihydro-15-keto-prostaglandin F(2 alpha) and nitric oxide, while LPS reduced vitamin C. These changes were especially inhibited (p < 0.05) by ENR + FM + high-dose DEX. LPS increased organ damages markers. Cardiac and hepatic damage was not completely inhibited by any treatment, whereas renal damage was inhibited by two treatments. This study suggested that ENR + FM + high-dose DEX is most effective in the LPS-caused oxidative stress and organ damages.

Topics: Animals; Ascorbic Acid; Autoanalysis; Biomarkers; Clonixin; Dexamethasone; Dinoprost; Disease Models, Animal; Drug Therapy, Combination; Enrofloxacin; Enzyme-Linked Immunosorbent Assay; Female; Fluoroquinolones; Heart Diseases; Kidney Diseases; Lipopolysaccharides; Liver Diseases; Male; Malondialdehyde; Multiple Organ Failure; Nitric Oxide; Oxidative Stress; Rats; Rats, Sprague-Dawley; Shock, Septic; Superoxide Dismutase; Time Factors

Septic shock (SS)-related multiorgan dysfunction has been associated with oxidative damage, but little is known about the temporal damage profile and its relationship to severity. The present work investigated prospectively 21 SS patients. Blood samples were obtained at diagnosis, 24, 72 hours, day 7, and at 3 months. At admission, thiobarbituric acid reactive substances (TBARSs), plasma protein carbonyls, plasma protein methionine sulfoxide (MS), ferric/reducing antioxidant power (FRAP), total red blood cell glutathione (RBCG), uric acid (UA), and bilirrubin levels were increased (P < .05). Total radical-trapping antioxidant potential (TRAP) and vitamin-E were similar to controls, and vitamin-C was decreased (P < .05). During evolution, TBARS and RBCG increased (P < .001), vitamin-E levels remained stable, whereas plasma protein carbonyls and MS, TRAP, vitamin-C, reduced glutathione, and UA levels decreased (P < .006). After 3 months, plasma protein carbonyls and MS persisted elevated. More severe patients exhibited higher TBARS, TRAP, FRAP, vitamin-C, UA, and bilirrubin levels. Our results suggest early and persistent oxidative stress during septic shock and a correlation between increasing levels of lipoperoxidation and sepsis severity.

Topics: Adult; Aged; Aged, 80 and over; Antioxidants; Ascorbic Acid; Bilirubin; Blood Proteins; Female; Glutathione; Humans; Kinetics; Lipid Peroxidation; Male; Middle Aged; Oxidation-Reduction; Oxidative Stress; Prospective Studies; Protein Carbonylation; Shock, Septic; Thiobarbituric Acid Reactive Substances; Time Factors; Vitamin E

Severe septic states in humans are responsible for intense intravascular oxidative stress, which induces numerous adaptive mechanisms. We determined time sequence changes in total plasma antioxidant capacity (TAC) and major plasma antioxidant concentrations, which have not been fully explained in septic conditions. A cohort of 56 consecutive septic patients (septic shock n = 37, severe sepsis n = 19) and six healthy volunteers. We compared TAC and antioxidant levels in patients with one of two degrees of septic states, at the onset of illness, to those of healthy volunteers. Thereafter, over a 10-day follow-up, we observed daily the time sequence changes of the two septic populations in terms of TAC and antioxidants. At the onset, there was no difference between the three groups in terms of TAC values (healthy subjects 2.18 +/- 0.04; severe sepsis 2.03 +/- 0.07; septic shock 2.09 +/- 0.09), then an equivalent time decline was observed in the two septic populations whatever the severity. TAC was statistically linked to uric acid, proteins in particular albumin and bilirubin (multivariate analysis), but no correlation was found with any vitamin (A, C and E). A sharp and persistent decrease in vitamin C concentrations was underlined. TAC, unaffected at first, deteriorated over time whatever the severity of the infection in these critically ill patients. TAC, unable to distinguish severe sepsis and septic shock, is unlikely to be a particularly useful outcome measure.

Topics: Adult; Aged; Analysis of Variance; Antioxidants; Ascorbic Acid; Bilirubin; Biomarkers; Chromatography, High Pressure Liquid; Cohort Studies; Critical Illness; Female; Humans; Lipids; Male; Middle Aged; Oxidative Stress; Sepsis; Serum Albumin; Severity of Illness Index; Shock, Septic; Uric Acid; Vitamin A; Vitamin E

We investigated whether cyclooxygenase (COX) isoforms (COX-1 and COX-2) and decreased NO availability contribute to endothelial dysfunction in endotoxemic rats. The involvement of reactive oxygen species (ROS) was also evaluated. Rats were injected with Salmonella-derived lipopolysaccharide or saline. After 6 h, endothelial function of mesenteric resistance arteries was evaluated. In controls, acetylcholine (ACh)-induced relaxation was inhibited by the nitric-oxide synthase inhibitor N(G)-monomethyl-l-arginine (l-NMMA) and unaffected by 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)-phenyl-2(5H)-furanone (DFU) (COX-2 inhibitor). In lipopolysaccharide (LPS)-treated rats, the response to ACh was blunted compared with controls, less sensitive to l-NMMA, and enhanced by DFU. COX-2 blockade also improved the inhibitory effect of l-NMMA on cholinergic relaxation. SC-560 [5-(4-clorophenyl)-1-(4-metoxyphenyl)-3-trifluoromethylpirazole] (COX-1 inhibitor) did not modify the response to ACh in both groups. LPS-induced endothelial dysfunction was unaffected by the thromboxane A(2) (TxA(2)) receptor antagonist SQ-29548 (7-[3-[[2-[(phenylamino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1] hept-2-yl]-[1S(1alpha,2alpha(Z),3alpha,4alpha)]-5-heptenoic acid). In vivo inducible nitric-oxide synthase (iNOS) inhibition by S-methylisothiourea partly attenuated LPS-induced endothelial dysfunction. The antioxidants ascorbic acid and superoxide dismutase normalized endothelium-dependent relaxation and restored the inhibitory action of l-NMMA on ACh. Responses to sodium nitroprusside were similar in both groups. In LPS-treated rats, reverse transcription-polymerase chain reaction showed a marked increase in mesenteric iNOS and COX-2 expressions, whereas endothelial nitric-oxide synthase and COX-1 were unchanged. LPS-induced COX-2 overexpression was reduced but not abrogated by S-methylisothiourea. LPS-induced COX-2 up-regulation was also documented by immunohistochemistry. In conclusion, mesenteric resistance vessels from endotoxemic rats show impaired endothelial function due to reduced NO availability, a condition that is partly ascribable to an iNOS-dependent enhanced COX-2 expression, whereas TxA(2) does not seem to be involved. Oxidative stress is the main mechanism responsible for reduced NO availability, and COX-2 might act as a source of ROS.

Topics: Acetylcholine; Animals; Ascorbic Acid; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Cytokines; Endothelium, Vascular; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Norepinephrine; omega-N-Methylarginine; Oxidative Stress; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Shock, Septic; Superoxide Dismutase; Vascular Resistance; Vasoconstriction

Numerous studies support the notion that an activation of sphingomyelinases and a subsequent increase of the concentration of the bioactive lipid mediator ceramide are critical in the concert of inflammatory stimuli and to the induction of apoptosis during inflammation. Here we show that patients with severe sepsis exhibit an enhanced sphingolytic activity in comparison with controls [262 pmol/(mlxh) vs. 123.6 pmol/(mlxh), P<0.005]. During the clinical course, a further increase was paralleled by the severity of illness and by fatal outcome. Moreover, we show that oxidative stress may partially account for the increased activity through posttranslational modification of the enzyme. In a murine endotoxic shock model, administration of a low molecular weight inhibitor diminished the rise in enzymatic activity and improved the survival rate. In liver specimen, inhibition of activity correlated with a reduced rate of hepato-cellular apoptosis. Our data support the concept that activation of the plasmatic isoform of sphingomyelinase may play a critical role in the development of apoptosis and organ failure in sepsis. An inhibition of the secreted isoform of sphingomyelinase should be explored further as a potential target in the complicated puzzle of sepsis.

Topics: Adult; Aged; Animals; Apoptosis; Ascorbic Acid; Blood Chemical Analysis; Ceramides; Desipramine; Disease Models, Animal; Dose-Response Relationship, Drug; Endotoxins; Female; Gene Expression Regulation, Enzymologic; Humans; Inflammation; Lipids; Liver; Male; Mice; Mice, Inbred BALB C; Mice, Transgenic; Middle Aged; Models, Statistical; Oxidative Stress; Sepsis; Shock, Septic; Sphingomyelin Phosphodiesterase; Time Factors; Treatment Outcome

Oxidative stress, associated with a high production of reactive oxygen species (ROS) by immune cells, is involved in the endotoxic shock caused by endotoxin. This oxidative stress is linked to the inability of the immune cells to maintain adequate levels of antioxidants with free radical-scavenging action. Glutathione (GSH) and ascorbic acid (AA) are intracellular and extracellular antioxidants (ROS scavengers) that improve the leukocyte functions. Therefore, in the present work we have determined the reduced GSH and AA content in axillary nodes, spleen, thymus and peritoneal mononuclear leukocytes from BALB/c mice subjected to lethal endotoxic shock produced by intraperitoneal injection of E. coli lipopolysaccharide (LPS, 100 mg/kg), at several times (0, 2, 4, 12 and 24 h) after LPS injection. Endotoxic shock decreased the levels of AA in the leukocytes from the three organs as well as the levels of GSH in axillary nodes and spleen cells while it increased the GSH levels in thymus and peritoneum. These results are in agreement with the oxidative stress and the altered function previously observed in those leukocytes, and they suggest that antioxidant administration may be useful for the treatment of endotoxic shock and other oxidative stress situations with altered immunological responses.

Topics: Animals; Ascorbic Acid; Female; Glutathione; Leukocytes, Mononuclear; Lipopolysaccharides; Mice; Mice, Inbred BALB C; Oxidative Stress; Shock, Septic

Oxidative stress associated with reactive oxygen species (ROS) and cytokines produced by immune cells, which is involved in septic shock caused by endotoxin, can be controlled to a certain degree by antioxidants with free radical scavenging action. N-acetylcysteine (NAC) and ascorbic acid (AA) are ROS scavengers that improve the immune response, and modulate macrophage function in mice with endotoxin-caused oxidative stress. Therefore, we have investigated the in vitro effects of these antioxidants on the functions of lymphocytes from BALB/c mice with lethal endotoxic shock caused by intraperitoneal injection of E. coli lipopolysaccharide (LPS) (100 mg/kg). Adherence to tissues and chemotaxis (the earliest two functions of lymphocytes in the immune response), as well as ROS levels and TNF alpha production were determined in the presence or absence of NAC or AA (0.001, 0.01, 0.1, 1 and 2.5 mM) in lymphocytes from peritoneum, axillary nodes, spleen and thymus obtained at several times (2, 4, 12 and 24 hours) after LPS injection. Endotoxic shock decreases the chemotaxis of lymphocytes from all the above localizations and increases their adherence, TNF alpha and ROS production. These changes in lymphocyte function were counteracted by NAC and AA, bringing these functions to values near those of control animals. Our data suggest that lymphocytes are important targets of endotoxins contributing to oxidative stress by septic shock, and that antioxidants can preserve the function of lymphocytes, preventing the homeostatic disturbances caused by endotoxin.

Topics: Acetylcysteine; Animals; Antioxidants; Ascorbic Acid; Cell Adhesion; Cells, Cultured; Chemotaxis; Escherichia coli; Female; In Vitro Techniques; Lipopolysaccharides; Lymphocytes; Mice; Mice, Inbred BALB C; Oxidative Stress; Phagocytosis; Reactive Oxygen Species; Shock, Septic; Tumor Necrosis Factor-alpha

Ascorbic acid (AA) is an important cytoplasmic antioxidant that mice synthesize in the liver, the intracellular levels of which decrease in an oxidative stress situation such as endotoxic shock. The present work deals with the changes in AA levels, that modulate the immune function, in the two main immune cells, namely macrophages and lymphocytes, from female BALB/c mice suffering endotoxic shock caused by intraperitoneal injection of Escherichia coli lipopolysaccharide (LPS) (100 mg/kg). The intake by cells of this antioxidant present in vitro at different concentrations was also studied. The animals show an oxidative stress, standardized in previous studies, that causes mortality at 30 h after LPS injection. The cells were obtained from the peritoneum at 2, 4, 12 and 24 h after LPS or PBS (control) injections and were incubated without or with AA at 0.01, 0.1 and 1 mM for 10, 30, 60, 120 or 180 min. The hepatic AA levels were also studied at 0, 2, 4, 12 and 24 h after LPS injection. The peritoneal cells obtained from animals injected with LPS showed increased AA levels in relation to the control cells at all times after LPS injection, with maximal effect at 12h. The AA levels decreased after this time, in agreement with changes in the AA hepatic levels. The increase was due to the AA of lymphocytes since macrophages showed a decrease in AA at different times after LPS injection. Both cells showed an increase in the intracellular levels of AA when this antioxidant was added in vitro. This takes place mainly at 30-60 min of incubation in cells from controls and at 10 min in cells from treated mice 12-24 h after LPS injection. The incorporation decreased at these times of endotoxic shock, a few hours before death. In all cases AA levels were higher in lymphocytes than in macrophages, and 1 mM was the most effective concentration. These results suggest that the immune cells need appropriate levels of antioxidants, such as AA, under oxidative stress conditions, and that while lymphocytes take and accumulate AA, macrophages use it.

Topics: Animals; Ascorbic Acid; Endotoxins; Female; Liver; Lymphocytes; Macrophages, Peritoneal; Mice; Mice, Inbred BALB C; Oxidative Stress; Shock, Septic; Time Factors

The toxic effects of oxygen radicals produced by immune cells can be controlled to certain degree by endogenous antioxidants because of their scavenger action. This control is specially important in a type of immune cell, i.e., the phagocyte, which produces oxygen-free radicals and uses antioxidants in order to support its functions. Antioxidants, such as ascorbic acid (AA), are free radical scavengers and improve the immune response. In the pathogenesis of endotoxic shock, a disease with high mortality caused by gram-negative bacterial endotoxin, the reactive oxygen species (ROS) produced by phagocytes have been implicated. In a previous study, we observed in peritoneal macrophages from BALB/c mice suffering lethal endotoxic shock caused by intraperitoneal (i.p.) injection of Escherichia coli lipopolysaccharide (LPS; 100 mg/kg) a high production of superoxide anion. Therefore, in the present work, we have studied the in vitro effect of AA, at different concentrations (0.001, 0.01, 0.1, 1 and 2.5 mM), on the various steps of the phagocytic process, i.e., adherence to substrate, chemotaxis, ingestion of particles and superoxide anion production of murine peritoneal macrophages obtained from BALB/c mice with that of endotoxic shock, at 2, 4, 12 and 24 h after LPS injection. The increased adherence, ingestion and superoxide anion production by macrophages from animals with endotoxic shock were lower in the presence of AA, reaching similar values to those of the control animals. The most effective AA concentration in cells from mice with endotoxic shock was 0.01 mM. These data suggest that AA can regulate the phagocytic process in endotoxic shock, principally decreasing free radical production and thus it could reduce endotoxic shock severity.

Topics: Animals; Antioxidants; Ascorbic Acid; Cell Adhesion; Chemotaxis; Escherichia coli; Female; Lipopolysaccharides; Macrophages; Mice; Mice, Inbred BALB C; Phagocytosis; Shock, Septic; Superoxides; Tumor Necrosis Factor-alpha

Injection of guinea pigs with a single dose of Escherichia coli lipopolysaccharide (3.2 mg/100 g) induces a reversible endotoxic shock that was evaluated by measuring plasma glucose levels and aspartate aminotransferase activity at 24 h after lipopolysaccharide injection. The hypoglycaemia and the increase in plasma aminotransferase activity observed, correlated with the alterations found during the recovery phase of endotoxic shock. When lipid peroxidation and some antioxidant systems were measured in lungs from treated animals, we only found differences in ascorbic acid content, that was decreased by 50%. Lipopolysaccharide treatment results in a depression of pulmonary phosphatidylcholine synthesis, that correlates with the surfactant deficiencies associated with respiratory illnesses in septic shock. Guinea pigs fed on a diet with a low content in ascorbic acid were more sensitive to endotoxin. In these animals we found no detectable levels of ascorbic acid in lung, whereas both vitamin E lung levels and pulmonary phosphatidylcholine synthesis were significantly decreased. Our results point out the significance of ascorbic acid in the protection against oxidative lung injury associated to endotoxaemia, and validate our shock model for further studies on the mechanisms of this pathological condition.

Topics: Animals; Antioxidants; Ascorbic Acid; Endotoxemia; Escherichia coli; Guinea Pigs; Lipid Peroxidation; Lipopolysaccharides; Lung; Male; Phosphatidylcholines; Shock, Septic; Superoxide Dismutase; Vitamin E

Topics: Age Factors; Animals; Ascorbic Acid; Avitaminosis; Endotoxins; Escherichia coli; Guinea Pigs; Lung; Myocardium; Scurvy; Shock, Septic