ascorbic-acid and Sepsis

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 high-incidence disease and demands intensive care. Finding effective treatment is the key to cure sepsis. Studies have shown a lower level of vitamin C in patients with sepsis. Therefore, vitamin C supplementation has become one of the measures to treat sepsis. However, the clinical studies of vitamin C in the treatment of sepsis have been controversial. We performed a meta-analysis to evaluate vitamin C's efficacy and safety in the treatment of sepsis. We searched four electronic databases: PubMed, Embase, Web of Science, and the Cochrane Library, and two researchers independently screened 24 eligible RCTs published in English. Our review demonstrates that intravenous (IV) vitamin C might improve short-term mortality (RR, 0.82; 95% CI, 0.65-1.02;

Topics: Ascorbic Acid; Humans; Multicenter Studies as Topic; Sepsis; 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

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, with a high morbidity and mortality rate. Exogenous vitamin C supplementation is a potential therapeutic option for the treatment of multi-organ dysfunction in sepsis due to the significantly lower levels of vitamin C in the circulating blood of sepsis patients compared to healthy subjects and the importance of vitamin C in many of the physiological processes of sepsis. Vitamin C may influence the function of numerous organs and systems, including the heart, lungs, kidneys, brain, and immune defences, by reducing oxidative stress, inhibiting inflammatory factor surges, regulating the synthesis of various mediators and hormones, and enhancing immune cell function. With the development of multiple clinical randomized controlled trials, the outcomes of vitamin C treatment for critically ill patients have been discussed anew. This review's objectives are to provide an overview of how vitamin C affects various organ functions in sepsis and to illustrate how it affects each organ. Understanding the pharmacological mechanism of vitamin C and the organ damage caused by sepsis may help to clarify the conditions and clinical applications of vitamin C.

Topics: Ascorbic Acid; Heart; Humans; Multiple Organ Failure; Oxidative Stress; Randomized Controlled Trials as Topic; Sepsis

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

To conduct a systematic review and meta-analysis to evaluate the impact of IV vitamin C on outcomes in critically ill patients.. Systematic search of MEDLINE, EMBASE, CINAHL, and the Cochrane Register of Controlled Trials.. Randomized controlled trials testing IV vitamin C in critically ill patients.. Two independent reviewers abstracted patient characteristics, treatment details, and clinical outcomes.. Fifteen studies involving 2,490 patients were identified. Compared with placebo, IV vitamin C administration is associated with a trend toward reduced overall mortality (relative risk, 0.87; 95% CI, 0.75-1.00; p = 0.06; test for heterogeneity I2 = 6%). High-dose IV vitamin C was associated with a significant reduction in overall mortality (relative risk, 0.70; 95% CI, 0.52-0.96; p = 0.03), whereas low-dose IV vitamin C had no effect (relative risk, 0.94; 95% CI, 0.79-1.07; p = 0.46; test for subgroup differences, p = 0.14). IV vitamin C monotherapy was associated with a significant reduction in overall mortality (relative risk, 0.64; 95% CI, 0.49-0.83; p = 0.006), whereas there was no effect with IV vitamin C combined therapy. No trial reported an increase in adverse events related to IV vitamin C.. IV vitamin C administration appears safe and may be associated with a trend toward reduction in overall mortality. High-dose IV vitamin C monotherapy may be associated with improved overall mortality, and further randomized controlled trials are warranted.

Topics: Antioxidants; Ascorbic Acid; Critical Illness; Dose-Response Relationship, Drug; Humans; Sepsis; Treatment Outcome

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

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

Topics: Animals; Ascorbic Acid; Critical Illness; Humans; Hydrocortisone; Sepsis; Sheep; Thiamine; Vitamins

Clinical rationale for study: Despite advancements in critical care, the mortality rate of sepsis remains high, with an overall poor prognosis. There is a complex pathophysiology of a lethal cascade of cytokines and inflammatory proteins underlying sepsis. The use of vitamin C can theoretically suppress the inflammatory cascade but remains a questionable practice due to a lack of conclusive evidence. Aims of the study: To appraise the therapeutic role of vitamin C in sepsis. Materials and methods: A systematic review was conducted on PubMed, Embase, and the Central Cochrane Registry. The study included randomized clinical trials (RCTs) with vitamin C as an intervention arm in the septic patient population. For continuous variables, the difference in means (MD) and for discrete variables, the odds ratio (OR) was used. For effect sizes, a confidence interval of 95% was used. A p-value of less than 0.05 was used for statistical significance. The analysis was performed using a random-effects model irrespective of heterogeneity. Heterogeneity was evaluated using the I2 statistic. Results: 23 studies were included with the total sample size of 2712 patients. In patients treated with vitamin C, there was a statistically significant reduction in the mortality: OR = 0.778 (0.635 to 0.954), p = 0.016; the sequential organ failure assessment score (SOFA): MD = −0.749 (−1.115 to −0.383), p < 0.001; and the duration of vasopressor requirement: MD = −1.034 days (−1.622 to −0.445), p = 0.001. No significant difference was found in the hospital or ICU length of stay. Conclusions and clinical implications: Vitamin C treatment regimens were associated with reduced mortality, SOFA score, and vasopressor requirement compared to the control in sepsis. Given its low cost and minimal adverse effects, we strongly encourage further large, randomized trials to establish vitamin C as a standard of care in sepsis management.

Topics: Ascorbic Acid; Critical Care; Humans; Organ Dysfunction Scores; Sepsis

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

Vitamin C, also known as ascorbic acid or ascorbate, is a water-soluble vitamin synthesized in plants as well as in animals except humans and several other animal species. Humans obtain vitamin C from dietary sources and via vitamin supplementation. Vitamin C possesses important biological functions, including serving as a cofactor for many enzymes, acting as an antioxidant and anti-inflammatory compound, and participating in regulating stem cell biology and epigenetics. The multifunctional nature of vitamin C contributes to its essentialness in maintaining and safeguarding physiological homeostasis, especially regulation of immunity and inflammatory responses. In this context, vitamin C has been investigated for its efficacy in treating diverse inflammatory disorders, including sepsis, one of the major causes of death globally and for which currently there is no cure. Accordingly, this Mini-Review surveys recent major research findings on the effectiveness of vitamin C and the underling molecular mechanisms in sepsis intervention in both experimental animal models and randomized controlled trials. To set a stage for discussing the effects and mechanisms of vitamin C in sepsis intervention, this Mini-Review begins with an overview of vitamin C redox biochemistry and its multifunctional properties.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Ascorbic Acid; Clinical Trials as Topic; Humans; Oxidation-Reduction; Sepsis

The aim of this study was to conduct a systematic review and meta-analysis of randomized controlled trials to investigate whether IV high-dose vitamin C improves the short-term mortality of patients with sepsis.. This study is a systematic review and meta-analysis of randomized controlled trials. We searched EMBASE, the Cochrane Central Register of Controlled Trials, and MEDLINE for randomized controlled trials that met inclusion criteria. The protocol was registered at the University hospital Medical Information Network Clinical Trials Registry (UMIN000040528). All analyses were presented with the use of random-effects models. The primary outcome was short-term mortality defined as 28-day, 30-day, or in-hospital mortality.. Two authors independently evaluated the following eligibility criteria: 1) randomized controlled trial, 2) patients with sepsis aged ≥18 years, and 3) received intravenous high-dose vitamin C in addition to standard of care, or standard of care alone. Then, two authors independently extracted the selected patient and study characteristics and outcomes from studies that met above eligibility criteria.. Eleven randomized controlled trials (n = 1,737 patients) were included in this meta-analysis. High-dose IV vitamin C was not associated with a significantly lower short-term mortality (risk ratio, 0.88; 95% CI, 0.73-1.06; p = 0.18; I2 = 29%) but was associated with a significantly shorter duration of vasopressor use (standardized mean difference, -0.35; 95% CI, -0.63 to -0.07; p < 0.01; I2 = 80%) and a significantly greater decline in the Sequential Organ Failure Assessment score at 72-96 hours (standardized mean difference, -0.20; 95% CI, -0.32 to -0.08; p < 0.01; I2 = 16%). One study reported significant association with hypernatremia, but adverse effects were rare, and high-dose vitamin C is deemed relatively safe.. In this meta-analysis, the use of IV high-dose vitamin C in patients with sepsis was not associated with lower short-term mortality although it was associated with significantly shorter duration of vasopressor use and greater decline in the Sequential Organ Failure Assessment score at 72-96 hours.

Topics: Ascorbic Acid; Dose-Response Relationship, Drug; Humans; Randomized Controlled Trials as Topic; Sepsis

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

Sepsis is a common condition in the ICU. Despite much research, its prognosis remains poor. In 2017, a retrospective before/after study reported promising results using a combination of thiamine, ascorbic acid, and hydrocortisone called "metabolic resuscitation cocktail" and several randomized controlled trials assessing its effectiveness were performed.. We conducted a systematic review and meta-analysis of randomized controlled trials in septic ICU patients to assess the effects of this combination therapy.. PubMed, Embase, and the Cochrane library databases were searched from inception to March of 2021. Data were extracted independently by two authors. The main outcome was the change in Sequential Organ Failure Assessment score within 72 hours. Secondary outcomes included renal composite endpoints (acute kidney injury) Kidney Disease - Improving Global Outcome organization stage 3 or need for renal replacement therapy, vasopressor duration, and 28-day mortality.. We included randomized controlled trials with patients admitted to the ICU with sepsis or septic shock.. The trials compared a combination of thiamine, ascorbic acid, and hydrocortisone to standard care or placebo in patients admitted to ICU with sepsis or septic shock.. We included eight randomized controlled trials (n = 1,335 patients). Within 72 hours, the median of mean improvement was -1.8 and -3.2 in the control and intervention groups, respectively (eight randomized controlled trials, n = 1,253 patients); weighted mean difference -0.82 (95% CI, -1.15 to -0.48). Data were homogeneous and the funnel plot did not suggest any publication bias. Duration of vasopressor requirement was significantly reduced in the intervention group (six randomized controlled trials). There was no evidence of a difference regarding the ICU mortality and the renal composite outcome (acute kidney injury KDIGO 3 or need for renal replacement therapy, seven randomized controlled trials).. Metabolic resuscitation cocktail administrated in ICU septic patients improves change in Sequential Organ Failure Assessment score within 72 hours. However, this improvement is modest and its clinical relevance is questionable. The impact on renal failure and mortality remains unclear.

Topics: Ascorbic Acid; Drug Combinations; Humans; Hydrocortisone; Metabolism; Ontario; Randomized Controlled Trials as Topic; Sepsis; Thiamine

To systematically evaluate the effect of hydrocortisone combined with vitamin C and vitamin B1 on the efficacy of patients with sepsis or septic shock.. Databases including CNKI, Sino Med, VIP, Wanfang, PubMed, the Cochrane Library, and Embase were searched from inception to January 2021 for the randomized controlled trial (RCT) about hydrocortisone combined with vitamin C and vitamin B1 to treat sepsis or septic shock. The experimental group was given intravenous injection of hydrocortisone, vitamin B1 and vitamin C based on conventional treatment; the control group was given conventional treatment or placebo/hydrocortisone/hydrocortisone+vitamin B1 based on conventional treatment. Outcome indicators included sequential organ failure assessment (SOFA), mortality, the duration of vasoactive drugs, new acute kidney injury (AKI) patients, length of stay in intensive care unit (ICU) and in hospital. Two researchers independently screened the literature, extracted data, and evaluated the risk of bias in the included studies. RevMan 5.3 software was then used to perform Meta-analysis. Funnel plot was used to test publication bias.. A total of 6 articles involving 816 patients were included, with 411 patients in the experimental group and 405 patients in the control group. The Meta-analysis results showed that the duration of vasoactive drugs in the experimental group was significantly shorter than that in the control group [mean difference (MD) = -24.02, 95% confidence interval (95%CI) was -32.36 to -15.68, P < 0.000 01]. However, there were no significant differences in SOFA, mortality, new AKI patients, the length of ICU stay and hospital stay between the two groups [SOFA: MD = -0.14, 95%CI was -1.15 to 0.87, P = 0.79; mortality: relative risk (RR) = 0.99, 95%CI was 0.81 to 1.21, P = 0.92; new AKI patients: RR = 1.10, 95%CI was 0.42 to 2.87, P = 0.84; length of ICU stay: MD = 1.33, 95%CI was -2.22 to 4.89, P = 0.46; length of hospital stay: MD = 1.02, 95%CI was -0.66 to 2.69, P = 0.23]. The funnel plot showed that most of the points were symmetrical and showed an inverted funnel shape, suggesting that the publication bias among the studies was small. There was no significant publication bias on this Meta-analysis.. Hydrocortisone combined with vitamin C and vitamin B1 can shorten the duration of vasoactive drugs in patients with sepsis or septic shock, but it cannot effectively reduce the SOFA score, mortality, new AKI patients, length of stay in ICU and in hospital. Limited by the number and quality of the included studies, further large-scale, multi-center, blinded, RCT are still needed for verification.

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

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 induced by bacteria or viruses can result in multiorgan dysfunction, which is a major cause of death in intensive care units. Current treatments are only supportive, and there are no treatments that reverse the pathophysiological effects of sepsis. Vitamin C has antioxidant, anti-inflammatory, anticoagulant and immune modulatory actions, so it is a rational treatment for sepsis. Here, we summarise data that support the use of megadose vitamin C as a treatment for sepsis and COVID-19. Megadose intravenous sodium ascorbate (150 g per 40 kg over 7 h) dramatically improved the clinical state and cardiovascular, pulmonary, hepatic and renal function and decreased body temperature, in a clinically relevant ovine model of Gram-negative bacteria-induced sepsis. In a critically ill COVID-19 patient, intravenous sodium ascorbate (60 g) restored arterial pressure, improved renal function and increased arterial blood oxygen levels. These findings suggest that megadose vitamin C should be trialled as a treatment for sepsis and COVID-19.

Topics: Animals; Ascorbic Acid; COVID-19; Humans; Multiple Organ Failure; SARS-CoV-2; Sepsis; Sheep

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

Previous studies have suggested the beneficial effects of vitamin C in patients with sepsis. However, the results could not be reproduced in the subsequent studies. This meta-analysis aimed to reevaluate the value of vitamin C treatment in patients with sepsis. Electronic databases were searched from inception to August 2019 for the studies comparing the effect of vitamin C versus non-vitamin C infusion in patients with sepsis. Data from 10 studies (4 randomized controlled trials [RCTs] and 6 retrospective studies) involving 1671 patients (495 in the vitamin C treatment group and 1176 in the control group) were included. The use of vitamin C did not reduce the risk of 28-day (OR = 0.84, P = 0.611, I

Topics: Ascorbic Acid; Drug Therapy, Combination; Hospital Mortality; Humans; Intensive Care Units; Length of Stay; Randomized Controlled Trials as Topic; Sepsis; Time Factors; Treatment Outcome; Vasoconstrictor Agents

Mitochondrial dysfunction seems to be the common denominator of several critical care conditions and particularly of sepsis. Faced with relative failure, and limited progress of sepsis therapies aiming at blocking some oxidative and/or inflammatory pathways, the question of antioxidants micronutrient therapy, particularly of selenium, ascorbic acid and thiamine remains open.. The rationale for the essentiality of numerous micronutrients within the mitochondria is well established. Many studies have tested single micronutrients in animal and in-vitro models and provide positive evidences in favor of reduction of organ failure (cardiac and renal mainly). In clinical settings, high-dose selenium administration in sepsis has been disappointing. The most recent high dose, short-term ascorbic acid trial in sepsis is promising though, with an associated reduction of mortality, but analysis of the impact of this intervention on the various organs remains to be conducted.. Results from animal and human studies indicate that there are indeed intervention options at the level of the mitochondria, but neither the optimal dose nor the optimal combination of micronutrients is yet identified.

Topics: Animals; Antioxidants; Ascorbic Acid; Critical Care; Critical Care Outcomes; Critical Illness; Humans; Micronutrients; Mitochondria; Nutrition Therapy; Oxidative Stress; Selenium; Sepsis; Thiamine

Sepsis, a life-threatening organ dysfunction due to a dysregulated host response to infection, is a leading cause of morbidity and mortality worldwide. Decades of research have failed to identify any specific therapeutic targets outside of antibiotics, infectious source elimination, and supportive care. More recently, vitamin C has emerged as a potential therapeutic agent to treat sepsis. Vitamin C has been shown to be deficient in septic patients and the administration of high dose intravenous as opposed to oral vitamin C leads to markedly improved and elevated serum levels. Its physiologic role in sepsis includes attenuating oxidative stress and inflammation, improving vasopressor synthesis, enhancing immune cell function, improving endovascular function, and epigenetic immunologic modifications. Multiple clinical trials have demonstrated the safety of vitamin C and two recent studies have shown promising data on mortality improvement. Currently, larger randomized controlled studies are underway to validate these findings. With further study, vitamin C may become standard of care for the treatment of sepsis, but given its safety profile, current treatment can be justified with compassionate use.

Topics: Administration, Intravenous; Ascorbic Acid; Humans; Sepsis; Vitamins

Nutrition therapy in sepsis is challenging and differs from the standard feeding approach in critically ill patients. The dysregulated host response caused by infection induces progressive physiologic alterations, which may limit metabolic capacity by impairing mitochondrial function. Hence, early artificial nutrition should be ramped-up and emphasis laid on the post-acute phase of critical illness. Caloric dosing is ideally guided by indirect calorimetry, and endogenous energy production should be considered. Proteins should initially be delivered at low volume and progressively increased to 1.3 g/kg/day following shock symptoms wane. Both the enteral and parenteral route can be (simultaneously) used to cover caloric and protein targets. Regarding pharmaconutrition, a low dose glutamine seems appropriate in patients receiving parenteral nutrition. Supplementing arginine or selenium is not recommended. High-dose vitamin C administration may offer substantial benefit, but actual evidence is too limited for advocating its routine use in sepsis. Omega-3 polyunsaturated fatty acids to modulate metabolic processes can be safely used, but non-inferiority to other intravenous lipid emulsions remains unproven in septic patients. Nutrition stewardship, defined as the whole of interventions to optimize nutritional approach and treatment, should be pursued in all septic patients but may be difficult to accomplish within a context of profoundly altered cellular metabolic processes and organ dysfunction caused by time-bound excessive inflammation and/or immune suppression. This review aims to provide an overview and practical recommendations of all aspects of nutritional therapy in the setting of sepsis.

Topics: Ascorbic Acid; Critical Care; Critical Illness; Enteral Nutrition; Fatty Acids, Omega-3; Glutamine; Humans; Nutrition Therapy; Nutritional Requirements; Nutritional Support; Parenteral Nutrition; Sepsis

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 is a global health issue, and there is a need for effective, low-cost adjunct metabolic treatments. Corticosteroids have been investigated in many trials for decades, and recently the administration of vitamin C, thiamine (vitamin B1), and vitamin D have been proposed as novel therapies in patients with sepsis.. APROCCHSS (N = 1241) and ADRENAL (N = 3800) trial reported inconsistent results in mortality outcome; however, both demonstrated a decreased duration of shock with low-dose corticosteroids. The CITRIS-ALI trial (N = 170) examined the effects of intravenous vitamin C 200 mg/kg/day and reported no effect on organ dysfunction or biomarkers. The VITAMINS trial (N = 216) compared combination therapy of vitamin C 6 g/day, thiamine 200 mg/day, and hydrocortisone 200 mg/day with hydrocortisone alone to find that the combination did not increase vasopressor free time. A single trial (N = 88) evaluating the effect of thiamine in patients with sepsis reported a neutral result. Two randomized trials (N = 475 and N = 1360) on the supplementation of vitamin D in the critically ill patients did not identify statistically significant reduction in mortality.. Evidence from high-quality research is still insufficient to support the use of vitamin C, thiamine, and vitamin D as metabolic support in sepsis treatment.

Topics: Adrenal Cortex Hormones; Ascorbic Acid; Humans; Sepsis; Thiamine; Vitamins

Sepsis care has evolved significantly since the initial early goal-directed therapy (EGDT) trials. Early fluid resuscitation, source control, and antibiotic therapy remain cornerstones of care but overall understanding is more nuanced, particularly regarding fluid selection, vasopressors, and inotropic support. Timely nutrition therapy and ventilatory support tend to receive less attention but also are important. Recent research has explored immunomodulation, β-blockade, and vitamin supplementation. A renewed emphasis on early, aggressive resuscitation reaffirms the importance of emergency medicine providers knowledgeable and skilled in sepsis management.

Topics: Angiotensin II; Anti-Bacterial Agents; Antioxidants; Ascorbic Acid; Blood Glucose; Blood Pressure; Cardiomyopathies; Cardiotonic Agents; Critical Illness; Emergency Service, Hospital; Enteral Nutrition; Fluid Therapy; Glucocorticoids; Hemodynamics; Humans; Organ Dysfunction Scores; Randomized Controlled Trials as Topic; Respiration, Artificial; Resuscitation; Sepsis; Vasoconstrictor Agents

There are limited proven therapies for COVID-19. Vitamin C's antioxidant, anti-inflammatory and immunomodulating effects make it a potential therapeutic candidate, both for the prevention and amelioration of COVID-19 infection, and as an adjunctive therapy in the critical care of COVID-19. This literature review focuses on vitamin C deficiency in respiratory infections, including COVID-19, and the mechanisms of action in infectious disease, including support of the stress response, its role in preventing and treating colds and pneumonia, and its role in treating sepsis and COVID-19. The evidence to date indicates that oral vitamin C (2-8 g/day) may reduce the incidence and duration of respiratory infections and intravenous vitamin C (6-24 g/day) has been shown to reduce mortality, intensive care unit (ICU) and hospital stays, and time on mechanical ventilation for severe respiratory infections. Further trials are urgently warranted. Given the favourable safety profile and low cost of vitamin C, and the frequency of vitamin C deficiency in respiratory infections, it may be worthwhile testing patients' vitamin C status and treating them accordingly with intravenous administration within ICUs and oral administration in hospitalised persons with COVID-19.

Topics: Administration, Intravenous; Administration, Oral; Anti-Inflammatory Agents; Ascorbic Acid; Ascorbic Acid Deficiency; Chemotherapy, Adjuvant; COVID-19; COVID-19 Drug Treatment; Critical Care; Hospitalization; Humans; Immunologic Factors; Intensive Care Units; Nutritional Status; Pandemics; Respiration, Artificial; Respiratory Tract Infections; SARS-CoV-2; Sepsis; 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-3 guidelines have implications in a deeper understanding of the biopathology of the disease. Further, the review focuses on timely topics and new literature on fluid resuscitation, the value of steroids in sepsis, and new therapeutic options such as angiotensin II, vitamin C, and thiamine as well as the emerging role of procalcitonin (PCT) in managing antibiotics.. Traditional therapies such as type of crystalloid fluid administration and steroid therapy for sepsis are currently under re-evaluation. Angiotensin II is investigated for reversing vasodilatory shock. The role of capillary endothelium leak and cellular metabolism can be affected by vitamin C and thiamine levels. Biomarker level trends, specifically PCT, can aid clinical suspicion of infection.. Sepsis-3 shifts the focus from a noninfectious inflammatory process and an emphasis on a dysregulated host response to infection. Hyperchloremic crystalloid resuscitation is associated with poor clinical outcomes. Steroid administration can reverse shock physiology; however, mortality benefits remain uncertain. Angiotensin II, vitamin C, and thiamine are novel treatment options that need further validation. PCT assays can help discern between infectious and noninfectious inflammation.

Topics: Angiotensin II; Anti-Bacterial Agents; Ascorbic Acid; Biomarkers; Combined Modality Therapy; Critical Care; Fluid Therapy; Glucocorticoids; Humans; Practice Guidelines as Topic; Procalcitonin; Resuscitation; Sepsis; Thiamine; Treatment Outcome

Although vitamin C is essentially a nontoxic vitamin; however, it is important to be aware regarding the safety of high doses before the wide clinical use.. Minor side effects of vitamin C have been reported, many being reported in earlier studies. High doses of vitamin C (up to 1.5 g/kg three times a week as intravenously) were safe in cancer patients with normal renal function and perfect glucose-6-phosphate dehydrogenase activity. As the dose and duration of administration of vitamin C in sepsis are lower and shorter than those used in cancer patients, it seems that it is relatively safe for this population. In ongoing trials, safety of high doses of vitamin C is considered.. Data regarding the safety of high doses of vitamin C are scant. Until more data become available, caution should be applied in the use of high doses of vitamin C in patients with hemochromatosis, glucose-6-phosphate dehydrogenase deficiency, renal dysfunction, kidney stone, oxaluria, and pediatrics.

Topics: Ascorbic Acid; Clinical Trials as Topic; Humans; Neoplasms; Sepsis

This narrative review summarizes recent insights into the role of vitamin C in sepsis.. Septic shock remains a major source of morbidity and mortality in critically ill patients. Although many nutritional supplements have previously been tested unsuccessfully, vitamins are still being explored as a therapeutic option in septic patients. In particular, vitamin C-containing regimens as adjunctive therapy in sepsis have received much attention.. In-vitro evidence supports a critical role for vitamin C in cellular mechanisms relevant to the pathophysiology of sepsis. However, whether this justifies therapeutic use of vitamin C in septic patients remains uncertain.

Topics: Ascorbic Acid; Critical Illness; Humans; Sepsis

A shortcut review was carried out to establish whether the use of intravenous vitamin C can reduce mortality or morbidity in patients diagnosed in the early phases of severe sepsis. Three directly relevant papers were found using the reported search strategy. The author, date and country of publication; patient group studied; study type; relevant outcomes; results and study weaknesses of the best papers are tabulated. It is concluded that there is insufficient high-quality research to justify the routine use of vitamin C in severe sepsis. Further multicentre, double-blinded randomised controlled trials are required in order to establish the role of vitamin C in sepsis.

Topics: Administration, Intravenous; Ascorbic Acid; Humans; Sepsis; Treatment Outcome

Most vertebrates can synthesize vitamin C with synthesis increasing during stress. Humans, however, have lost the ability to synthesize vitamin C. Vitamin C is an important anti-oxidant and an enzyme cofactor for many important biological reactions. Sepsis results in the overwhelming production of reactive oxygen species with widespread endothelial, cellular and mitochondrial injury leading to progressive organ failure. Sepsis is associated with an acute deficiency of vitamin C. In experimental sepsis models, intravenous vitamin C reduces organ injury and improves survival. In addition, emerging evidence suggests that the combination of vitamin C, corticosteroids and thiamine may act synergistically to reverse sepsis induced organ dysfunction. These findings are supported by a recent observational study. Randomized controlled trials are underway to investigate this novel approach to the treatment of sepsis.

Topics: Adrenal Cortex Hormones; Animals; Antioxidants; Ascorbic Acid; Critical Illness; Humans; Sepsis; Thiamine; Vitamins

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: Antioxidants; Ascorbic Acid; Burns; Hemorrhage; Humans; Sepsis; Wounds and Injuries

Evidence is emerging that parenteral administration of high-dose vitamin C and thiamine may be a beneficial adjuvant therapy of severe sepsis and septic shock. Despite modern practices in critical care medicine, sepsis and severe sepsis remain a leading cause of morbidity and mortality in the critical care unit.

Topics: Antioxidants; Ascorbic Acid; Critical Care; Hospital Mortality; Humans; Intensive Care Units; Sepsis; Thiamine; Vitamin B Complex

The combination of thiamine, ascorbic acid, and hydrocortisone has recently emerged as a potential adjunctive therapy to antibiotics, infectious source control, and supportive care for patients with sepsis and septic shock. In the present manuscript, we provide a comprehensive review of the pathophysiologic basis and supporting research for each element of the thiamine, ascorbic acid, and hydrocortisone drug combination in sepsis. In addition, we describe potential areas of synergy between these therapies and discuss the strengths/weaknesses of the two studies to date which have evaluated the drug combination in patients with severe infection. Finally, we describe the current state of current clinical practice as it relates to the thiamine, ascorbic acid, and hydrocortisone combination and present an overview of the randomized, placebo-controlled, multi-center Ascorbic acid, Corticosteroids, and Thiamine in Sepsis (ACTS) trial and other planned/ongoing randomized clinical trials.

Topics: Adrenal Cortex Hormones; Anti-Bacterial Agents; Ascorbic Acid; Drug Therapy, Combination; Humans; Hydrocortisone; Models, Biological; Sepsis; Thiamine

Sepsis is a devastating disease that carries an enormous toll in terms of human suffering and lives lost. Over 100 novel pharmacologic agents that targeted specific molecules or pathways have failed to improve the outcome of sepsis. Preliminary data suggests that the combination of Hydrocortisone, Ascorbic Acid and Thiamine (HAT therapy) may reduce organ failure and mortality in patients with sepsis and septic shock. HAT therapy is based on the concept that a combination of readily available, safe and cheap agents, which target multiple components of the host's response to an infectious agent, will synergistically restore the dysregulated immune response and thereby prevent organ failure and death. This paper reviews the rationale for HAT therapy with a focus on vitamin C.

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

This narrative review summarizes the role of vitamin C in mitigating oxidative injury-induced microcirculatory impairment and associated organ failure in ischemia/reperfusion or sepsis. Preclinical studies show that high-dose vitamin C can prevent or restore microcirculatory flow impairment by inhibiting activation of nicotinamide adenine dinucleotide phosphate-oxidase and inducible nitric oxide synthase, augmenting tetrahydrobiopterin, preventing uncoupling of oxidative phosphorylation, and decreasing the formation of superoxide and peroxynitrite, and by directly scavenging superoxide. Vitamin C can additionally restore vascular responsiveness to vasoconstrictors, preserve endothelial barrier by maintaining cyclic guanylate phosphatase and occludin phosphorylation and preventing apoptosis. Finally, high-dose vitamin C can augment antibacterial defense. These protective effects against overwhelming oxidative stress due to ischemia/reperfusion, sepsis or burn seems to mitigate organ injury and dysfunction, and promote recovery after cardiac revascularization and in critically ill patients, in the latter partially in combination with other antioxidants. Of note, several questions remain to be solved, including optimal dose, timing and combination of vitamin C with other antioxidants. The combination obviously offers a synergistic effect and seems reasonable during sustained critical illness. High-dose vitamin C, however, provides a cheap, strong and multifaceted antioxidant, especially robust for resuscitation of the circulation. Vitamin C given as early as possible after the injurious event, or before if feasible, seems most effective. The latter could be considered at the start of cardiac surgery, organ transplant or major gastrointestinal surgery. Preoperative supplementation should consider the inhibiting effect of vitamin C on ischemic preconditioning. In critically ill patients, future research should focus on the use of short-term high-dose intravenous vitamin C as a resuscitation drug, to intervene as early as possible in the oxidant cascade in order to optimize macrocirculation and microcirculation and limit cellular injury.

Topics: Animals; Antioxidants; Ascorbic Acid; Capillary Permeability; Critical Care; Endothelium, Vascular; Heart; Humans; Microcirculation; Multiple Organ Failure; Oxidative Stress; Reactive Oxygen Species; Reperfusion Injury; Sepsis; Vitamins

Evidence is emerging that parenteral administration of high-dose vitamin C may warrant development as an adjuvant therapy for patients with sepsis.. Sepsis increases risk of death and disability, but its treatment consists only of supportive therapies because no specific therapy is available. The characteristics of severe sepsis include ascorbate (reduced vitamin C) depletion, excessive protein nitration in microvascular endothelial cells, and microvascular dysfunction composed of refractive vasodilation, endothelial barrier dysfunction, and disseminated intravascular coagulation. Parenteral administration of ascorbate prevents or even reverses these pathological changes and thereby decreases hypotension, edema, multiorgan failure, and death in animal models of sepsis.. Dehydroascorbic acid appears to be as effective as ascorbate for protection against microvascular dysfunction, organ failure, and death when injected in sepsis models, but information about pharmacodynamics and safety in human subjects is only available for ascorbate. Although the plasma ascorbate concentration in critically ill and septic patients is normalized by repletion protocols that use high doses of parenteral ascorbate, and such doses are tolerated well by most healthy subjects, whether such large amounts of the vitamin trigger adverse effects in patients is uncertain.. Further study of sepsis models may determine if high concentrations of ascorbate in interstitial fluid have pro-oxidant and bacteriostatic actions that also modify disease progression. However, the ascorbate depletion observed in septic patients receiving standard care and the therapeutic mechanisms established in models are sufficient evidence to support clinical trials of parenteral ascorbate as an adjuvant therapy for sepsis.

Topics: Animals; Anticoagulants; Ascorbic Acid; Blood Coagulation; Chemotherapy, Adjuvant; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Humans; Microvessels; Sepsis

Bacterial bloodstream infection causes septic syndromes that range from systemic inflammatory response syndrome (SIRS) and encephalopathy to severe sepsis and septic shock. Microvascular dysfunction, comprising impaired capillary blood flow and arteriolar responsiveness, precedes multiple organ failure. Vitamin C (ascorbate) levels are low in critically ill patients. The impact of ascorbate administered orally is moderate because of its limited bioavailability. However, intravenous injection of ascorbate raises plasma and tissue concentrations of the vitamin and may decrease morbidity. In animal models of polymicrobial sepsis, intravenous ascorbate injection restores microvascular function and increases survival. The protection of capillary blood flow and arteriolar responsiveness by ascorbate may be mediated by inhibition of oxidative stress, modulation of intracellular signaling pathways, and maintenance of homeostatic levels of nitric oxide. Ascorbate scavenges reactive oxygen species (ROS) and also inhibits the NADPH oxidase that synthesizes superoxide in microvascular endothelial cells. The resulting changes in redox-sensitive signaling pathways may diminish endothelial expression of inducible nitric oxide synthase (iNOS), tissue factor and adhesion molecules. Ascorbate also regulates nitric oxide concentration by releasing nitric oxide from adducts and by acting through tetrahydrobiopterin (BH4) to stimulate endothelial nitric oxide synthase (eNOS). Therefore, it may be possible to improve microvascular function in sepsis by using intravenous vitamin C as an adjunct therapy.

Topics: Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Brain Diseases; Humans; Hypotension; Regional Blood Flow; Sepsis

Sepsis is a complex multifaceted response to a local infectious insult. One important facet is the circulatory system dysfunction, which includes capillary bed plugging. This review addresses the mechanisms of capillary plugging and highlights our recent discoveries on the roles of NO, ROS, and activated coagulation in platelet adhesion and blood flow stoppage in septic mouse capillaries. We show that sepsis increases platelet adhesion, fibrin deposition and flow stoppage in capillaries, and that NADPH oxidase-derived ROS, rather than NO, play a detrimental role in this adhesion/stoppage. P-selectin and activated coagulation are required for adhesion/stoppage. Further, platelet adhesion in capillaries (i) strongly predicts capillary flow stoppage, and (ii) may explain why severe sepsis is associated with a drop in platelet count in systemic blood. Significantly, we also show that a single bolus of the antioxidant ascorbate (injected intravenously at clinically relevant dose of 10 mg/kg) inhibits adhesion/stoppage. Our data suggest that eNOS-derived NO at the platelet-endothelial interface is anti-adhesive and required for the inhibitory effect of ascorbate. Because of the critical role of ROS in capillary plugging, ascorbate bolus administration may be beneficial to septic patients whose survival depends on restoring microvascular perfusion.

Topics: Animals; Ascorbic Acid; Blood Coagulation; Blood Flow Velocity; Blood Platelets; Capillaries; Fibrin; Humans; Mice; Models, Biological; Nitric Oxide; Oxidative Stress; Platelet Adhesiveness; Reactive Oxygen Species; Sepsis

The purpose of this review is to highlight recent publications examining nitric oxide production in health and disease and its association with clinical nutrition and alterations in metabolism.. The role of the cofactor tetrahydrobiopterin in nitric oxide production and its relation with arginine availability is indicated as an important explanation for the arginine paradox. This offers potential for nitric oxide regulation by dietary factors such as arginine or its precursors and vitamin C. Because diets with a high saturated fat content induce high plasma fatty acid levels, endothelial nitric oxide production is often impaired due to a reduction in nitric oxide synthase 3 phosphorylation. Increasing the arginine availability by arginine therapy or arginase inhibition was, therefore, proposed as a potential therapy to treat hypertension. Recent studies in septic patients and transgenic mice models found that inadequate de-novo arginine production from citrulline reduces nitric oxide production. Citrulline supplementation may, therefore, be a novel therapeutic approach in conditions of arginine deficiency.. Both lack and excess of nitric oxide production in diseases can have various important implications in which dietary factors can play a modulating role. Future research is needed to expand our understanding of the regulation and adequate measurement of nitric oxide production at the organ level and by the different nitric oxide synthase isoforms, also in relation to clinical nutrition.

Topics: Animals; Arginase; Arginine; Ascorbic Acid; Biopterins; Citrulline; Diet; Dietary Fats; Endothelium; Humans; Hypertension; Mice; Nitric Oxide; Nitric Oxide Synthase Type III; Sepsis

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

Dysregulation of the immuno-inflammatory response, as seen in sepsis, may culminate in host cell and organ damage. Lipopolysaccharide from Gram-negative bacterial cell walls induces gene activation and subsequent inflammatory mediator expression. Gene activation is regulated by a number of transcription factors at the nuclear level, of which nuclear factor kappaB appears to have a central role. The redox (reduction-oxidation) cellular balance is important for normal cellular function, including transcription factor regulation. In sepsis, a state of severe oxidative stress is encountered, with host endogenous antioxidant defences overcome. This has implications for cellular function and the regulation of gene expression. This review gives an overview of the mechanisms by which transcription factor activation and inflammatory mediator overexpression occur in sepsis, together with the events surrounding the state of oxidative stress encountered and the effects on the host's antioxidant defences. The effect of oxidative stress on transcription factor regulation is considered, together with the role of antioxidant repletion in transcription factor activation and in sepsis in general. Other interventions that may modulate transcription factor activation are also highlighted.

Topics: Animals; Antioxidants; Ascorbic Acid; Binding Sites; Dimethyl Sulfoxide; Gene Expression; Gene Expression Regulation; Glutathione; Humans; Lipopolysaccharides; NF-kappa B; Oxidation-Reduction; Oxidative Stress; Oxygen; Promoter Regions, Genetic; Reactive Oxygen Species; Sepsis; Transcription, Genetic; Transcriptional Activation; Vitamin E

Dehydroascorbic acid (DHA) is abundant in the human diet and also is generated from vitamin C (ascorbic acid, AA) in the lumen of the gastrointestinal tract. DHA is absorbed from the lumen of the small intestine and reduced to AA, which subsequently circulates in the blood. Utilization of AA as an antioxidant and enzyme cofactor causes its oxidation to DHA in extracellular fluid and cells. DHA has an important role in many cell types because it can be used to regenerate AA. Both physiological (e.g. insulin, insulin-like growth factor I, cyclic AMP) and pathological (e.g. oxidative stress, diabetes, sepsis) factors alter the transport and metabolic mechanisms responsible for this DHA recycling.

Topics: Animals; Ascorbic Acid; Biological Transport; Dehydroascorbic Acid; Diabetes Mellitus; Humans; Inflammation; Oxidation-Reduction; Reperfusion Injury; Sepsis

The LOVIT trial examined the effect of vitamin C on sepsis patients, and concluded that in adults with sepsis receiving vasopressor therapy in the ICU, those who received 4-day intravenous vitamin C had a higher risk of death or persistent organ dysfunction at 28 days than those who received placebo. The aim of this study was to determine whether the abrupt termination of vitamin C administration could explain the increased mortality in the vitamin C group.. We used Cox regression with two time periods to model the distribution of deaths over the first 11 days in the LOVIT trial.. Compared with a uniform difference between vitamin C and placebo groups over the 11-day follow-up period, addition of a separate vitamin C effect starting from day 5 improved the fit of the Cox model (p = 0.026). There was no difference in mortality between the groups during the 4-day vitamin C administration with RR = 0.97 (95% CI: 0.65-1.44). During the week after the sudden termination of vitamin C, there were 57 deaths in the vitamin C group, but only 32 deaths in the placebo group, with RR = 1.9 (95% CI: 1.2-2.9; p = 0.004).. The increased mortality in the vitamin C group in the LOVIT trial is not explained by ongoing vitamin C administration, but by the abrupt termination of vitamin C. The LOVIT trial findings should not be interpreted as evidence against vitamin C therapy for critically ill patients.

Topics: Adult; Ascorbic Acid; Humans; Intensive Care Units; Sepsis; Vitamins

Sepsis is associated with long-term cognitive impairment and worse psychological and functional outcomes. Potential mechanisms include intracerebral oxidative stress and inflammation, yet little is known about the effects of early antioxidant and anti-inflammatory therapy on cognitive, psychological, and functional outcomes in sepsis survivors.. To describe observed differences in long-term cognitive, psychological, and functional outcomes of vitamin C, thiamine, and hydrocortisone between the intervention and control groups in the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) randomized clinical trial.. This prespecified secondary analysis reports the 6-month outcomes of the multicenter, double-blind, placebo-controlled VICTAS randomized clinical trial, which was conducted between August 2018 and July 2019. Adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction who survived to discharge or day 30 were recruited from 43 intensive care units in the US. Participants were randomized 1:1 to either the intervention or control group. Cognitive, psychological, and functional outcomes at 6 months after randomization were assessed via telephone through January 2020. Data analyses were conducted between February 2021 and December 2022.. The intervention group received intravenous vitamin C (1.5 g), thiamine hydrochloride (100 mg), and hydrocortisone sodium succinate (50 mg) every 6 hours for 96 hours or until death or intensive care unit discharge. The control group received matching placebo.. Cognitive performance, risk of posttraumatic stress disorder and depression, and functional status were assessed using a battery of standardized instruments that were administered during a 1-hour telephone call 6 months after randomization.. After exclusions, withdrawals, and deaths, the final sample included 213 participants (median [IQR] age, 57 [47-67] years; 112 males [52.6%]) who underwent long-term outcomes assessment and had been randomized to either the intervention group (n = 108) or control group (n = 105). The intervention group had lower immediate memory scores (adjusted OR [aOR], 0.49; 95% CI, 0.26-0.89), higher odds of posttraumatic stress disorder (aOR, 3.51; 95% CI, 1.18-10.40), and lower odds of receiving mental health care (aOR, 0.38; 95% CI, 0.16-0.89). No other statistically significant differences in cognitive, psychological, and functional outcomes were found between the 2 groups.. In survivors of sepsis, treatment with vitamin C, thiamine, and hydrocortisone did not improve or had worse cognitive, psychological, and functional outcomes at 6 months compared with patients who received placebo. These findings challenge the hypothesis that antioxidant and anti-inflammatory therapy during critical illness mitigates the development of long-term cognitive, psychological, and functional impairment in sepsis survivors.. ClinicalTrials.gov Identifier: NCT03509350.

Topics: Adult; Antioxidants; Ascorbic Acid; Cognition; Humans; Hydrocortisone; Male; Middle Aged; Sepsis; Steroids; Thiamine; Vitamins

The Lessening Organ Dysfunction with Vitamin C trial showed a harmful effect of vitamin C on 28-day death or persistent organ dysfunction. To maximize interpretation, we present a post hoc Bayesian reanalysis.. Bayesian reanalysis of a randomized placebo-controlled trial.. Thirty-five ICUs.. Adults with proven or suspected infection, vasopressor support, and no more than 24 hours of ICU admission.. Patients were allocated to receive either vitamin C (50 mg/kg of body weight) or placebo every 6 hours for up to 96 hours.. The primary outcome was the composite of death or persistent organ dysfunction (i.e., vasopressor use, invasive mechanical ventilation, or new renal replacement therapy) at 28 days. We used Bayesian log-binomial models with random effects for hospital site and varying informative prior beliefs for the effect of vitamin C to estimate risk ratios (RRs) with 95% credible intervals (Crls) in the intention to treat population (vitamin C, 435 patients; placebo, 437 patients). Using weakly neutral priors, patients allocated to vitamin C had a higher risk of death or persistent organ dysfunction at 28 days (RR, 1.20; 95% Crl, 1.04-1.39; probability of harm, 99%). This effect was consistent when using optimistic (RR, 1.14; 95% Crl, 1.00-1.31; probability of harm, 98%) and empiric (RR, 1.09; 95% Crl, 0.97-1.22; probability of harm, 92%) priors. Patients allocated to vitamin C also had a higher risk of death at 28 days under weakly neutral (RR, 1.17; 95% Crl, 0.98-1.40; probability of harm, 96%), optimistic (RR, 1.10; 95% Crl, 0.94-1.30; probability of harm, 88%), and empiric (RR, 1.05; 95% Crl, 0.92-1.19; probability of harm, 76%) priors.. The use of vitamin C in adult patients with proven or suspected infection and vasopressor support is associated with high probability of harm.

Topics: Adult; Ascorbic Acid; Bayes Theorem; Humans; Multiple Organ Failure; Sepsis; Vitamins

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

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

Topics: Ascorbic Acid; Humans; Sepsis; Vitamins

Studies that have evaluated the use of intravenous vitamin C in adults with sepsis who were receiving vasopressor therapy in the intensive care unit (ICU) have shown mixed results with respect to the risk of death and organ dysfunction.. In this randomized, placebo-controlled trial, we assigned adults who had been in the ICU for no longer than 24 hours, who had proven or suspected infection as the main diagnosis, and who were receiving a vasopressor to receive an infusion of either vitamin C (at a dose of 50 mg per kilogram of body weight) or matched placebo administered every 6 hours for up to 96 hours. The primary outcome was a composite of death or persistent organ dysfunction (defined by the use of vasopressors, invasive mechanical ventilation, or new renal-replacement therapy) on day 28.. A total of 872 patients underwent randomization (435 to the vitamin C group and 437 to the control group). The primary outcome occurred in 191 of 429 patients (44.5%) in the vitamin C group and in 167 of 434 patients (38.5%) in the control group (risk ratio, 1.21; 95% confidence interval [CI], 1.04 to 1.40; P = 0.01). At 28 days, death had occurred in 152 of 429 patients (35.4%) in the vitamin C group and in 137 of 434 patients (31.6%) in the placebo group (risk ratio, 1.17; 95% CI, 0.98 to 1.40) and persistent organ dysfunction in 39 of 429 patients (9.1%) and 30 of 434 patients (6.9%), respectively (risk ratio, 1.30; 95% CI, 0.83 to 2.05). Findings were similar in the two groups regarding organ-dysfunction scores, biomarkers, 6-month survival, health-related quality of life, stage 3 acute kidney injury, and hypoglycemic episodes. In the vitamin C group, one patient had a severe hypoglycemic episode and another had a serious anaphylaxis event.. In adults with sepsis receiving vasopressor therapy in the ICU, those who received intravenous vitamin C had a higher risk of death or persistent organ dysfunction at 28 days than those who received placebo. (Funded by the Lotte and John Hecht Memorial Foundation; LOVIT ClinicalTrials.gov number, NCT03680274.).

Topics: Adult; Ascorbic Acid; Humans; Hypoglycemic Agents; Intensive Care Units; Multiple Organ Failure; Quality of Life; Sepsis; Vasoconstrictor Agents; Vitamins

Vitamin C has shown benefits in patients with sepsis in addition to standard therapy recently. However, further evidence is required to verify the efficacy of vitamin C in clinical practice. This study aimed to investigate the effect of adjunctive intravenous high-dose vitamin C treatment on hospital mortality in patients with sepsis.. One hundred seventeen patients with sepsis in our department from June 2017 to May 2019 were randomly divided into two groups: the control group (56 cases) and the vitamin C group (61 cases). The control group was treated by the routine and basic therapy with intravenous drip of 5% dextrose and placebo (100 ml/time, 2 times/day), while the vitamin C group was administered intravenously by 3.0 g vitamin C dissolved into 5% dextrose (100 ml/time, 2 times/day) based on the control group. The mortality and efficacy were statistically analyzed and compared between the two groups.. The 28-day mortality differed significantly between the control group and the vitamin C group (42.97% vs. 27.93%) (p < 0.05). The changes in the sepsis-related organ failure assessment (ΔSOFA) scores at 72 h after ICU admission (4.2 vs. 2.1), the application time of vasoactive drugs (25.6 vs. 43.8), and the procalcitonin clearance (79.6% vs. 61.3%) differed significantly between groups (p < 0.05).. The early treatment of sepsis with intravenous high-dose vitamin C in combination with standard therapy showed a beneficial effect on sepsis, in terms of the reduced 28-day mortality, the decreased SOFA score, and the increased clearance rate of procalcitonin.

Topics: Ascorbic Acid; Humans; Intensive Care Units; Procalcitonin; Prognosis; Retrospective Studies; ROC Curve; Sepsis

Sepsis is a common syndrome with substantial morbidity and mortality. A combination of vitamin C, thiamine, and corticosteroids has been proposed as a potential treatment for patients with sepsis.. To determine whether a combination of vitamin C, thiamine, and hydrocortisone every 6 hours increases ventilator- and vasopressor-free days compared with placebo in patients with sepsis.. Multicenter, randomized, double-blind, adaptive-sample-size, placebo-controlled trial conducted in adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction. Participants were enrolled in the emergency departments or intensive care units at 43 hospitals in the United States between August 2018 and July 2019. After enrollment of 501 participants, funding was withheld, leading to an administrative termination of the trial. All study-related follow-up was completed by January 2020.. Participants were randomized to receive intravenous vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) every 6 hours (n = 252) or matching placebo (n = 249) for 96 hours or until discharge from the intensive care unit or death. Participants could be treated with open-label corticosteroids by the clinical team, with study hydrocortisone or matching placebo withheld if the total daily dose was greater or equal to the equivalent of 200 mg of hydrocortisone.. The primary outcome was the number of consecutive ventilator- and vasopressor-free days in the first 30 days following the day of randomization. The key secondary outcome was 30-day mortality.. Among 501 participants randomized (median age, 62 [interquartile range {IQR}, 50-70] years; 46% female; 30% Black; median Acute Physiology and Chronic Health Evaluation II score, 27 [IQR, 20.8-33.0]; median Sequential Organ Failure Assessment score, 9 [IQR, 7-12]), all completed the trial. Open-label corticosteroids were prescribed to 33% and 32% of the intervention and control groups, respectively. Ventilator- and vasopressor-free days were a median of 25 days (IQR, 0-29 days) in the intervention group and 26 days (IQR, 0-28 days) in the placebo group, with a median difference of -1 day (95% CI, -4 to 2 days; P = .85). Thirty-day mortality was 22% in the intervention group and 24% in the placebo group.. Among critically ill patients with sepsis, treatment with vitamin C, thiamine, and hydrocortisone, compared with placebo, did not significantly increase ventilator- and vasopressor-free days within 30 days. However, the trial was terminated early for administrative reasons and may have been underpowered to detect a clinically important difference.. ClinicalTrials.gov Identifier: NCT03509350.

Topics: Adult; Aged; Anti-Inflammatory Agents; Ascorbic Acid; Critical Illness; Double-Blind Method; Drug Therapy, Combination; Early Termination of Clinical Trials; Female; Humans; Hydrocortisone; Length of Stay; Male; Middle Aged; Organ Dysfunction Scores; Respiration, Artificial; Respiratory Insufficiency; Sepsis; Thiamine; Treatment Outcome; Vasoconstrictor Agents; Vitamins

Sepsis is a health problem of global importance; treatments focus on controlling infection and supporting failing organs. Recent clinical research suggests that intravenous vitamin C may decrease mortality in sepsis. We have designed a randomized controlled trial (RCT) to ascertain the effect of vitamin C on the composite endpoint of death or persistent organ dysfunction at 28 days in patients with sepsis.. LOVIT (Lessening Organ dysfunction with VITamin C) is a multicenter, parallel-group, blinded (participants, clinicians, study personnel, Steering Committee members, data analysts), superiority RCT (minimum n = 800). Eligible patients have sepsis as the diagnosis for admission to the intensive care unit (ICU) and are receiving vasopressors. Those admitted to the ICU for more than 24 h are excluded. Eligible patients are randomized to high-dose intravenous vitamin C (50 mg/kg every 6 h for 96 h) or placebo. The primary outcome is a composite of death or persistent organ dysfunction (need for vasopressors, invasive mechanical ventilation, or new and persisting renal replacement therapy) at day 28. Secondary outcomes include persistent organ dysfunction-free days to day 28, mortality and health-related quality of life at 6 months, biomarkers of dysoxia, inflammation, infection, endothelial function, and adverse effects (hemolysis, acute kidney injury, and hypoglycemia). Six subgroup analyses are planned.. This RCT will provide evidence of the effect of high-dose intravenous vitamin C on patient-important outcomes in patients with sepsis.. clinicaltrials.gov, NCT03680274, first posted 21 September 2018.

Topics: Acute Kidney Injury; Administration, Intravenous; Adult; Antioxidants; Ascorbic Acid; Clinical Trials, Phase III as Topic; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Hemolysis; Hospital Mortality; Humans; Hypoglycemia; Intensive Care Units; Male; Middle Aged; Multiple Organ Failure; Quality of Life; Sepsis; Treatment Outcome; Vasoconstrictor Agents

Sepsis is a major public health burden resulting in 25% to 30% in-hospital mortality and accounting for over 20 billion dollars of US hospital costs.. Does hydrocortisone, ascorbic acid, thiamine (HAT) therapy improve clinical outcomes in sepsis and septic shock?. This was a randomized, double-blinded, placebo-controlled trial conducted from February 2018 to June 2019, assessing an HAT treatment bundle for the management of septic and septic shock patients admitted to an ICU. The primary outcomes were resolution of shock and change in Sequential Organ Failure Assessment (SOFA) score. Secondary outcomes included 28-day mortality, ICU mortality, hospital mortality, procalcitonin clearance (PCT-c), hospital length of stay (LOS), ICU LOS, and ventilator-free days.. One hundred thirty-seven patients were randomized to the treatment group (n = 68) and comparator group (n = 69), respectively, with no significant differences in baseline characteristics. A statistically significant difference was found in the time patients required vasopressors, indicating quicker reversal of shock in the HAT group compared with the comparator group (27 ± 22 vs 53 ± 38 hours, P < .001). No statistically significant change in SOFA score was found between groups 3 (1 - 6) vs 2 (0 - 4), P = .17. No significant differences were found between study arms in ICU and hospital mortality, ICU and hospital LOS, ventilator free days, and PCT-c.. Our results suggest that the combination of IV ascorbic acid, thiamine, and hydrocortisone significantly reduced the time to resolution of shock. Additional studies are needed to confirm these findings and assess any potential mortality benefit from this treatment.. ClinicalTrials.gov; No.: NCT03422159; URL: www.clinicaltrials.gov.

Topics: Aged; Aged, 80 and over; Ascorbic Acid; Critical Care; Double-Blind Method; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Hydrocortisone; Male; Middle Aged; Sepsis; Survival Rate; Thiamine; Vasoconstrictor Agents; Vitamins

Experimental data suggest that intravenous vitamin C may attenuate inflammation and vascular injury associated with sepsis and acute respiratory distress syndrome (ARDS).. To determine the effect of intravenous vitamin C infusion on organ failure scores and biological markers of inflammation and vascular injury in patients with sepsis and ARDS.. The CITRIS-ALI trial was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 7 medical intensive care units in the United States, enrolling patients (N = 167) with sepsis and ARDS present for less than 24 hours. The study was conducted from September 2014 to November 2017, and final follow-up was January 2018.. Patients were randomly assigned to receive intravenous infusion of vitamin C (50 mg/kg in dextrose 5% in water, n = 84) or placebo (dextrose 5% in water only, n = 83) every 6 hours for 96 hours.. The primary outcomes were change in organ failure as assessed by a modified Sequential Organ Failure Assessment score (range, 0-20, with higher scores indicating more dysfunction) from baseline to 96 hours, and plasma biomarkers of inflammation (C-reactive protein levels) and vascular injury (thrombomodulin levels) measured at 0, 48, 96, and 168 hours.. Among 167 randomized patients (mean [SD] age, 54.8 years [16.7]; 90 men [54%]), 103 (62%) completed the study to day 60. There were no significant differences between the vitamin C and placebo groups in the primary end points of change in mean modified Sequential Organ Failure Assessment score from baseline to 96 hours (from 9.8 to 6.8 in the vitamin C group [3 points] and from 10.3 to 6.8 in the placebo group [3.5 points]; difference, -0.10; 95% CI, -1.23 to 1.03; P = .86) or in C-reactive protein levels (54.1 vs 46.1 μg/mL; difference, 7.94 μg/mL; 95% CI, -8.2 to 24.11; P = .33) and thrombomodulin levels (14.5 vs 13.8 ng/mL; difference, 0.69 ng/mL; 95% CI, -2.8 to 4.2; P = .70) at 168 hours.. In this preliminary study of patients with sepsis and ARDS, a 96-hour infusion of vitamin C compared with placebo did not significantly improve organ dysfunction scores or alter markers of inflammation and vascular injury. Further research is needed to evaluate the potential role of vitamin C for other outcomes in sepsis and ARDS.. ClinicalTrials.gov Identifier: NCT02106975.

Topics: Adult; Aged; Ascorbic Acid; Biomarkers; C-Reactive Protein; Double-Blind Method; Female; Humans; Infusions, Intravenous; Intensive Care Units; Male; Middle Aged; Multiple Organ Failure; Organ Dysfunction Scores; Respiratory Distress Syndrome; Sepsis; Thrombomodulin; Vitamins

Observational research suggests that combined therapy with Vitamin C, thiamine and hydrocortisone may reduce mortality in patients with septic shock.. The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) trial is a multicenter, double-blind, adaptive sample size, randomized, placebo-controlled trial designed to test the efficacy of combination therapy with vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) given every 6 h for up to 16 doses in patients with respiratory or circulatory dysfunction (or both) resulting from sepsis. The primary outcome is ventilator- and vasopressor-free days with mortality as the key secondary outcome. Recruitment began in August 2018 and is ongoing; 501 participants have been enrolled to date, with a planned maximum sample size of 2000. The Data and Safety Monitoring Board reviewed interim results at N = 200, 300, 400 and 500, and has recommended continuing recruitment. The next interim analysis will occur when N = 1000. This update presents the statistical analysis plan. Specifically, we provide definitions for key treatment and outcome variables, and for intent-to-treat, per-protocol, and safety analysis datasets. We describe the planned descriptive analyses, the main analysis of the primary end point, our approach to secondary and exploratory analyses, and handling of missing data. Our goal is to provide enough detail that our approach could be replicated by an independent study group, thereby enhancing the transparency of the study.. ClinicalTrials.gov, NCT03509350. Registered on 26 April 2018.

Topics: Ascorbic Acid; Data Interpretation, Statistical; Double-Blind Method; Drug Therapy, Combination; Humans; Hydrocortisone; Prospective Studies; Randomized Controlled Trials as Topic; Research Design; Sample Size; Sepsis; Thiamine

Sepsis accounts for 30% to 50% of all in-hospital deaths in the United States. Other than antibiotics and source control, management strategies are largely supportive with fluid resuscitation and respiratory, renal, and circulatory support. Intravenous vitamin C in conjunction with thiamine and hydrocortisone has recently been suggested to improve outcomes in patients with sepsis in a single-center before-and-after study. However, before this therapeutic strategy is adopted, a rigorous assessment of its efficacy is needed.. The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) trial is a prospective, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled trial. It will enroll patients with sepsis causing respiratory or circulatory compromise or both. Patients will be randomly assigned (1:1) to receive intravenous vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) every 6 h or matching placebos until a total of 16 administrations have been completed or intensive care unit discharge occurs (whichever is first). Patients randomly assigned to the comparator group are permitted to receive open-label stress-dose steroids at the discretion of the treating clinical team. The primary outcome is consecutive days free of ventilator and vasopressor support (VVFDs) in the 30 days following randomization. The key secondary outcome is mortality at 30 days. Sample size will be determined adaptively by using interim analyses with pre-stated stopping rules to allow the early recognition of a large mortality benefit if one exists and to refocus on the more sensitive outcome of VVFDs if an early large mortality benefit is not observed.. VICTAS is a large, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled trial that will test the efficacy of vitamin C, thiamine, and hydrocortisone as a combined therapy in patients with respiratory or circulatory dysfunction (or both) resulting from sepsis. Because the components of this therapy are inexpensive and readily available and have very favorable risk profiles, demonstrated efficacy would have immediate implications for the management of sepsis worldwide.. ClinicalTrials.gov Identifier: NCT03509350 . First registered on April 26, 2018, and last verified on December 20, 2018. Protocol version: 1.4, January 9, 2019.

Topics: Administration, Intravenous; Ascorbic Acid; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Hospital Mortality; Humans; Hydrocortisone; Multicenter Studies as Topic; Prospective Studies; Randomized Controlled Trials as Topic; Sample Size; Sepsis; Thiamine; Time Factors; Treatment Outcome; United States

Parenterally administered ascorbic acid modulates sepsis-induced inflammation and coagulation in experimental animal models. The objective of this randomized, double-blind, placebo-controlled, phase I trial was to determine the safety of intravenously infused ascorbic acid in patients with severe sepsis.. Twenty-four patients with severe sepsis in the medical intensive care unit were randomized 1:1:1 to receive intravenous infusions every six hours for four days of ascorbic acid: Lo-AscA (50 mg/kg/24 h, n = 8), or Hi-AscA (200 mg/kg/24 h, n = 8), or Placebo (5% dextrose/water, n = 8). The primary end points were ascorbic acid safety and tolerability, assessed as treatment-related adverse-event frequency and severity. Patients were monitored for worsened arterial hypotension, tachycardia, hypernatremia, and nausea or vomiting. In addition Sequential Organ Failure Assessment (SOFA) scores and plasma levels of ascorbic acid, C-reactive protein, procalcitonin, and thrombomodulin were monitored.. Mean plasma ascorbic acid levels at entry for the entire cohort were 17.9 ± 2.4 μM (normal range 50-70 μM). Ascorbic acid infusion rapidly and significantly increased plasma ascorbic acid levels. No adverse safety events were observed in ascorbic acid-infused patients. Patients receiving ascorbic acid exhibited prompt reductions in SOFA scores while placebo patients exhibited no such reduction. Ascorbic acid significantly reduced the proinflammatory biomarkers C-reactive protein and procalcitonin. Unlike placebo patients, thrombomodulin in ascorbic acid infused patients exhibited no significant rise, suggesting attenuation of vascular endothelial injury.. Intravenous ascorbic acid infusion was safe and well tolerated in this study and may positively impact the extent of multiple organ failure and biomarkers of inflammation and endothelial injury.. ClinicalTrials.gov identifier NCT01434121.

Topics: Adult; Aged; Aged, 80 and over; Ascorbic Acid; Biomarkers; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Demography; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Multiple Organ Failure; Placebos; Protein Precursors; Sepsis; Thrombomodulin

To investigate the effect of parenteral administration of vitamin C on neutrophil apoptosis by determining Fas receptor expression and caspase-3, poly (ADP-ribose) polymerase (PARP), and Bcl-2 levels in neutrophils from septic abdominal surgery patients.. Twenty septic abdominal surgery patients were studied in a prospective, randomized, double-blinded clinical trial. A group of healthy volunteers (n = 10) constituted a reference group for baseline parameter values. The patients were randomly assigned to a vitamin C-treated (n = 10) or placebo-treated (n = 10) group. For a 6-d period from 12 h post-surgery, the vitamin C group received 450 mg/d of the vitamin in 3 doses and the placebo group an identical administration of 5% dextrose. Early-morning peripheral blood samples were obtained daily from 24 h after vitamin C administration until d 6 post-surgery (T1d-T6d).. Vitamin C group showed a nonsignificant reduction in Fas (CD95) expression on CD15-positive peripheral blood neutrophils, significantly decreased caspase-3, and PARP levels (caspase-3: T4d: P < 0.05, T5d: P < 0.05, T6d P < 0.01; and PARP: T3d: P < 0.05, T4d: P < 0.05, T6d: P < 0.05), and significantly increased Bcl-2 levels (T3d: P = 0.001) versus placebo group.. Postoperative vitamin C treatment of septic abdominal surgery patients exerts an antiapoptotic effect on peripheral blood neutrophils, reducing caspase-3 and PARP levels, and increasing Bcl-2 levels. However, these antiapoptotic effects are not maintained at all time points.

Topics: Aged; Antioxidants; Apoptosis; Ascorbic Acid; Caspase 3; Digestive System Surgical Procedures; Double-Blind Method; fas Receptor; Female; Humans; Male; Middle Aged; Neutrophils; Poly(ADP-ribose) Polymerases; Postoperative Care; Prospective Studies; Proto-Oncogene Proteins c-bcl-2; Sepsis

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

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

This study investigated the synergistic protective effects of melatonin (MEL) and ascorbic acid (vitamin C, ASA) in treating sepsis-induced lung injury in rats. Rats were divided into five groups: control, cecal ligation and puncture (CLP), CLP + MEL, CLP + ASA and CLP + MEL + ASA. The effects of MEL (10 mg/kg), ASA (100 mg/kg) and their combination on oxidative stress, inflammation and histopathology were evaluated in septic rats' lung tissues. Sepsis-induced oxidative stress and inflammation were evident through increased levels of malondialdehyde (MDA), myeloperoxidase (MPO), total oxidant status (TOS) and oxidative stress index (OSI); decreased levels of superoxide dismutase (SOD), glutathione (GSH), catalase (CAT) and glutathione peroxidase (GPx); and elevated levels of tumour necrosis factor-α (TNF-α) and interleukin-1 β (IL-1β) in the lung tissue. Treatment with MEL, ASA and their combination significantly improved antioxidant capacity and reduced oxidative stress, with the combination treatment being more effective. The combination treatment also significantly reduced TNF-α and IL-1β levels and improved peroxisome proliferator-activated receptor (PPAR), arylesterase (ARE) and paraoxonase (PON) levels in the lung tissue. Histopathological examination showed reduced oedema and lymphocyte infiltration with a lung tissue appearance similar to the control group. Immunohistochemical staining for caspase 3 demonstrated reduced immune positivity in the treatment groups. In conclusion, this study supports the potential synergistic protective effects of MEL and ASA in treating sepsis-induced lung injury. The combination therapy could effectively reduce oxidative stress, inflammation and improve antioxidant capacity in septic rats, suggesting a promising strategy for treating sepsis-induced lung injury.

Topics: Animals; Antioxidants; Ascorbic Acid; Glutathione; Inflammation; Lung; Lung Injury; Melatonin; Oxidative Stress; Rats; Sepsis; Tumor Necrosis Factor-alpha

To investigate the combined therapeutic potential of melatonin and ascorbic acid in mitigating sepsis-induced heart and kidney injury in male rats and assess the combination therapy's effects on inflammation, cellular damage, oxidative stress, and vascular function-related markers.. Cecal ligation and puncture (CLP) induced sepsis in male rats, which were divided into five groups: Sham, CLP, MEL (melatonin), ASA (ascorbic acid), and MEL+ASA (melatonin and ascorbic acid). Rats were treated, and heart and kidney tissues were collected for biochemical and histopathological analyses. Inflammatory markers (presepsin, procalcitonin, NF-κB, IL-1β, IL-6, TNF-α), cellular damage marker (8-OHDG), oxidative status, nitric oxide (NO), vascular endothelial growth factor (VEGF), and sirtuin 1 (SIRT1) levels were assessed.. Melatonin and ascorbic acid treatment reduced inflammatory and cellular damage markers compared to the CLP group. Combined treatment improved NO, VEGF levels, and increased SIRT1 expression, suggesting a synergistic effect in mitigating sepsis-induced inflammation, cellular damage, and oxidative stress. Histopathological analyses supported these findings, revealing reduced heart and kidney injury in the MEL+ASA group.. Our study highlights potential benefits of combining melatonin and ascorbic acid as a therapeutic strategy for alleviating sepsis-induced heart and kidney injury. The synergistic effects of these agents may provide stronger protection against inflammation, oxidative stress, and tissue damage, opening new avenues for future research and clinical applications in sepsis management.

Topics: Animals; Ascorbic Acid; Inflammation; Kidney; Male; Melatonin; Rats; Rats, Sprague-Dawley; Sepsis; Sirtuin 1; Vascular Endothelial Growth Factor A

Topics: Ascorbic Acid; Bayes Theorem; Humans; Randomized Controlled Trials as Topic; Research Design; Sepsis; Vitamins

There is ongoing research on treatments that promote antioxidant and anti-inflammatory mechanisms, which will reduce mortality in sepsis. In this study, we compared the anti-inflammatory and antioxidant activities of quercetin and ascorbic acid using a sepsis model induced in infant rats.. A total of 28 infant rats 21-days-old that had just completed the lactation period were divided into four groups: control, sepsis, sepsis + quercetin, and sepsis + ascorbic acid. The sepsis model was created with an intraperitoneal injection of bacterial lipopolysaccharide. After 24 hours, blood samples were collected for analysis of serum levels of inflammatory cytokines (IL-1β, IL-6, TNF-α, and CRP) and antioxidants (CAT, GPx, SOD, and GST).. The superoxide dismutase levels were significantly higher in the sepsis + ascorbic acid group compared to the sepsis and sepsis + quercetin groups. The levels of the most active cytokines in sepsis were significantly lower in the serum samples of the septic subjects who received quercetin and ascorbic acid.. The antioxidant activity, which is impaired in sepsis, was increased by both molecules. We observed that these two molecules, which are free of side effects, have a positive influence on the progression of sepsis to severe and fatal sepsis in childhood (Tab. 2, Ref. 38).

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Ascorbic Acid; Biomarkers; Cytokines; Female; Humans; Oxidative Stress; Quercetin; Rats; Sepsis; Tumor Necrosis Factor-alpha

Topics: Antioxidants; Ascorbic Acid; COVID-19; COVID-19 Drug Treatment; Humans; Sepsis; Vitamins

The efficacy of vitamin C for hospitalized patients with COVID-19 is uncertain.. To determine whether vitamin C improves outcomes for patients with COVID-19.. Two prospectively harmonized randomized clinical trials enrolled critically ill patients receiving organ support in intensive care units (90 sites) and patients who were not critically ill (40 sites) between July 23, 2020, and July 15, 2022, on 4 continents.. Patients were randomized to receive vitamin C administered intravenously or control (placebo or no vitamin C) every 6 hours for 96 hours (maximum of 16 doses).. The primary outcome was a composite of organ support-free days defined as days alive and free of respiratory and cardiovascular organ support in the intensive care unit up to day 21 and survival to hospital discharge. Values ranged from -1 organ support-free days for patients experiencing in-hospital death to 22 organ support-free days for those who survived without needing organ support. The primary analysis used a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented efficacy (improved survival, more organ support-free days, or both), an OR less than 1 represented harm, and an OR less than 1.2 represented futility.. Enrollment was terminated after statistical triggers for harm and futility were met. The trials had primary outcome data for 1568 critically ill patients (1037 in the vitamin C group and 531 in the control group; median age, 60 years [IQR, 50-70 years]; 35.9% were female) and 1022 patients who were not critically ill (456 in the vitamin C group and 566 in the control group; median age, 62 years [IQR, 51-72 years]; 39.6% were female). Among critically ill patients, the median number of organ support-free days was 7 (IQR, -1 to 17 days) for the vitamin C group vs 10 (IQR, -1 to 17 days) for the control group (adjusted proportional OR, 0.88 [95% credible interval {CrI}, 0.73 to 1.06]) and the posterior probabilities were 8.6% (efficacy), 91.4% (harm), and 99.9% (futility). Among patients who were not critically ill, the median number of organ support-free days was 22 (IQR, 18 to 22 days) for the vitamin C group vs 22 (IQR, 21 to 22 days) for the control group (adjusted proportional OR, 0.80 [95% CrI, 0.60 to 1.01]) and the posterior probabilities were 2.9% (efficacy), 97.1% (harm), and greater than 99.9% (futility). Among critically ill patients, survival to hospital discharge was 61.9% (642/1037) for the vitamin C group vs 64.6% (343/531) for the control group (adjusted OR, 0.92 [95% CrI, 0.73 to 1.17]) and the posterior probability was 24.0% for efficacy. Among patients who were not critically ill, survival to hospital discharge was 85.1% (388/456) for the vitamin C group vs 86.6% (490/566) for the control group (adjusted OR, 0.86 [95% CrI, 0.61 to 1.17]) and the posterior probability was 17.8% for efficacy.. In hospitalized patients with COVID-19, vitamin C had low probability of improving the primary composite outcome of organ support-free days and hospital survival.. ClinicalTrials.gov Identifiers: NCT04401150 (LOVIT-COVID) and NCT02735707 (REMAP-CAP).

Topics: Ascorbic Acid; Bayes Theorem; COVID-19; Critical Illness; Female; Hospital Mortality; Humans; Male; Middle Aged; Randomized Controlled Trials as Topic; Sepsis; Vitamins

Sepsis-associated acute kidney injury is associated with high morbidity and mortality in critically ill patients. Cell-free hemoglobin (CFH) is released into the circulation of patients with severe sepsis and the levels of CFH are independently associated with mortality. CFH treatment increased cytotoxicity in the human tubular epithelial cell line HK-2. To better model the intact kidney, we cultured human kidney organoids derived from induced pluripotent stem cells. We treated human kidney organoids grown using both three-dimensional and transwell protocols with CFH for 48 h. We found evidence for increased tubular toxicity, oxidative stress, mitochondrial fragmentation, endothelial cell injury and injury-associated transcripts compared to those of the untreated control group. To evaluate the protective effect of clinically available small molecules, we co-treated CFH-injured organoids with ascorbate (vitamin C) or acetaminophen for 48 h. We found significantly decreased toxicity, preservation of endothelial cells and reduced mitochondrial fragmentation in the group receiving ascorbate following CFH treatment. This study provides direct evidence that ascorbate or ascorbic acid protects human kidney cells from CFH-induced damage such as that in sepsis-associated acute kidney injury.

Topics: Acute Kidney Injury; Ascorbic Acid; Endothelial Cells; Hemoglobins; Humans; Kidney; Sepsis

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

Sepsis manifests due to the host's dysregulated immune response to infection. High-dose ascorbic acid (AA) has emerged as a potential treatment of sepsis, yet little is known regarding how AA influences the immune system in sepsis, such as monocytes. The objective of this study is to investigate the effects of high-dose AA on monocyte polarization and cytokine production in vitro. Monocytes isolated from healthy donors (n = 6) were polarized in vitro for 48 h using LPS or lipoteichoic acid (LTA). Polarization was confirmed by surface marker expression using flow cytometry. In parallel, monocytes from septic patients (n = 3) were analyzed for polarization markers as a comparison with the in vitro polarization. The effect of AA on monocyte polarization was then evaluated. Finally, monocytes were analyzed for cytokine production by intracellular staining. Both LPS and LTA induced polarization in healthy monocytes in vitro, with increased expression of both pro (M1) (CD40 and PDL1, p < 0.05) and anti-inflammatory (M2) (CD16 and CD163, p < 0.05) polarization markers. This pattern resembled that of monocytes from septic patients. Treatment with AA significantly inhibited surface expression of CD16 and CD163 (p < 0.05) in a dose-dependent manner. Finally, AA attenuated LPS- or LTA-induced cytokine production of IL-1ß, IL-6, IL-8, and TNF. In conclusion, AA attenuates proinflammatory cytokine production and diminishes up-regulation of CD16 and CD163, but not of CD40 and PDL-1 in LPS- or LTA-polarized monocytes. This study provides important insight into the effects of high-dose AA on monocytes and potential implications in sepsis.

Topics: Ascorbic Acid; Cytokines; Humans; Lipopolysaccharides; Monocytes; Sepsis

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

Topics: Ascorbic Acid; Child; Humans; Resuscitation; Sepsis; Vitamins

To determine circulating levels of ascorbic acid (VitC) and thiamine (VitB1) in neonates and children with blood culture-proven sepsis.. Nested single-center study of neonates and children prospectively included in the Swiss Pediatric Sepsis Study.. One tertiary care academic hospital.. Sixty-one neonates and children 0-16 years old.. None.. VitC and VitB1 were quantified in serum of patients (median age, 10.5 mo; interquartile range [IQR], 0.5-62.1 mo) with blood culture-proven sepsis. Median time between sepsis onset and sampling for measurement of vitamins was 3 days (IQR, 2-4 d). Median serum levels of VitC and VitB1 were 32.4 μmol/L (18.9-53.3 μmol/L) and 22.5 nmol/L (12.6-82 nmol/L); 36% of the patients (22/61) had low VitC and 10% (6/61) had VitC deficiency; and 72% (44/61) had low VitB1 and 13% (8/61) had VitB1 deficiency. Children with low VitC were older (p = 0.007) and had higher C-reactive protein (p = 0.004) compared with children with VitC within the normal range. Children with low VitB1 levels were older (p = 0.0009) and were less frequently receiving enteral or parenteral vitamin supplementation (p = 0.0000003) compared with children with normal VitB1 levels.. In this cohort of newborns and children with sepsis, low and deficient VitC and VitB1 levels were frequently observed. Age, systemic inflammation, and vitamin supplementation were associated with vitamin levels during sepsis.

Topics: Adolescent; Ascorbic Acid; Child; Child, Preschool; Humans; Infant; Infant, Newborn; Sepsis; Switzerland; Thiamine; Vitamins

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

To study the metabolic mechanism of neonatal sepsis at different stages by analyzing the metabolic pathways involving the serum metabolites with significant differences in neonates with sepsis at different time points after admission.. A total of 20 neonates with sepsis who were hospitalized in the Department of Neonatology, Hunan Provincial People's Hospital, from January 1, 2019 to January 1, 2020 were enrolled as the sepsis group. Venous blood samples were collected on days 1, 4, and 7 after admission. Ten healthy neonates who underwent physical examination during the same period were enrolled as the control group. Ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry was used for the metabonomic analysis of serum samples to investigate the change in metabolomics in neonates with sepsis at different time points.. On day 1 after admission, the differentially expressed serum metabolites between the sepsis and control groups were mainly involved in the biosynthesis of terpenoid skeleton. For the sepsis group, the differentially expressed serum metabolites between days 1 and 4 after admission were mainly involved in pyruvate metabolism, and those between days 4 and 7 after admission were mainly involved in the metabolism of cysteine and methionine. The differentially expressed serum metabolites between days 1 and 7 after admission were mainly involved in ascorbic acid metabolism.. The metabolic mechanism of serum metabolites varies at different stages in neonates with sepsis and is mainly associated with terpenoid skeleton biosynthesis, pyruvate metabolism, cysteine/methionine metabolism, and ascorbic acid metabolism.

Topics: Ascorbic Acid; Cysteine; Humans; Infant, Newborn; Metabolomics; Methionine; Neonatal Sepsis; Pyruvates; Sepsis

Topics: Administration, Intravenous; Adult; Ascorbic Acid; Humans; Sepsis; Vitamins

Multiple clinical trials failed to demonstrate the efficacy of hydrocortisone, ascorbic acid, and thiamine (HAT) in sepsis. These trials were dominated by patients with pulmonary sepsis and have not accounted for differences in the inflammatory responses across varying etiologies of injury/illness. Hydrocortisone, ascorbic acid, and thiamine have previously revealed tremendous benefits in animal peritonitis sepsis models (cecal ligation and puncture [CLP]) in contradiction to the various clinical trials. The impact of HAT remains unclear in pulmonary sepsis. Our objective was to investigate the impact of HAT in pneumonia, consistent with the predominate etiology in the discordant clinical trials. We hypothesized that, in a pulmonary sepsis model, HAT would act synergistically to reduce end-organ dysfunction by the altering the inflammatory response, in a unique manner compared with CLP.. Using Pseudomonas aeruginosa pneumonia, a pulmonary sepsis model (pneumonia [PNA]) was compared directly to previously investigated intra-abdominal sepsis models. Machine learning applied to early vital signs stratified animals into those predicted to die (pDie) versus predicted to live (pLive). Animals were then randomized to receive antibiotics and fluids (vehicle [VEH]) vs. HAT). Vitals, cytokines, vitamin C, and markers of liver and kidney function were assessed in the blood, bronchoalveolar lavage, and organ homogenates.. PNA was induced in 119 outbred wild-type Institute of Cancer Research mice (predicted mortality approximately 50%) similar to CLP. In PNA, interleukin 1 receptor antagonist in 72-hour bronchoalveolar lavage was lower with HAT (2.36 ng/mL) compared with VEH (4.88 ng/mL; p = 0.04). The remaining inflammatory cytokines and markers of liver/renal function showed no significant difference with HAT in PNA. PNA vitamin C levels were 0.62 mg/dL (pDie HAT), lower than vitamin C levels after CLP (1.195 mg/dL). Unlike CLP, PNA mice did not develop acute kidney injury (blood urea nitrogen: pDie, 33.5 mg/dL vs. pLive, 27.6 mg/dL; p = 0.17). Furthermore, following PNA, HAT did not significantly reduce microscopic renal oxidative stress (mean gray area: pDie, 16.64 vs. pLive, 6.88; p = 0.93). Unlike CLP where HAT demonstrated a survival benefit, HAT had no impact on survival in PNA.. Hydrocortisone, ascorbic acid, and thiamine therapy has minimal benefits in pneumonia. The inflammatory response induced by pulmonary sepsis is unique compared with the response during intra-abdominal sepsis. Consequently, different etiologies of sepsis respond differently to HAT therapy.

Topics: Animals; Ascorbic Acid; Biomarkers; Cecum; Cytokines; Disease Models, Animal; Hydrocortisone; Ligation; Machine Learning; Mice; Pneumonia; Sepsis; Thiamine

Topics: Administration, Intravenous; Adult; Ascorbic Acid; Humans; Intensive Care Units; Sepsis; Vitamins

Topics: Ascorbic Acid; Fluid Therapy; Humans; Sepsis

Topics: Ascorbic Acid; Humans; Sepsis; Vitamins

Topics: Animals; Anti-Inflammatory Agents; Ascorbic Acid; COVID-19 Drug Treatment; Dexamethasone; Disease Models, Animal; Drug Combinations; Magnesium Sulfate; Mice; Niacinamide; Pantothenic Acid; Pyridoxine; Riboflavin; Sepsis; Thiamine

Topics: Ascorbic Acid; Humans; Sepsis; Vitamins

Sepsis is one of the leading causes of death in intensive care units worldwide. Vitamins C and E are natural antioxidants and anti-inflammatory agents. Suppressing the inflammation is an important treatment target because it plays a role in the pathophysiology of sepsis. The purpose of this study was to investigate the effect of vitamins C and E treatment in rats with sepsis-induced lung damage.. In this animal study, fecal intraperitoneal injection procedure (FIP) was performed on 30 of 40 rats included for creating a sepsis model. Rats were randomly assigned into four groups: Group 1, control group (no procedure was applied, n = 10), Group 2, FIP (untreated septic group n = 10), Group 3, FIP+vitC (treated with 500 mg/kg/day ascorbic acid, n = 10), and Group 4, FIP+vitE (treated with 300 mg/kg/day alpha-tocopherol, n = 10). Chest CT was performed in all rats and density of the lungs was measured by using Hounsfield unit (HU). Histopathological examination of lung damage was performed, and blood samples were collected for biochemical analysis.. TNF-α, CRP, IL 1-β, IL-6, and MDA plasma levels in groups treated with vitamin C or vitamin E were lower than in the FIP group. Histological scores in groups treated either with vitamin C or vitamin E were significantly lower as compared to those in the FIP group. The HU value of lung in groups treated wither with vitamin C or vitamin E were lower than that in the FIP group (p < 0.05).. The rats treated either with vitamin C or E showed improved results for sepsis. We think that they can be used as adjuvant therapy for septic patients because of their effectivity and low costs (Tab. 3, Fig. 2, Ref. 27).

Topics: alpha-Tocopherol; Animals; Anti-Inflammatory Agents; Antioxidants; Ascorbic Acid; Interleukin-1; Interleukin-6; Lung; Rats; Sepsis; Tomography, X-Ray Computed; Tumor Necrosis Factor-alpha; Vitamin E; Vitamins

Background: Acute kidney injury (AKI) occurs frequently in septic patients and correlates with increased mortality. Because clinical studies investigating hydrocortisone, ascorbic acid, and thiamine (HAT) have demonstrated discordant results, studies were performed using mortality stratification for therapy to identify candidates for therapy and determine mechanisms of organ injury. Methods: Sepsis was induced using the cecal ligation and puncture (CLP) model of sepsis with fluid and antibiotic support. Heart rate (HR) measurements obtained 6 hours after CLP stratified mice into live predicted (P-Live) or die predicted (P-Die). Stratified mice were then randomized for treatment with HAT or vehicle given 7 hours after CLP. Physiologic measurements were taken again at 24 hours, and mice were killed to collect blood and organs. Results: The following five groups were created: (1) P-Live vehicle, (2) P-Live HAT, (3) P-Die vehicle, (4) P-Die HAT, and (5) naive mice. Comparisons were made to test the hypotheses that (1) P-Die vehicle mice will have significant deterioration compared with P-Live mice targeting the kidney and (2) HAT will correct these deleterious changes in P-Die mice. Compared with P-Live, P-Die mice had a significant decline in all measured physiologic parameters (HR, cardiac output, breath rate, and temperature), which were corrected with HAT therapy (P < 0.05 for all parameters). The P-Die mice had declines in the ascorbic acid within the blood, peritoneal lavage, and kidney homogenate compared with P-Live mice indicating consumption, and the decline was corrected with HAT. Elevated IL-6, KC, Macrophage Inflammatory Protein-2, and IL-1RA were found in P-Die mice and decreased with HAT. Markers of endothelial cell injury (glypican 1 and glypican 4) were elevated in the P-Die mice, and these values were decreased with HAT therapy. Low oxygen levels with subsequent oxidative stress (OS) in the kidney were visualized in histologic sections using hypoxyprobe and also with carbonyl proteins and 8-iso-prostaglandin F2α in kidney homogenates. The P-Die mice had significant elevations of renal OSs, which was ameliorated with HAT. Kidney injury was evident in the P-Die mice compared with P-Live mice with elevations in blood urea nitrogen and cystatin C, which were significantly reduced with HAT. There was no evidence of global hypoxia or organ injury because hepatic parameters remained normal. Conclusions: Our data show that in CLP-induced sepsis, P-D

Topics: Acute Kidney Injury; Animals; Ascorbic Acid; Hydrocortisone; Kidney; Mice; Oxidative Stress; Sepsis; Thiamine

The efficacy of vitamin C in sepsis remains controversial. Whether vitamin C can alleviate lipopolysaccharide (LPS)-induced myocardial injury by inhibiting pyroptosis has not been studied. This study aimed to evaluate the effects of vitamin C on LPS-induced myocardial injury in vitro.. H9C2 cells were treated with indicated concentrations of LPS, and the cell viability was then assessed by CCK-8 assay. The levels of lactate dehydrogenase (LDH), CK-MB, IL-18 and IL-1β were examined by enzyme-linked immunosorbent assay (ELISA). The levels of intracellular reactive oxygen species (ROS) were measured using the fluorescent probe dichlorodihydrofluorescein diacetate (DCFH-DA). Western blot assays were conducted to determine the levels of the ROS-associated protein nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) and pyroptosis-associated proteins, such as NOD-like receptor (NLR) family pyrin domain containing 3 (NLRP3), caspase-1 and gasdermin D (GSDMD). The AKT inhibitor MK-2206 was then applied to explore the signalling pathway. Finally, H9C2 cells were divided into the control group, LPS group, vitamin C + LPS group, and N-acetyl-L-cysteine (NAC) + LPS group. The intracellular ROS, levels of associated proteins, cell viability, and release of LDH, CK-MB, IL-18 and IL-1β were examined.. LPS decreased cell viability and induced ROS and pyroptosis in H9C2 cells in a dose-dependent manner. Moreover, LPS activated the AKT/mTOR pathway in H9C2 cells. The AKT inhibitor MK-2206 protected H9C2 cells from LPS-induced death by suppressing pyroptosis, without changing intracellular ROS level. Vitamin C significantly inhibited intracellular ROS and cell pyroptosis in LPS-treated H9C2 cells. Moreover, vitamin C suppressed the activation of the AKT/mTOR pathway.. Our data suggest that vitamin C alleviates LPS-induced myocardial injury by inhibiting pyroptosis via the ROS-AKT/mTOR signalling pathway and thus provide novel insights into the prevention of sepsis-induced myocardial dysfunction.

Topics: Ascorbic Acid; Humans; Interleukin-18; Lipopolysaccharides; NLR Family, Pyrin Domain-Containing 3 Protein; Proto-Oncogene Proteins c-akt; Pyroptosis; Reactive Oxygen Species; Sepsis; TOR Serine-Threonine Kinases; Vitamins

In this article, I discuss the potential pitfalls of interpreting

Topics: Ascorbic Acid; Bayes Theorem; Humans; Sepsis

The effects of vitamin C on clinical outcomes in critically ill patients remain controversial due to inconclusive studies. This retrospective observational cohort study evaluated the effects of vitamin C therapy on acute kidney injury (AKI) and mortality among septic patients.. Electronic medical records of 1390 patients from an academic hospital who were categorized as Treatment (received at least one dose of 1.5 g IV vitamin C, n = 212) or Comparison (received no, or less than 1.5 g IV vitamin C, n = 1178) were reviewed. Propensity score matching was conducted to balance a number of covariates between groups. Multivariate logistic regressions were conducted predicting AKI and in-hospital mortality among the full sample and a sub-sample of patients seen in the ICU.. Data revealed that vitamin C therapy was associated with increases in AKI (OR = 2.07 95% CI [1.46-2.93]) and in-hospital mortality (OR = 1.67 95% CI [1.003-2.78]) after adjusting for demographic and clinical covariates. When stratified to examine ICU patients, vitamin C therapy remained a significant risk factor of AKI (OR = 1.61 95% CI [1.09-2.39]) and provided no protective benefit against mortality (OR = 0.79 95% CI [0.48-1.31]).. Ongoing use of high dose vitamin C in sepsis should be appraised due to observed associations with AKI and death.

Topics: Acute Kidney Injury; Administration, Intravenous; Age Factors; Ascorbic Acid; Female; Hospital Mortality; Humans; Intensive Care Units; Length of Stay; Male; Middle Aged; Propensity Score; Regression Analysis; Retrospective Studies; Sepsis

Sepsis is a common cause of death in intensive care unit. Some retrospective studies had shown the combination of hydrocortisone, ascorbic acid and thiamine (HAT therapy) could lower mortality rate of patients with sepsis or septic shock. Recently, multiple randomized controlled trials(RCTs) related to the efficacy of combination therapy don't reach a consensus. Though one meta-analysis indicated beneficial effect of HAT regimen on decreasing mortality rate of patients with sepsis or septic shock, improving SOFA score and reducing use of vasopressor. However, controversy still exist in the target population, timing, dose and duration of HAT regimen. Thus, the optimized RCTs are needed to provide more definitive evidence.. 脓毒症是重症监护病房患者死亡的常见原因，有回顾性研究显示联合氢化可的松、维生素C、硫胺素（即HAT方案）可降低脓毒症及感染性休克患者的病死率，而近期多项随机对照试验（RCTs）结果并不统一。有荟萃分析显示，HAT方案可降低脓毒症及感染性休克患者病死率、改善序贯器官衰竭评分（SOFA评分）、减少血管活性药物使用，但在HAT方案的适应人群、启用时间、应用剂量、疗程、药物安全性等方面仍存在争议，需优化目前RCTs设计以提供更为确切的证据。.

Topics: Ascorbic Acid; Humans; Hydrocortisone; Retrospective Studies; Sepsis; Thiamine

Intravenous vitamin C therapy has been associated with reduced mortality in patients with sepsis. Of potential concern with this therapy are falsely elevated point-of-care (POC) blood glucose values vs laboratory analyzed (LA) readings. The purpose of this study was to compare POC and LA blood glucose measurements in patients receiving intravenous vitamin C therapy.. All adults (≥18 years old) admitted from January 2017 to December 2018 who received at least two doses of intravenous vitamin C and had at least one paired blood glucose collection were eligible for inclusion. The primary endpoint was the accuracy in paired blood glucose values determined using the International Organization for Standardization (ISO) 15197:2013 criteria. Paired values were assessed for clinical impact using the Parkes consensus error grid analysis. A subgroup analysis was conducted to determine the impact of impaired renal function on outcomes.. Fourteen patients were included for analysis with 46 paired blood glucose levels. Compliance with ISO15197:2013 criteria was met in 34 (73.9%) paired values, which did not meet the minimum criteria for accuracy. Subgroup analysis showed that the paired values from patients with impaired renal function did not meet the minimum requirements for compliance, while those from patients without impaired renal function did. The Parkes error grid showed that the variation in POC measurements likely had minimal clinical impact.. Our study suggests that most patients receiving vitamin C for sepsis may still be monitored at POC with the glucose meter used in our study with minimal clinical impact.

Topics: Administration, Intravenous; Adolescent; Adult; Ascorbic Acid; Blood Glucose; Humans; Point-of-Care Systems; Sepsis

Sepsis is a life-threatening complication of pneumonia, including coronavirus disease-2019 (COVID-19)-induced pneumonia. Evidence of the benefits of vitamin C (VC) for the treatment of sepsis is accumulating. However, data revealing the targets and molecular mechanisms of VC action against sepsis are limited. In this report, a bioinformatics analysis of network pharmacology was conducted to demonstrate screening targets, biological functions, and the signaling pathways of VC action against sepsis. As shown in network assays, 63 primary causal targets for the VC action against sepsis were identified from the data, and four optimal core targets for the VC action against sepsis were identified. These core targets were epidermal growth factor receptor (EGFR), mitogen-activated protein kinase-1 (MAPK1), proto-oncogene c (JUN), and signal transducer and activator of transcription-3 (STAT3). In addition, all biological processes (including a top 20) and signaling pathways (including a top 20) potentially involved in the VC action against sepsis were identified. The hub genes potentially involved in the VC action against sepsis and interlaced networks from the Kyoto Encyclopedia of Genes and Genomes Mapper assays were highlighted. Considering all the bioinformatic findings, we conclude that VC antisepsis effects are mechanistically and pharmacologically implicated with suppression of immune dysfunction-related and inflammation-associated functional processes and other signaling pathways. These primary predictive biotargets may potentially be used to treat sepsis in future clinical practice.

Topics: Ascorbic Acid; Computational Biology; COVID-19; Gene Expression; Humans; Protein Interaction Maps; Proto-Oncogene Mas; SARS-CoV-2; Sepsis; Signal Transduction

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

Oxidative stress appears to initiate organ failure in sepsis, justifying treatment with antioxidants such as vitamin C at megadoses. We have therefore investigated the safety and efficacy of megadose sodium ascorbate in sepsis.. Interventional study.. Research Institute.. Adult Merino ewes.. Sheep were instrumented with pulmonary and renal artery flow-probes, and laser-Doppler and oxygen-sensing probes in the kidney. Conscious sheep received an infusion of live Escherichia coli for 31 hours. At 23.5 hours of sepsis, sheep received fluid resuscitation (30 mL/kg, Hartmann solution) and were randomized to IV sodium ascorbate (0.5 g/kg over 0.5 hr + 0.5 g/kg/hr for 6.5 hr; n = 5) or vehicle (n = 5). Norepinephrine was titrated to restore mean arterial pressure to baseline values (~80 mm Hg).. Sepsis-induced fever (41.4 ± 0.2°C; mean ± se), tachycardia (141 ± 2 beats/min), and a marked deterioration in clinical condition in all cases. Mean arterial pressure (86 ± 1 to 67 ± 2 mm Hg), arterial Po2 (102.1 ± 3.3 to 80.5 ± 3.4 mm Hg), and renal medullary tissue Po2 (41 ± 5 to 24 ± 2 mm Hg) decreased, and plasma creatinine doubled (71 ± 2 to 144 ± 15 µmol/L) (all p < 0.01). Direct observation indicated that in all animals, sodium ascorbate dramatically improved the clinical state, from malaise and lethargy to a responsive, alert state within 3 hours. Body temperature (39.3 ± 0.3°C), heart rate (99.7 ± 3 beats/min), and plasma creatinine (32.6 ± 5.8 µmol/L) all decreased. Arterial (96.5 ± 2.5 mm Hg) and renal medullary Po2 (48 ± 5 mm Hg) increased. The norepinephrine dose was decreased, to zero in four of five sheep, whereas mean arterial pressure increased (to 83 ± 2 mm Hg). We confirmed these physiologic findings in a coronavirus disease 2019 patient with shock by compassionate use of 60 g of sodium ascorbate over 7 hours.. IV megadose sodium ascorbate reversed the pathophysiological and behavioral responses to Gram-negative sepsis without adverse side effects. Clinical studies are required to determine if such a dose has similar benefits in septic patients.

Topics: Animals; Antioxidants; Ascorbic Acid; Bacteremia; Disease Models, Animal; Dose-Response Relationship, Drug; Escherichia coli Infections; Sepsis; Sheep

High-dose vitamin C is an essential adjunctive drug for sepsis treatment. This study aimed to determine if high-dose vitamin C could lead to erroneous point-of-care glucose testing results.. This retrospective, single-center, observational case series involved septic patients treated with high-dose vitamin C. We monitored their paired point-of-care glucose and laboratory glucose levels for statistical analysis. The glucose oxidase-peroxidase colorimetric method and hexokinase spectrophotometric method were applied for point-of-care glucose and laboratory glucose monitoring, respectively. Parkes Consensus Error Grid Analysis was used to assess the clinical influence of paired blood glucose values. Subgroup analyses were conducted to explore the effect of different vitamin C dosages and various renal function levels on point-of-care glucose readings.. During a 3-year period, 82 eligible septic patients who accepted at least three days of high-dose vitamin C treatment were included in this study. Compliance with ISO15197:2013 criteria was met in 30 (36.59%) paired values, a proportion considerably lower than the minimum criteria for accuracy. Subgroup analysis showed that worse renal function or higher vitamin C dosage could lead to greater bias in point-of-care glucose readings; however, these inaccuracies rarely represented a clinical risk.. High-dose intravenous ascorbate acid infusion may interfere with point-of-care glucose testing results. Thus, laboratory glucose measurements are recommended for more accurate results. Nonetheless, the inaccuracies magnitude of point-of-care glucose readings does not represent a significant clinical risk when physicians alter clinical action based on these results.

Topics: Ascorbic Acid; Blood Glucose; Humans; Point-of-Care Systems; Retrospective Studies; Sepsis

Topics: Ascorbic Acid; Humans; Sepsis; Vitamins

Topics: Ascorbic Acid; Clinical Trials Data Monitoring Committees; Humans; Hydrocortisone; Sepsis; Thiamine; Ventilators, Mechanical

Topics: Ascorbic Acid; Humans; Hydrocortisone; Sepsis; Thiamine; Ventilators, Mechanical

Topics: Adrenal Cortex Hormones; Ascorbic Acid; Clinical Trials as Topic; Communication; COVID-19 Drug Treatment; Decision Making; Humans; Hydroxychloroquine; Judgment; Mass Media; Persuasive Communication; SARS-CoV-2; Sepsis; Social Media

Ascorbate (Vitamin C) has been proposed as a promising therapeutic agent against sepsis in clinical trials, but there is little experimental evidence on its anti-septic efficacy. We report that Toll-like receptor 4 (TLR4) activation by LPS stimuli augments ascorbate uptake in murine and human tubular cells through upregulation of two ascorbate transporters SVCT-1 and -2 mediated by Fn14/SCF

Topics: Acute Kidney Injury; Animals; Ascorbic Acid; Cell Line; Disease Models, Animal; Humans; Kidney Tubules; Lipopolysaccharides; Male; Mice; Mitochondria; Mitophagy; Protein Kinases; Sepsis; Signal Transduction; Ubiquitin-Protein Ligases; Vitamins

Vitamin C (ascorbic acid) is a normal liver metabolite in most animals, with humans being a notable exception due to random genetic mutations that have occurred during our evolution [...].

Topics: Ascorbic Acid; Bacterial Infections; Epigenesis, Genetic; Humans; Neoplasms; Sepsis

Vitamin C deficiency often occurs in critical illness and especially in patients with sepsis. Low plasma levels correlate with organ dysfunction and outcome parameters. Vitamin C offers pleiotropic effects possibly attenuating pathophysiology in sepsis. This includes antioxidative effects like scavenging reactive oxygen species or restoring other antioxidants. Vitamin C is a cofactor for norepinephrine biosynthesis and it protects endothelial function. In addition, it modulates immune response. A combined therapy with vitamin C, hydrocortisone and thiamine could be beneficial because of synergistic effects. Some clinical studies have shown reduced mortality due to vitamin C alone or in combination with hydrocortisone and thiamine, others do not. Adverse events are rare. So data supporting a therapy with vitamin C is still unclear. Further randomised controlled trials are necessary.. Die Sepsis ist eine häufige und schwere Erkrankung mit vielfältigen pathophysiologischen Veränderungen. Wiederholt wurde versucht, mit neuen Therapieansätzen den Verlauf der Sepsis positiv zu beeinflussen. Als neue Therapieoption rückte in den letzten Jahren Vitamin C in den Fokus der Sepsisforschung. Ob Vitamin C diese Hoffnungen erfüllen kann, soll in diesem Beitrag erläutert werden.

Topics: Ascorbic Acid; Humans; Hydrocortisone; Sepsis; Thiamine; Vitamins

Sepsis is common in foals and several treatments are used to facilitate recovery. Evidence in people suggests an association between low blood concentrations of thiamine, ascorbic acid, and cortisol and sepsis, with further evidence suggesting that administration of hydrocortisone, thiamine, and ascorbic acid may improve outcome. No information is available with regard to these treatments in foals.. To compare blood concentrations of thiamine, ascorbic acid, and cortisol in healthy and ill foals.. Fifteen healthy and 27 ill (septic and sick-nonseptic [SNS]) foals were evaluated at admission. Fewer healthy and ill foals were available for sampling at 72 and 120 hours.. Prospective study. Blood was collected from healthy foals at 12 (n = 15), 72 (n = 11), and 120 (n = 9) hours of age and from ill foals <48 hours old at admission (n = 27), 72 (n = 8), and 120 (n = 8) hours after presentation. Thiamine, ascorbic acid, and cortisol concentrations were measured in blood samples and compared between groups of foals.. Blood concentrations of thiamine were significantly lower in septic compared to healthy foals at 72 (median, 1.72 ng/mL; P = .02) and 120 (median, 2.0 ng/mL; P = .04) hours after admission; blood concentrations of ascorbic acid also were significantly lower in septic compared to healthy foals at 72 (median, 4.4 μg/mL; P = .02) and 120 hours (median, 4.8 μg/mL; P = .03). Blood concentrations of ascorbic acid were lower in SNS compared to healthy foals at 72 (median, 6.9 μg/mL; P = .03) and 120 (median, 6.4 μg/mL; P = .04) hours after admission. Serum cortisol concentrations were significantly higher at admission in septic (median, 4.23 μg/dL) compared to SNS (median, 1.8 μg/dL; P = .01) and healthy (median, 2.2 μg/dL; P = .002) foals.. A potential association exists between illness in foals and lower blood concentrations of thiamine and ascorbic acid during hospitalization. Additional studies are needed to examine a larger population of foals and determine the clinical impact of low vitamin concentrations, if any, on morbidity and mortality.

Topics: Animals; Animals, Newborn; Ascorbic Acid; Horse Diseases; Horses; Hydrocortisone; Prospective Studies; Sepsis; Thiamine; Vitamins

The dysregulated host response and organ damage following systemic infection that characterizes a septic event predisposes individuals to a chronic immunoparalysis state associated with severe transient lymphopenia and diminished lymphocyte function, thereby reducing long-term patient survival and quality of life. Recently, we observed lasting production of reactive oxygen species (ROS) in mice that survive sepsis. ROS production is a potent mechanism for targeting infection, but excessive ROS production can prove maladaptive by causing organ damage, impairing lymphocyte function, and promoting inflammaging, concepts paralleling sepsis-induced immunoparalysis. Notably, we observed an increased frequency of ROS-producing immature monocytes in septic hosts that was sustained for greater than 100 days postsurgery. Recent clinical trials have explored the use of vitamin C, a potent antioxidant, for treating septic patients. We observed that therapeutic vitamin C administration for sepsis limited ROS production by monocytes and reduced disease severity. Importantly, we also observed increased ROS production by immature monocytes in septic patients both at admission and ∼28 days later, suggesting a durable and conserved feature that may influence the host immune response. Thus, lasting ROS production by immature monocytes is present in septic patients, and early intervention strategies to reduce it may improve host outcomes, potentially reducing sepsis-induced immunoparalysis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Antioxidants; Ascorbic Acid; Case-Control Studies; Disease Models, Animal; Female; Healthy Volunteers; Humans; Leukocytes, Mononuclear; Male; Mice; Middle Aged; Reactive Oxygen Species; Sepsis; Severity of Illness Index; Young Adult

Here, we demonstrate that the two distinct formulations of our anti-sepsis drug candidate Rejuveinix (RJX), have a very favorable safety profile in Wistar Albino rats at dose levels comparable to the projected clinical dose levels. 14-day treatment with RJX-P (RJX PPP.18.1051) or RJX-B (RJX-B200702-CLN) similarly elevated the day 15 tissue levels of the antioxidant enzyme superoxide dismutase (SOD) as well as ascorbic acid in both the lungs and liver in a dose-dependent fashion. The activity of SOD and ascorbic acid levels were significantly higher in tissues of RJX-P or RJX-B treated rats than vehicle-treated control rats (p < 0.0001). There was no statistically significant difference between tissue SOD activity or ascorbic acid levels of rats treated with RJX-P vs. rats treated with RJX-B (p > 0.05). The observed elevations of the SOD and ascorbic acid levels were transient and were no longer detectable on day 28 following a 14-day recovery period. These results demonstrate that RJX-P and RJX-B are bioequivalent relative to their pharmacodynamic effects on tissue SOD and ascorbic acid levels. Furthermore, both formulations showed profound protective activity in a mouse model of sepsis. In agreement with the PD evaluations in rats and their proposed mechanism of action, both RJX-P and RJX-B exhibited near-identical potent and dose-dependent anti-oxidant and anti-inflammatory activity in the LPS-GalN model of ARDS and multi-organ failure in mice.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Ascorbic Acid; Dose-Response Relationship, Drug; Drug Combinations; Drug Compounding; Female; Lipopolysaccharides; Magnesium Sulfate; Male; Mice, Inbred BALB C; Niacinamide; Oxidative Stress; Pantothenic Acid; Pyridoxine; Rats; Rats, Sprague-Dawley; Rats, Wistar; Riboflavin; Sepsis; Superoxide Dismutase; Thiamine

Sepsis survivors present long-term cognitive deficits. The present study was to investigate the effect of early administration of high-dose vitamin C on cognitive function in septic rats and explore its possible cerebral protective mechanism. Rat sepsis models were established by cecal ligation and puncture (CLP). Ten days after surgery, the Morris water maze test was performed to evaluate the behavior and cognitive function. Histopathologic changes in the hippocampus were evaluated by nissl staining. The inflammatory cytokines, activities of antioxidant enzymes (superoxide dismutase or SOD) and oxidative products (malondialdehyde or MDA) in the serum and hippocampus were tested 24 h after surgery. The activity of matrix metalloproteinase-9 (MMP-9) and expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1(HO-1) in the hippocampus were measured 24 h after surgery. Compared with the sham group in the Morris water maze test, the escape latency of sepsis rats was significantly (P = 0.001) prolonged in the navigation test, whereas the frequency to cross the platform and the time spent in the target quadrant were significantly (P = 0.003) reduced. High-dose vitamin C significantly decreased the escape latency (P = 0.01), but increased the time spent in the target quadrant (P = 0.04) and the frequency to cross the platform (P = 0.19). In the CLP+ saline group, the pyramidal neurons were reduced and distributed sparsely and disorderly, the levels of inflammatory cytokines of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10 in the serum and hippocampus were significantly increased (P = 0.000), the blood brain barrier (BBB) permeability in the hippocampus was significantly (P = 0.000) increased, the activities of SOD in the serum and hippocampus were significantly (P = 0.000 and P = 0.03, respectively) diminished while the levels of MDA in the serum and hippocampus were significantly (P = 0.007) increased. High-dose vitamin C mitigated hippocampus histopathologic changes, reduced systemic inflammation and neuroinflammation, attenuated BBB disruption, inhibited oxidative stress in brain tissue, and up-regulated the expression of nuclear and total Nrf2 and HO-1. High-dose vitamin C significantly (P < 0.05) decreased the levels of tumor necrosis factor- (TNF)-α, interleukin-6 (IL-6), MDA in the serum and hippocampus, and the activity of MMP-9 in the hippocampus, but significantly (P < 0.05) increased the levels of SOD, the

Topics: Animals; Ascorbic Acid; Blood-Brain Barrier; Cognitive Dysfunction; Disease Models, Animal; Dose-Response Relationship, Drug; Heme Oxygenase (Decyclizing); Hippocampus; Inflammation; Male; NF-E2-Related Factor 2; Oxidative Stress; Protective Agents; Rats, Sprague-Dawley; Sepsis

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 is an extremely complex clinical syndrome, usually involving an excessive inflammatory response including an overshooting cytokine release that damages tissue and organs of the patient. Due to the severity of this condition, it is estimated that over 11 million people die from sepsis each year. Despite intensive research in the field, there is still no specific therapy for sepsis. Many sepsis patients show a marked deficiency of vitamin C. 9 out of 10 sepsis patients have a hypovitaminosis C, and every third patient even shows a clinical deficiency in the scurvy range. In addition, low vitamin C levels of intensive care sepsis patients correlate with a higher need for vasopressors, higher Sequential Organ Failure Assessment (SOFA) scores, and increased mortality. Based on this observation and the conducted clinical trials using vitamin C as sepsis therapy in intensive care patients, the aim of the present ex vivo study was to evaluate the effects of high-dose vitamin C alone and in a triple combination supplemented with vitamin B1 (thiamine) and hydrocortisone on the lipopolysaccharide (LPS)-induced cytokine response in peripheral blood mononuclear cells (PBMCs) from healthy human donors. We found that all corticosteroid combinations strongly reduced the cytokine response on RNA- and protein levels, while high-dose vitamin C alone significantly diminished the PBMC mediated secretion of the cytokines interleukin (IL)-10, IL-23, and monocyte chemo-attractant protein (MCP-1), which mediate the inflammatory response. However, vitamin C showed no enhancing effect on the secretion of further cytokines studied. This data provides important insights into the possible immunomodulatory function of vitamin C in an ex vivo setting of human PBMCs and the modulation of their cytokine profile in the context of sepsis. Since vitamin C is a vital micronutrient, the restoration of physiologically adequate concentrations should be integrated into routine sepsis therapy, and the therapeutic effects of supraphysiological concentrations of vitamin C in sepsis patients should be further investigated in clinical trials.

Topics: Adult; Anti-Inflammatory Agents; Ascorbic Acid; Cells, Cultured; Cytokines; Drug Therapy, Combination; Female; Gene Expression Regulation; Humans; Hydrocortisone; Inflammation Mediators; Leukocytes, Mononuclear; Male; Middle Aged; Sepsis; Thiamine; Young Adult

脓毒症患者普遍存在维生素C缺乏，并与疾病严重程度相关。目前，脓毒症仍有较高的发病率和病死率。脓毒症时机体可出现微循环障碍，甚至发展为器官衰竭。外源性补充维生素C，可能是脓毒症有效的辅助治疗措施之一，既可改善机体微循环，亦可通过参与机体去甲肾上腺素的合成、改善外周血管阻力、提高灌注压而影响患者预后。但近年来亦有许多不同的研究结果。本文就维生素C改善脓毒症患者微循环的作用机制、安全性及目前所开展的临床研究等方面做一概述。.

Topics: Ascorbic Acid; Humans; Microcirculation; Sepsis; Vitamins

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

Sepsis, a condition caused by severe infections, affects more than 30 million people worldwide every year and remains the leading cause of death in hospitals

Topics: Adoptive Transfer; Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Ascorbic Acid; Cathepsin B; Drug Carriers; Drug Resistance, Multiple, Bacterial; Lipids; Liposomes; Macrophages; Mice; Mice, Inbred C57BL; Nanoparticles; RAW 264.7 Cells; RNA, Messenger; Sepsis; Vitamins

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

The efficacy of vitamin C (VitC) and thiamine (THMN) in patients admitted to the intensive care unit (ICU) with sepsis is unclear. The purpose of this study was to evaluate the effect of VitC and THMN on mortality and lactate clearance in ICU patients. We hypothesized that survival and lactate clearance would be improved when treated with thiamine and/or VitC.. The Philips eICU database version 2.0 was queried for patients admitted to the ICU in 2014 to 2015 for 48 hours or longer and patients with sepsis and an elevated lactate of 2.0 mmol/L or greater. Subjects were categorized according to the receipt of VitC, THMN, both, or neither. The primary outcome was in-hospital mortality. Secondary outcome was lactate clearance defined as lactate less than 2.0 mmol/L achieved after maximum lactate. Univariable comparisons included age, sex, race, Acute Physiology Score III, Acute Physiology and Chronic Health Evaluation (APACHE) IVa score, Sequential Organ Failure Assessment, surgical ICU admission status, intubation status, hospital region, liver disease, vasopressors, steroids, VitC and THMN orders. Kaplan-Meier curves, logistic regression, propensity score matching, and competing risks modeling were constructed.. Of 146,687 patients from 186 hospitals, 7.7% (n = 11,330) were included. Overall mortality was 25.9% (n = 2,930). Evidence in favor of an association between VitC and/or THMN administration, and survival was found on log rank test (all p < 0.001). After controlling for confounding factors, VitC (adjusted odds ratio [AOR], 0.69 [0.50-0.95]) and THMN (AOR, 0.71 [0.55-0.93]) were independently associated with survival and THMN was associated with lactate clearance (AOR, 1.50 [1.22-1.96]). On competing risk model VitC (AOR, 0.675 [0.463-0.983]), THMN (AOR, 0.744 [0.569-0.974]), and VitC+THMN (AOR, 0.335 [0.13-0.865]) were associated with survival but not lactate clearance. For subgroup analysis of patients on vasopressors, VitC+THMN were associated with lactate clearance (AOR, 1.85 [1.05-3.24]) and survival (AOR, 0.223 [0.0678-0.735]).. VitC+THMN is associated with increased survival in septic ICU patients. Randomized, multicenter trials are needed to better understand their effects on outcomes.. Therapeutic Study, Level IV.

Topics: Aged; APACHE; Ascorbic Acid; Female; Hospital Mortality; Humans; Intensive Care Units; Lactates; Male; Middle Aged; Organ Dysfunction Scores; Propensity Score; Sepsis; Survival Rate; Thiamine

Topics: Ascorbic Acid; Biomarkers; Humans; Inflammation; Respiratory Insufficiency; Sepsis; Vascular System Injuries

Topics: Ascorbic Acid; Biomarkers; Humans; Inflammation; Respiratory Insufficiency; Sepsis; Vascular System Injuries

Topics: Ascorbic Acid; Humans; Respiratory Distress Syndrome; Respiratory Insufficiency; Sepsis; Vitamins

Vitamin C (ascorbate, ASC) is a critical antioxidant in the body with specific roles in the brain. Despite a recent interest in vitamin C therapies for critical care medicine, little is known about vitamin C regulation during acute inflammation and critical illnesses such as sepsis. Using a cecal slurry (CS) model of sepsis in mice, we determined ASC and inflammatory changes in the brain following the initial treatment. ASC levels in the brain were acutely decreased by approximately 10% at 4 and 24 h post CS treatment. Changes were accompanied by a robust increase in liver ASC levels of up to 50%, indicating upregulation of synthesis beginning at 4 h and persisting up to 7 days post CS treatment. Several key cytokines interleukin 6 (IL-6), interleukin 1β (IL-1β), tumor necrosis factor alpha (TNFα), and chemokine (C-X-C motif) ligand 1 (CXCL1, KC/Gro) were also significantly elevated in the cortex at 4 h post CS treatment, although these levels returned to normal by 48 h. These data strongly suggest that ASC reserves are directly challenged throughout illness and recovery from sepsis. Given the timescale of this response, decreases in cortical ASC are likely driven by hyper-acute neuroinflammatory processes. However, future studies are required to confirm this relationship and to investigate how this deficiency may subsequently impact neuroinflammation.

Topics: Animals; Antioxidants; Ascorbic Acid; Brain; Cytokines; Disease Models, Animal; Inflammation; Mice; Mice, Inbred C57BL; Organ Specificity; Sepsis

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

ClinicalTrials.gov: NCT03509350. Registered on 26 April 2018.

Topics: Anti-Inflammatory Agents; Ascorbic Acid; Drug Therapy, Combination; Humans; Hydrocortisone; Sepsis; Thiamine; Time-to-Treatment; Treatment Outcome; Vitamin B Complex

Topics: Ascorbic Acid; Humans; Intensive Care Units; Randomized Controlled Trials as Topic; Sepsis; Steroids; Thiamine

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: Ascorbic Acid; Humans; Hydrocortisone; Sepsis; Thiamine; Vitamins

Topics: Ascorbic Acid; Humans; Sepsis; Vitamins

Oxidative stress and the production of intracellular reactive oxygen species (ROS) have been implicated in the pathogenesis of sepsis. In excess, oxidative stress is not deemed an unbalanced biochemical reaction in the critically ill rats, but it is a key pathological factor in driving systemic inflammatory response that can result in multiple organ failure in sepsis. Thus, we aimed to explore whether antioxidant nutrients could reduce or delay the oxidative stress condition of sepsis rats, and then play a prospective role in the oxidative stress condition of critical disease. In this investigation, the ability of exogenous and endogenous antioxidant nutrients (ascorbate, taurine and glutathione) to prevent sepsis-induced changes in liver injury was examined using a rat model of sepsis induced by cecal ligation and puncture (CLP), and the underlying mechanisms were also investigated. The effects of three antioxidants on sepsis were assessed based on biochemical assays in combination with an NMR-based metabolomics approach and correlation network analysis. Our results suggested that ascorbate, taurine and glutathione had broadly similar protective effects on reducing oxidative stress. Compared with CLP rats, antioxidant-treated rats exhibited alleviated (P<.05) organ dysfunction and improved liver pathology. Moreover, taurine showed a better efficacy compared with ascorbate and glutathione, evidenced by significantly reversed metabolomics profiles toward normal state. Under conditions of sepsis, antioxidants suppressed inflammatory responses by restraining key signaling pathways, including the redox-sensitive transcription factor pathways of NF-κB and MAPK. Collectively, our findings suggested that antioxidant nutrients exerted beneficial effects on septic rats via protecting mitochondrial.

Topics: Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Glutathione; Liver Diseases; Magnetic Resonance Spectroscopy; Male; Metabolome; Metabolomics; Nutrients; Oxidative Stress; Rats; Sepsis; Taurine

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

Vitamin C deficiency has been described in patients with sepsis. The post-cardiac arrest syndrome shares similarities to sepsis, however vitamin C levels in post-arrest patients have been incompletely characterized. We assessed vitamin C levels in a post-arrest population.. This was a retrospective observational study at a tertiary care center. A convenience sample of post-arrest, sepsis, and healthy control patients was selected from prior studies. Vitamin C levels were measured from samples obtained within 6-h of emergency department admission. A subset of cardiac arrest patients had vitamin C levels additionally measured 24-h later.. A total of 84 patients (34 healthy controls, 25 post-arrest, and 25 septic patients) were included. The median baseline vitamin C level in cardiac arrest patients was 0.33 mg/dL (0.05-0.83), as compared to 0.91 mg/dL (0.69-1.48) in the healthy control group (p < 0.01) and 0.28 mg/dL (0.11-0.59) in the septic group (p = 0.36). Vitamin C levels for cardiac arrest patients fell between the two time points, but the change was not statistically significant (median decrease 0.26 mg/dL, p = 0.08).. Serum vitamin C levels were lower in post-arrest patients compared to controls and were similar to patients with sepsis. Future studies of vitamin C levels and supplementation following cardiac arrest may be warranted.

Topics: Ascorbic Acid; Humans; Out-of-Hospital Cardiac Arrest; Retrospective Studies; Sepsis; Survivors

Topics: Adult; Antineoplastic Agents; Ascorbic Acid; Glucosephosphate Dehydrogenase Deficiency; Humans; Sepsis

A small clinical trial showed HAT therapy improved survival but no studies have been reported in animal models to examine potential mechanisms.. Sepsis was induced in female mice using the cecal ligation and puncture (CLP) model. Physiologic parameters including heart rate (HR), pulse distension (PD), and respiratory rate (RR) were measured noninvasively at baseline, 6 and 24 h post CLP. These measurements stratified mice into predicted to live (Live-P) or die (Die-P). Mice were randomized to receive HAT therapy or vehicle. Oxidative stress was measured in peritoneal exudative cells 24 h after CLP.. HR, PD, and RR all declined within the first 6 h of sepsis and were significantly lower in the Die-P mice compared with Live-P. HR 6 h post-CLP best predicted mortality and continued to decline between 6 and 24 h post CLP. Oxidative stress in peritoneal cells harvested 24 h post CLP (determined by 8 isoprostaglandin F2α and protein carbonyl derivatives) was significantly higher in the Die-P mice. HAT therapy was initiated 7 h post-CLP after mortality prediction and stratification. HAT significantly reduced oxidative stress in the Die-P mice without altering these parameters in the Live-P mice. HAT treatment prevented the decline in HR, again only in the Die-P mice. Mice treated with HAT therapy had significantly better survival.. Physiologic parameters accurately predicted mortality. Die-P mice had significant oxidative stress compared with Live-P. HAT therapy significantly decreased oxidative stress, increased HR, and improved survival in the Die-P mice. These data suggest that HAT exerts a beneficial effect through reducing oxidative stress and improving cardiovascular function.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Ascorbic Acid; Blood Pressure; Disease Models, Animal; Female; Heart Rate; Hydrocortisone; Mice; Mice, Inbred ICR; Oxidative Stress; Sepsis; Thiamine; Vitamin B Complex

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

Emerging data suggest that intravenous ascorbic acid (AA) may be beneficial in patients with sepsis. Clinicians require data on stability of diluted AA for safe administration. We evaluated the stability of AA diluted in normal saline (NS) or 5% dextrose in water (D5W) solutions over 14 days at 25 °C and at 4 °C, protected from light, using concentrations of 37 mg/mL and 77 mg/mL (Sandoz) and 40 mg/mL and 92 mg/mL (Mylan). We also assessed stability of a 40 mg/mL solution (Mylan) at 25 °C exposed to light for 75 h. Concentrations were measured using liquid chromatographic separation with ultraviolet light detection on days 0, 0.33, 1, 1.33, 2, 3, 4, 7, 10 and 14. By day 14, solutions at 4 °C retained >97.72% of the initial concentration; at 25 °C, solutions retained >88.02% of the initial concentration, but visual changes were evident after day 2. Multiple linear regression demonstrated that study day and temperature (

Topics: Ascorbic Acid; Drug Compounding; Drug Packaging; Drug Stability; Drug Storage; Glucose; Humans; Infusions, Intravenous; Light; Photolysis; Saline Solution; Sepsis; Temperature; Time Factors

Topics: Ascorbic Acid; Biomarkers; Humans; Respiratory Insufficiency; Sepsis; Vascular System Injuries

Topics: Ascorbic Acid; Biomarkers; Humans; Inflammation; Respiratory Distress Syndrome; Respiratory Insufficiency; Sepsis; Vascular System Injuries

Topics: Ascorbic Acid; Biomarkers; Humans; Inflammation; Respiratory Distress Syndrome; Respiratory Insufficiency; Sepsis; Vascular System Injuries

Topics: Antioxidants; Ascorbic Acid; Humans; Reactive Oxygen Species; Sepsis; Survival Analysis; Thiamine

Topics: Ascorbic Acid; Biomarkers; Humans; Hydrocortisone; Procalcitonin; Sepsis; Thiamine

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

Increased endothelial permeability is central to shock and organ dysfunction in sepsis but therapeutics targeted to known mediators of increased endothelial permeability have been unsuccessful in patient studies. We previously reported that cell-free hemoglobin (CFH) is elevated in the majority of patients with sepsis and is associated with organ dysfunction, poor clinical outcomes and elevated markers of oxidant injury. Others have shown that Vitamin C (ascorbate) may have endothelial protective effects in sepsis. In this study, we tested the hypothesis that high levels of CFH, as seen in the circulation of patients with sepsis, disrupt endothelial barrier integrity.. Human umbilical vein endothelial cells (HUVEC) were grown to confluence and treated with CFH with or without ascorbate. Monolayer permeability was measured by Electric Cell-substrate Impedance Sensing (ECIS) or transfer of. CFH increased permeability in a dose- and time-dependent manner with 1 mg/ml of CFH increasing inulin transfer by 50% without affecting cell viability. CFH (1 mg/ml) also caused a dramatic reduction in intracellular ascorbate in the same time frame (1.4 mM without CFH, 0.23 mM 18 h after 1 mg/ml CFH, p < 0.05). Pre-treatment of HUVECs with ascorbate attenuated CFH induced permeability.. CFH increases endothelial permeability in part through depletion of intracellular ascorbate. Supplementation of ascorbate can attenuate increases in permeability mediated by CFH suggesting a possible therapeutic approach in sepsis.

Topics: Antioxidants; Ascorbic Acid; Capillary Permeability; Endothelium, Vascular; Hemoglobins; Human Umbilical Vein Endothelial Cells; Humans; Sepsis

Critically ill polytrauma patients have increased production of free radicals (FRs) and consequent alterations in biochemical pathways, as well as disruption of cellular integrity, due to increased lipid peroxidation. The aim of this study was to investigate several biomarkers associated with increased oxidative stress in critically ill polytrauma patients, and to evaluate the effect of antioxidant treatment on the clinical outcome in these patients. A total of 67 polytrauma patients from an intensive care unit met the selection criteria. Antiox group included 35/67 patients who received antioxidant therapy, while 32/67 patients without antioxidant treatment were considered as control group. Antioxidant therapy consisted of simultaneous administration of Vitamin C (sodium ascorbate) and N-acetylcysteine, through continuous intravenous infusion. Clinical and paraclinical evaluation of the patients was performed daily until discharge or death. At admission, laboratory parameters did not differ significantly between two groups. At discharge/upon death, statistically significant differences in favor of Antiox group were observed in the following parameters: thrombocytes, activated partial thromboplastin time, prothrombin time, total bilirubin, total cholesterol, high-density lipoproteins, low-density lipoproteins, erythrocyte sedimentation rate, interleukin 6 (all p = 0.0001), total protein (p = 0.0005), serum albumin (p = 0.0004), lactate dehydrogenase (p = 0.0006), and C-reactive protein (p = 0.0014). Starting from day 5, the APACHE II score was significantly decreased in Antiox versus control group (p < 0.05). Finally, the sepsis incidence and mortality rate were significantly lower in Antiox group (p < 0.05). Decreasing the level of oxidative stress by antioxidant substances significantly correlated with a better prognosis and outcome in our patients. Further studies should elucidate more clearly the mechanism of action of antioxidants in critically ill polytrauma patients.

Topics: Acetylcysteine; Adult; Antioxidants; APACHE; Ascorbic Acid; Biomarkers; Critical Care; Critical Illness; Female; Humans; Inflammation; Lipid Peroxidation; Lipids; Male; Middle Aged; Multiple Trauma; Oxidative Stress; Partial Thromboplastin Time; Prospective Studies; Sepsis; Treatment Outcome

Topics: Ascorbic Acid; History, Ancient; History, Medieval; Humans; Scurvy; Sepsis

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: Antioxidants; Ascorbic Acid; Clinical Trials as Topic; Critical Care; Humans; Sepsis

High-dose intravenous vitamin C is a potential treatment option for patients with sepsis and may interfere with point-of-care (POC) blood glucose (BG) testing. This study aimed to determine if vitamin C dosing used for sepsis affected POC BG level results.. Prospective observational pilot study.. Intensive care unit in a large academic tertiary care medical center.. Five consecutive critically ill adults hospitalized between April 1 and June 1, 2017, who received two or more doses of intravenous vitamin C 1500 mg for the treatment of sepsis and had at least two paired POC BG levels and laboratory venous BG levels measured within 1 hour of each other during vitamin C therapy.. The performance of POC BG level measurement was compared with the reference method of laboratory BG level measurement. The concordance to minimum accuracy criteria for BG meters set forth by the International Organization for Standardization (ISO) 15197:2013, the measurement of agreement between POC BG level and laboratory BG level using the Bland-Altman method, and the clinical accuracy through Parkes error grid analysis were assessed. A total of 16 paired POC and laboratory BG level measurements from the five patients were included. The accuracy of POC BG with laboratory BG level measurements during vitamin C administration according to ISO 15197:2013 criteria was 81.3%, which did not meet the minimum accuracy criteria of 95%. The Bland-Altman analysis showed a mean difference between POC and laboratory BG levels of 8.9 mg/dl, and the Parkes error grid analysis showed that the differences between POC and laboratory BG level measurements would not have resulted in a change in clinical action.. The accuracy and agreement of POC and laboratory BG level measurements in critically ill patients receiving vitamin C were consistent with previously published reports in critically ill patients not receiving vitamin C and did not demonstrate clinically significant interference due to vitamin C dosing for sepsis.

Topics: Administration, Intravenous; Antioxidants; Ascorbic Acid; Blood Glucose; Critical Illness; Female; Humans; Intensive Care Units; Male; Middle Aged; Pilot Projects; Point-of-Care Systems; Prospective Studies; Reference Standards; Reproducibility of Results; Sepsis

Hospital mortality of severe sepsis and septic shock is still around 40 % according to recent studies. In accordance to the current sepsis definition, sepsis is a life-threatening organ dysfunction caused by a dysregulated response of the organism to infection. Septic shock is defined by vasopressor-dependent circulatory failure and lactic acidosis. Patients with sepsis and septic shock are often old and/or characterized by severe comorbidities, e. g. tumor or liver disease. These factors also predispose to malnutrition and hence to a corresponding deficiency of essential nutritional components e. g. vitamins. A number of recent studies and reviews have addressed the question whether deficiencies in certain vitamins may facilitate the transition from infection to septic shock. In addition, studies have investigated the effect of high-dose vitamin therapies on sepsis mortality and sepsis-associated organ dysfunctions. This article would like to summarize this current discussion with a focus on vitamin B. Vitamin C besitzt multiple biologische Funktionen, die sich im Rahmen einer Sepsis günstig auswirken könnten. Die Applikation von hochdosiertem Vitamin C in Kombination mit Thiamin und Hydrokortison war in einer viel diskutierten, 2017 veröffentlichten klinischen Studie mit einer drastischen Senkung der Sepsisletalität assoziiert. In mehreren prospektiven randomisierten Studien wird die Wirksamkeit dieses Therapiekonzepts derzeit unabhängig voneinander überprüft.. Auch der Einsatz von Vitamin D

Topics: Ascorbic Acid; Avitaminosis; Humans; Sepsis; Vitamin D; Vitamin K

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

The aim of this study was to verify the protective effects of ascorbic acid (AsA) against lipopolysaccharide (LPS)-induced sepsis. The study was conducted using osteogenic disorder Shionogi (ODS) rats, which are unable to synthesize AsA. Male ODS rats (6 wk old) were fed either an AsA-free diet (AsA-deficient group), a diet supplemented with 300 mg/kg AsA (control group), or a diet supplemented with 3,000 mg/kg AsA (high-AsA group) for 8 d. On day 8, all the rats were intraperitoneally injected with LPS (15 mg/kg body weight). Forty-eight hours after the injection, the survival rates of the rats in the control (39%) and the high-AsA (61%) groups were significantly higher than that in the AsA-deficient group (5.5%). Next, we measured several inflammatory parameters during 10 h after administering LPS. At 6 h, elevated serum levels of markers for hepatic and systemic injuries were suppressed in rats fed AsA. Similarly, 10 h after LPS injection, the elevation in the serum levels of markers for renal injury were also suppressed proportionally to the amount of AsA in the diet. The elevated serum concentrations of TNFα and IL-1β by LPS in the AsA-deficient group decreased in groups fed AsA. Hematic TNFα mRNA levels at 6 h after the LPS injection were also lowered by feeding AsA. These results demonstrated that the dietary intake of AsA improved the survival rates and suppressed the inflammatory damage, in a dose-dependent manner, caused during sepsis induced by LPS in ODS rats.

Topics: Animals; Anti-Inflammatory Agents; Ascorbic Acid; Ascorbic Acid Deficiency; Diet; Dietary Supplements; Inflammation; Interleukin-1beta; Kidney; Kidney Diseases; Lipopolysaccharides; Liver; Liver Diseases; Male; Nutritional Status; Osteogenesis; Rats; Rats, Inbred Strains; Sepsis; Tumor Necrosis Factor-alpha; 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

Sepsis refers to the dysregulated host immune response elicited by microbial infections resulting in life-threatening organ dysfunction. Sepsis represents a medical challenge, since it is associated with a rate of death as high as 60%. Septic shock is strongly associated with vascular dysfunction and elevated pulmonary capillary permeability. We recently reported that the combination of hydrocortisone (HC), ascorbic acid (vitC), and thiamine dramatically improves outcomes and reduces mortality in patients with sepsis. In the present study, we provide experimental evidence in support of the hypothesis that the combination of HC and vitC enhances endothelial barrier function.. Human lung microvascular endothelial cells were exposed to lipopolysaccharide (LPS) in the absence or presence of HC and vitC.. LPS alone induced profound hyperpermeability, as reflected in decreased values of transendothelial electrical resistance. vitC alone did not exhibit barrier enhancement properties nor did it affect the LPS-induced hyperpermeability. Similarly, HC alone exhibited only a minor barrier-enhancing and protective effect. Conversely, the combination of HC and vitC, either as before or after treatment, dramatically reversed the LPS-induced barrier dysfunction. The barrier-protective effects of HC and vitC were associated with reversal of LPS-induced p53 and phosphorylated cofilin downregulation and LPS-induced RhoA activation and myosin light chain phosphorylation.. These data provide a novel mechanism of endothelial barrier protection and suggest one possible pathway that may contribute to the therapeutic effects of HC and vitC in patients with sepsis.

Topics: Anti-Inflammatory Agents; Antioxidants; Ascorbic Acid; Capillary Permeability; Cells, Cultured; Drug Synergism; Drug Therapy, Combination; Endothelium, Vascular; Humans; Hydrocortisone; Lipopolysaccharides; Lung; Sepsis; Signal Transduction; Vasodilation

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

Topics: Ascorbic Acid; Humans; Sepsis; Vitamins

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

Topics: Ascorbic Acid; Humans; Sepsis; Vitamins

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

Topics: Ascorbic Acid; Humans; Sepsis; Thiamine; Vitamin B Complex

Topics: Ascorbic Acid; Humans; Hydrocortisone; Sepsis; Thiamine; 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; Humans; Sepsis; Vitamins

Plugging of the capillary bed can lead to organ failure and mortality in sepsis. We have reported that intravenous ascorbate injection reduces platelet adhesion to the capillary wall and capillary plugging in septic mice. Both platelet adhesion and capillary plugging require P-selectin, a key adhesion molecule. To elucidate the beneficial effect of ascorbate, we hypothesized that ascorbate reduces platelet-endothelial adhesion by reducing P-selectin surface expression in endothelial cells. We used mouse platelets, and monolayers of cultured microvascular endothelial cells (mouse skeletal muscle origin) stimulated with lipopolysaccharide, to examine platelet-endothelial adhesion. P-selectin mRNA expression in endothelial cells was determined by real-time PCR and P-selectin protein expression at the surface of these cells by immunofluorescence. Secretion of von Willebrand factor from cells into the supernatant (a measure of P-selectin-containing granule exocytosis) was determined by ELISA. Lipopolysaccharide (10 μg/ml, 1 h) increased platelet-endothelial adhesion. P-selectin-blocking antibody inhibited this adhesion. Lipopolysaccharide also increased P-selectin mRNA in endothelial cells, P-selectin expression at the endothelial surface, and von Willebrand factor secretion. Ascorbate pretreatment (100 μmol/l, 4 h) inhibited the increased platelet adhesion, surface expression of P-selectin, and von Willebrand factor secretion, but not the increase in P-selectin mRNA. The lipopolysaccharide-induced increase in platelet-endothelial adhesion requires P-selectin presence at the endothelial surface. Ascorbate's ability to reduce this presence could be important in reducing both platelet adhesion to the capillary wall and capillary plugging in sepsis.

Topics: Animals; Ascorbic Acid; Endothelial Cells; Humans; Mice; Mice, Inbred C57BL; P-Selectin; Platelet Adhesiveness; Sepsis

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

The impact of ascorbate on oxidative stress-related diseases is moderate because of its limited oral bioavailability and rapid clearance. However, recent evidence of the clinical benefit of parenteral vitamin C administration has emerged, especially in critical care. Heatstroke is defined as a form of excessive hyperthermia associated with a systemic inflammatory response that results in multiple organ dysfunctions in which central nervous system disorders such as delirium, convulsions, and coma are predominant. The thermoregulatory, immune, coagulation and tissue injury responses of heatstroke closely resemble those observed during sepsis and are likely mediated by similar cellular mechanisms. This study was performed by using the characteristic high lethality rate and sepsis-mimic systemic inflammatory response of a murine model of heat stroke to test our hypothesis that supra-physiological doses of ascorbate may have therapeutic use in critical care. We demonstrated that parenteral administration of ascorbate abrogated the lethality and thermoregulatory dysfunction in murine model of heat stroke by attenuating heat stroke-induced accelerated systemic inflammatory, coagulation responses and the resultant multiple organ injury, especially in hypothalamus. Overall, our findings support the hypothesis and notion that supra-physiological doses of ascorbate may have therapeutic use in critical care.

Topics: Animals; Ascorbic Acid; Death; Heat Stroke; Humans; Hypothalamus; Inflammation; Mice; Neurons; Sepsis

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

One of the major causes of mortality in the world is represented by multiple traumas. Thoracic trauma is commonly associated with polytraumas. A series of physiopathological complications follow polytraumas, leading to a significant decrease in the survival rate. As a result of injuries, significant quantities of free radicals (FR) are produced, responsible for oxidative stress (OS). To minimize the effects of OS, we recommend the administration of antioxidant substances. In this study we want to highlight statistically significant correlations between antioxidant therapy and a series of clinical variables.. This retrospective study included 132 polytrauma patients admitted to the ICU-CA between January 2013 and December 2014. The selection criteria were: injury severity score (ISS) ≥ 16, ≥ 18 years, presence of thoracic trauma (abbreviated injury scale, AIS ≥ 3). Eligible patients (n = 82) were divided into two groups: Group 1 (n = 32, antioxidant free, patients from 2013) and Group 2 (n = 50 antioxidant therapy, patients from 2014). Antioxidant therapy consisted in the administration of vitamin C (i.v.), vitamin B1 (i.v.), and N-acetylcysteine (i.v.). Clinical and biological tests were repeated until discharge from ICU-CA or death.. Between Group 1 and Group 2 statistically significant differences were highlighted regarding the ISS score (p = 0.0030). 66% of patients from Group 2 were admitted at more than 24 hours after the trauma, in contrast to the patients from Group 1, where 62.5% were directly admitted to the ICU (p = 0.0114). Compared with the patients from Group 1, patients who received antioxidant therapy show improved parameters: leukocytes (p < 0.0001), platelets (p = 0.0489), urea (p = 0.0199), total bilirubin (p = 0.0111), alanine transaminase (p = 0.0010), lactat dehydrogenase (p < 0.0001). Between the two groups there were no statistically significant differences regarding the length of stay in the ICU-CA (p = 0.4697) and mortality (p = 0.1865).. Following the study, we can affirm that due to the administration of antioxidant substances, posttraumatic complications are greatly reduced. Moreover, the administration of high dose of antioxidants remarkably improves the clinical status of the critical patient.

Topics: Abbreviated Injury Scale; Acetylcysteine; Adult; Aged; Antioxidants; Ascorbic Acid; Critical Illness; Female; Humans; Incidence; Inflammation; Injury Severity Score; Length of Stay; Male; Middle Aged; Multiple Organ Failure; Multiple Trauma; Oxidation-Reduction; Oxidative Stress; Respiration, Artificial; Retrospective Studies; Sepsis; Thiamine; Thoracic Injuries

The microcirculation during sepsis fails due to capillary plugging involving microthrombosis. We demonstrated that intravenous injection of ascorbate reduces this plugging, but the mechanism of this beneficial effect remains unclear. We hypothesize that ascorbate inhibits the release of the antifibrinolytic plasminogen activator inhibitor-1 (PAI-1) from endothelial cells and platelets during sepsis. Microvascular endothelial cells and platelets were isolated from mice. Cells were cultured and stimulated with lipopolysaccharide (LPS), tumor necrosis factor alpha (TNFα), or thrombin (agents of sepsis), with/without ascorbate for 1-24 h. PAI-1 mRNA was determined by quantitative PCR. PAI-1 protein release into the culture medium was measured by ELISA. In platelets, PAI-1 release was measured after LPS, TNFα, or thrombin stimulation, with/without ascorbate. In endothelial cells, LPS and TNFα increased PAI-1 mRNA after 6-24 h, but no increase in PAI-1 release was observed; ascorbate did not affect these responses. In platelets, thrombin, but not LPS or TNFα, increased PAI-1 release; ascorbate inhibited this increase at low extracellular pH. In unstimulated endothelial cells and platelets, PAI-1 is released into the extracellular space. Thrombin increases this release from platelets; ascorbate inhibits it pH-dependently. The data suggest that ascorbate promotes fibrinolysis in the microvasculature under acidotic conditions in sepsis.

Topics: Animals; Antioxidants; Ascorbic Acid; Blood Platelets; Cells, Cultured; Endothelial Cells; Gene Expression Regulation; Male; Mice; Mice, Inbred C57BL; Plasminogen Activator Inhibitor 1; RNA, Messenger; Sepsis

High mobility group box 1 (HMGB1) is now recognized as a late mediator of sepsis. We tested hypothesis that ascorbic acid (AscA) induces heme oxygenase (HO)-1 which inhibits HMGB1 release in lipopolysaccharide (LPS)-stimulated cells and increases survival of septic mice. AscA increased HO-1 protein expression in a concentration- and time-dependent manner via Nrf2 activation in RAW 264.7 cells. HO-1 induction by AscA was significantly reduced by Nrf2 siRNA-transfected cells. Mutation of cysteine to serine of keap-1 proteins (C151S, C273S, and C288S) lost the ability of HO-1 induction by AscA, due to failure of translocation of Nrf-2 to nucleus. The PI3 kinase inhibitor, LY294002, inhibited HO-1 induction by AscA. Oxyhemoglobin (HbO2), LY294002, and ZnPPIX (HO-1 enzyme inhibitor) reversed effect of AscA on HMGB1 release. Most importantly, administration of AscA (200mg/kg, i.p.) significantly increased survival in LPS-induced endotoxemic mice. In cecal ligation and puncture (CLP)-induced septic mice, AscA reduced hepatic injury and serum HMGB1 and plasminogen activator inhibitor (PAI)-1 in a ZnPPIX-sensitive manner. In addition, AscA failed to increase survival in Nrf2 knockout mice by LPS. Thus, we concluded that high dose of AscA may be useful in the treatment of sepsis, at least, by activation of Nrf2/HO-1 signals.

Topics: Active Transport, Cell Nucleus; Animals; Ascorbic Acid; Carbon Monoxide; Cell Line; Cell Nucleus; Chlorocebus aethiops; Enzyme Activation; Heme Oxygenase-1; HMGB1 Protein; Lipopolysaccharides; Liver; Macrophage Activation; Macrophages; Male; Membrane Proteins; Mice, Inbred ICR; NF-E2-Related Factor 2; NF-kappa B; Organometallic Compounds; Phosphatidylinositol 3-Kinases; Sepsis

Amphotericin B (Ampho B) isa fungicidal drug that causes cell wall injury. Pharmacological ascorbate induces the extracellular prooxidants, which might enter the Ampho B-induced cell wall porosity and act synergistically.W e tested low-dose Ampho B with a short course of pharmacological ascorbate using a mouse model of sepsis preconditioned with an injection of Candida albicans 6 h prior to cecal ligation and puncture (CLP). In this model, candidemia reappeared as early as 6 h after CLP with a predictably high mortality rate. This characteristic mimics sepsis in the phase of immunosuppression inpatients. Using the model, at 12- and 18-h post-CLP, we administered isotonic (pH neutralized) pharmacological ascorbate intravenously with low-dose Ampho B or sodium deoxycholate, vehicle-controlled, administered IP. The survival rate of low-dose Ampho B plus ascorbate was 53%, compared with < 11% for low-dose Ampho B or high-dose Ampho B alone. In addition, a beneficial effect was demonstrated in terms of kidney damage,liver injury, spleen histopathology, and serum markers at 24 h after CLP. Kidney injury was less severe in low-dose Ampho B plus ascorbate combination therapy due to less severe sepsis. Moreover, ascorbate enhanced the effectiveness of phagocytosis against C. albicans in human phagocytic cells. Taken together, the data indicate that the new mouse model simulates sepsis-induced immunosuppression and that the combination of pharmacological ascorbate with an antifungal drug is a potentially effective treatment that may reduce nephrotoxicity, and perhaps also increase fungicidal activity in patients with systemic candidiasis caused by Candida albicans.

Topics: Amphotericin B; Animals; Ascorbic Acid; Candidemia; Disease Models, Animal; Drug Combinations; Kidney; Liver; Male; Mice, Inbred BALB C; Sepsis; Spleen

Critically ill patients with severe sepsis or septic shock may need relatively high colistin daily doses for efficacy against multidrug-resistant and extensively drug-resistant gram-negative rods. However, acute kidney injury (AKI) may represent a major dose-limiting adverse effect of colistin. We sought to determine AKI occurrence and to identify factors influencing AKI risk in severely ill patients receiving colistin according to a recently proposed dosing strategy.. A prospective, observational, cohort study involving patients with severe sepsis or septic shock who received colistin was performed. AKI was defined according to Acute Kidney Injury Network criteria. Colistin administration was driven by a modified pharmacokinetics-pharmacodynamics (PK/PD)-based dosing approach.. Of 70 patients who received colistin at a median daily dose of 9 million IU (MIU; interquartile range, 5.87-11.1 MIU), 31 (44%) developed AKI. In univariate analysis, age, Acute Physiology and Chronic Health Evaluation (APACHE) II score, Sequential Organ Failure Assessment (SOFA), score and baseline renal impairment were significantly associated with AKI. Moreover, patients with AKI were less frequently treated with adjuvant ascorbic acid (P = .003). In multivariate analysis, independent predictors of AKI were baseline renal impairment (adjusted hazard ratio, 4.15; 95% confidence interval, 1.9-9.2; P < .001) and age (1.03; 1.0-1.05; P = .028), whereas a strong independent renal-protective role emerged for ascorbic acid (0.27; .12-.57; P < .001).. In severely ill patients receiving colistin according to a PK/PD-driven dosing approach, baseline renal impairment and older age strongly predict AKI occurrence, but concomitant administration of ascorbic acid markedly reduces AKI risk, allowing safer use of colistin.

Topics: Acute Kidney Injury; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Antidotes; Ascorbic Acid; Blighia; Colistin; Critical Illness; Female; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Prospective Studies; Risk Factors; Sepsis; Young Adult

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

Multiple organ dysfunction syndrome (MODS) is the principal cause of death in patients with sepsis. Recent work supports the notion that parenteral vitamin C (VitC) is protective in sepsis through pleiotropic mechanisms. Whether suboptimal levels of circulating VitC increase susceptibility to sepsis-induced MODS is unknown.. Unlike mice, humans lack the ability to synthesize VitC because of loss of L-gulono-γ-lactone oxidase (Gulo), the final enzyme in the biosynthesis of VitC. To examine whether physiological levels of VitC are required for defense against a catastrophic infection, we induced sepsis in VitC sufficient and VitC deficient Gulo(-/-) mice by intraperitoneal infusion of a fecal stem solution (FIP). Some VitC deficient Gulo(-/-) mice received a parenteral infusion of ascorbic acid (AscA, 200 mg/kg) 30 minutes after induction of FIP. We used molecular, histological, and biochemical analyses to assess for MODS as well as abnormalities in the coagulation system and circulating blood cells.. FIP produced injury to lungs, kidneys and liver (MODS) in VitC deficient Gulo(-/-) mice. MODS was not evident in FIP-exposed VitC sufficient Gulo(-/-) mice and attenuated in VitC deficient Gulo(-/-) mice infused with AscA. Septic VitC deficient Gulo(-/-) mice developed significant abnormalities in the coagulation system and circulating blood cells. These were attenuated by VitC sufficiency/infusion in septic Gulo(-/-) mice.. VitC deficient Gulo(-/-) mice were more susceptible to sepsis-induced MODS. VitC sufficiency or parenteral infusion of VitC, following induction of sepsis, normalized physiological functions that attenuated the development of MODS in sepsis.

Topics: Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Blood Cells; Blood Coagulation; Infusions, Parenteral; Kidney; L-Gulonolactone Oxidase; Liver; Lung; Mice, Knockout; Multiple Organ Failure; Sepsis; Vitamins

Sepsis, a potential risk associated with surgery, leads to a systemic inflammatory response including the plugging of capillary beds. This plugging may precipitate organ failure and subsequent death. We have shown that capillary plugging can be reversed rapidly within 1 h by intravenous injection of ascorbate in mouse skeletal muscle. It is unknown whether, in parallel with this effect, ascorbate negatively affects the protective responses to sepsis involving the fibrinolytic and immune systems. We hypothesized that treatment with ascorbate for 1 h does not alter bacterial content, plasminogen activator inhibitor 1 (PAI-1), and neutrophil infiltration in lung, kidney, spleen, and liver (organs with high immune response) of septic mice.. Sepsis was induced by feces injection into the peritoneum. Mice were injected intravenously with ascorbate at 6 h (10 mg/kg), and samples of peritoneal fluid, arterial blood, and organs collected at 7 h were subjected to analyses of bacterial content, PAI-1 messenger RNA and enzymatic activity, and myeloperoxidase (MPO) (a measure of neutrophil infiltration).. Sepsis increased bacterial content in all fluids and organs and increased PAI-1 messenger RNA and enzymatic activity in the lung and liver. Sepsis increased the myeloperoxidase level in the lung and liver, and lowered it in the spleen. Except for decreasing the bacterial content in blood, these responses to sepsis were not altered by ascorbate.. The rapid effect of ascorbate against capillary plugging in the septic mouse skeletal muscle is not accompanied by alterations in PAI-1 or myeloperoxidase responses in the organs with high immune response.

Topics: Animals; Ascorbic Acid; Bacteria; Male; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; Peroxidase; Plasminogen Activator Inhibitor 1; RNA, Messenger; Sepsis

Plugging of the capillary bed in tissues correlates with organ failure during sepsis. In septic mouse skeletal muscle, we showed that blood in capillaries becomes hypercoagulable and that ascorbate injection inhibits capillary plugging. In the present study, we hypothesized that ascorbate promotes fibrinolysis, reversing this plugging. Sepsis in mice was induced by fecal injection into peritoneum. Mice were injected intravenously with a bolus of streptokinase (fibrinolytic agent) or ascorbate at 5-6 h. Both agents reversed capillary plugging in muscle at 7 h. Sepsis increased mRNA expression of urokinase plasminogen activator (u-PA) (profibrinolytic) and plasminogen activator inhibitor 1 (PAI-1) (antifibrinolytic) in muscle and liver homogenates at 7 h. Ascorbate did not affect u-PA mRNA in either tissue, but it inhibited PAI-1 mRNA in muscle, suggesting enhanced fibrinolysis in this tissue. However, ascorbate did not affect increased PAI-1 mRNA in the liver (dominant source of soluble PAI-1 in systemic blood). Consistently, ascorbate affected neither elevated PAI-1 protein/enzymatic activity in septic liver nor lowered plasmin antiplasmin level in septic blood. Furthermore, hypocoagulability of septic blood revealed by thrombelastography and thrombin-induced PAI-1 release from isolated platelets (ex-vivo model of sepsis) were not affected by ascorbate. Based on the PAI-1 protein data, the present study does not support the hypothesis that ascorbate promotes fibrinolysis in sepsis.

Topics: Animals; Ascorbic Acid; Fibrinolysis; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; RNA, Messenger; Sepsis; Serpin E2; Thrombelastography; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator

Recent studies showed that both sepsis and antibiotic therapy are associated with cell death and linked to reactive oxygen species generation. This study investigated the effects of intratracheal administration of combinations of antioxidants (n-acetyl cysteine (NAC), vitamins C and E) in the treatment of sepsis-induced lung injury.. Ninety-six male Wistar rats subjected to sepsis were treated with ceftriaxone plus NAC with or without vitamins C and E and compared to appropriate controls. As an index of oxidative damage protein carbonyls, sulfhydryl groups, lipid peroxidation and superoxide anion were measured, as well as superoxide dismutase and catalase. Histopathological alterations and mortality rate were also analyzed.. Twenty-four hours after sepsis induction, markers of oxidative stress increased in all lungs examined. Ceftriaxone plus intratracheal combination of NAC, vitamins C and E decreased lung injury in infected animals by reducing superoxide anion production (54%), lipid peroxidation (53%) and protein carbonyl (58%) and restored the redox status (7.5 times). This therapy also reduced the imbalance of antioxidant enzymes activities and attenuated the alveolar architectural disorganization, inflammatory cell infiltration and pulmonary oedema. Survival increased from 66.6% with ceftriaxone to 83.2% with ceftriaxone plus antioxidants.. Ceftriaxone plus intratracheal co-administration of antioxidants provides better protection, by decreasing pulmonary oxidative stress, limiting histophatological alterations and improving survival. Antioxidants should be explored as a co-adjuvant in the treatment of severe lung injury.

Topics: Acetylcysteine; Animals; Anti-Bacterial Agents; Antioxidants; Ascorbic Acid; Ceftriaxone; Disease Models, Animal; Drug Administration Routes; Drug Therapy, Combination; Lung Injury; Male; Rats; Rats, Wistar; Sepsis; Trachea; Vitamin E

The use of vitamin C against different diseases has been controversially and emotionally discussed since Linus Pauling published his cancer studies. In vitro and animal studies showed promising results and explained the impact of vitamin C, particularly in cases with endothelial dysfunction. Indeed, studies (reviewed in this issue of Critical Care by Oudemans-van Straaten and colleagues) using high-dose vitamin C and the parenteral route of application seem to be more successful than oral vitamin C delivery.

Topics: Animals; Antioxidants; Ascorbic Acid; Humans; Oxidative Stress; Reperfusion Injury; Sepsis; Vitamins

Compromised perfusion of the capillary bed can lead to organ failure and mortality in sepsis. We have reported that intravenous injection of ascorbate inhibits platelet adhesion and plugging in septic capillaries. In this study, we hypothesized that ascorbate reduces aggregation of platelets and their surface expression of P-selectin (a key adhesion molecule) in mice.. Platelets were isolated from control mice and subjected to agents known to be released into the bloodstream during sepsis (thrombin, ADP or U46619, thromboxane A2 analog). Platelet aggregation was analyzed by aggregometry and P-selectin expression by flow cytometry.. Platelet-activating agents increased aggregation and P-selectin expression. Ascorbate inhibited these increases. This inhibitory effect was NOS-independent (LNAME had no effect). In contrast to the platelet-activating agents, direct stimuli lipopolysaccharide, TNFα, or plasma from septic mice did not increase aggregation/expression, a finding consistent with the literature. The results suggest a complex mechanism of platelet aggregation and P-selectin expression in sepsis, where generation of platelet-activating stimuli is required first, before platelet aggregation and adhesion in capillaries occur.. The ability of ascorbate to reduce platelet aggregation and P-selectin expression could be an important mechanism by which ascorbate inhibits capillary plugging in sepsis.

Topics: Animals; Antioxidants; Ascorbic Acid; Gene Expression Regulation; Inflammation Mediators; Mice; Models, Biological; Nitric Oxide; P-Selectin; Platelet Aggregation; Sepsis

Quantitative monitoring of the redox status is the foundation for redox-related treatment. The purpose of this study was to evaluate the reliability of a new depolarization curve method for plasma redox potential (ORP) monitoring.. Using the new method, we performed redox determinations for the first time under different sample-handling conditions, including redox titration experiments using KMnO4 and vitamin C and dynamic redox monitoring in burn patients. The relative ORP value (ΔORP) method (improved traditional method) was used as the reference.. The new method's better reliability, electrochemical specificity and practicability, and known group validity, which are closely associated with the redox-related pathological processes of severe burns, were confirmed. Furthermore, bidirectional change in the redox status in severe burn patients was also observed for the first time.. This simple, stable new method could be a better practical tool for making the dynamic monitoring of the redox status feasible and for providing useful quantitative information for the judgment of redox-related pathological process, thus improving corresponding individualized treatments that rely on quantitative adjustments to the redox status.

Topics: Abbreviated Injury Scale; Adult; Ascorbic Acid; Blood Chemical Analysis; Burns; Electrochemistry; Electrodes; Female; Humans; Male; Methemoglobin; Middle Aged; Monitoring, Physiologic; Oxidation-Reduction; Oxidative Stress; Potassium Permanganate; Reperfusion Injury; Reproducibility of Results; Sensitivity and Specificity; Sepsis; Shock; Uric Acid

Neutrophil extracellular trap (NET) formation was recently identified as a novel mechanism to kill pathogens. However, excessive NET formation in sepsis can injure host tissues. We have recently shown that parenteral vitamin C (VitC) is protective in sepsis. Whether VitC alters NETosis is unknown.. We used Gulo-/- mice as they lack the ability to synthesize VitC. Sepsis was induced by intraperitoneal infusion of a fecal stem solution (abdominal peritonitis, FIP). Some VitC deficient Gulo-/- mice received an infusion of ascorbic acid (AscA, 200 mg/kg) 30 min after induction of FIP. NETosis was assessed histologically and by quantification for circulating free DNA (cf-DNA) in serum. Autophagy, histone citrullination, endoplasmic reticulum (ER) stress, NFκB activation and apoptosis were investigated in peritoneal PMNs.. Sepsis produced significant NETs in the lungs of VitC deficient Gulo-/- mice and increased circulating cf-DNA. This was attenuated in the VitC sufficient Gulo-/- mice and in VitC deficient Gulo-/- mice infused with AscA. Polymorphonuclear neutrophils (PMNs) from VitC deficient Gulo-/- mice demonstrated increased activation of ER stress, autophagy, histone citrullination, and NFκB activation, while apoptosis was inhibited. VitC also significantly attenuated PMA induced NETosis in PMNs from healthy human volunteers.. Our in vitro and in vivo findings identify VitC as a novel regulator of NET formation in sepsis. This study complements the notion that VitC is protective in sepsis settings.

Topics: Animals; Apoptosis; Ascorbic Acid; Autophagy; Endoplasmic Reticulum Stress; Histones; Humans; Hydrolases; Lung; Mice; Mice, Knockout; Neutrophils; NF-kappa B; Peritonitis; Protein-Arginine Deiminase Type 4; Real-Time Polymerase Chain Reaction; RNA, Messenger; Sepsis; Signal Transduction; Up-Regulation

Vascular leakage in multiple organs is a characteristic pathological change in sepsis. Our recent study revealed that ascorbate protects endothelial barrier function in microvascular endothelial cell monolayers through inhibiting serine/threonine protein phosphatase 2A (PP2A) activation (Han M, Pendem S, Teh SL, Sukumaran DK, Wu F, Wilson JX. Free Radic Biol Med 48: 128-135, 2010). The present study addressed the mechanism of protection by ascorbate against vascular leakage in cecal ligation and puncture (CLP)-induced septic peritonitis in mice. CLP caused NADPH oxidase activation and endothelial nitric oxide synthase (eNOS) uncoupling to produce superoxide, increased NO production by inducible NOS (iNOS) and neuronal NOS (nNOS) activity, and elevated 3-nitrotyrosine (a product of peroxynitrite) formation and PP2A activity in the hindlimb skeletal muscles at 12 h after CLP. The increase in PP2A activity was associated with decreased levels of phosphorylated serine and threonine in occludin, which was immunoprecipitated from freshly harvested endothelial cells of the septic skeletal muscles. Moreover, CLP increased the vascular permeability to fluorescent dextran and Evans blue dye in skeletal muscles. An intravenous bolus injection of ascorbate (200 mg/kg body wt), given 30 min prior to CLP, prevented eNOS uncoupling, attenuated the increases in iNOS and nNOS activity, decreased 3-nitrotyrosine formation and PP2A activity, preserved the phosphorylation state of occludin, and completely inhibited the vascular leakage of dextran and Evans blue. A delayed ascorbate injection, given 3 h after CLP, also prevented the vascular permeability increase. We conclude that ascorbate injection protects against vascular leakage in sepsis by sequentially inhibiting excessive production of NO and superoxide, formation of peroxynitrite, PP2A activation, and occludin dephosphorylation. Our study provides a scientific basis for injection of ascorbate as an adjunct treatment for vascular leakage in sepsis.

Topics: Animals; Antioxidants; Ascorbic Acid; Capillary Permeability; Cecum; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Muscle, Skeletal; NADPH Oxidases; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Occludin; Peritonitis; Protein Phosphatase 2; Sepsis; Superoxides; Tyrosine

Bacterial infections of the lungs and abdomen are among the most common causes of sepsis. Abdominal peritonitis often results in acute lung injury (ALI). Recent reports demonstrate a potential benefit of parenteral vitamin C [ascorbic acid (AscA)] in the pathogenesis of sepsis. Therefore we examined the mechanisms of vitamin C supplementation in the setting of abdominal peritonitis-mediated ALI. We hypothesized that vitamin C supplementation would protect lungs by restoring alveolar epithelial barrier integrity and preventing sepsis-associated coagulopathy. Male C57BL/6 mice were intraperitoneally injected with a fecal stem solution to induce abdominal peritonitis (FIP) 30 min prior to receiving either AscA (200 mg/kg) or dehydroascorbic acid (200 mg/kg). Variables examined included survival, extent of ALI, pulmonary inflammatory markers (myeloperoxidase, chemokines), bronchoalveolar epithelial permeability, alveolar fluid clearance, epithelial ion channel, and pump expression (aquaporin 5, cystic fibrosis transmembrane conductance regulator, epithelial sodium channel, and Na(+)-K(+)-ATPase), tight junction protein expression (claudins, occludins, zona occludens), cytoskeletal rearrangements (F-actin polymerization), and coagulation parameters (thromboelastography, pro- and anticoagulants, fibrinolysis mediators) of septic blood. FIP-mediated ALI was characterized by compromised lung epithelial permeability, reduced alveolar fluid clearance, pulmonary inflammation and neutrophil sequestration, coagulation abnormalities, and increased mortality. Parenteral vitamin C infusion protected mice from the deleterious consequences of sepsis by multiple mechanisms, including attenuation of the proinflammatory response, enhancement of epithelial barrier function, increasing alveolar fluid clearance, and prevention of sepsis-associated coagulation abnormalities. Parenteral vitamin C may potentially have a role in the management of sepsis and ALI associated with sepsis.

Topics: Abdomen; Acute Lung Injury; Animals; Ascorbic Acid; Biomarkers; Blood Coagulation; Bronchoalveolar Lavage; Cell Line; Cytoskeletal Proteins; Humans; Inflammation; Ion Channels; Ion Transport; Lung; Male; Mice; Mice, Inbred C57BL; Neutrophils; Peritonitis; Permeability; Pulmonary Alveoli; Respiratory Mucosa; Sepsis; Sodium-Potassium-Exchanging ATPase

Phosphate ester of vitamin C and vitamin E (EPCK1), a strong antioxidant, is a water- and lipid-soluble phosphate ester of vitamin C and vitamin E. In the current study, we tested whether EPCK1 inhibits oxidative stress and prevents systemic inflammation.. Mice were randomly divided into a negative control group, a lipopolysaccharide (LPS)-induced sepsis group, and a group treated with an intraperitoneal infusion of EPCK1 (10 mg/kg) prior to or following LPS administration. In addition, RAW 264.7 cells were treated with LPS in the presence or absence of EPCK1. We examined levels of high mobility group box 1 (HMGB1) protein and inducible nitric oxide synthase (iNOS) in both in vivo and in vitro experiments, and liver histopathology in the in vivo experiment.. Liver histopathology significantly improved in the EPCK1 group compared with the LPS group. Although LPS administration increased HMGB1 and nitric oxide (NO) secretion, EPCK1 decreased the secretion of these mediators in vitro and in vivo.. Our findings suggest that EPCK1 may inhibit inflammation and potentially function as a novel anti-inflammatory therapeutic agent.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Ascorbic Acid; Cell Line; Disease Models, Animal; Esters; HMGB1 Protein; Inflammation; Lipopolysaccharides; Liver; Macrophages; Male; Mice; Mice, Inbred BALB C; Nitric Oxide; Nitric Oxide Synthase Type II; Oxidative Stress; Phosphates; Sepsis; Survival Rate; Vitamin E

Sepsis-induced lung injury is a persisting clinical problem with no direct therapy. Recent work suggests that intravenously infused ascorbic acid improves the circulatory dysfunction of sepsis. We used a model of endotoxin-induced acute lung injury to determine whether parenteral ascorbic acid modulates the dysregulated proinflammatory, procoagulant state that leads to lung injury.. C57BL/6 mice were exposed to lethal lipopolysaccharide doses (10 μg/g of body weight) to induce acute lung injury.. Laboratory investigation.. Wild-type C57BL/6 mice.. Ascorbic acid or its oxidized form (dehydroascorbic acid) was administered intraperitoneally at 200 mg/kg 30 mins after the lethal lipopolysaccharide dose.. We quantified survival, lung capillary leak, proinflammatory chemokine expression, and lung microvascular thrombosis. Lipopolysaccharide induced 100% lethality in mice within 28 hrs of exposure and in lung we observed intense neutrophil sequestration, loss of capillary barrier function, exuberant pulmonary inflammation, and extensive microthrombus formation. A time-delayed infusion protocol of both ascorbic acid and dehydroascorbic acid significantly prolonged survival. Both ascorbic acid and dehydroascorbic acid preserved lung architecture and barrier function while attenuating proinflammatory chemokine expression and microvascular thrombosis. Ascorbic acid and dehydroascorbic acid attenuated nuclear factor kappa B activation and normalized coagulation parameters.. Ascorbic acid administered in an interventional manner following lipopolysaccharide infusion attenuates proinflammatory, procoagulant states that induce lung vascular injury in an animal model of sepsis.

Topics: Acute Lung Injury; Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Escherichia coli; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Sepsis

The history of ascorbic acid (AA) and cancer has been marked with controversy. Clinical studies evaluating AA in cancer outcome continue to the present day. However, the wealth of data suggesting that AA may be highly beneficial in addressing cancer-associated inflammation, particularly progression to systemic inflammatory response syndrome (SIRS) and multi organ failure (MOF), has been largely overlooked. Patients with advanced cancer are generally deficient in AA. Once these patients develop septic symptoms, a further decrease in ascorbic acid levels occurs. Given the known role of ascorbate in: a) maintaining endothelial and suppression of inflammatory markers; b) protection from sepsis in animal models; and c) direct antineoplastic effects, we propose the use of ascorbate as an adjuvant to existing modalities in the treatment and prevention of cancer-associated sepsis.

Topics: Ascorbic Acid; Ascorbic Acid Deficiency; Endothelium; Humans; Immunity; Injections, Intravenous; Neoplasms; Sepsis

We report the case of the case of a 56 year old female with sepsis on a background of rheumatoid arthritis and steroid use manifesting with overt clinical features of scurvy. Ascorbic acid assays were able to demonstrate severe deficiency and confirm a diagnosis of scurvy. Clinical resolution of signs and symptoms following commencement of vitamin C replacement was rapid. The intensivist and dietitian need to consider this diagnosis even in the first world setting, particularly in the presence of sepsis, inflammatory conditions, steroid use and importantly malnutrition.

Topics: Ascorbic Acid; Ascorbic Acid Deficiency; Female; Humans; Intensive Care Units; Middle Aged; Military Personnel; Plague; Scurvy; Sepsis

Topics: Animals; Antioxidants; Ascorbic Acid; Humans; Sepsis

Sepsis/multiple organ dysfunction syndrome (MODS) is a major cause of high mortality in the intensive care unit. We have recently reported that 100% oxygen treatment is beneficial to mice with zymosan-induced sterile inflammation by increasing antioxidant enzymatic activities. Yet, the use of hyperoxia is hindered by concerns that it could exacerbate organ injury by increasing free radical formation. It is believed that systemic inflammation and overproduction of reactive oxygen species (ROS) contribute to the mechanism underlying sepsis/MODS. A ROS scavenger has been proven to protect against sepsis/MODS in some animal models. Therefore, we hypothesized that ROS scavenger pretreatment might enhance the protective action of 100% oxygen treatment against zymosan-induced sterile inflammation in mice. In the present study, we showed that 100% oxygen treatment prevented the abnormal changes in serum biochemical parameters, tissue oxygenation, and organ histopathology, and improved the 14-day survival rate in zymosan-stimulated mice, indicating that 100% oxygen treatment had a protective action on sterile inflammation. We found that pretreatment with a ROS scavenger (N-acetylcysteine, vitamin C, or dimethylthiourea) abolished this protective action of 100% oxygen treatment. We also showed that 100% oxygen treatment decreased the levels of serum proinflammatory cytokines (TNF-alpha, IL-6, and high-mobility group box 1), increased the level of serum anti-inflammatory cytokine (IL-10), and upregulated the activities of serum and tissue antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase) in zymosan-stimulated mice, which were reversed by the pretreatment with a ROS scavenger (N-acetylcysteine, vitamin C, or dimethylthiourea). We thus conclude that ROS scavenger pretreatment partly abolishes the protective effects of 100% oxygen treatment on sterile inflammation in mice by regulating inflammatory cytokines as well as antioxidant enzymes.

Topics: Acetylcysteine; Animals; Antioxidants; Ascorbic Acid; Cytokines; Free Radical Scavengers; Heart; Inflammation; Kidney; Liver; Lung; Male; Mice; Multiple Organ Failure; Myocardium; Oxygen; Reactive Oxygen Species; Sepsis; Thiourea; Zymosan

Endothelial barrier dysfunction contributes to morbidity in sepsis. We tested the hypothesis that raising the intracellular ascorbate concentration protects the endothelial barrier from septic insult by inhibiting protein phosphatase type 2A. Monolayer cultures of microvascular endothelial cells were incubated with ascorbate, dehydroascorbic acid (DHAA), the NADPH oxidase inhibitors apocynin and diphenyliodonium, or the PP2A inhibitor okadaic acid and then were exposed to septic insult (lipopolysaccharide and interferon-gamma). Under standard culture conditions that depleted intracellular ascorbate, septic insult stimulated oxidant production and PP2A activity, dephosphorylated phosphoserine and phosphothreonine residues in the tight junction-associated protein occludin, decreased the abundance of occludin at cell borders, and increased monolayer permeability to albumin. NADPH oxidase inhibitors prevented PP2A activation and monolayer leak, showing that these changes required reactive oxygen species. Okadaic acid, at a concentration that inhibited PP2A activity and monolayer leak, prevented occludin dephosphorylation and redistribution, implicating PP2A in the response of occludin to septic insult. Incubation with ascorbate or DHAA raised intracellular ascorbate concentrations and mitigated the effects of septic insult. In conclusion, ascorbate acts within microvascular endothelial cells to inhibit septic stimulation of oxidant production by NADPH oxidase and thereby prevents PP2A activation, PP2A-dependent dephosphorylation and redistribution of occludin, and disruption of the endothelial barrier.

Topics: Animals; Antioxidants; Ascorbic Acid; Cells, Cultured; Endothelial Cells; Membrane Proteins; Mice; Microvessels; Occludin; Phosphorylation; Protein Phosphatase 2; Sepsis

To determine the roles of nitric oxide synthase (NOS) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the impairment of capillary blood flow in sepsis and in the reversal of this impairment by ascorbate.. Prospective, controlled laboratory study.. Animal laboratory in research institute.. Adult male wild type (WT), neuronal nitric oxide synthase (nNOS)-/-, inducible NOS (iNOS)-/-, endothelial NOS (eNOS)-/-, and gp91phox-/- mice.. Sepsis was induced by feces injection into peritoneum (FIP). A bolus of ascorbate or NADPH oxidase inhibitor apocynin was injected intravenously at 6 hrs post-FIP. Alternatively, NOS cofactor (6R)-5,6,7,8-tetrahydro-L-biopterin (BH4) or nitric oxide donor S-nitroso-N-acetylpenicillamine was superfused on the surface of the extensor digitorum longus muscle.. Capillary blood flow impairment and NOS activity in the extensor digitorum longus muscle were measured by intravital microscopy and by enzymatic assay, respectively. Sepsis at 6 hrs impaired flow in WT mice. Apocynin, and knockout of gp91phox but not of any NOS isoforms, rescued this impairment. Constitutive NOS activity was unaffected by sepsis, but it was abolished by nNOS knockout (iNOS activity was negligible in all mice). Ascorbate rapidly (10 mins) rescued impaired flow in WT, nNOS-/-, iNOS-/- but not eNOS-/- mice. Ascorbate also improved survival of WT mice after FIP. BH4 and SNAP rescued flow in WT mice, while BH4 failed to rescue it in eNOS-/- mice.. Capillary blood flow impairment in septic skeletal muscle requires NADPH oxidase but not NOS, and it is rapidly reversed by ascorbate and BH4 through an eNOS-dependent mechanism.

Topics: Acetophenones; Animals; Antioxidants; Ascorbic Acid; Capillaries; Male; Mice; Mice, Knockout; Microcirculation; Muscle, Skeletal; NADP; NADPH Oxidases; Nitric Oxide Synthase; Sepsis

Topics: Animals; Antioxidants; Ascorbic Acid; Critical Care; Endothelium, Vascular; Humans; Hyperglycemia; Mice; Microcirculation; Nitric Oxide Synthase Type III; Oxidative Stress; Sepsis

Apoptotic endothelial damage contributes to multiorgan failure in Plasmodium falciparum malaria and in sepsis. In malaria, endothelial apoptosis is amplified by neutrophils and their secretory products, and reduced by inhibitors of neutrophil-derived substances in vitro. We compared the mechanisms of endothelial apoptosis in malaria and in sepsis, using the human umbilical vein endothelial cell as a model.. Endothelial cells were incubated with patient sera (P. falciparum malaria, Escherichia coli sepsis, Staphylococcus aureus sepsis) or culture supernatants of the respective organisms, with or without neutrophils. Ascorbic acid or ulinastatin was used to neutralize reactive oxygen species or elastase secreted by neutrophils. Transwell sieve inserts or antibodies against leukocyte function antigen 1 or intercellular adhesion molecule 1 was used to study the effect of direct interaction between neutrophils and endothelial cells. The rate of apoptotic endothelial cells was determined by TUNEL and annexin staining.. Incubation of endothelial cells with patient sera or culture supernatants (P. falciparum, E. coli, S. aureus) lead to higher apoptosis rates, compared with incubation with control sera or control supernatants. Addition of neutrophils augmented the apoptosis rate further. Addition of ascorbic acid or ulinastatin reduced endothelial apoptosis in the presence of neutrophils. Separation of neutrophils from endothelial cells with Transwell sieve inserts, or addition of anti-leukocyte function antigen-1 antibodies also reduced endothelial cell apoptosis. However, addition of anti-intercellular adhesion molecule-1 antibodies restored high apoptosis rates that had been reduced by Transwell inserts.. These in vitro results show how neutrophils can contribute to endothelial damage in malaria and in sepsis, both by their secretory products and by binding to intercellular adhesion molecule-1 on endothelial cells. The presence of similar pathomechanisms suggests that similar antiapoptotic strategies may offer potential benefit in malaria and in sepsis.

Topics: Antioxidants; Apoptosis; Ascorbic Acid; Cells, Cultured; Coculture Techniques; Endothelial Cells; Endothelium, Vascular; Escherichia coli; Glycoproteins; Humans; Malaria, Falciparum; Neutrophils; Pancreatic Elastase; Reactive Oxygen Species; Sepsis; Staphylococcus aureus

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

To measure the prevalence of transferrin saturation (TS) <12%, and iron-deficiency anemia (IDA) in Lebanese children, and their association with dietary habits, sociodemographic characteristics, and blood lead levels.. A cross-sectional study was performed over a period of 2 years. Of 268 children studied, 142 (53%) were boys and 126 (47%) were girls with an age range of 11 to 75 months. Information collected included nutritional status, blood counts, TS, and blood lead levels.. The total prevalence of TS<12% and IDA were 33.6% and 20.5%, respectively, and were associated with not having received iron supplements. IDA was more prevalent among males (P=0.04). TS<12% and IDA were significantly associated with elevated blood lead levels in the first age group (11 to 23 mo) (P=0.04, odds ratio=3.19) and (P=0.006, odds ratio=4.59), respectively.. IDA is common in Lebanese children and is associated with increased blood lead levels, lack of iron supplementation, and cultural dietary habits. Remedial measures such as iron fortification of commonly consumed food are needed on the national level. Lead exposure must be controlled and awareness must be raised about the potentially devastating consequences of combined iron deficiency and lead poisoning on young children.

Topics: Anemia, Iron-Deficiency; Animals; Ascorbic Acid; Child; Child, Preschool; Cross-Sectional Studies; Female; Humans; Infant; Lead; Lebanon; Male; Milk; Phlebotomy; Sepsis; Transferrin

Information on oxidative damage during sepsis in children is not available, we undertook this study to assess the levels of certain antioxidants in blood of children with sepsis.. Study group had 38 children with sepsis (<5 yr) and 39 age-and sex-matched controls admitted to a tertiary care hospital. Red cell glutathione (GSH), superoxide dismutase (SOD) and thiobarbituric acid reactive substance (TBARS) and plasma vitamin C were estimated by standard techniques.. There was no significant change in erythrocyte GSH, SOD and TBARS levels in sepsis when compared to controls. This may be due to the adaptive response of the body to combat the oxidative stress. However, plasma vitamin C levels were significantly reduced in patients aged one year one month to five years which may be due to active phagocytosis and due to its role as a free radical scavenger.. Our findings show that children affected by sepsis probably adapt to the free radical toxicity induced by this condition. Further studies need to be done on a larger sample to confirm the findings.

Topics: Ascorbic Acid; Child, Preschool; Glutathione; Humans; Lipid Peroxidation; Oxidative Stress; Sepsis; Statistics, Nonparametric; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

The effect of vitamins C and E on the activity and gene expression of hepatic microsomal cytochrome P450 (CYP) during polymicrobial sepsis was studied. The serum aminotransferase and lipid peroxidation levels increased 24 h after the cecal ligation and puncture, and this increase was attenuated by vitamins C and E. The hepatic concentrations of the reduced glutathione decreased in the septic animals, which was inhibited by vitamin C. Both the activities and mRNA expression of CYP1A1 and CYP2E1 decreased after cecal ligation and puncture, which was prevented by vitamins C and E. The decrease in CYP1A2 activity in the liver from cecal ligation and puncture was prevented by vitamins C and E. Our findings suggest that vitamins C and E improve hepatic drug metabolizing dysfunction as indicated by abnormalities in CYP isoforms during sepsis, and this protection is, in major part, caused by decreased oxidant stress and lipid peroxidation.

Topics: Animals; Antioxidants; Ascorbic Acid; Base Sequence; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2E1; Cytochromes; Gene Expression Regulation; Glutathione; Heme Oxygenase (Decyclizing); Liver; Male; Molecular Sequence Data; Nitric Oxide Synthase Type II; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sepsis; Transaminases; Tumor Necrosis Factor-alpha; Vitamin E

The observation that antioxidant vitamins fail to confer protective benefits in large, well-designed randomized clinical trials has led many to question the role of oxidative stress in the pathogenesis of disease. However, there is little evidence that proposed antioxidants actually scavenge reactive intermediates in vivo. Ascorbate reacts rapidly with oxidants produced by activated neutrophils in vitro, and neutrophils markedly increase their oxidant production when mice are infected intraperitoneally with the gram-negative bacterium Klebsiella pneumoniae. To explore the antioxidant properties of ascorbate in vivo, we therefore used K. pneumoniae infection as a model of oxidative stress. When mice deficient in L-gulono-gamma-lactone oxidase (Gulo(-/-)), the rate-limiting enzyme in ascorbate synthesis, were depleted of ascorbate and infected with K. pneumoniae, they were three times as likely as ascorbate-replete Gulo(-/-)mice to die from infection. Mass spectrometric analysis of peritoneal lavage fluid revealed a marked increase in the levels of oxidized amino acids and of F2-isoprostanes (sensitive and specific markers of lipid oxidation) in infected animals. Surprisingly, there were no significant differences in the levels of the oxidation products in the ascorbate-deficient and -replete Gulo(-/-)mice. Our observations suggest that ascorbate plays a previously unappreciated role in host defense mechanisms against invading pathogens but that the vitamin does not protect amino acids and lipids from oxidative damage during acute inflammation. To examine the oxidation hypothesis of disease, optimal antioxidant regimens that block oxidative reactions in animals and humans need to be identified.

Topics: Amino Acids; Animals; Antioxidants; Ascorbic Acid; Inflammation; Klebsiella Infections; Klebsiella pneumoniae; L-Gulonolactone Oxidase; Lipid Peroxidation; Mice; Mice, Knockout; Oxidation-Reduction; Sepsis

The 22 supersetnd Hohenheim Consensus Workshop took place in at the University of Stuttgart-Hohenheim. The subject of this conference was vitamin C and its role in the treatment of endothelial dysfunction. Scientists, who had published and reviewed scientific and regulatory papers on that topic were invited, among them basic researchers, toxicologists, clinicians and nutritionists. The participants were presented with eleven questions, which were discussed and answered at the workshop, with the aim of summarising the current state of knowledge. The explicatory text accompanying the short answers was produced and agreed on after the conference and was backed up by corresponding references. The therapeutic relevance of administration of the physiological antioxidant vitamin C in high parenteral doses in Endothelial Dependent Pathophysiological Conditions (EDPC) was discussed. Endothelial dysfunction is defined as including disturbed endothelial dependant relaxation of resistance vessels, breakdown of the microvascular endothelial barrier and/or loss of anti-adhesive function. It occurs in severe burn injury, intoxications, acute hyperglycemia, sepsis, trauma, and ischemic-reperfusion tissue injury and is induced by oxidative stress. Reduced plasma ascorbate levels are a hallmark of oxidative stress and occur in severe burns, sepsis, severe trauma, intoxication, chemotherapy/radiotherapy and organ transplantation. Vitamin C directly enhances the activity of nitric oxide synthase, the acyl CoA oxidase system and inhibits the actions of proinflammatory lipids. There is experimental evidence that parenteral high-dose vitamin C restores endothelial function in sepsis. In vitro, supraphysiological concentrations (> 1mM) of ascorbate restore nitric oxide bioavailability and endothelial function. Only parenterally, can enough vitamin C be administered to combat oxidative stress. There is no evidence that parenteral vitamin C exerts prooxidant effects in humans. Theoretical concerns in relation to competitive interactions between vitamin C and glucose cellular uptake are probably only relevant for oxidised vitamin C (dehydroascorbate).

Topics: Acute Disease; Acyl-CoA Oxidase; Ascorbic Acid; Burns; Endothelium, Vascular; Glucose; Heart Failure; Humans; Hyperglycemia; Infusions, Parenteral; Myocardial Ischemia; Nitric Oxide Synthase Type III; Oxidative Stress; Poisoning; Reperfusion Injury; Sepsis

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

Although early administration of ascorbate has been shown to protect against the microvascular dysfunction in sepsis, it is not clear if a delayed introduction of ascorbate also yields beneficial effects. The main objective was to determine the therapeutic window for treatment of an animal model of sepsis with bolus injection of ascorbate. We also determined if sepsis per se affects urinary excretion of ascorbate.. Prospective, controlled laboratory study.. Animal laboratory in a university-affiliated research institute.. Male Sprague-Dawley rats, 300-400 g of body weight.. Rats were made septic by cecal ligation and perforation (CLP) and volume resuscitated by continuous saline infusion. Ascorbate bolus (7.6 mg/100 g of body weight) or saline vehicle was injected intravenously at 1, 6, or 24 hrs after CLP.. At 24 hrs post-CLP, sepsis caused antidiuresis and decreased plasma ascorbate concentration, but it did not affect urinary excretion of ascorbate in rats that received only saline. Sepsis also caused maldistribution of capillary blood flow in skeletal muscle. This maldistribution of flow was prevented by ascorbate injected at 6 hrs post-CLP. At 48 hrs post-CLP, in addition to the flow maldistribution, sepsis caused systemic arterial hypotension and fever that were prevented by both immediate (1 hr post-CLP) and delayed injections of ascorbate (24 hrs post-CLP).. Despite volume resuscitation, the present model of sepsis resulted in maldistribution of capillary blood flow within 24 hrs and hypotension within 48 hrs. Our finding that intravenous bolus of ascorbate can protect against these deficits even if delayed 6-24 hrs after the septic insult shows, for the first time, that ascorbate can reverse microcirculatory dysfunction after the onset of sepsis.

Topics: Analysis of Variance; Animals; Antioxidants; Ascorbic Acid; Blood Pressure; Body Temperature; Male; Microcirculation; Muscle, Skeletal; Oxidative Stress; Prospective Studies; Rats; Rats, Sprague-Dawley; Sepsis; Survival Analysis; Time Factors

Topics: Antioxidants; Ascorbic Acid; Humans; Microcirculation; Muscle, Skeletal; Oxidative Stress; Sepsis

Sepsis causes brain dysfunction. Because neurotransmission requires high ascorbate and low dehydroascorbic acid (DHAA) concentrations in brain extracellular fluid, the effect of septic insult on ascorbate recycling (i.e., uptake and reduction of DHAA) and export was investigated in primary rat and mouse astrocytes. DHAA raised intracellular ascorbate to physiological levels but extracellular ascorbate only slightly. Septic insult by lipopolysaccharide and interferon-gamma increased ascorbate recycling in astrocytes permeabilized with saponin but decreased it in those with intact plasma membrane. The decrease was due to inhibition of the glucose transporter (GLUT1) that translocates DHAA because septic insult slowed uptake of the nonmetabolizable GLUT1 substrate 3-O-methylglucose. Septic insult also abolished stimulation by glutamate of ascorbate export. Specific nitric oxide synthase (NOS) inhibitors and nNOS and iNOS deficiency failed to alter the effects of septic insult. Inhibitors of NADPH oxidase generally did not protect against septic insult, because only one of those tested (diphenylene iodonium) increased GLUT1 activity and ascorbate recycling. We conclude that astrocytes take up DHAA and use it to synthesize ascorbate that is exported in response to glutamate. This mechanism may provide the antioxidant on demand to neurons under normal conditions, but it is attenuated after septic insult.

Topics: 3-O-Methylglucose; Animals; Ascorbic Acid; Astrocytes; Biological Transport; Dehydroascorbic Acid; Glucose Transporter Type 1; Glutamic Acid; Mice; Mice, Inbred Strains; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Rats; Rats, Wistar; Sepsis

The aim of this study was to investigate the effects of ascorbic acid on hepatic vasoregulatory gene expression during polymicrobial sepsis. Rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP). Rats received either vehicle (n = 10) or ascorbic acid (AA, 100 mg/kg, n = 10) intravenously immediately after the CLP procedure. Serum aminotransferase levels and hepatic lipid peroxides markedly increased 24 h after CLP and this increase was attenuated by AA treatment. The hepatic concentrations of reduced glutathione decreased in CLP animals. This decrease was inhibited by AA. CLP significantly increased the mRNA level of ET-1 (p < 0.01) and ETB receptor (p < 0.01) in livers; an increase that was prevented by AA treatment. There were no significant changes in ETA mRNA expression among any of the experimental groups. There were significant increases in the mRNA expression of nitric oxide synthases (p < 0.01) and heme oxygenase-1 (p < 0.01) in livers from CLP animals. This increase was prevented by AA treatment. The expression of tumor necrosis factor-alpha and cyclooxygenase-2 mRNAs significantly increased 4.9-fold (p < 0.01) and 4.4-fold (p < 0.01) in livers from CLP animals, respectively. This increase was attenuated by AA treatment. Our data suggest that AA reduces oxidative stress and lipid peroxidation, regulates the hepatic vasoregulatory gene expression in polymicrobial sepsis and thus it could reduce hepatic microvascular dysfunction during sepsis.

Topics: Analysis of Variance; Animals; Ascorbic Acid; Cyclooxygenase 2; DNA Primers; Endothelin-1; Gene Expression Regulation; Glutathione; Isoenzymes; Lipid Peroxidation; Liver; Male; Oxidative Stress; Prostaglandin-Endoperoxide Synthases; Rats; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sepsis; Transaminases; Tumor Necrosis Factor-alpha

Compromised microvascular responsiveness is one of the key factors associated with mortality of septic patients. The present study addresses the mechanism of protection by ascorbate against impaired vasoconstriction in septic mice. Sepsis (i.e., cecal ligation and puncture (CLP) model) elevated both plasma protein carbonyl (i.e., an index of oxidative stress) and plasma nitrite/nitrate (NOx) levels, reduced baseline mean arterial blood pressure (MABP), and inhibited the MABP pressor response to angiotensin II (Ang II) at 6 h post-CLP. At the microvascular level, sepsis increased the inducible nitric oxide synthase (iNOS) mRNA level in cremaster muscle arterioles (18-25 microm diameter) at 3 h post-CLP, and impaired vasoconstriction to Ang II in these arterioles at 6 h post-CLP. At 24 h post-CLP, sepsis resulted in 9% survival. An intravenous bolus of ascorbate (200 mg/kg body wt) given 30 min prior to CLP prevented the protein carbonyl and NOx increases, partially restored the baseline arterial pressure, and completely protected against all arteriolar iNOS mRNA increases, arteriolar constriction hyporesponsiveness, and pressor response impairment. Survival increased to 65%. In septic mice, iNOS gene knockout resulted in protection of arteriolar constriction and pressor responses identical to that provided by ascorbate. Ascorbate bolus given 3 h post-CLP protected against the increase in plasma NOx concentration and against the pressor response impairment. We conclude that ascorbate may protect arteriolar vasoconstrictor responsiveness in sepsis by inhibiting excessive NO production.

Topics: Angiotensin II; Animals; Arterioles; Ascorbic Acid; Blood Pressure; Cecum; Drug Administration Schedule; Enzyme Induction; Intestinal Perforation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Skeletal; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitrites; Oxidative Stress; RNA, Messenger; Sepsis; Vasoconstriction

Inducible nitric oxide synthase (iNOS) expression in blood vessels contributes to the vascular hyporeactivity characteristic of sepsis. Our previous work demonstrated in vitro that ascorbate inhibits iNOS expression in lipopolysaccharide- and interferon-gamma-stimulated skeletal muscle endothelial cells (ECs) through an antioxidant mechanism. The present study evaluated in vivo the hypothesis that administration of ascorbate decreases oxidative stress, prevents endothelial iNOS expression, and improves vascular reactivity in septic skeletal muscle. Sepsis was induced in C57BL/6 mice by cecal ligation and puncture (CLP). Plasma nitrite and nitrate (NOx) levels were elevated by 6 h after CLP. Prior ascorbate bolus injection (200 mg/kg body wt iv) blocked the elevation of plasma NOx and abolished the expression of iNOS protein and activity in the septic skeletal muscle. We also demonstrated that iNOS mRNA determined by RT-PCR was induced in the microvascular ECs of the muscle at 3 h after CLP. This induction was attenuated by prior ascorbate administration. Ascorbate inhibition of iNOS expression was associated with decreased oxidant levels in the septic muscle. Moreover, ascorbate administration restored partially the baseline arterial pressure and preserved completely the microvascular constriction and arterial pressure responses to norepinephrine in CLP mice. These results suggest that early administration of ascorbate may be a valuable adjunct treatment of sepsis.

Topics: Animals; Antioxidants; Ascorbic Acid; Blood Pressure; Cecum; Gene Expression Regulation, Enzymologic; Ligation; Male; Mice; Mice, Inbred C57BL; Microcirculation; Muscle, Skeletal; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Norepinephrine; Oxidative Stress; RNA, Messenger; Sepsis; Vasoconstriction; Vasoconstrictor Agents

In addition to the known beneficial effects of ascorbic acid on wound healing and the immune response, it is also a potent extracellular antioxidant. Recent work in septic rats suggests that high-dose ascorbic acid total parenteral nutrition (TPN) supplementation may protect cells from free radical injury and improve survival. In this study, we determined ascorbic acid levels in the immediate post-injury/illness period and evaluated the ability of early short-term high levels of ascorbic acid in TPN to normalize plasma levels.. Ascorbic acid levels were determined in 12 critically injured patients and 2 patients with severe surgical infections. Each patient received TPN supplemented with increasing doses of ascorbic acid over a 6-day period. Therapeutic responses were determined by plasma and urine measurements using high-pressure liquid chromatography.. The initial mean +/- SEM baseline plasma ascorbic acid concentration was depressed (0.11 +/- 0.03 mg/dl) and unresponsive following 2 days on 300 mg/day supplementation (0.14 +/- 0.03; P = 1.0) and only approached low normal plasma levels following 2 days on 1000 mg/day (0.32 +/- 0.08; P = 0.36). A significant increase was noted following 2 days on 3000 mg/day (1.2 +/- 0.03; P = 0.005).. We confirmed extremely low plasma levels of ascorbic acid following trauma and infection. Maximal early repletion of this vitamin requires rapid pool filling early in the post-injury period using supraphysiologic doses for 3 or more days.

Topics: Adult; Antioxidants; Ascorbic Acid; Critical Illness; Female; Humans; Male; Middle Aged; Parenteral Nutrition, Total; Sepsis; Time Factors; Wounds and Injuries

A 66-year-old female patient developed severe Serratia liquefaciens sepsis following vitamin C infusion treatment by a naturopathic practitioner. The clinical course of the infection was characterized by several complications, and the direct costs of the hospital stay amounted to about 40000 Euro. Genotypically identical S. liquefaciens was isolated from the residue of the infusate given to the patient, as well as from the washbasin overflow and from two other infusion bottles. A careful inspection of the dispensing facilities and review of procedures used to prepare the infusate revealed several indications of poor hygiene. However, the source of contamination could not be fully clarified. This case report raises questions about the local facilities and personal qualifications required for naturopathic practitioners to conduct invasive procedures and demonstrates that lapses in hygiene can lead to severe morbidity and high cost.

Topics: Aged; Ascorbic Acid; Female; Humans; Naturopathy; Sepsis; Serratia; Serratia Infections; Treatment Outcome

Septic encephalopathies rapidly affect brain function without the involvement of a specific area causing a broad range of reversible neurologic symptoms. Capillary leakage including dysfunction of the blood-brain barrier has been proposed as a potential pathogenic mechanism in this entity. We tested the hypothesis that oxidative stress measured in plasma and cerebrospinal fluid (CSF) of patients suffering from septic encephalopathy could be linked to the neurologic symptoms of the disease. The neurologic symptoms of eleven patients with septic encephalopathy were described semiquantitatively through a score system. The ascorbate levels were significantly lower in both plasma and CSF from patients with septic encephalopathy than controls, and in CSF but not plasma this decrease correlated with the severity of neurologic symptoms. No significant changes were found for alpha-tocopherol. Our findings suggest that the short-term oxidative stress may be an important factor in the development of septic encephalopathy, possibly through dysregulation of the blood-brain barrier.

Topics: alpha-Tocopherol; Antioxidants; Ascorbic Acid; Brain Diseases; Case-Control Studies; Female; Humans; Lipids; Male; Middle Aged; Oxidation-Reduction; Oxidative Stress; Sepsis

Sepsis is associated with oxidative stress and impaired glutamatergic transmission in brain. We investigated whether sepsis impairs accumulation of the antioxidant, ascorbate, and uptake of glutamate by astrocytes. Bacterial endotoxin (Escherichia coli lipopolysaccharide, LPS) and the inflammatory cytokine, interferon-gamma (IFNgamma), were applied to primary astrocyte cultures to model sepsis. In the absence of ascorbate, the combination of LPS and IFNgamma (LPS + IFNgammay) up-regulated inducible nitric oxide synthase (iNOS) and decreased the initial rate of glutamate uptake by 50% within 24 h. Cell viability and facilitated glucose transport activity were not affected at 24 h. Pre-treatment with ascorbate-2-O-phosphate increased intracellular ascorbate concentration and attenuated the induction of iNOS and inhibition of glutamate uptake caused by LPS + IFNgamma. Subsequent experiments examined the mechanisms by which cells accumulate ascorbate. LPS + IFNy decreased slightly the initial rate of uptake of ascorbate and inhibited markedly the rate with which intracellular dehydroascorbic acid (DHAA) was reduced to ascorbate. We conclude that septic insult impairs astrocytic clearance of DHAA from the extracellular fluid and decreases intracellular ascorbate concentration. Furthermore, sepsis induces iNOS and inhibits glutamate uptake by astrocytes through mechanisms that can be modulated by intracellular ascorbate. These results indicate treatments that increase intracellular ascorbate concentration may be beneficial for patients at risk for neurologic complication in sepsis.

Topics: Animals; Ascorbic Acid; Astrocytes; Biological Transport; Cell Survival; Cells, Cultured; Dehydroascorbic Acid; Enzyme Induction; Enzyme Inhibitors; Extracellular Space; Glial Fibrillary Acidic Protein; Glucose; Glutamic Acid; Interferon-gamma; Intracellular Fluid; Lipopolysaccharides; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Oxidation-Reduction; Rats; Rats, Wistar; Sepsis; Up-Regulation

Septic patients have low plasma ascorbate concentrations and compromised microvascular perfusion. The purpose of the present experiments was to determine whether ascorbate improves capillary function in volume-resuscitated sepsis. Cecal ligation and perforation (CLP) was performed on male Sprague-Dawley rats. The concentration of ascorbate in plasma and urine, mean arterial blood pressure, and density of continuously perfused capillaries in the extensor digitorum longus muscle were measured 24 h after surgery. CLP caused a 50% decrease (from 56 +/- 4 to 29 +/- 2 microM) in plasma ascorbate concentration, 1,000% increase (from 46 +/- 13 to 450 +/- 93 microM) in urine ascorbate concentration, 20% decrease (from 115 +/- 2 to 91 +/- 2 mmHg) in mean arterial pressure, and 30% decrease (from 24 +/- 1 to 17 +/- 1 capillaries/mm) in the density of perfused capillaries, compared with time-matched controls. A bolus of intravenous ascorbate (7.6 mg/100 g body wt) administered immediately after the CLP procedure increased plasma ascorbate concentration and restored both blood pressure and density of perfused capillaries to control levels. In vitro experiments showed that ascorbate (100 microM) inhibited replication of bacteria and prevented hydrogen peroxide injury to cultured microvascular endothelial cells. These results indicate that ascorbate is lost in the urine during sepsis and that a bolus of ascorbate can prevent microvascular dysfunction in the skeletal muscle of septic animals. Our study supports the view that ascorbate may be beneficial for patients with septic syndrome.

Topics: Animals; Ascorbic Acid; Capillaries; Carbon Dioxide; Cecum; Endothelium, Vascular; Hemoglobins; Hydrogen Peroxide; Infusions, Intravenous; Male; Microcirculation; Muscle, Skeletal; Oxygen; Rats; Rats, Sprague-Dawley; Resuscitation; Sepsis; Survival; Uric Acid

Recently, marked oxygen dependence of respiration by isolated mitochondria after exposure to prolonged hypoxia has been described. Because mitochondrial oxygen-dependent respiration could significantly influence oxygen consumption during critical illness, we sought to confirm the oxygen-dependent behavior of mitochondria. We hypothesized that mitochondria isolated during sepsis would exhibit increased oxygen dependence. We isolated rat liver mitochondria 16 h after cecal ligation and puncture and found a 30-40% greater oxygen uptake compared with control rats under state 3 conditions. Mitochondria incubated in deoxygenated buffer were studied for oxygen dependence at 10-min intervals for 90 min. Mitochondrial respiration after reoxygenation was stable over a 60-min period of hypoxia for control rats and decreased slightly for septic rats (10-15%). State 3 respiration was 10% lower when mitochondria were reoxygenated at low (15-25 Torr) versus high (90-100 Torr) and low (10-15 Torr) versus intermediate (40-45 Torr) oxygen tension. Oxygen consumption with ascorbate+N, N, N', N'-tetramethyl-p-phenylenediamine was 20% lower at low versus high oxygen tension. No increase in oxygen dependence was observed during 1 h of hypoxic incubation. Our data indicate only a modest oxygen dependence of respiration between 10 and 100 Torr, which is similar for septic and control mitochondria. Additionally, oxygen dependence did not increase significantly during a 1-h hypoxic exposure for well-coupled mitochondrial preparations.

Topics: Animals; Ascorbic Acid; Cecum; Hypoxia; Kinetics; Male; Mitochondria, Liver; Oxygen Consumption; Rats; Rats, Sprague-Dawley; Reference Values; Sepsis; Tetramethylphenylenediamine; Time Factors

The effect of acute endotoxin-induced septic shock on myocardium oxidative stress after low or high vitamin C and/or E dietary supplementation was studied in guinea pigs, laboratory animals which, like human, do not have capacity for ascorbate synthesis. Neither the antioxidant enzymes or GSH were modified by endotoxin and vitamin treatments. Vitamin E showed a strong capacity to protect the myocardium against both enzymatic and non-enzymatic lipid peroxidation even in the presence of endotoxin. Vitamin C supplementation increased heart ascorbate whereas endotoxic shock totally depleted the heart ascorbate of vitamin C supplemented animals without changing vitamin E. Endotoxin significantly increased myocardium uric acid, a marker of ischemia induced oxidative stress, in animals fed with low vitamin C levels. This increase was totally prevented in vitamin C supplemented, but not in vitamin E supplemented animals. Strongly depressed levels of plasma vitamin C have been recently described in sepsis in human patients. The results suggest that ascorbate is a primary antioxidant target in the heart of endotoxin treated mammals lacking the capacity to synthesize ascorbate and that ascorbate can have a protective value against endotoxin-induced free radical damage in the myocardium. Implications of these results for the possible preventive role of vitamin C in humans during sepsis are discussed.

Topics: Analysis of Variance; Animals; Antioxidants; Ascorbic Acid; Catalase; Endotoxins; Escherichia coli; Glutathione; Glutathione Peroxidase; Guinea Pigs; Heart; Humans; Lipid Peroxidation; Lipopolysaccharides; Male; Myocardium; Oxidative Stress; Sepsis; Uric Acid; Vitamin E

Patients with sepsis have low concentrations of antioxidants, including ascorbic acid, and also have increased concentrations of markers of free radical damage. Although ascorbic acid is a potent antioxidant, it can act as a prooxidant by promoting iron-catalysed reactions. We measured baseline total vitamin C and bleomycin-detectable "free" iron levels and ascorbyl radical concentrations before and after intravenous infusion of 1 g ascorbic acid in patients with sepsis and healthy control subjects. Vitamin C concentrations were decreased in patients compared to healthy subjects (p < 0.0001), and "free" iron was increased (p < 0.002). Preinfusion ascorbyl radical concentrations were not different in patients and controls. Postinfusion ascorbyl radical levels increased in both controls and patients, with larger increases in healthy subjects (p < 0.0001), suggesting suboptimal basal vitamin C levels and increased scavenging of a constant oxidant pool by ascorbate in the controls. In the patients, who were all vitamin C deficient, infused ascorbate was rapidly consumed, either via the promotion of redox cycling of iron or as a result of radical scavenging. This study demonstrates markedly different handling of infused ascorbate in patients with sepsis and healthy subjects, and further studies are needed to elucidate the relative anti- and pro-antioxidant mechanisms of ascorbate in patients with raised "free" iron levels.

Topics: Anti-Bacterial Agents; Antioxidants; Ascorbic Acid; Benzoquinones; Bleomycin; Cyclic N-Oxides; Dose-Response Relationship, Drug; Electron Spin Resonance Spectroscopy; Female; Free Radicals; Humans; Iron; Male; Nitrogen Oxides; Sepsis; Spin Labels

The blood of healthy men and patients with methemoglobinemia of different genesis was incubated with chromosmon, ascorbic acid, riboflavin and glutathione, the percentage of erythrocytes with thorn-shaped protuberances-echinocytes being subsequently determined in the blood smears. The absorbtion spectra at the range 400-650 nm were investigated both in the smooth erythrocytes and in echinocytes. A correlation was found between the percentage of echinocytes and the methemoglobin content in the blood. The methemoglobin amount in the echinocytes was determined to be higher than in the smooth erythrocytes. It is discovered that effects of chromosmon, glutathione and riboflavin on production of methemoglobin depend on the dose, individual peculiarities of erythrocytes and on the illness that caused methemoglobinemia. The calculation of echinocyte percentage may be used as an express-diagnostics of methemoglobinemia and for purposes of studying the effect of methemoglobin-producing substances and drugs.

Topics: Ascorbic Acid; Bronchitis; Chronic Disease; Dose-Response Relationship, Drug; Erythrocytes; Glutathione; Hemoglobins; Humans; Methemoglobin; Methemoglobinemia; Methylene Blue; Pulmonary Heart Disease; Riboflavin; Sepsis; Shock, Traumatic; Spectrophotometry

Topics: Anti-Infective Agents, Local; Ascorbic Acid; Borates; Humans; Mouthwashes; Sepsis; Sodium; Tooth Extraction

Topics: Adrenal Glands; Animals; Antibody Formation; Ascorbic Acid; Bursa of Fabricius; Escherichia coli Infections; Glucosidases; Hemagglutination Tests; Organ Size; Poultry; Poultry Diseases; Sepsis; Spleen; Stress, Physiological

Topics: Anti-Bacterial Agents; Ascorbic Acid; Blood; Blood Protein Electrophoresis; Blood Proteins; Drug Therapy; Endocarditis; Endocarditis, Bacterial; Humans; Meningitis; Meningoencephalitis; Oximetry; Peritonitis; Ristocetin; Sepsis; Urine

Topics: Abscess; Ascorbic Acid; Coumarins; Humans; Meningitis; Palatine Tonsil; Penicillins; Peritonsillar Abscess; Sepsis; Sinus Thrombosis, Intracranial; Streptomycin; Sulfonamides; Vitamin B Complex