The Emerging Role of Vitamin C as a Treatment for Sepsis.
ABSTRACT: 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.
Project description:We sought to explore potential mechanisms underlying hospital sepsis case volume-mortality associations by investigating implementation of evidence-based processes of care.Retrospective cohort study. We determined associations of sepsis case volume with three evidence-based processes of care (lactate measurement during first hospital day, norepinephrine as first vasopressor, and avoidance of starch-based colloids) and assessed their role in mediation of case volume-mortality associations.Enhanced administrative data (Premier, Charlotte, NC) from 534 U.S. hospitals.A total of 287,914 adult patients with sepsis present at admission between July 2010 and December 2012 of whom 58,045 received a vasopressor for septic shock during the first 2 days of hospitalization.None.Among patients with sepsis, 1.9% received starch, and among patients with septic shock, 68.3% had lactate measured and 64% received norepinephrine as initial vasopressor. Patients at hospitals with the highest case volume were more likely to have lactate measured (adjusted odds ratio quartile 4 vs quartile 1, 2.8; 95% CI, 2.1-3.7) and receive norepinephrine as initial vasopressor (adjusted odds ratio quartile 4 vs quartile 1, 2.1; 95% CI, 1.6-2.7). Case volume was not associated with avoidance of starch products (adjusted odds ratio quartile 4 vs quartile 1, 0.73; 95% CI, 0.45-1.2). Adherence to evidence-based care was associated with lower hospital mortality (adjusted odds ratio, 0.81; 95% CI, 0.70-0.94) but did not strongly mediate case volume-mortality associations (point estimate change ? 2%).In a large cohort of U.S. patients with sepsis, select evidence-based processes of care were more likely implemented at high-volume hospitals but did not strongly mediate case volume-mortality associations. Considering processes and case volume when regionalizing sepsis care may maximize patient outcomes.
Project description:BACKGROUND:Observational research suggests that combined therapy with Vitamin C, thiamine and hydrocortisone may reduce mortality in patients with septic shock. METHODS AND DESIGN:The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) trial is a multicenter, double-blind, adaptive sample size, randomized, placebo-controlled trial designed to test the efficacy of combination therapy with vitamin C (1.5?g), thiamine (100?mg), and hydrocortisone (50?mg) given every 6?h for up to 16 doses in patients with respiratory or circulatory dysfunction (or both) resulting from sepsis. The primary outcome is ventilator- and vasopressor-free days with mortality as the key secondary outcome. Recruitment began in August 2018 and is ongoing; 501 participants have been enrolled to date, with a planned maximum sample size of 2000. The Data and Safety Monitoring Board reviewed interim results at N =?200, 300, 400 and 500, and has recommended continuing recruitment. The next interim analysis will occur when N =?1000. This update presents the statistical analysis plan. Specifically, we provide definitions for key treatment and outcome variables, and for intent-to-treat, per-protocol, and safety analysis datasets. We describe the planned descriptive analyses, the main analysis of the primary end point, our approach to secondary and exploratory analyses, and handling of missing data. Our goal is to provide enough detail that our approach could be replicated by an independent study group, thereby enhancing the transparency of the study. TRIAL REGISTRATION:ClinicalTrials.gov, NCT03509350. Registered on 26 April 2018.
Project description:Background:Low plasma levels of vitamin C are associated with adverse outcomes, including increased mortality, in critically ill patients. Several trials have suggested that the administration of intravenous vitamin C in this setting may have beneficial effects, such as reducing the incidence of organ failure and improving survival. However, these studies have generally involved combination therapies consisting of vitamin C along with other antioxidants, confounding the effects of vitamin C alone. The primary objective of this meta-analysis is to investigate the effects of isolated intravenous supplementation of vitamin C in adults with critical illness. Methods:A database search was conducted for studies on the use of intravenous vitamin C in adult patients with critical illness. The primary outcome assessed was mortality at the longest follow-up time available. Secondary outcomes were the duration of mechanical ventilation, duration of vasopressor support, fluid requirements, and urine output in the first 24 h of intensive care unit admission. Results:Five studies (four randomized controlled trials and one retrospective review) enrolling a total of 142 patients were included in this meta-analysis. Compared with controls, the administration of intravenous vitamin C was associated with a decreased need for vasopressor support (standardized mean difference -0.71; 95% confidence interval (-1.16 to -0.26); p = 0.002) and decreased duration of mechanical ventilation (standardized mean difference -0.5; 95% confidence interval (-0.93 to -0.06); p = 0.03), but no difference was found in mortality (odds ratio 0.76; 95% confidence interval (0.27 to 2.16); p = 0.6). Trends were also noted toward decreased fluid requirements and increased urine output. No adverse effects were reported. Conclusion:The administration of intravenous vitamin C may lead to vasopressor sparing effects and a reduced need for mechanical ventilation in the critically ill, without affecting overall mortality. However, these results should be interpreted in light of the limitations of the primary literature and should serve as a preview of upcoming trials in this area.
Project description:Importance:It is unclear whether vitamin C, hydrocortisone, and thiamine are more effective than hydrocortisone alone in expediting resolution of septic shock. Objective:To determine whether the combination of vitamin C, hydrocortisone, and thiamine, compared with hydrocortisone alone, improves the duration of time alive and free of vasopressor administration in patients with septic shock. Design, Setting, and Participants:Multicenter, open-label, randomized clinical trial conducted in 10 intensive care units in Australia, New Zealand, and Brazil that recruited 216 patients fulfilling the Sepsis-3 definition of septic shock. The first patient was enrolled on May 8, 2018, and the last on July 9, 2019. The final date of follow-up was October 6, 2019. Interventions:Patients were randomized to the intervention group (n?=?109), consisting of intravenous vitamin C (1.5 g every 6 hours), hydrocortisone (50 mg every 6 hours), and thiamine (200 mg every 12 hours), or to the control group (n?=?107), consisting of intravenous hydrocortisone (50 mg every 6 hours) alone until shock resolution or up to 10 days. Main Outcomes and Measures:The primary trial outcome was duration of time alive and free of vasopressor administration up to day 7. Ten secondary outcomes were prespecified, including 90-day mortality. Results:Among 216 patients who were randomized, 211 provided consent and completed the primary outcome measurement (mean age, 61.7 years [SD, 15.0]; 133 men [63%]). Time alive and vasopressor free up to day 7 was 122.1 hours (interquartile range [IQR], 76.3-145.4 hours) in the intervention group and 124.6 hours (IQR, 82.1-147.0 hours) in the control group; the median of all paired differences was -0.6 hours (95% CI, -8.3 to 7.2 hours; P?=?.83). Of 10 prespecified secondary outcomes, 9 showed no statistically significant difference. Ninety-day mortality was 30/105 (28.6%) in the intervention group and 25/102 (24.5%) in the control group (hazard ratio, 1.18; 95% CI, 0.69-2.00). No serious adverse events were reported. Conclusions and Relevance:In patients with septic shock, treatment with intravenous vitamin C, hydrocortisone, and thiamine, compared with intravenous hydrocortisone alone, did not significantly improve the duration of time alive and free of vasopressor administration over 7 days. The finding suggests that treatment with intravenous vitamin C, hydrocortisone, and thiamine does not lead to a more rapid resolution of septic shock compared with intravenous hydrocortisone alone. Trial Registration:ClinicalTrials.gov Identifier: NCT03333278.
Project description:BACKGROUND: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. METHODS: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. DISCUSSION: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. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT03509350 . First registered on April 26, 2018, and last verified on December 20, 2018. Protocol version: 1.4, January 9, 2019.
Project description:INTRODUCTION: The benefits and use of low-dose corticosteroids (LDCs) in severe sepsis and septic shock remain controversial. Surviving sepsis campaign guidelines suggest LDC use for septic shock patients poorly responsive to fluid resuscitation and vasopressor therapy. Their use is suspected to be wide-spread, but paucity of data regarding global practice exists. The purpose of this study was to compare baseline characteristics and clinical outcomes of patients treated or not treated with LDC from the international PROGRESS (PROmoting Global Research Excellence in Severe Sepsis) cohort study of severe sepsis. METHODS: Patients enrolled in the PROGRESS registry were evaluated for use of vasopressor and LDC (equivalent or lesser potency to hydrocortisone 50 mg six-hourly plus 50 microg 9-alpha-fludrocortisone) for treatment of severe sepsis at any time in intensive care units (ICUs). Baseline characteristics and hospital mortality were analyzed, and logistic regression techniques used to develop propensity score and outcome models adjusted for baseline imbalances between groups. RESULTS: A total of 8,968 patients with severe sepsis and sufficient data for analysis were studied. A total of 79.8% (7,160/8,968) of patients received vasopressors, and 34.0% (3,051/8,968) of patients received LDC. Regional use of LDC was highest in Europe (51.1%) and lowest in Asia (21.6%). Country use was highest in Brazil (62.9%) and lowest in Malaysia (9.0%). A total of 14.2% of patients on LDC were not receiving any vasopressor therapy. LDC patients were older, had more co-morbidities and higher disease severity scores. Patients receiving LDC spent longer in ICU than patients who did not (median of 12 versus 8 days; P <0.001). Overall hospital mortality rates were greater in the LDC than in the non-LDC group (58.0% versus 43.0%; P <0.001). After adjusting for baseline imbalances, in all mortality models (with vasopressor use), a consistent association remained between LDC and hospital mortality (odds ratios varying from 1.30 to 1.47). CONCLUSIONS: Widespread use of LDC for the treatment of severe sepsis with significant regional and country variation exists. In this study, 14.2% of patients received LDC despite the absence of evidence of shock. Hospital mortality was higher in the LDC group and remained higher after adjustment for key determinates of mortality.
Project description:This study aimed to identify septic phenotypes in patients receiving vitamin C, hydrocortisone, and thiamine using temperature and white blood cell count. Data were obtained from septic shock patients who were also treated using a vitamin C protocol in a medical intensive care unit. Patients were divided into groups according to the temperature measurements as well as white blood cell counts within 24 h before starting the vitamin C protocol. In the study, 127 patients included who met the inclusion criteria. In the cohort, four groups were identified: "Temperature ?37.1 °C, white blood cell count ?15.0 1000/mm3" (group A; n = 27), "?37.1 °C, <15.0 1000/mm3" (group B; n = 30), "<37.1 °C, ?15.0 1000/mm3" (group C; n = 35) and "<37.1 °C, <15.0 1000/mm3" (group D; n = 35). The intensive care unit mortality rates were 15% for group A, 33% for group B, 34% for group C, and 49% for group D (p = 0.051). The temporal improvement in organ dysfunction and vasopressor dose seemed more apparent in group A patients. Our results suggest that different subphenotypes exist among sepsis patients treated using a vitamin C protocol, and clinical outcomes might be better for patients with the hyperinflammatory subphenotype.
Project description:Heart rate variability (HRV) reflects autonomic nervous system tone as well as the overall health of the baroreflex system. We hypothesized that loss of complexity in HRV upon intensive care unit (ICU) admission would be associated with unsuccessful early resuscitation of sepsis.We prospectively enrolled patients admitted to ICUs with severe sepsis or septic shock from 2009 to 2011. We studied 30 minutes of electrocardiogram, sampled at 500 Hz, at ICU admission and calculated heart rate complexity via detrended fluctuation analysis. Primary outcome was vasopressor independence at 24 hours after ICU admission. Secondary outcome was 28-day mortality.We studied 48 patients, of whom 60% were vasopressor independent at 24 hours. Five (10%) died within 28 days. The ratio of fractal alpha parameters was associated with both vasopressor independence and 28-day mortality (P = .04) after controlling for mean heart rate. In the optimal model, Sequential Organ Failure Assessment score and the long-term fractal ? parameter were associated with vasopressor independence.Loss of complexity in HRV is associated with worse outcome early in severe sepsis and septic shock. Further work should evaluate whether complexity of HRV could guide treatment in sepsis.
Project description:OBJECTIVES:To describe haemodynamic resuscitation practices in ED patients with suspected sepsis and hypotension. METHODS:This was a prospective, multicentre, observational study conducted in 70 hospitals in Australia and New Zealand between September 2018 and January 2019. Consecutive adults presenting to the ED during a 30-day period at each site, with suspected sepsis and hypotension (systolic blood pressure?<100?mmHg) despite at least 1000?mL fluid resuscitation, were eligible. Data included baseline demographics, clinical and laboratory variables and intravenous fluid volume administered, vasopressor administration at baseline and 6- and 24-h post-enrolment, time to antimicrobial administration, intensive care admission, organ support and in-hospital mortality. RESULTS:A total of 4477 patients were screened and 591 were included with a mean (standard deviation) age of 62 (19) years, Acute Physiology and Chronic Health Evaluation II score 15.2 (6.6) and a median (interquartile range) systolic blood pressure of 94?mmHg (87-100). Median time to first intravenous antimicrobials was 77?min (42-148). A vasopressor infusion was commenced within 24?h in 177 (30.2%) patients, with noradrenaline the most frequently used (n = 138, 78%). A median of 2000?mL (1500-3000) of intravenous fluids was administered prior to commencing vasopressors. The total volume of fluid administered from pre-enrolment to 24?h was 4200?mL (3000-5661), with a range from 1000 to 12?200?mL. Two hundred and eighteen patients (37.1%) were admitted to an intensive care unit. Overall in-hospital mortality was 6.2% (95% confidence interval 4.4-8.5%). CONCLUSION:Current resuscitation practice in patients with sepsis and hypotension varies widely and occupies the spectrum between a restricted volume/earlier vasopressor and liberal fluid/later vasopressor strategy.
Project description:BACKGROUND:The ProCESS, ARISE, and ProMISe trials have failed to show that early goal-directed therapy (EGDT) reduces mortality in patients with severe sepsis and septic shock. Although lactate-guided therapy (LGT) has been shown to result in significantly lower mortality, its use remains controversial. Therefore, we performed a meta-analysis to evaluate EGDT vs. LGT or usual care (UC) in adult patients with severe sepsis and septic shock. METHODS:Relevant randomized controlled trials published from January 1, 2001 to March 30, 2017 were identified in PubMed, EMBASE, Web of Science, and the Cochrane Library. The primary outcome was mortality; secondary outcomes included red cell transfusions, dobutamine use, vasopressor infusion, and mechanical ventilation support within the first 6 h and Acute Physiology and Chronic Health Evaluation II (APACHE II) score. RESULTS:Sixteen studies enrolling 5968 patients with 2956 in EGDT, 2547 in UC, and 465 in LGT were included in this meta-analysis. Compared with UC, EGDT was associated with a lower mortality (10 trials; RR 0.85, 95% CI 0.74-0.97, P?=?0.01), and this difference was more pronounced in the subgroup of UC patients with mortality?>?30%. In addition, EGDT patients received more red cell transfusions, dobutamine, and vasopressor infusions within the first 6 h. Compared with LGT, EGDT was associated with higher mortality (6 trials; RR 1.42, 95% CI 1.19-1.70, P?=?0.0001) with no heterogeneity (P?=?0.727, I2?=?0%). CONCLUSION:EGDT seems to reduce mortality in adult patients with severe sepsis and septic shock, and the benefit may primarily be attributed to red cell transfusions, dobutamine administration, and vasopressor infusions within the first 6 h. However, LGT may result in a greater mortality benefit than EGDT.