Efficacy of dietary supplements on mortality and clinical outcomes in adults with sepsis and septic shock: A systematic review and network meta-analysis.

AIM: The aim of this network meta-analysis (NMA) was to investigate the effects of different dietary supplements on the mortality and clinical status of adults with sepsis. METHODS: We searched PubMed, EMBASE, and the Cochrane Library Central Register of Controlled Trials until February 2023. The inclusion criteria were: 1) randomized controlled trials (RCT)s; 2) adults suffering sepsis or septic shock; 3) evaluation of short- or long-mortality; and 4) publications between 1994 and 2023. The general information of studies and details of interventions were extracted. The primary outcome was short-term mortality (<90 days), and the secondary outcomes were long-term mortality (≥90 days), length of ICU and hospital stays, and duration of mechanical ventilation (MV). The risk of bias of RCTs was assessed using the Cochrane risk of bias tool 2 (ROB2). A random effect NMA was performed to rank the effect of each intervention using a frequentist approach. RESULTS: Finally, 56 RCTs with 5957 participants met the criteria. Approximately, one-third of RCTs were low risk of bias. NMA analysis revealed that there was no treatment more effective in short- or long-term mortality than control or other interventions, except for magnesium (RR: 0.33, 95% CI: 0.14, 0.79; GRADE = low) and vitamin C (RR: 0.81, 95% CI: 0.67, 0.99; low certainty evidence), which had beneficial effects on short-term mortality. Moreover, eicosapentaenoic acid, gamma-linolenic acid, and antioxidants (EPA + GLA + AOs) combination was the most effective, and magnesium, vitamin D and vitamin C were the other effective approaches in terms of duration of MV, and ICU length of stay. There was no beneficial dietary supplement for hospital stay in these patients. CONCLUSIONS: In septic patients, none of the dietary supplements had a substantial effect on mortality except for magnesium and vitamin C, which were linked to lower short-term mortality with low certainty of evidence. Further investigation into high-quality studies with the use of dietary supplements for sepsis should be highly discouraged.

Impact of Vitamin C on Inflammatory Response and Myocardial Injury in Sepsis Patients.

Background: Amidst the complexities of sepsis-induced inflammatory responses and myocardial injury, this study investigates the therapeutic potential of vitamin C in mitigating sepsis complications. The findings offer crucial insights into the prospective use of vitamin C, shaping future strategies for enhanced patient care. Objective: To investigate the impact of vitamin C on the inflammatory response and myocardial damage in individuals with sepsis. Methods: A total of 83 sepsis patients treated in our hospital from January 2021 to January 2023 were randomly divided into a control group (n=41, receiving basic treatment) and a study group (n=42, receiving vitamin C in addition to basic treatment). To evaluate the impact of treatment, we compared organ dysfunction, inflammatory response index, myocardial injury index, and morbidity/mortality rates before and after the intervention in both groups. It allowed for a comprehensive analysis of the treatment's effects on these key parameters. Results: After therapy, the study group exhibited lower SOFA ratings compared to the control group (P < .05). Levels of Hypersensitive C-reactive Protein (hs-CRP), Tumor Necrosis Factor (TNF), High Mobility Group Protein B1 (HMGB1), Creatine Kinase Isoenzyme (CK-MB), Troponin I (cTnI), and B-type brain natriuretic peptide (BNP) were significantly lower in the study group than in the control group after treatment (P < .05). The study group also demonstrated a lower morbidity and mortality rate (9.52%) compared to the control group (29.27%) (P < .05). Conclusions: Vitamin C supplementation holds significant therapeutic value, contributing to reduced inflammatory response, myocardial injury, morbidity, and mortality rates in sepsis patients. This intervention enhances clinical efficacy, fostering disease regression.

Effect of an Herbal-Based Injection on 28-Day Mortality in Patients With Sepsis: The EXIT-SEP Randomized Clinical Trial.

Importance: Previous research has suggested that Xuebijing injection (XBJ), an herbal-based intravenous preparation, may reduce mortality among patients with sepsis. Objective: To determine the effect of XBJ vs placebo on 28-day mortality among patients with sepsis. Design, Setting, and Participants: The Efficacy of Xuebijing Injection in Patients With Sepsis (EXIT-SEP) trial was a multicenter, randomized double-blind, placebo-controlled trial conducted in intensive care units at 45 sites and included 1817 randomized patients with sepsis (sepsis 3.0) present for less than 48 hours. Patients aged 18 to 75 years with a Sequential Organ Failure Assessment score of 2 to 13 were enrolled. The study was conducted from October 2017 to June 2019. The final date of follow-up was July 26, 2019. Data analysis was performed from January 2020 to August 2022. Interventions: The patients were randomized to receive either intravenous infusion of XBJ (100 mL, n = 911) or volume-matched saline placebo (n = 906) every 12 hours for 5 days. Main Outcomes and Measures: The primary outcome was 28-day mortality. Results: Among the 1817 patients who were randomized (mean [SD] age, 56.5 [13.5] years; 1199 [66.0%] men), 1760 (96.9%) completed the trial. In these patients, the 28-day mortality rate was significantly different between the placebo group and the XBJ group (230 of 882 patients [26.1%] vs 165 of 878 patients [18.8%], respectively; P < .001). The absolute risk difference was 7.3 (95% CI, 3.4-11.2) percentage points. The incidence of adverse events was 222 of 878 patients (25.3%) in the placebo group and 200 of 872 patients (22.9%) in the XBJ group. Conclusions and Relevance: In this randomized clinical trial among patients with sepsis, the administration of XBJ reduced 28-day mortality compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT03238742.

Clinical outcome from hematopoietic cell transplant patients with bloodstream infection caused by carbapenem-resistant P. aeruginosa and the impact of antimicrobial combination in vitro.

Bloodstream infection (BSI) caused by carbapenem-resistant P. aeruginosa (CRPA) has high mortality in hematopoietic stem cell transplant (HSCT) recipients. We performed MIC, checkerboard, time-kill assay, PFGE, PCR, and whole genome sequence and described the clinical outcome through Epi Info comparing the antimicrobial combination in vitro. Mortality was higher in BSI caused by CRPA carrying the lasB virulence gene. The isolates were 97% resistant to meropenem displaying synergistic effect to 57% in combination with colistin. Seventy-three percent of the isolates harbored blaSPM-1 and Tn4371 and belonged to ST277. The synergistic effect in vitro with meropenem with colistin appeared to be a better therapeutic option.

IV Vitamin C in Critically Ill Patients: A Systematic Review and Meta-Analysis.

OBJECTIVES: To conduct a systematic review and meta-analysis to evaluate the impact of IV vitamin C on outcomes in critically ill patients. DATA SOURCES: Systematic search of MEDLINE, EMBASE, CINAHL, and the Cochrane Register of Controlled Trials. STUDY SELECTION: Randomized controlled trials testing IV vitamin C in critically ill patients. DATA ABSTRACTION: Two independent reviewers abstracted patient characteristics, treatment details, and clinical outcomes. DATA SYNTHESIS: 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. CONCLUSIONS: 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.

Decursinol Angelate Mitigates Sepsis Induced by Methicillin-Resistant Staphylococcus aureus Infection by Modulating the Inflammatory Responses of Macrophages.

The herbal plant Angelica gigas (A. gigas) has been used in traditional medicine in East Asian countries, and its chemical components are reported to have many pharmacological effects. In this study, we showed that a bioactive ingredient of A. gigas modulates the functional activity of macrophages and investigated its effect on inflammation using a sepsis model. Among 12 different compounds derived from A. gigas, decursinol angelate (DA) was identified as the most effective in suppressing the induction of TNF-α and IL-6 in murine macrophages. When mice were infected with a lethal dose of methicillin-resistant Staphylococcus aureus (MRSA), DA treatment improved the mortality and bacteremia, and attenuated the cytokine storm, which was associated with decreased CD38+ macrophage populations in the blood and liver. In vitro studies revealed that DA inhibited the functional activation of macrophages in the expression of pro-inflammatory mediators in response to microbial infection, while promoting the bacterial killing ability with an increased production of reactive oxygen species. Mechanistically, DA treatment attenuated the NF-κB and Akt signaling pathways. Intriguingly, ectopic expression of an active mutant of IKK2 released the inhibition of TNF-α production by the DA treatment, whereas the inhibition of Akt resulted in enhanced ROS production. Taken together, our experimental evidence demonstrated that DA modulates the functional activities of pro-inflammatory macrophages and that DA could be a potential therapeutic agent in the management of sepsis.

Effect of IV High-Dose Vitamin C on Mortality in Patients With Sepsis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: 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. DESIGN: 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. PATIENTS: 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. MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSIONS: 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.

The impact of selenium administration on severe sepsis or septic shock: a meta-analysis of randomized controlled trials.

INTRODUCTION: The efficacy of selenium administration to treat severe sepsis or septic shock remains controversial. We conduct a systematic review and meta-analysis to explore the impact of selenium administration on severe sepsis or septic shock. METHODS: We search PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through May 2020 for randomized controlled trials (RCTs) assessing the effect of selenium administration on severe sepsis or septic shock. Meta-analysis is performed using the random-effect model. RESULTS: Five RCTs involving 1482 patients are included in the meta-analysis. Overall, compared with control group in septic patients, selenium administration is not associated with reduced 28-day mortality (RR=0.93; 95% CI=0.73 to 1.19; P=0.58), but results in substantially decreased all-cause mortality (RR=0.78; 95% CI=0.63 to 0.98; P=0.03) and length of hospital stay (MD=-3.09; 95% CI=-5.68 to -0.50; P=0.02). CONCLUSION: Selenium administration results in notable decrease in all-cause mortality and length of hospital stay, but shows no substantial influence on the 28-day mortality, length of ICU stay, duration of vasopressor therapy, the incidence of acute renal failure, adverse events, and serious adverse events for septic patients.

Effects of different lipid emulsions on serum adipokines, inflammatory markers and mortality in critically ill patients with sepsis: A prospective observational cohort study.

BACKGROUND & AIMS: Intravenous lipid emulsions in parenteral nutrition may cause different metabolic responses and immune effects in critically ill patients with sepsis. The aim of this study is to investigate the effects of different lipid emulsions on changes in concentrations of adipokine and cytokine and their relationship with mortality in patients. METHODS: Patients enrolled in this prospective, single-center, observational cohort study, were estimated to require more than ten days of parenteral nutrition. They were treated with soybean oil-based or olive oil-based parenteral lipid emulsions. Adipokine and cytokine concentrations of septic patients were determined at enrollment and ten days after, in accordance with the diagnostic criteria of SEPSIS-3. The concentrations levels were measured in an enzyme-linked immunosorbent assay. Mortality was analyzed using the Kaplan-Meier method and Cox regressions. RESULTS: Over a 25-month period, 145 patients were assessed for eligibility and consequently, 40 patients were analyzed. On admission, both groups had comparable physiological scores, comorbidities, malnutrition risk, anthropometric measurements, metabolic/hematologic biomarkers and concentrations of adipokines and cytokines (p > .05). Serum leptin, resistin, and cytokines (IL-6, IL-10, IL-1ß and TNF-α) decreased significantly in the entire cohort over ten days following sepsis (p < .05). Serum resistin decreased in both olive oil-based and soybean oil-based lipid emulsions groups. Serum adiponectin only decreased in soybean oil-based lipid emulsions group (p < .05). There was association between survival and percentage changes in adiponectin, resistin and visfatin concentrations (log rank test: p < .05). CONCLUSION: Adipokine and cytokine responses are affected by medical nutritional therapy in the sepsis process and adipokines may represent functional prognostic biomarkers in critically ill patients with sepsis.

Rapid versus standard antimicrobial susceptibility testing to guide treatment of bloodstream infection.

BACKGROUND: Rapid antimicrobial susceptibility tests are expected to reduce the time to clinically important results of a blood culture. This might enable clinicians to better target therapy to a person's needs, and thereby, improve health outcomes (mortality, length of hospital stay), and reduce unnecessary prescribing of broad-spectrum antibiotics; thereby reducing antimicrobial resistance rates. OBJECTIVES: To assess the effects of rapid susceptibility testing versus standard susceptibility testing for bloodstream infections (BSIs). SEARCH METHODS: To identify studies with selected outcomes, we searched the Cochrane Infectious Diseases Group Specialised Register, CENTRAL, MEDLINE, LILACS, and two trials registries, between 1987 and October 2020. We used 'bloodstream infection' and 'antimicrobial susceptibility tests' as search terms. We had no language or publication status limitations. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing rapid antimicrobial susceptibility testing (with a time-to-result of ≤ 8 hours) versus conventional antimicrobial susceptibility testing in people with a BSI caused by any bacteria, as identified by a positive blood culture. DATA COLLECTION AND ANALYSIS: Two review authors independently screened references, full-text reports of potentially relevant studies, extracted data from the studies, and assessed risk of bias. Any disagreement was discussed and resolved with a third review author. For mortality, a dichotomous outcome, we extracted the number of events in each arm, and presented a risk ratio (RR) with 95% confidence interval (CI) to compare rapid susceptibility testing to conventional methods. We used Review Manager 5.4 to meta-analyse the data. For other outcomes, which are time-to-event outcomes (time-to-discharge from hospital, time-to-first appropriate antibiotic change), we conducted qualitative narrative synthesis, due to heterogeneity of outcome measures.  MAIN RESULTS: We included six trials, with 1638 participants. For rapid antimicrobial susceptibility testing compared to conventional methods, there was little or no difference in mortality between groups (RR 1.10, 95% CI 0.82 to 1.46; 6 RCTs, 1638 participants; low-certainty evidence). In subgroup analysis, for rapid genotypic or molecular antimicrobial susceptibility testing compared to conventional methods, there was little or no difference in mortality between groups (RR 1.02, 95% CI 0.69 to 1.49; 4 RCTs, 1074 participants; low-certainty evidence). For phenotypic rapid susceptibility testing compared to conventional methods, there was little or no difference in mortality between groups  (RR 1.37, 95% CI 0.80 to 2.35; 2 RCTs, 564 participants; low-certainty evidence). In qualitative analysis, rapid susceptibility testing may make little or no difference in time-to-discharge (4 RCTs, 1165 participants; low-certainty evidence). In qualitative analysis, rapid genotypic susceptibility testing compared to conventional testing may make little or no difference in time-to-appropriate antibiotic (3 RCTs, 929 participants; low-certainty evidence). In subgroup analysis, rapid phenotypic susceptibility testing compared to conventional testing may improve time-to-appropriate antibiotic (RR -17.29, CI -45.05 to 10.47; 2 RCTs, 564 participants; low-certainty evidence).  AUTHORS' CONCLUSIONS: The theoretical benefits of rapid susceptibility testing have not been demonstrated to directly improve mortality, time-to-discharge, or time-to-appropriate antibiotic in these randomized studies. Future large prospective studies should be designed to focus on the most clinically meaningful outcomes, and aim to optimize blood culture pathways.

Colistin resistance increases 28-day mortality in bloodstream infections due to carbapenem-resistant Klebsiella pneumoniae.

Mortality due to K. pneumoniae bacteremia is on rise, particularly in regions with high rates of carbapenem and colistin resistance. We aimed to define risk factors for colistin resistance and its impact on mortality. Patients diagnosed with "carbapenem-resistant K. pneumoniae (CRKp)" bacteremia between 2014 and 2018 were divided into two groups as "colistin susceptible (ColS)" and "colistin resistant (ColR)" based on broth microdilution method. Retrospective case-control study was conducted to compare characteristics and outcomes. Multiple logistic regression model was used to define independent risk factors for acquired colistin resistance and Cox proportional hazard model for 28-day mortality. A total of 82 patients (39 ColS and 43 ColR) were included. Mean age was 61.5 years, and 50 (61%) were male. Colistin resistance was significantly increased with duration of hospital stay (p = 0.007) and prior colistin use (p = 0.007). Overall, the 28-day mortality rate was 66%. Age (p = 0.014) and colistin resistance significantly increased 28-day (p = 0.009) mortality. Microbiological response to treatment within 7 days favors survival. PFGE analysis revealed an outbreak with K. pneumoniae ST78 and ST45 clones. Patients treated with combined antimicrobials had significantly lower 28-day mortality (p = 0.045) in comparison to monotherapy. However, types of combinations did not show significant superiority on each other. Colistin resistance increases 28-day mortality in CRKp bacteremia. Although combined regimens are more effective than monotherapy, existing antibacterial combinations have no apparent superiority to each other. New treatment options are pivotal.

Epidemiology, species distribution, and outcome of nosocomial Candida spp. bloodstream infection in Shanghai: an 11-year retrospective analysis in a tertiary care hospital.

BACKGROUND: The incidence of Candida bloodstream infections (BSIs), has increased over time. In this study, we aimed to describe the current epidemiology of Candida BSI in a large tertiary care hospital in Shanghai and to determine the risk factors of 28-day mortality and the impact of antifungal therapy on clinical outcomes. METHODS: All consecutive adult inpatients with Candida BSI at Ruijin Hospital between January 1, 2008, and December 31, 2018, were enrolled. Underlying diseases, clinical severity, species distribution, antifungal therapy, and their impact on the outcomes were analyzed. RESULTS: Among the 370 inpatients with 393 consecutive episodes of Candida BSI, the incidence of nosocomial Candida BSI was 0.39 episodes/1000 hospitalized patients. Of the 393 cases, 299 (76.1%) were treated with antifungal therapy (247 and 52 were treated with early appropriate and targeted antifungal therapy, respectively). The overall 28-day mortality rate was 28.5%, which was significantly lower in those who received early appropriate (25.5%) or targeted (23.1%) antifungal therapy than in those who did not (39.4%; P = 0.012 and P = 0.046, respectively). In multivariate Cox regression analysis, age, chronic renal failure, mechanical ventilation, and severe neutropenia were found to be independent risk factors of the 28-day mortality rate. Patients who received antifungal therapy had a lower mortality risk than did those who did not. CONCLUSIONS: The incidence of Candida BSI has increased steadily in the past 11 years at our tertiary care hospital in Shanghai. Antifungal therapy influenced short-term survival, but no significant difference in mortality was observed between patients who received early appropriate and targeted antifungal therapy.

Xuebijing injection in septic rats mitigates kidney injury, reduces cortical microcirculatory disorders, and suppresses activation of local inflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Xuebijing injections originate from the traditional Chinese medicine (TCM) prescription XuefuZhuyu Decoction. It is composed of five Chinese herbal extracts; Carthami flos, Paeoniae radix rubra, Chuanxiong rhizoma, Salviae miltiorrhizae, and Angelicae Sinensis radix. The China Food and Drug Administration approved Xuebijing injections as a TCM preparation for the adjuvant treatment of sepsis. AIM OF THE STUDY: This study aims to determine the effects of Xuebijing injections as an adjuvant to antibiotics for the treatment of renal microcirculatory dysfunction and renal inflammation in rats with sepsis. MATERIALS AND METHODS: The rats received a sham operation (Sham), sham operation followed by Xuebijign injection (Sxbj), cecal ligation and puncture (CLP), or CLP followed by Xuebijing injection (Cxbj). Renal microvascular perfusion in the cortex and oxygenation were assessed at different times after sepsis induction. Renal levels of interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α, and high mobility group box (HMGB)-1 were measured. Urinary TIMP-2 × IGFBP-7 and neutrophil gelatinase-associated lipocalin (NGAL) were measured as kidney biomarkers, and serum creatinine (SCr) was used to assess kidney injury. Tissue samples were stained for histologic evaluation. RESULTS: The induction of sepsis increased local inflammation and decreased renal microvascular perfusion and oxygenation. Compared with the CLP group, the Cxbj group displayed improvements in microvascular perfusion and oxygenation (p < 0.05). The CLP group had significant increases in renal inflammatory biomarkers (IL-1ß, IL-6, TNF-α, and HMGB-1; p < 0.05) and Xuebijing injection reduced the levels of these markers. The levels of urinary TIMP-2 × IGFBP-7, NAGL, and SCr were lower in the Cxbj group than in the CLP group (p < 0.05), and the CLP group had a higher Paller score than the Cxbj group (p < 0.05). However, the CLP and Cxbj groups had no significant difference in mortality. CONCLUSIONS: This study into the early stages of sepsis in a rat model indicated that as an adjuvant therapy to antibiotics, Xuebijing injection improved renal perfusion and oxygenation, suppressed renal inflammation, and ameliorated kidney dysfunction. However, Xuebijing injection had no impact on mortality.

Evaluation of the association between extravascular lung water and prognosis of sepsis: A protocol of systematic review.

BACKGROUND: The purpose of this study is to explore the association between extravascular lung water (EVLW) and prognosis of sepsis (PS). METHODS: We will carry out comprehensive literature search in electronic databases (PUBMED/MEDLINE, EMBASE, CENTRAL, WorldSciNet, PsycINFO, Allied and Complementary Medicine Database, CBM, and CNKI) and additional sources. All electronic databases will be searched from their initial to the present without language restrictions. Case-controlled studies reporting the association between EVLW and PS will be evaluated for inclusion. Outcomes of interest will include mortality rate, extravascular lung water index, pulmonary vascular permeability index, blood lactate clearance, oxygenation index, blood gas analysis, PaO2/FiO2, cardiac output index, global end diastolic volume index, intrathoracic blood volume index, systemic resistance index, acute physiology and chronic health scoring system II, and infection-related organ failure scoring system. Study quality will be evaluated using Newcastle-Ottawa Tool, and statistical analysis will be performed utilizing RevMan 5.4 software. RESULTS: This study will summarize the most recent evidence to investigate the association between EVLW and PS. CONCLUSIONS: The results of this study will provide an exhaustive view of the association between EVLW and PS. STUDY REGISTRATION OSF: osf.io/vhnxw.

Vitamin D status was associated with sepsis in critically ill children: A PRISMA compliant systematic review and meta-analysis.

BACKGROUND: Sepsis leads to the high mortality in critically ill infants and children. It is still controversial whether vitamin D deficiency was associated with the incidence of sepsis. Thus we designed the systematic review and meta-analysis. METHODS: The Ovid Medline, Embase, PubMed, and Cochrane library were systematically searched until April 5, 2020. The 25 hydroxyvitamin D (25-OHD) level was recorded and set 20 ng/mL as cut-off in cohort study to divide the lower and higher 25-OHD group. The odds ratio (OR) and 95% confidence intervals (CIs) were calculated for comparing the impact of vitamin D deficiency on the incidence of sepsis in critically ill children. RESULTS: A total of 27 studies were included with 17 case-control studies and 10 cohort studies. In those case-control studies, the maternal 25-OHD level and neonatal 25-OHD level in sepsis group was significant lower than non-sepsis group (P < .001). The percentage of severe vitamin D deficiency was significant higher in sepsis group comparing to non-sepsis group (odds ratio [OR] = 2.66, 95% CI = 1.13-6.25, P < .001). In those cohort studies, the incidence of sepsis in lower 25-OHD group was 30.4% comparing with 18.2% in higher 25-OHD level group. However, no statistical significant difference in terms of mechanical ventilation rate and 30-day mortality. CONCLUSION: We demonstrated that critically ill infants and children with sepsis could have a lower 25-OHD level and severe vitamin D deficiency comparing to those without sepsis. Future studies should focus on the association of vitamin D supplement and the occurrence of sepsis in critically ill children.

Reduning injection and its effective constituent luteoloside protect against sepsis partly via inhibition of HMGB1/TLR4/NF-κB/MAPKs signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Reduning injection (RDN), a popular traditional Chinese medicine, formulated by three herbs (i.e., Artemisia carvifolia Buch.-Ham. ex Roxb., Lonicera japonica Thunb., and Gardenia jasminoides J. Ellis), has been widely used to treat upper respiratory infectious diseases in China. AIM OF THE STUDY: To investigate the protective effect of RDN on both lipopolysaccharides (LPS)- and cecal ligation and puncture (CLP)-induced septic mice. To identify the potentially effective constituent, and to determine its protective effect and underlying mechanism in vivo and in vitro. MATERIALS AND METHODS: Male C57BL/6 mice were used to establish septic model by tail intravenous injection of 4 mg/kg LPS or CLP surgery. After modeling, mice were administered by tail intravenous injection of RDN in the dose of 16 or 8 mL/kg/day. The mortality, histopathology, plasma levels of inflammatory cytokines were evaluated respectively. In addition, we screened the potentially effective substances of RDN against sepsis by detecting the nitric oxide (NO) production in LPS-stimulated Raw 264.7 cells and verified the effect of luteoloside in CLP-induced septic mice subsequently. Finally, the underlying mechanisms of RDN and luteoloside were investigated in the inflammatory model in vitro. RESULTS: Administration of RDN significantly reduced the mortality and increased the survival rate in both LPS- and CLP-induced septic mice. Meanwhile, RDN reduced the release of inflammatory cytokines accompanied by alleviating the organs damage of lung, liver, and kidney in CLP-induced septic mice. Moreover, several components from Gardenia jasminoides J. Ellis extract (ZZ) or Lonicera japonica Thunb and Artemisia carvifolia Buch.-Ham. ex Roxb extract (JQ) as well as the constituents of luteoloside, quercetin, and caffeic acid were screened out to have obvious anti-inflammatory activity, which may be the potentially effective substances of RDN against sepsis. We further verified the protective role of luteoloside in CLP-induced septic mice. In addition, RDN and luteoloside significantly inhibited both the secretion and translocation of mobility group box (HMGB)1, and HMGB1-mediated activation of TLR4/NF-κB/MAPKs signaling pathways. CONCLUSION: RDN and its effective constituent luteoloside exhibited a significant protective effect against sepsis, which were potential candidate drugs for treatment of sepsis. The mechanism of antisepsis partly was related to inhibition of HMGB1/TLR4/NF-κB/MAPKs signaling pathways. The results provide an evidence base for the follow-up clinical application of RDN in treatment of sepsis.

The Effect of L-Carnitine on Mortality Rate in Septic Patients: A Systematic Review and Meta-Analysis on Randomized Clinical Trials.

BACKGROUND: Recent clinical trial studies have reported that L-carnitine supplementation can reduce the mortality rate in patients with sepsis, but there are no definitive results in this context. The current systematic review and meta-analysis aimed to evaluate the effect of L-carnitine supplementation on 28-day and one-year mortality in septic patients. METHODS: A systematic search conducted on Pubmed, Scopus and Cochrane Library databases up to June 2019 without any language restriction. The publications were reviewed based on the Cochrane handbook and preferred reporting items for systematic reviews and meta-analyses (PRISMA). To compare the effects of L-carnitine with placebo, Risk Ratio (RR) with 95% confidence intervals (CI) were pooled according to the random effects model. RESULTS: Across five enrolled clinical trials, we found that L-carnitine supplementation reduce one-year mortality in septic patients with SOFA> 12 (RR: 0.68; 95% CI: 0.49 to 0.96; P= 0.03) but had no significant effect on reducing 28-day mortality ((RR: 0.93; 95% CI: 0.68 to 1.28; P= 0.65) compared to placebo. Finally, we observed that based on current trials, L-carnitine supplementation may not have clinically a significant effect on mortality rate. CONCLUSION: L-carnitine patients with higher SOFA score can reduce the mortality rate. However, the number of trials, study duration and using a dosage of L-carnitine are limited in this context and further large prospective trials are required to clarify the effect of L-carnitine on mortality rate in septic patients.

The Effect of Xinmailong Infusion on Sepsis-Induced Myocardial Dysfunction: a Pragmatic Randomized Controlled Trial.

ABSTRACT: Sepsis-induced myocardial dysfunction (SIMD) contributes significantly to cardiovascular dysfunction during septic shock. We aimed to evaluate the potential role of Xinmailong injection (XMLI), a polypeptide medicine extracted from Periplaneta americana, in reversing the progression of myocardial damage to SIMD in sepsis patients. This was a multicenter, randomized, double-blind, parallel-group trial. We recruited all patients consecutively admitted to intensive care units (ICUs) who were aged 18 to 85 years old and met the sepsis 3.0 criteria. The primary outcome measure was the incidence of sepsis-induced myocardial dysfunction while in the ICU. Of the 192 patients, 96 were assigned to the treatment group, and 96 to the control group. Subsequently, 41 patients [41/96 (42.7%)] in the XMLI group and 61 patients in the placebo group [61/96 (63.5%)] were confirmed to have diastolic dysfunction on the fifth day (D5). The incidence of diastolic SIMD was significantly different between the two groups (P = 0.004). There were 36 deaths in the two groups during the 28-day follow-up, with a general mortality rate of 18.8% (36/192). The 28-day mortality rates were not significantly different between the groups (P = 0.45). However, the brain natriuretic peptide (BNP) plasma concentration trends on D0, D2, and D5 significantly differed between the two groups (P = 0.049). In septic patients, XMLI decreased the occurrence rate of diastolic SIMD more effectively than the placebo. The improvement in serum BNP concentration was also greater in the XMLI group. XMLI may, therefore, effectively and safely improve cardiac function in patients with sepsis.

ß-Lapachone Increases Survival of Septic Mice by Regulating Inflammatory and Oxidative Response.

Sepsis is characterized by a dysregulated immune response to infection characterized by an early hyperinflammatory and oxidative response followed by a subsequent immunosuppression phase. Although there have been some advances in the treatment of sepsis, mortality rates remain high, urging for the search of new therapies. ß-Lapachone (ß-Lap) is a natural compound obtained from Tabebuia avellanedae Lorentz ex Griseb. with several pharmacological properties including bactericidal, anti-inflammatory, and antioxidant activity. Thus, the aim of this study was to evaluate the effects of ß-Lap in a mouse sepsis model. To this, we tested two therapeutic protocols in mice submitted to cecal ligation and puncture- (CLP-) induced sepsis. First, we found that in pretreated animals, ß-Lap reduced the systemic inflammatory response and improved bacterial clearance and mouse survival. Moreover, ß-Lap also decreased lipid peroxidation and increased the total antioxidant capacity in the serum and peritoneal cavity of septic animals. In the model of severe sepsis, the posttreatment with ß-Lap was able to increase the survival of animals and maintain the antioxidant defense function. In conclusion, the ß-Lap was able to increase the survival of septic animals by a mechanism involving immunomodulatory and antioxidant protective effects.

Postimplementation Evaluation of a Machine Learning-Based Deterioration Risk Alert to Enhance Sepsis Outcome Improvements.

Machine learning-based early warning systems (EWSs) can detect clinical deterioration more accurately than point-score tools. In patients with sepsis, however, the timing and scope of sepsis interventions relative to an advanced EWS alert are not well understood. The objectives of this study were to evaluate the timing and frequency of fluid bolus therapy, new antibiotics, and Do Not Resuscitate (DNR) status relative to the time of an advanced EWS alert. We conducted 2 rounds of chart reviews of patients with an EWS alert admitted to community hospitals of a large integrated health system in Northern California (round 1: n = 21; round 2: n = 47). We abstracted patient characteristics and process measures of sepsis intervention and performed summary statistics. Sepsis decedents were older and sicker at admission and alert time. Most EWS alerts occurred near admission, and most sepsis interventions occurred before the first alert. Of 14 decedents, 12 (86%) had a DNR order before death. Fluid bolus therapy and new intravenous antibiotics frequently occurred before the alert, suggesting a potential overlap between sepsis care in the emergency department and the first alert following admission. Two tactics to minimize alerts that may not motivate new sepsis interventions are (1) locking out the alert during the immediate time after hospital admission; and (2) triaging and reviewing patients with alerts outside of the unit before activating a bedside response. Some decedents may have been on a palliative/end-of-life trajectory, because DNR orders were very common among decedents. Nurse leaders sponsoring or leading machine learning projects should consider tactics to reduce false-positive and clinically meaningless alerts dispatched to clinical staff.