Outcome Of Septic Patients Research Articles

The effect of intravenous Vitamin C, thiamine and hydrocortisone on the outcome of septic patients

The effect of intravenous Vitamin C, thiamine and hydrocortisone on the outcome of septic patients

Interleukin-17 as predictor mortality of septic patients: a systematic review and meta-analysis.

Aim: This study aimed to prove the role of IL-17 on the clinical outcomes of septic patients. Materials and Methods: This study used a systematic review and meta-analysis design. Data were obtained by searching articles published between January 2001 and June 2022 in Pubmed, Science Direct, Scopus, and Medline databases to evaluate Interleukin-17 on clinical outcomes in septic patients. Only human studies were used in this study. Meta-analysis was undertaken using random effects models. Results: Fourteen published studies were eligible, and four studies were included in the meta-analysis. Meta-analysis of the ratio of means (RoM) IL-17 concentration demonstrated a 5.96-fold higher level in non-survivor septic patients compared with survivors (four studies; n = 194 patients; RoM=5.96; 95% CI, 3.51-10.31; p < 0.00001; I2 = 92%). Conclusions: IL-17 levels were significantly elevated in non-survivor and predicted mortality of septic patients.

Irg1/itaconate activates Nrf2/HO-1 pathway and mitigates septic liver injury in mice

Objectives: Immune-responsive gene 1 ( Irg1)-catalyzed production of itaconate is a bioactive metabolite with antibacterial, anti-inflammatory and antioxidant properties. Liver injury is closely related to poor outcomes in septic patients, while prevention of liver injury is essential for the pharmacological control of sepsis. This study investigated the pathological and pharmacological significance of Irg1/itaconate in septic liver injury. Methods: Septic liver injury was induced in mice by injecting lipopolysaccharide (LPS; 15 mg/kg) intraperitoneally. The hepatic mRNA and protein contents of Irg1 were detected. To investigate the pathological meaning of Irg1, septic liver injury was induced in Irg1 knockout mice and their wild-type (WT) littermates, and the degree of liver injury, hepatic inflammation, oxidative stress and the activation of nuclear erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) were subsequently determined. Finally, to explore the gene’s pharmacological potential, 4-octyl itaconate (4-OI; 50 mg/kg), a derivative of itaconate that could cross cell membranes, was administered intraperitoneally. The mobilization of Nrf2/HO-1 and liver injury were then evaluated. Results: The level of Irg1 expression was dramatically enhanced in mice with septic liver injury. Additionally, Irg1 deletion leaded to higher ALT and AST levels, elevated inflammatory and oxidative-stress indicators and compromised stimulation of the Nrf2/HO-1 pathway. However, administering 4-OI restored the Nrf2/HO-1 pathway which mitigated liver injury and inhibited hepatic inflammation and oxidative stress. Conclusions: The results figured that elevation of Irg1 might be a protective event that control the progress of septic liver injury, while 4-OI might have latent significance for the pharmaceutical intervention of septic liver injury.

Thrombin worsens extravascular lung water and outcomes of septic patients with acute respiratory distress syndrome: A case control study.

Endothelial cell (EC) activation may increase systemic vascular permeability, causing extravascular lung water (EVLW) in sepsis with acute respiratory distress syndrome (ARDS). However, the correlation between thrombin and EVLW in sepsis and ARDS has not yet been addressed. Patients with sepsis and ARDS were prospectively enrolled between 2014 and 2016, and EVLW and serum thrombin levels on days 1 and 3 were measured and compared between surviving and non-surviving patients. Additionally, morphological changes in human umbilical vein endothelial cells (HUVECs) in the serum of patients with high and low EVLW were evaluated. The levels of EVLW, endothelial cells, and thrombin may positively correlate with the survival of patients with severe sepsis and ARDS. Twenty-seven patients were enrolled, and baseline characteristics, including age, sex, Acute Physiology and Chronic Health Evaluation (APACHE) II, prior 24-h fluid balance, body mass index, and shock status, were similar between survivors and non-survivors; however, day 1 EVLW was higher in non-survivors (27.5 ± 8.4 vs 22 ± 6.5 mL/kg, P = .047). EVLW of survivors improved from day 1 to day 3 (22 ± 6.5 vs 11 ± 3.8 mL/kg, P < .001), but did not improve in non-survivors (27.5 ± 8.4 vs 28 ± 6.7 mL/kg, P = .086), which means that patients had significantly lower EVLW on day 3 than on day 1. Thrombin levels of survivors significantly improved (1.03 ± 0.55 vs 0.87 ± 0.25 U/mL, P = .04) but did not improve in non-survivors (1.97 ± 0.75 vs 2.2 ± 0.75 U/mL, P = .08) from day 1 to day 3. EVLW and thrombin levels were positively correlated (r2 = 0.71, P < .0001). In vitro, the morphology and junctions of HUVECs changed when the serum from patients with high EVLW was added. The intercellular distances among the control, high EVLW, and low EVLW groups were 5.25 ± 1.22, 21.33 ± 2.15, and 11.17 ± 1.64 µm, respectively (P < .05).

Different subtypes of nonthyroidal illness syndrome on the prognosis of septic patients: a two-centered retrospective cohort study.

Nonthyroidal illness syndrome (NTIS) is a common endocrine dysfunction predicting unfavorable outcomes in critical illness. The objective of the study is to evaluate the association between different NTIS subtypes with outcomes in septic patients. Septic patients in two Chinese academic centers from October 2012 and October 2022 are enrolled in analysis. Multivariable regressions are used to assess associations between NTIS and outcomes. Outcomes include in-hospital mortality, length of stay in hospital (LOS), non-invasive ventilation failure and weaning failure. Patients with NTIS are categorized into 4 types according to the different levels of FT4 and TSH. The association between different NTIS subtypes and mortality are further analyzed. Survival curve is plotted using the Kaplan-Meier method. After screening, a total of 1226 septic patients with complete thyroid hormones result are eventually enrolled. Among them, 520 (42.4%) patients are diagnosed as NTIS. In multivariable regression analysis, NTIS is independently associated with increased 30-days mortality (OR=1.759, CI 1.009-3.104, p=0.047), but has no association with 60-days mortality (OR=1.524, CI 0.893-2.618, p=0.123), 90-days mortality (OR=1.411, CI 0.831-2.408, p=0.203), LOS, non-invasive ventilation failure or weaning failure. In NTIS subtypes, NTIS patients with low FT3 and TSH levels, regardless of the FT4 values, have significantly higher mortality than euthyroid patients (30-days mortality, OR= 6.488, CI 1.546-27.808, p=0.01; 60-days mortality, OR=3.973, CI 1.006-15.579, p=0.046; 90-days mortality, OR=3.849, CI 0.977-15.088, p=0.051). This result is consistent in patients with low FT3 and FT4 levels, regardless of the TSH values (30-days mortality, OR=3.349, CI 1.402-7.957, p=0.006; 60-days mortality, OR= 2.594, CI 1.122-5.930, p=0.024; 90-days mortality, OR=2.55, CI 1.110-5.804, p=0.025). There is no survival difference between NTIS patients with low FT3 only and euthyroid patients. Survival plot shows the worst prognosis is in NTIS patients with low FT3, FT4 and TSH level. NTIS is frequent in sepsis. A reduction of FT3 together with FT4 or TSH, but not FT3 only, is associated with an increased risk of mortality.

Using Body Composition Analysis for Improved Nutritional Intervention in Septic Patients: A Prospective Interventional Study.

The study aimed to determine whether using body composition data acquired through bio-electrical impedance analysis (BIA) to adjust diet formulas could improve outcomes in septic patients. There were 132 septic patients in medical intensive care units enrolled in the prospective, randomized, double-blind, interventional study. For the intervention group, dietitians had access to BIA data for adjusting diet formulas according to body composition variables on days 1, 3, and 8. The patients were also stratified based on nutritional risk using the modified Nutrition Risk in Critically ill (mNUTRIC) score. Patients with intervention were more likely to achieve caloric and protein intake goals compared to the control group, especially in the low-risk group. The intervention did not significantly affect mortality, but the survival curves suggested potential benefits. The high-risk group had longer ICU stays and mechanical ventilation duration, which were mitigated by the intervention. Certain body composition variables (e.g., extracellular water to total body water ratio and phase angle) showed differences between high-risk and low-risk groups and may be related to patient outcomes. Non-invasive body composition assessment using BIA can help dietitians adjust diet formulas for critically ill septic patients. Body composition variables may be associated with sepsis outcomes, but further research with larger patient numbers is needed to confirm these findings.

Safety and Efficacy of Ivabradine as a Rate Control for the Heart in Sepsis

Abstract Background Sepsis and septic shock represent a major health problem among the critically ill patients all over the world, with associated substantial morbidity and mortality rates ranging from 18 % to 50 %. The incidence of sepsis has increased steadily over the last three decades, at least in part because of aging western population. Despite our increased understanding, improved support and more powerful antibiotic therapy, sepsis is still reported as the second leading cause of death in non-coronary intensive care units, and the tenth-mostcommon cause of death overall (the first being heart disease). Children under 12 months and elderly have the highest incidence of severe sepsis). Objective Evaluation of the role of heart rate control using enteral Ivabradine in the management of patients with sepsis. Assessment of the effect of enteral Ivabradine on outcome of septic patients regarding need for vasopressor therapy, mechanical ventilation, renal replacement therapy, length of ICU stay, in- hospital mortality and 30 days mortality. Patients and Methods The study was comparative prospective case / control study conducted on 60 critically ill patients admitted with sepsis and or septic shock to the Critical Care Department at Kobry Elkoba Military complex at 12 month from 8/2019 up to 8/ 2020. Results Significant decrease in follow up lactate at end of Ivabradine treatment, compared to control group without Ivabradine treatment (p = 0.025). Significant decrease in follow up of crp level in group A than group B at day 2 and day 4 with (p = 0.013), (p = 0.018) respectively. Significant decrease in heart rate in group A in comparison with group B during first 48 hour with (p = 0.008). Significant difference between group A and group B regarding weaning from mechanical ventilation with (p = 0.001). There was no statistically significant difference found between group A and group B regarding rate of mortality with p-value = 0.606. Conclusion Use of enteral Ivabradine can reduce pathologically elevated heart rate in patients with sepsis but didn‘t affect survival, length of ICU stay, between septic patient.

Midodrine as Adjunction Support for Weaning off Norepinephrine in Septic Shock

Abstract Background Septic shock is the most severe form of sepsis, in which profound underlying abnormalities in circulatory and cellular/metabolic parameters lead to substantially increased mortality. Objective To evaluate whether oral administration of midodrine is an effective adjunct to standard therapy to reduce the duration of IV norepinephrine and allow earlier discharge from ICU compared to control patients. Patients and Methods This was a Prospective comparative study. The population of the study included 60 patients whom were admitted to adult ICU department with septic shock. This study was included 60 critically ill patients who was fulfilled the diagnostic criteria for septic shock were randomly assigned to one of two group each one was included 30 patients. Results Concerning the effect of midodrine on the outcome of septic patients, our study showed that there was highly significant effect on the ICU length of stay and ICU mortality. (The ICU length of stay (days) in midodrine group = 6.2 VS 8.3 in control group (p = less than 0.001) and the ICU survival in midodrine group = 96.7%VS 60% in control group (p = 0.001). A number of confounding factors may have influenced this endpoint, including the provider confidence in patient stability, bed availability on floor or step-down units or continued need for ICU monitoring for other reasons. Conclusion Use of midodrine significantly reduces duration of IV vasopressor infusion during the recovery phase of septic shock. Use of midodrine has great impact on overall survival, length of ICU stay and ICU survival. Administration of midodrine improved MAP &amp; serum lactate in midodrine group.

Quantitative evaluation of myocardial layer-specific strain using two-dimensional speckle tracking echocardiography in septic patients

BackgroundAlthough global longitudinal strain (GLS) is proven to be reduced and associated with adverse outcomes in septic patients, it has not been elucidated whether or not layer-specific strains are reduced. We aimed to explore the layer-specific strains of left ventricular (LV) for assessing myocardial dysfunction in septic patients.MethodsA prospective observational study of patients with sepsis was conducted in a tertiary hospital in China. Routine two-dimensional speckle tracking echocardiography was performed within 24 h of enrollment. Demographic data, laboratory values, and clinical outcomes were collected.ResultsWe recruited 79 septic patients finally. The mean age of septic patients was 59.4 years old and 45 (57.0%) were male. The median Acute Physiology Age and Chronic Health Evaluation (APACHE II) score, and mean sequential organ failure assessment (SOFA) score of all patients were 19.0 and 7.7, respectively. According to the left ventricular ejection fraction (LVEF) value of 50%, the patients were categorized into two groups: SICM (sepsis-induced cardiomyopathy, LVEF < 50%, n = 22) and non-SICM group ( LVEF ≥ 50%, n = 57). The median LVEF of SICM and non-SICM patients were 41.9% and 58.7%, and SICM patients had less negative layer-specific strain and global strain than that of non-SICM patients. The echocardiographic comparison of non-SICM and healthy controls was conducted to explore the myocardial injuries of non-SICM patients and the non-SICM had worse LS-epi than that of controls (-18.5% vs. -21.4%, p = 0.024).ConclusionThere were 72.2% (57) septic patients presented with non-SICM (LVEF ≥ 50%), and the strain value of epicardium of them was less negative than healthy controls.

U-SHAPED ASSOCIATION BETWEEN SERUM CALCIUM LEVELS AND 28-DAY MORTALITY IN PATIENTS WITH SEPSIS: A RETROSPECTIVE ANALYSIS OF THE MIMIC-III DATABASE.

Background: Serum calcium levels disorder have been reported to be associated with poor prognosis in different diseases. Studies on the association between serum calcium and outcomes of septic patients remained limited. The aim of this study is to investigate the association between serum calcium and 28-day mortality in septic patients. Method: Patients diagnosed with sepsis in the Medical Information Mart for Intensive Care III database were included. Patients were divided into five groups according to the quintiles of serum calcium levels, and their baseline characteristics were compared. Multivariate Cox regression models were used to assess the association between serum calcium and 28-day mortality. Smooth curve fitting and segmented regression models were used to visualize the association between serum calcium levels and 28-day mortality risk. The 28-day survival probability between five groups was analyzed using Kaplan-Meier curves. Results: A total of 3,016 patients with sepsis were enrolled, and the 28-day mortality rate was 35.64%. After adjusting for confounders, compared with the reference quintile (Q4: 9.00-9.50), the lowest serum calcium level quintile (Q1: 5.70-8.20) was independently associated with an increased risk of 28-day mortality (hazard ratio [HR], 2.12; 95% CI, 1.76-2.56). Smooth spline fitting revealed a U-shaped association between serum calcium and 28-day mortality. When serum calcium was <9.0 mg/dL, 28-day mortality risk increased by 58% per unit decrease in serum calcium (HR, 0.42; 95% CI, 0.37-0.48). When serum calcium was >9.0 mg/dL, the 28-day mortality risk increased by 12% per unit increase in serum calcium (HR, 1.12; 95% CI, 1.04-1.20). Conclusion: A U-shaped association was observed between serum calcium levels and 28-day mortality in septic patients. Lower or higher serum calcium levels were associated with increased risk of 28-day mortality in septic patients.

PAI-1 genetic polymorphisms influence septic patients' outcomes by regulating neutrophil activity.

Plasminogen activator inhibitor-1 (PAI-1) plays an important role in the pathophysiology of sepsis, but the exact mechanism remains debatable. In this study, we investigated the associations among the serum levels of PAI-1, the incidence of 4G/5G promoter PAI-1 gene polymorphisms, immunological indicators, and clinical outcomes in septic patients. A total of 181 patients aged 18-80 years with sepsis between November 2016 and August 2018 in the intensive care unit in the Xinhua Hospital were recruited in this retrospective study, with 28-day mortality as the primary outcome. The initial serum level of PAI-1 and the presence of rs1799768 single nucleotide polymorphisms (SNPs) were examined. Univariate logistic regression and multivariate analyses were performed to determine the factors associated with different genotypes of PAI-1, serum level of PAI-1, and 28-day mortality. The logistic analysis suggested that a high serum level of PAI-1 was associated with the rs1799768 SNP of PAI-1 (4G/4G and 4G/5G) (Odds ratio [OR]: 2.49; 95% confidence interval [CI]: 1.09, 5.68). Furthermore, a high serum level of PAI-1 strongly influenced 28-day mortality (OR 3.36; 95% CI 1.51, 7.49). The expression and activation of neutrophils (OR 0.96; 95% CI 0.93, 0.99), as well as the changes in the expression patterns of cytokines and chemokine-associated neutrophils (OR: 1.00; 95% CI: 1.00, 1.00), were both regulated by the genotype of PAI-1. Genetic polymorphisms of PAI-1 can influence the serum levels of PAI-1, which might contribute to mortality by affecting neutrophil activity. Thus, patients with severe sepsis might clinically benefit from enhanced neutrophil clearance and the resolution of inflammation via the regulation of PAI-1 expression and activity.

SEPSIS UNIT IN THE EMERGENCY DEPARTMENT: IMPACT ON MANAGEMENT AND OUTCOME OF SEPTIC PATIENTS.

Study hypothesis : Implementation of a new pathway dedicated to septic patients within the emergency department (ED) would improve early management, organ dysfunction, and outcome. Methods: During phase 1, all consecutive adult patients with infection and qualifying quick Sequential Organ Failure Assessment (qSOFA) score upon ED admission were managed according to standards of care. A multifaceted intervention was then performed (implementation phase): educational program, creation of a sepsis alert upon ED admission incorporated in the professional software, together with severity scores and Surviving Sepsis Campaign (SSC) bundle reminders, and dedication of two rooms to the management of septic patients (sepsis unit). During phase 2, patients were managed according to this new organization. Results: Of the 89,040 patients admitted to the ED over the two phases, 2,643 patients (3.2%) had sepsis including 277 with a qualifying qSOFA score on admission (phase 1, 141 patients; phase 2, 136 patients). Recommendations of SSC 3-h bundle significantly improved between the two periods regarding lactate measurement (87% vs. 96%, P = 0.006), initiation of fluid resuscitation (36% vs. 65%, P < 0.001), blood cultures sampling (83% vs. 93%, P = 0.014), and administration of antibiotics (18% vs. 46%, P < 0.001). The Sequential Organ Failure Assessment score between H0 and H12 varied significantly more during phase 2 (1.9 ± 1.9 vs. 0.8 ± 2.6, P < 0.001). Mortality significantly decreased during the second phase, on day 3 (28% vs. 15%, P = 0.008) and on day 28 (40% vs. 28%, P = 0.013). Conclusion: Systematic detection, education, and per protocol organization with a sepsis unit dedicated to the early management of septic patients appear to improve compliance with SSC bundles, organ dysfunction, and short-term mortality. These results warrant to be confirmed by prospective studies.

The Role of Gut Microbiota in the Clinical Outcome of Septic Patients: State of the Art and Future Perspectives.

Sepsis is a life-threatening multiple-organ dysfunction caused by a dysregulated host response to infection, with high mortality worldwide; 11 million deaths per year are attributable to sepsis in high-income countries. Several research groups have reported that septic patients display a dysbiotic gut microbiota, often related to high mortality. Based on current knowledge, in this narrative review, we revised original articles, clinical trials, and pilot studies to evaluate the beneficial effect of gut microbiota manipulation in clinical practice, starting from an early diagnosis of sepsis and an in-depth analysis of gut microbiota.

The association between the presence and burden of periodic discharges and outcome in septic patients: an observational prospective study

BackgroundSepsis-associated encephalopathy (SAE) is frequent in septic patients. Electroencephalography (EEG) is very sensitive to detect early epileptic abnormalities, such as seizures and periodic discharges (PDs), and to quantify their duration (the so-called burden). However, the prevalence of these EEG abnormalities in septic patients, as well as their effect on morbidity and mortality, are still unclear. The aims of this study were to assess whether the presence of electrographic abnormalities (i.e. the absence of reactivity, the presence and burden of seizures and PDs) was associated with functional outcome and mortality in septic patients and whether these abnormalities were associated with sepsis-associated encephalopathy (SAE).MethodsWe prospectively included septic patients, without known chronic or acute intracranial disease or pre-existing acute encephalopathy, requiring ICU admission in a tertiary academic centre. Continuous EEG monitoring was started within 72 h after inclusion and performed for up to 7 days. A comprehensive assessment of consciousness and delirium was performed twice daily by a trained neuropsychologist. Primary endpoints were unfavourable functional outcome (UO, defined as a Glasgow Outcome Scale-Extended—GOSE—score < 5), and mortality collected at hospital discharge and secondary endpoint was the association of PDs with SAE. Mann–Whitney, Fisher’s exact and χ2 tests were used to assess differences in variables between groups, as appropriate. Multivariable logistic regression analysis with in-hospital mortality, functional outcome, SAE or PDs as the dependent variables were performed.ResultsWe included 92 patients. No seizures were identified. Nearly 25% of patients had PDs. The presence of PDs and PDs burden was associated with UO in univariate (n = 15 [41%], p = 0.005 and p = 0.008, respectively) and, for PDs presence, also in multivariate analysis after correcting for disease severity (OR 3.82, IC 95% [1.27–11.49], p = 0.02). The PDs burden negatively correlated with GOSE (Spearman’s coefficient ρ = − 0.2, p = 0.047). The presence of PDs was also independently associated with SAE (OR 8.98 [1.11–72.8], p = 0.04). Reactivity was observed in the majority of patients and was associated with outcomes (p = 0.044 for both functional outcome and mortality).ConclusionOur findings suggest that PDs and PDs burden are associated with SAE and might affect outcome in septic patients.

ANALYSIS OF THE RELATIONSHIP BETWEEN EARLY SERUM PHOSPHATE LEVELS AND SHORT-TERM MORTALITY IN SEPTIC PATIENTS: A RETROSPECTIVE STUDY BASED ON MIMIC-IV.

Objective: The aim of the study is to explore the impact of early serum phosphate levels on the prognosis of critically ill patients with sepsis. Methods: In this retrospective large cohort study, data of patients with sepsis were obtained from the Medical Information Mart for Intensive Care IV database. Patients were retrospectively divided into a control group and three study groups according to their daily serum phosphate levels within 2 days of intensive care unit (ICU) admission. A Cox regression model was used to evaluate the association between serum phosphate levels and 28-day morbidity. Results: This study included 9,691 patients diagnosed with sepsis. During the first 2 days of ICU admission, patients with hyperphosphatemia in either of the 2 days had higher 28-day mortality, while patients in the hypophosphatemia group had lower 28-day mortality (first day, 32.9% vs. 16.3%; second day, 36.3% vs. 14.7%). After adjusting for potential confounders, hyperphosphatemia was significantly associated with 28-day mortality; however, only hypophosphatemia on the second day was independently associated with reduced 28-day mortality. After stratification in the hypophosphatemia group, subgroup analysis showed that only the association between the mild hypophosphatemia group and 28-day mortality reached statistical significance (hazard ratio = 0.76, 95% CI = 0.65-0.89, P = 0.001). Conclusions: Mild hypophosphatemia might improve the short-term prognosis of patients with sepsis, and hyperphosphatemia is an independent risk factor for the outcomes of septic patients. After ICU admission, the serum phosphate levels on the second day had a better independent correlation with 28-day mortality, which prompted us to reconsider the optimal timing of phosphate evaluation.

Association between minimal decrease in platelet counts and outcomes in septic patients: a retrospective observational study

ObjectivesAlthough platelets have been linked to inflammatory development in sepsis, knowledge on their role as an indicator in sepsis treatment is scarce. Here, we investigated the association between time-dependent changes...

LOW DOSE OF ESMOLOL ATTENUATES SEPSIS-INDUCED IMMUNOSUPPRESSION VIA MODULATING T-LYMPHOCYTE APOPTOSIS AND DIFFERENTIATION.

Background: Immunosuppression caused by immune cell apoptosis and an imbalance of T helper 2 cells (T H 2) and T helper 1 cells (T H 1), is associated with poor outcomes in septic patients. Esmolol was reported to improve survival by modulating immune responses in septic shock. Whether esmolol could alleviate sepsis-induced immunosuppression and the optimal dose are unclear. Methods: Four hours after cecal ligation and puncture (CLP), Wistar rats were randomized into CLP, CLP + E-5 (esmolol: 5 mg·kg -1 ·h -1 ) and CLP + E-18 (esmolol: 18 mg·kg -1 ·h -1 ) groups. Eight rats were underwent sham operation. Eighteen hours after CLP, hemodynamics and organ histological injuries were evaluated, peripheral blood mononuclear cells apoptosis and T-lymphocyte subsets counts were determined by flow cytometry, and the expression of p-Akt, Bcl-2, cleaved Caspase-3, and p-Erk1/2 in splenic CD4 + T-lymphocytes was determined by western blot and immunohistochemistry. β 1 -Adrenoreceptor expressions were evaluated using real-time polymerase chain reaction and immunohistochemistry. Results: Cecal ligation and puncture induced tachycardia, hypotension, hyperlactatemia, and multiple organ injury. Heart rate was unchanged in the CLP + E-5 group but decreased in the CLP + E-18 group. Hypotension, lactatemia, and multiple organ injuries were improved only in the CLP + E-5 group. T-lymphocyte apoptosis and T H 2/T H 1 ratio was decreased in CLP + E-5 but not in CLP + E-18. p-Akt and Bcl-2 expressions were increased, while cleaved Caspase-3 and p-Erk1/2 expressions were decreased in CLP + E-5. β 1 -Adrenoreceptor expressions were unchanged in both CLP + E-5 and CLP + E-18 groups. Conclusions: Low dose of esmolol reduced T-lymphocyte apoptosis and restored T H 2/T H 1 ratio in septic shock. Esmolol might modulate Akt/Bcl-2/Caspase-3 pathway to relieve T-lymphocyte apoptosis and inhibit Erk1/2 activity to decrease T H 0 differentiation to T H 2. Esmolol may be a potential immunoregulator of septic shock.

Repositioning linifanib as a potent anti-necroptosis agent for sepsis

Sepsis is a systemic inflammatory syndrome (SIRS) caused by acute microbial infection, and it has an extremely high mortality rate. Tumor necrosis factor-α (TNF-α)-induced necroptosis contributes to the pathophysiology of sepsis, so inhibiting necroptosis might be expected to improve clinical outcomes in septic patients. Here we predicted candidate drugs for treating sepsis in silico by combining genes differentially expressed in septic patients and controls combined with interrogation of the Library of Integrated Network-based Cellular Signatures (LINCS) L1000 perturbation database. Sixteen candidate drugs were screened out through bioinformatics analysis, and the top candidate linifanib was validated in cellular and mouse models of TNF-α-induced necroptosis. Cell viability was measured using a luminescent ATP assay, while the effects of linifanib on necroptosis were investigated by western blotting, immunoprecipitation, and RIPK1 kinase assays. Linifanib effectively protected cells from necroptosis and rescued SIRS mice from TNF-α-induced shock and death. In vitro, linifanib directly suppressed RIPK1 kinase activity. In vivo, linifanib effectively reduced overexpressed IL-6, a marker of sepsis severity, in the lungs of SIRS mice. Our preclinical evidence using an integrated in silico and experimental drug repositioning approach supports the potential clinical utility of linifanib in septic patients. Further clinical validation is now warranted.

Early Lactate Clearance as a Determinant of Survival in Patients with Sepsis: Findings from a Low-resource Country.

Single lactate measurements have been reported to have prognostic significance, however, there is a lack of data in local literature from Pakistan. This study was done to determine prognostic role of lactate clearance in sepsis patients being managed in our lower-middle income country. This prospective cohort study was conducted from September 2019-February 2020 at the Aga Khan University Hospital, Karachi. Patients were enrolled using consecutive sampling and categorized based on their lactate clearance status. Lactate clearance was defined as decrease by 10% or greater in repeat lactate from the initial measurement (or both initial and repeat levels <=2.0 mmol/L). A total 198 patients were included in the study, 51% (101) were male. Multi-organ dysfunction was reported in 18.6% (37), 47.7% (94) had single organ dysfunction, and 33.8% (67) had no organ dysfunction. Around 83% (165) were discharged and 17% (33) died. There were missing data for 25.8% (51) of the patients for the lactate clearance, whereas 55% (108) patients had early lactate clearance and 19.7% (39) had delayed lactate clearance.On univariate analysis, mortality rate was higher in patients with delayed lactate clearance (38.4% vs 16.6%) and patients were 3.12 times (OR = 3.12; [95% CI: 1.37-7.09]) more likely to die as compared with early lactate clearance. Patients with delayed lactate clearance had higher organ dysfunction (79.4% vs 60.1%) and were 2.56 (OR = 2.56; [95% CI: 1.07-6.13]) times likely to have organ dysfunction. On multivariate analysis, after adjusting for age and co-morbids, patients with delayed lactate clearance were 8 times more likely to die than patients with early lactate clearance [aOR = 7.67; 95% CI:1.11-53.26], however, there was no statistically significant association between delayed lactate clearance [aOR = 2.18; 95% CI: 0.87-5.49)] and organ dysfunction. Lactate clearance is a better determinant of sepsis and septic shock effective management. Early lactate clearance is related to better outcomes in septic patients.

Usefulness of EUCAST rapid antibiotic susceptibility breakpoints and screening cut-off values directly from blood cultures for the inference of β-lactam resistance mechanisms in Enterobacterales.

Reducing the turnaround time for reporting antimicrobial susceptibility testing (AST) results is important for adjusting empirical treatments and may impact clinical outcomes of septic patients, particularly in settings with high antimicrobial resistance. Disc diffusion could be useful for inferring β-lactam resistance mechanisms. To evaluate the usefulness of EUCAST rapid AST (RAST) disc diffusion breakpoints for the screening of resistance mechanisms (sRAST) and interpretive reading of resistance phenotypes to infer ESBL and carbapenemases production in Enterobacterales. Blood cultures were artificially spiked with Enterobacterales clinical isolates with well-characterized β-lactam resistance mechanisms (n = 93), WT phenotypes (n = 26) and ATCC strains (n = 8). AST was performed by disc diffusion directly from blood cultures and inhibition zones were manually measured at 4, 6 and 8 h. To infer the presence of resistance mechanisms, EUCAST RAST breakpoints and screening cut-off values (sRAST) combined with the double-disc synergy test (DDS) for ESBLs or aztreonam susceptibility for carbapenemases detection were used. DDS together with sRAST detected all ESBL producers as early as at 4 h incubation. Cefotaxime was the antibiotic with the highest discriminatory power. The suspicion of carbapenemase production by sRAST at 8 h was possible in 73% of Klebsiella pneumoniae and in 100% of Escherichia coli carbapenemase-producing isolates. Phenotypic analysis improves the detection of some low hydrolytic carbapenemases (OXA-48 or KPC-3 mutants). Early detection of β-lactam resistance mechanisms directly from positive blood cultures was possible using sRAST together with the interpretive reading of antibiotic resistance phenotypes. Some carbapenemase types such as OXA-48 might be difficult to infer. Screening-positive isolates should be confirmed using an alternative technique.