Effect of neutrophil to lymphocyte ratio on prognosis of elderly patients with severe sepsis combined with diabetes mellitus.

BACKGROUND: To investigate the predictive value of neutrophil-to-lymphocyte ratio (NLR) in the short-term prognosis of elderly patients with severe sepsis combined with diabetes mellitus (DM). METHODS: The clinical data of 162 elderly patients with severe sepsis combined with DM from January 2018 to December 2022 were retrospectively collected. These patients were divided into a survival group (n = 104) and a death group (n = 58) according to 90-day prognosis. The number of neutrophils, lymphocytes, and NLR were compared. The optimal cut-off value for NLR to predict 90-day prognosis in elderly patients with severe sepsis combined with DM was determined using Receiver Operator Characteristic (ROC) curves, and the patients were divided into high and low NLR groups depending on the optimal cut-off value. The Kaplan-Meier method was used to plot the survival curves of the high and low NLR groups. Risk factors for the 90-day death in elderly patients with severe sepsis combined with DM were analyzed by a multivariate cox regression model. RESULTS: There were no significant differences in gender, age, history of hypertension and hyperlipidemia, intensive care unit (ICU) stay, duration of mechanical ventilation, and oxygenation index between the survival group and death group (p > 0.05). However, acute physiological and chronic health evaluation II (APACHE II) scores, and sepsis-related organ failure assessment (SOFA) scores were significantly lower in the survival group compared with the death group (p < 0.05). In the survival group, neutrophils counts and NLR were much lower than those in the death group, while lymphocytes counts were much higher (p < 0.05). ROC curves showed that the optimal cut-off value for NLR to predict 90-day mortality in elderly patients with severe sepsis combined with DM was 3.482. Patients were divided into high NLR and low NLR groups based on whether NLR was ≥ 3.482. In terms of the log-rank test results, patients in the low NLR group had a significantly higher 90-day survival rate than those in the high NLR group (Logrank χ2 = 8.635, p = 0.003). The multivariate cox regression model showed that the length of ICU stay longer than 15 days and NLR ≥ 3.482 were independent risk factors for 90-day prognosis in elderly patients with severe sepsis combined with DM. CONCLUSION: NLR ≥ 3.482 can be used to predict whether poor prognosis occurs in the short term after illness in elderly patients with severe sepsis combined with DM, and has good assessment value.

Core sepsis-related competencies for medical students: an international consensus by Delphi technique.

BACKGROUND: Sepsis is a life-threatening condition which may arise from infection in any organ system and requires early recognition and management. Healthcare professionals working in any specialty may need to manage patients with sepsis. Educating medical students about this condition may be an effective way to ensure all future doctors have sufficient ability to diagnose and treat septic patients. However, there is currently no consensus on what competencies medical students should achieve regarding sepsis recognition and treatment. This study aims to outline what sepsis-related competencies medical students should achieve by the end of their medical student training in both high or upper-middle incomes countries/regions and in low or lower-middle income countries/regions. METHODS: Two separate panels from high or upper-middle income and low or lower-middle income countries/regions participated in a Delphi method to suggest and rank sepsis competencies for medical students. Each panel consisted of 13-18 key stakeholders of medical education and doctors in specialties where sepsis is a common problem (both specialists and trainees). Panelists came from all continents, except Antarctica. RESULTS: The panels reached consensus on 38 essential sepsis competencies in low or lower-middle income countries/regions and 33 in high or upper-middle incomes countries/regions. These include competencies such as definition of sepsis and septic shock and urgency of antibiotic treatment. In the low or lower-middle income countries/regions group, consensus was also achieved for competencies ranked as very important, and was achieved in 4/5 competencies rated as moderately important. In the high or upper-middle incomes countries/regions group, consensus was achieved in 41/57 competencies rated as very important but only 6/11 competencies rated as moderately important. CONCLUSION: Medical schools should consider developing curricula to address essential competencies, as a minimum, but also consider addressing competencies rated as very or moderately important.

Hyperferritinemic sepsis, macrophage activation syndrome, and mortality in a pediatric research network: a causal inference analysis.

BACKGROUND: One of five global deaths are attributable to sepsis. Hyperferritinemic sepsis (> 500 ng/mL) is associated with increased mortality in single-center studies. Our pediatric research network's objective was to obtain rationale for designing anti-inflammatory clinical trials targeting hyperferritinemic sepsis. METHODS: We assessed differences in 32 cytokines, immune depression (low whole blood ex vivo TNF response to endotoxin) and thrombotic microangiopathy (low ADAMTS13 activity) biomarkers, seven viral DNAemias, and macrophage activation syndrome (MAS) defined by combined hepatobiliary dysfunction and disseminated intravascular coagulation, and mortality in 117 children with hyperferritinemic sepsis (ferritin level > 500 ng/mL) compared to 280 children with sepsis without hyperferritinemia. Causal inference analysis of these 41 variables, MAS, and mortality was performed. RESULTS: Mortality was increased in children with hyperferritinemic sepsis (27/117, 23% vs 16/280, 5.7%; Odds Ratio = 4.85, 95% CI [2.55-9.60]; z = 4.728; P-value < 0.0001). Hyperferritinemic sepsis had higher C-reactive protein, sCD163, IL-22, IL-18, IL-18 binding protein, MIG/CXCL9, IL-1ß, IL-6, IL-8, IL-10, IL-17a, IFN-γ, IP10/CXCL10, MCP-1/CCL2, MIP-1α, MIP-1ß, TNF, MCP-3, IL-2RA (sCD25), IL-16, M-CSF, and SCF levels; lower ADAMTS13 activity, sFasL, whole blood ex vivo TNF response to endotoxin, and TRAIL levels; more Adenovirus, BK virus, and multiple virus DNAemias; and more MAS (P-value < 0.05). Among these variables, only MCP-1/CCL2 (the monocyte chemoattractant protein), MAS, and ferritin levels were directly causally associated with mortality. MCP-1/CCL2 and hyperferritinemia showed direct causal association with depressed ex vivo whole blood TNF response to endotoxin. MCP-1/CCL2 was a mediator of MAS. MCP-1/CCL2 and MAS were mediators of hyperferritinemia. CONCLUSIONS: These findings establish hyperferritinemic sepsis as a high-risk condition characterized by increased cytokinemia, viral DNAemia, thrombotic microangiopathy, immune depression, macrophage activation syndrome, and death. The causal analysis provides rationale for designing anti-inflammatory trials that reduce macrophage activation to improve survival and enhance infection clearance in pediatric hyperferritinemic sepsis.

Increasing incidence of acute kidney injury in pediatric severe sepsis and related adverse hospital outcomes.

BACKGROUND: Pediatric severe sepsis (PSS) is associated with increased mortality, and acute kidney injury (AKI) is an independent risk factor of mortality in PSS. However, there is little data on impact of AKI on hospital outcomes in PSS. METHODS: We analyzed non-overlapping years of the Kids' Inpatient Database (KID) and National Inpatient Sample (NIS) database between 2003 and 2019 of all pediatric patients with severe sepsis between 1 and 18 years of age. Using ICD diagnosis codes, patients were divided into two groups based on AKI status and compared for outcomes measures including in-hospital mortality and healthcare resource utilization using length of stay and inflation-adjusted hospitalization charges. RESULTS: We analyzed 192,712 hospitalizations due to PSS during the 17-year period. Prevalence of AKI was 23.6% with overall increasing trend, P<0.001. Prevalence of AKI was significantly increased in patients with diabetes mellitus, organ transplantation, HIV, urinary tract anomalies, and malnutrition, P<0.001. Mortality rate was significantly higher among patients with AKI (19.8% vs. 8.1%, P<0.001). PSS with AKI had significantly higher median length of stay (14 vs. 11 days) and total hospitalization charges ($168,106 vs. 100,906), P<0.001. Multivariate logistic regression analysis showed that AKI without kidney replacement therapy (KRT) was associated with 3.02 times increased odds of mortality (95% CI 2.99-3.17, P<0.001) and those requiring KRT had 6.4 times increased odds of mortality (95%CI 6.1-6.7, P<0.001). AKI without KRT was associated with 7.7 (95% CI 7.3-8.05) additional days of hospitalization and 154,536 (95% CI 149,500-159,572) additional US dollars in hospitalization charges. CONCLUSION: Almost 1 in 4 hospitalizations with PSS had AKI and was associated with >3 times increased risk of mortality and need for KRT further adversely impacts mortality and healthcare utilization. A higher resolution version of the Graphical abstract is available as Supplementary information.

Dexmedetomidine improves the outcomes for pediatric severe sepsis with mechanical ventilation.

BACKGROUND: The sedative dexmedetomidine has been shown to reduce mortality in adult patients with severe sepsis, but it is not known whether children benefit. This study explored the effects of dexmedetomidine on the outcomes of children with severe sepsis with mechanical ventilation. METHODS: In this retrospective cohort study, children with severe sepsis requiring mechanical ventilation from 2016 to 2020 were categorized as dexmedetomidine and non-dexmedetomidine group. The propensity score matching was performed to match cases in both groups. The primary outcome was 28-day mortality, and the secondary outcomes were acute kidney injury, ventilator-free days, lengths of PICU and hospital stays. The Kaplan-Meier method and was the log-rank test used to estimate the 28-day mortality rate and assess between-group differences. RESULTS: In total, 250 patients were eligible patients: 138 in the dexmedetomidine group and 112 in the non-dexmedetomidine group. After 1:1 propensity score matching, 61 children in each group. dexmedetomidine group showed more lower 28-day mortality (9.84% vs. 26.23%, P = 0.008). During the 7-day observation period after PICU admission, the dexmedetomidine group showed significantly lower neurological and renal sub-scores at day 7 and serum creatinine level at day 3 and day 7. There were no statistical differences in the incidence of acute kidney injury, ventilator-free days, lengths of PICU and hospital stays between the two groups. CONCLUSIONS: dexmedetomidine treatment in children with severe sepsis is associated with better outcomes and should therefore be considered for the sedation strategy.

Machine learning derivation of four computable 24-h pediatric sepsis phenotypes to facilitate enrollment in early personalized anti-inflammatory clinical trials.

BACKGROUND: Thrombotic microangiopathy-induced thrombocytopenia-associated multiple organ failure and hyperinflammatory macrophage activation syndrome are important causes of late pediatric sepsis mortality that are often missed or have delayed diagnosis. The National Institutes of General Medical Science sepsis research working group recommendations call for application of new research approaches in extant clinical data sets to improve efficiency of early trials of new sepsis therapies. Our objective is to apply machine learning approaches to derive computable 24-h sepsis phenotypes to facilitate personalized enrollment in early anti-inflammatory trials targeting these conditions. METHODS: We applied consensus, k-means clustering analysis to our extant PHENOtyping sepsis-induced Multiple organ failure Study (PHENOMS) dataset of 404 children. 24-hour computable phenotypes are derived using 25 available bedside variables including C-reactive protein and ferritin. RESULTS: Four computable phenotypes (PedSep-A, B, C, and D) are derived. Compared to all other phenotypes, PedSep-A patients (n = 135; 2% mortality) were younger and previously healthy, with the lowest C-reactive protein and ferritin levels, the highest lymphocyte and platelet counts, highest heart rate, and lowest creatinine (p < 0.05); PedSep-B patients (n = 102; 12% mortality) were most likely to be intubated and had the lowest Glasgow Coma Scale Score (p < 0.05); PedSep-C patients (n = 110; mortality 10%) had the highest temperature and Glasgow Coma Scale Score, least pulmonary failure, and lowest lymphocyte counts (p < 0.05); and PedSep-D patients (n = 56, 34% mortality) had the highest creatinine and number of organ failures, including renal, hepatic, and hematologic organ failure, with the lowest platelet counts (p < 0.05). PedSep-D had the highest likelihood of developing thrombocytopenia-associated multiple organ failure (Adj OR 47.51 95% CI [18.83-136.83], p < 0.0001) and macrophage activation syndrome (Adj OR 38.63 95% CI [13.26-137.75], p < 0.0001). CONCLUSIONS: Four computable phenotypes are derived, with PedSep-D being optimal for enrollment in early personalized anti-inflammatory trials targeting thrombocytopenia-associated multiple organ failure and macrophage activation syndrome in pediatric sepsis. A computer tool for identification of individual patient membership ( www.pedsepsis.pitt.edu ) is provided. Reproducibility will be assessed at completion of two ongoing pediatric sepsis studies.

Varying Estimates of Sepsis among Adults Presenting to US Emergency Departments: Estimates from a National Dataset from 2002-2018.

BACKGROUND: A variety of approaches to defining sepsis using administrative datasets have been previously reported. We aimed to compare estimates, demographics, treatment factors, outcomes and longitudinal trends of patients identified with sepsis in United States emergency departments (EDs) using differing sets of sepsis criteria. METHODS: We performed a cross-sectional study using the National Healthcare Ambulatory Medical Care Survey, a complex survey of nonfederal US ED encounters between 2002 to 2018. We obtained survey-weighted population-adjusted encounters of sepsis using the following criteria: explicit sepsis, severe sepsis, and quick Sequential Organ Failure Assessment (qSOFA) score combined with the presence of infection. RESULTS: Age-adjusted for US adults, 18.6, 16.1 and 8.9 encounters per 10 000 population were identified when using the explicit, severe sepsis and qSOFA definitions, respectively. A higher proportion of the explicit cohort was hospitalized and had blood cultures performed, compared to cohorts ascertained using severe sepsis and qSOFA criteria, though confidence intervals overlapped. Antibiotic use was highest in encounters meeting qSOFA criteria. When inspecting unweighted encounters meeting each set of criteria, there was minimal overlap, with only 3% meeting all three. Encounters meeting the explicit and severe sepsis criteria were increasing over time. CONCLUSION: The explicit, severe sepsis and qSOFA criteria generated similar annual rates of presentation when applied to US ED encounters, with some evidence of the explicit sepsis cohort being higher acuity. There was minimal overlap of cases and instability in estimates when assessed longitudinally. Our findings inform research efforts to accurately identify sepsis among ED encounters using administrative data.

Risk factors for progression of Urolith Associated with Obstructive Urosepsis to severe sepsis or septic shock.

INTRODUCTION: To analyze the risk factors for progression of urolith associated with obstructive urosepsis to severe sepsis or septic shock, we had done the retrospective cross-sectional study, which would facilitate the early identification of high-risk patients. MATERIALS AND METHODS: Datas were retrospectively reviewed from 160 patients, suffering from obstructive urosepsis associated with urolith between December 2013 and December 2019. There were 49 patients complicating by severe sepsis (severe sepsis group), 12 patients complicating by septic shock (septic shock group), and 99 patients without progressing to severe sepsis or septic shock (sepsis group). The data covered age, gender, BMI (body mass index), time interval from ED (emergency department) to admission, WBC count (white blood cell count), NLR (neutrophil/lymphocyte ratio), HGB (hemoglobin), etc. Datas were analyzed by univariate analyses and multivariate logistic regression analysis. The corresponding nomogram prediction model was drawn according to the regression coefficients. RESULTS: Univariate analysis showed that the differences of age, the time interval from ED to admission, history of diabetes mellitus, history of CKI (chronic kidney disease), NLR, HGB, platelet count, TBil (total bilirubin), SCr (serum creatinine), ALB (albumin), PT (prothrombin time), APTT (activated partial thromboplastin time), INR (international normalized ratio), PCT (procalcitonin), and positive rate of pathogens in blood culture were statistically significant (P < 0.05). Multivariatelogistic regression analysis showed that age, SCr, and history of CKI were independent risk factors for progression to severe sepsis, or septic shock (P < 0.05). CONCLUSIONS: Aged ≥ 65 years, SCr ≥ 248 mol/L, and history of CKI were independent risk factors for progression of urolith associated with obstructive urosepsis to severe sepsis or septic shock. We need to pay more attention to these aspects, when coming across the patients with urolithic sepsis.

Epidemiology of pediatric severe sepsis and septic shock in Turkey: Prevalence, Results and Treatments Study.

AIM: This study was aimed at characterizing the prevalence, management, and outcomes of pediatric severe sepsis and septic shock in tertiary pediatric intensive care units (PICUs) in Turkey. METHODS: A point prevalence study was conducted on five days over the course of one year in 29 PICUs in Turkey. Outcomes included severe sepsis and septic shock point prevalence, therapies used, duration of PICU stay, and mortality at day 28. RESULTS: Of the 1757 children who were admitted to the PICU during the study period, 141 (8.0%) children met the consensus criteria for severe sepsis and 23 (1.3%) children met the criteria for septic shock. Pediatric severe sepsis and septic shock accounted for 8% and 1.3% of all PICU admissions, respectively. The median age of the patients was 2.6 years (interquartile range (IQR), 0.7-8.6 years). Enteral nutrition (79.3%) was preferred compared to parenteral nutrition (31.1%) for the first 3 days after PICU admission. A total of 39 patients died while in the PICU, for a 23.8% mortality rate, which did not vary by age. CONCLUSION: The mortality rate was similar to that in other studies. Hematologic-immunologic comorbidity, parenteral nutrition and the use of vasoactive drugs were independently associated with mortality.

Prediction of sepsis onset in hospital admissions using survival analysis.

To determine the efficacy of modern survival analysis methods for predicting sepsis onset in ICU, emergency, medical/surgical, and TCU departments. We performed a retrospective analysis on ICU, med/surg, ED, and TCU cases from multiple Mercy Health hospitals from August 2018 to March 2020. Patients in these departments were monitored by the Mercy Virtual vSepsis team and sepsis cases were determined and documented in the Mercy EHR via a rule-based engine utilizing clinical data. We used survival-based modeling methods to predict sepsis onset in these cases. The three survival methods that were used to predict the onset of severe sepsis and septic shock produced AUC values > 0.85 and each provided a median lead time of > 20 h prior to disease onset. This methodology improves upon previous work by demonstrating excellent model performance when generalizing survival-based prediction methods to both severe sepsis and septic shock as well as non-ICU departments.IRB InformationTrial Registration ID: 1,532,327-1.Trial Effective Date: 12/02/2019.

A case of Mediterranean spotted fever mimicking severe sepsis.

Mediterranean spotted fever (MSF) is a tick-borne acute endemic infectious disease caused by Rickettsia conorii. While MSF may progress asymptomatically, it may lead to clinical pictures like severe hemorrhagic fever. In this article, we are presenting an MSF case with signs of high fever, headache, nausea, weakness and generalized maculopapular rash. The diagnosis of the female patient who had a history of contact with a tick-infested dog was confirmed with her clinical and laboratory data. The clinical and laboratory findings of the patient who was given doxycycline by 200 mg/day for 7 days were improved in a short time. Rickettsia conorii serology by indirect immunofluorescence assay method confirmed the diagnosis of MSF. In cases of severe sepsis accompanied by high fever and generalized maculopapular rash where the source of the infection cannot be determined in the short term, carefully questioning exposure to ticks by considering the existing geographical, seasonal and endemic environmental factors may be life-saving in terms of early diagnosis and treatment of MSF, which may become fatal even in the absence of eschars (tache noire). The symptomatology of hemorrhagic fever associated with Rickettsia conorii may be confused with that of sepsis in clinical practice.

Mild hypothermia in rat with acute myocardial ischaemia-reperfusion injury complicating severe sepsis.

Myocardial ischemia-reperfusion injury (MIRI) with concurrent severe sepsis has led to substantial mortality. Mild hypothermia (MHT) has been proved to have a therapeutic effect in either MIRI or severe sepsis, which suggests it might be beneficial for MIRI complicating severe sepsis. In this study, Sprague-Dawley rats with MIRI complicating severe sepsis were allotted in either MHT (33 ± 0.5°C) group or normothermia (NT, 37 ± 0.5°C) group; as control, rats receiving sham surgery and normal saline were kept at NT. After 2h of temperature maintenance, blood and heart tissue were acquired for detections. Lactate dehydrogenase (LDH) and MB isoenzyme of creatine kinase (CK-MB) in blood, triphenyl tetrazolium chloride and Evans blue staining, hematoxylin and eosin staining for myocardium were employed to detect myocardial damage. Tumor necrosis factor (TNF)-α and caspase-3 was performed by immunohistochemistry to exam myocardial inflammation and apoptosis. Detection of NADPH oxidase (NOX) 2 was for myocardial oxidative stress. In MHT group, systolic blood pressure was improved significantly compared with NT group. Myocardial infarct size, morphological change, LDH and CK-MB levels were attenuated compared to NT group. Moreover, less expressions of TNF-α, caspase-3 and NOX2 in MHT group were presented compared with NT group. MHT showed cardioprotection by improving cardiac dysfunction, reducing myocardial infarct size and attenuating myocardial injury, inflammation, apoptosis and oxidative stress.

Infectious Diseases Society of America Position Paper: Recommended Revisions to the National Severe Sepsis and Septic Shock Early Management Bundle (SEP-1) Sepsis Quality Measure.

The Centers for Medicare & Medicaid Services' Severe Sepsis and Septic Shock Early Management Bundle (SEP-1) measure has appropriately established sepsis as a national priority. However, the Infectious Diseases Society of America (IDSA and five additional endorsing societies) is concerned about SEP-1's potential to drive antibiotic overuse because it does not account for the high rate of sepsis overdiagnosis and encourages aggressive antibiotics for all patients with possible sepsis, regardless of the certainty of diagnosis or severity of illness. IDSA is also concerned that SEP-1's complex "time zero" definition is not evidence-based and is prone to inter-observer variation. In this position paper, IDSA outlines several recommendations aimed at reducing the risk of unintended consequences of SEP-1 while maintaining focus on its evidence-based elements. IDSA's core recommendation is to limit SEP-1 to septic shock, for which the evidence supporting the benefit of immediate antibiotics is greatest. Prompt empiric antibiotics are often appropriate for suspected sepsis without shock, but IDSA believes there is too much heterogeneity and difficulty defining this population, uncertainty about the presence of infection, and insufficient data on the necessity of immediate antibiotics to support a mandatory treatment standard for all patients in this category. IDSA believes guidance on managing possible sepsis without shock is more appropriate for guidelines that can delineate the strengths and limitations of supporting evidence and allow clinicians discretion in applying specific recommendations to individual patients. Removing sepsis without shock from SEP-1 will mitigate the risk of unnecessary antibiotic prescribing for noninfectious syndromes, simplify data abstraction, increase measure reliability, and focus attention on the population most likely to benefit from immediate empiric broad-spectrum antibiotics.

The protective role of YTHDF1-knock down macrophages on the immune paralysis of severe sepsis rats with ECMO.

OBJECTIVE: To examine the role of YTHDF1 knock-down macrophages on the immunity of severe sepsis rats with ECMO. METHODS: 15 SD rats were randomly allocated into 3 groups: mild sepsis (I), severe sepsis with ECMO (II), and YTHDF1 knock-down macrophages treatment groups (III). Blood biochemical indexes, different immune factors and brain changes were detected by RT-PCR, ELISA, ELISPOT and HE staining. Isolated macrophages subtypes and signal proteins were detected by flow cytometry, western blot and m6A RNA methylation test. RESULTS: The levels of HMGB1, RAGE, YTHDF1 and IL-17 in peripheral blood were significantly higher (p < 0.01), while the level of CXCL9 and TNF-α, and LPS-specific CD8+CTL function were significantly decreased in group II compared with group I (p < 0.01). The ratio of CD63+ macrophages (p < 0.05) and CD64+ macrophages (p< 0.05) decreased and the level of elastase (p < 0.01) and CCR2highCX3CR1low/CCR2lowCX3CR1high (p < 0.01) of macrophages increased in group II. The above were consistent with the severity of biochemical indicators, the increasing endothelial injury factor (Ang2/Ang1), lower endothelial protective factor (sTie2), severer brain injury in group II. After YTHDF1 knock-down macrophages treatment, the above indexes' changes were opposite when Group III versus Group II through the down-regulation of m6A RNA methylation of JAK2/STAT3 (p < 0.01) and protein expression of PJAK2/PSTAT3 (p < 0.05) in isolated macrophages. CONCLUSIONS: YTHDF1 knock-down macrophages improved the immune paralysis of macrophages, Th1/Th17 and CTL and reduced the entry of macrophages into the brain to cause endothelial damage of severe sepsis rats with ECMO through the inhibition of HMGB1/RAGE and YTHDF1, m6A RNA methylation of JAK2/STAT3 and PJAK2/PSTAT3 proteins expression in macrophages.

Early Prognosis Effect of Cellular Immune Paralysis on Brain Complications of Extracorporeal Membrane Oxygenation Children with Severe Sepsis.

OBJECTIVE: The aim of the study was to explore the relationship between criticality, brain complications, and immune mechanisms in extracorporeal membrane oxygenation (ECMO) children with pneumonia and severe sepsis. METHODS: Patients with simple pneumonia (group I), ECMO patients with pneumonia and severe sepsis accompanied by brain complications (group II), and those without brain complication (group III) admitted to our pediatric intensive care unit were selected to be investigated. The relationship among the peripheral blood subgroups of immune cells, immune factors, adaptive immune responses, endothelial factors, and criticality and brain complications was then studied. RESULTS: Severe paralysis of normal immunity, excess abnormal immunity, and endothelial injury were consistent with the increase in the absolute value of base excess, lactic acid (Lac) content, and average hospitalization days and brain complications involved in group II (vs. group I). The ratio of CD63+ macrophage and CD63+ neutrophil subpopulation increased (p < 0.05); the expression levels of elastase+ neutrophil denatured subgroup (p < 0.05), the ratio of CCR2highCX3CR1low/CCR2lowCX3CR1high of macrophages and neutrophils (p < 0.0001), high-mobility group box 1 (HMGB1), YTHDF1, interleukin-17 protein and mRNA, and RAGE gene decreased to some extent (p < 0.05); the expression levels of Th1 cells chemokine CXCL9 protein and mRNA and sTIE2 protein increased to some extent (p < 0.05); the adaptive immune response of CD8+ CTL stimulated by lipopolysaccharide (LPS) was slightly enhanced (p < 0.05) in group III(vs. group II), which was consistent with the improvement of criticality, average hospitalization days, and the absence of brain complications in group III (vs. group II). CONCLUSION: ECMO support with brain complication was related to the upregulation of HMGB1 and YTHDF1 protein; the decreased number of CD63+ macrophages and neutrophils; the increased denatured neutrophil subgroup, especially the upregulated ratio of CCR2highCX3CR1low/CCR2lowCX3CR1high of macrophages and neutrophils; the imbalance of Th17/Th1, LPS-specific CD8+ CTL adaptive immune response paralysis; and the reduced endothelial sTIE2 protein expression level which caused clinical deterioration and prolonged average hospitalization days.

Cytokine Levels in Critically Ill Children With Severe Sepsis and Their Relation With the Severity of Illness and Mortality.

OBJECTIVE: To study the baseline cytokine levels and their relation with the severity of illness and mortality in critically ill children with severe sepsis. DESIGN: Subgroup analysis of a randomized, double-blind, placebo-controlled trial. SETTING: Pediatric intensive care unit of a tertiary level teaching hospital in India. PATIENTS: Fifty children with severe sepsis aged 3 months to 12 years. MATERIAL AND METHODS: Blood was collected at admission for estimation of pro-inflammatory (interleukin 6 [IL-6], IL-12p70, IL-17, and tumor necrotic factor α [TNF-α]) and anti-inflammatory (IL-10 and transforming growth factor ß1 [TGF-ß1]) cytokines. PRIMARY OUTCOME: To find out correlation between cytokine levels and severity of illness scores (Pediatric Risk of Mortality [PRISM] III score, Sequential Organ Failure Assessment [SOFA], and Vasoactive-Inotropic Score [VIS]). SECONDARY OUTCOMES: To compare cytokine levels among survivors and nonsurvivors. RESULTS: Baseline pro-inflammatory cytokine levels (median [interquartile range]) were IL-6: 189 (35-285) pg/mL, IL-12p: 48 (28-98) pg/mL, IL-17: 240 (133-345) pg/mL, and TNF-α: 296 (198-430) pg/mL; anti-inflammatory cytokine levels were IL-10: 185 (62-395) pg/mL and TGF-ß1: 204 (92-290) ng/mL. Pro-inflammatory cytokines showed positive correlation with PRISM III score: IL-6 (Spearman correlation coefficient, ρ = 0.273, P = .06), IL-12 (ρ = 0.367, P = .01), IL-17 (ρ = 0.197, P = .17), and TNF-α (ρ = 0.284, P = .05), and anti-inflammatory cytokines showed negative correlation: IL-10 (ρ = -0.257, P = .09) and TGF-ß (ρ = -0.238, P = .11). Both SOFA and VIS also showed weak positive correlation with IL-12 (ρ = 0.32, P = .03 and ρ = 0.31, P = .03, respectively). Among nonsurvivors (n = 5), the levels of all the measured pro-inflammatory cytokines were significantly higher as compared to survivors, IL-6: 359 (251-499) pg/mL versus 157 (97-223) pg/mL, P < .0001, IL-12p70: 167 (133-196) pg/mL versus 66 (30-100) pg/mL, P < .0001, IL-17: 400 (333-563) pg/mL versus 237 (122-318) pg/mL, P = .009, and TNF-α: 409 (355-503) pg/mL versus 330 (198-415) pg/mL, P = .002, respectively. CONCLUSION: In critically ill children with severe sepsis, pro-inflammatory cytokines (especially IL-12p70) showed a weak positive correlation with severity of illness and were significantly higher among nonsurvivors.

Severe sepsis and septic shock in patients transported by prehospital services versus walk in patients to the emergency department.

BACKGROUND: Sepsis is a leading cause of death in the hospital for which aggressive treatment is recommended to improve patient outcomes. It is possible that sepsis patients brought in by emergency medical services (EMS) have a unique advantage in the emergency department (ED) which could improve sepsis bundle compliance. OBJECTIVE: To evaluate patient care processes and outcome differences between severe sepsis and septic shock patients in the emergency department who were brought in by EMS compared to non-EMS patients. METHODS: We performed a retrospective chart review of all severe sepsis and septic shock patients who declared in the ED during January 2012 thru December 2014. We compared differences in patient characteristics, patient care processes, sepsis bundle compliance metrics, and outcomes between both groups. RESULTS: Of the 1066 patients included in the study, 387 (36.6%) were brought in by EMS and 679 (63.7%) patients arrived via non-EMS transport. In the multivariate regression model, time of triage to sepsis declaration (coeff = -0.406; 95% CI = -0.809, -0.003; p = 0.048) and time of triage to physician (coeff = -0.543; 95% CI = -0.864, -0.221; p = 0.001) was significantly shorter for EMS patients. We found no statistical difference in adjusted individual sepsis compliance metrics, overall bundle compliance, or mortality between both groups. CONCLUSION: EMS transported patients have quicker sepsis declaration times and are seen sooner by ED providers. However, we found no statistical difference in bundle compliance or patient outcomes between walk in patients and EMS transported patients.

Prehospital lactate clearance is associated with reduced mortality in patients with septic shock.

BACKGROUND: Assessment of disease severity in patients with septic shock (SS) is crucial in determining optimal level of care. In both pre- and in-hospital settings, blood lactate measurement is broadly used in combination with the clinical evaluation of patients as the clinical picture alone is not sufficient for assessing disease severity and outcomes. METHODS: From 15th April 2017 to 15th April 2019, patients with SS requiring prehospital mobile Intensive Care Unit intervention (mICU) were prospectively included in this observational study. Prehospital blood lactate clearance was estimated by the difference between prehospital (time of first contact between the patients and the mICU prior to any treatment) and in-hospital (at hospital admission) blood lactate levels divided by prehospital blood lactate. RESULTS: Among the 185 patients included in this study, lactate measurement was missing for six (3%) in the prehospital setting and for four (2%) at hospital admission, thus 175 (95%) were analysed for prehospital blood lactate clearance (mean age 70 ± 14 years). Pulmonary, digestive and urinary infections were probably the cause of the SS in respectively 56%, 22% and 10% of the cases. The 30-day overall mortality was 32%. Mean prehospital blood lactate clearance was significantly different between patients who died and those who survived (respectively 0.41 ± 2.50 mmol.l-1 vs 1.65 ± 2.88 mmol.l-1, p = 0.007). Cox regression analysis showed that 30-day mortality was associated with prehospital blood lactate clearance > 10% (HRa [CI95] = 0.49 [0.26-0.92], p = 0.028) and prehospital blood lactate clearance < 10% (HRa [CI95] = 2.04 [1.08-3.84], p = 0.028). CONCLUSION: A prehospital blood lactate clearance < 10% is associated with 30-day mortality increase in patients with SS handled by the prehospital mICU. Further studies will be needed to evaluate if prehospital blood lactate clearance alone or combined with clinical scores could affected the triage decision-making process for those patients.

Aggressive versus conservative fluid resuscitation in septic hemodialysis patients.

PURPOSE: Sepsis and bacterial infections are common in patients with end-stage renal disease (ESRD). We aimed to compare patients with ESRD on hemodialysis presenting to hospital with severe sepsis or septic shock who received <20 ml/kg of intravenous fluid to those who received ≥20 ml/kg during initial resuscitation. MATERIALS AND METHODS: We conducted a retrospective chart review of adult patients with ICD codes for discharge diagnosis of sepsis, severe sepsis, septic shock, ESRD, and hemodialysis admitted to our institution between 2015 and 2018. RESULTS: We present outcomes for a total of 104 patients - 51 patients in conservative group and 53 in aggressive group. The mean age was 69.5 ± 11.2 years and 71 ± 11.5 years in the conservative group and aggressive group, respectively. There was no significant difference in the rate of ICU admission, and ICU or hospital length of stay between the two groups. Complications such as volume overload, rate of intubation, and urgent dialysis were not found to be significantly different. CONCLUSION: We found that aggressive fluid resuscitation with ≥20 ml/kg may not be detrimental in the initial resuscitation of ESRD patients with SeS or SS. However, a clinical decision of volume responsiveness should be made on a case-by-case basis rather than a universal approach for fluid resuscitation in ESRD patients.

The role of resistin and myeloperoxidase in severe sepsis and septic shock: Results from the ALBIOS trial.

BACKGROUND: Inflammatory biomarkers are useful in detecting patients with sepsis. The prognostic role of resistin and myeloperoxidase (MPO) has been investigated in sepsis. MATERIALS AND METHODS: Plasma resistin and MPO were measured on days 1, 2 and 7 in 957 patients enrolled in the Albumin Italian Outcome Sepsis (ALBIOS) trial. The association between resistin and MPO levels on day 1, 2 and 7 and 90-day mortality was assessed. RESULTS: Plasma resistin and MPO concentrations were higher at day 1 and decreased until day 7. Both biomarkers were positively correlated with each other and with physiological parameters. Higher levels of resistin and MPO on day 1 were associated with the development of new organ failures. Patients experiencing death at 90 days showed higher levels of resistin and MPO compared with survivors. At day 1, only MPO in the 4th quartile (Q4), but not resistin, was found to predict 90-day death (adjusted hazard ratio [aHR] 1.55 vs Q1). At day 2, resistin in the Q3 and Q4 predicted a > 40% increase in mortality as also did MPO in the Q4. On day 7, Q4 resistin was able to predict 90-day mortality, while all quartiles of MPO were not. CONCLUSIONS: High levels of MPO, but not of resistin, on day 1 were able to predict 90-day mortality. These findings may either suggest that early hyper-activation of neutrophils is detrimental in patients with sepsis or reflect the burden of the inflammatory process caused by sepsis. Further studies are warranted to deepen these aspects (ALBIOS ClinicalTrials.gov Identifier: NCT00707122).