Sepsis Nonsurvivors Research Articles

Risk Factors for Sepsis with Worse Outcomes in the ICU Critically Ill Adult Admissions

Background: Sepsis is a life-threatening organ dysfunction caused by infection. What is the major risk factor of sepsis with poor outcomes? This remains unclear. We aimed to investigate the risk factors of sepsis with worse outcomes in a single intensive care unit (ICU) of China. Methods: A retrospective cohort study linked data from the Affiliated Shuyang Hospital of Xuzhou Medical University (Jan 2018–Nov 2019), China. Acute critically ill patients who were undergone a brain-chest-abdomen computed tomograph (CT) scan before arriving at the ICU were selected as an eligibility criteria. The primary outcome measure was mortality at the first 28 days. Outcomes were compared between patients who were survivors and those who were not. Findings: Of 520 ICU admissions, 214 (41.2%) critically ill adults with sepsis and 82.2% (176/214) of community-acquired sepsis were diagnosed by sepsis-3 criteria. The CT scan in this study has showed that more than 80% of sepsis was caused by community-acquired chest infection/pneumonia and was associated with an increased dynamic profile of inflammatory mediators in the blood. In multivariate analyses, risk factors for sepsis with worse outcomes were presentation with a higher sequential organ function assessment (SOFA) score (OR, 1.5; 95% CI, 1.18-2.04) and a higher systemic inflammatory storm syndrome (SISS) score (OR, 8.1; 95% CI, 2.64-26.38). In Cox regression analysis, acute hypoxemic respiratory failure (AHRF)/ARDS was associated with high risk of death in sepsis nonsurvivors, with HR over 6 times as high in sepsis survivors at 28 days. Interpretation: Sepsis cases are mainly from community-acquired pneumonia. Severe SISS and APRF/ARDS are two major risk factors for sepsis with worse outcomes. Funding: Funding was provided from National Clinical Key Specialty Construction Project. Declaration of Interest: None to declare. Ethical Approval: The study was approved by the ethical committee on clinical research of the Affiliated Shuyang Hospital of Xuzhou Medical University

What's New in Shock, July 2021?

What's New in Shock, July 2021?

Platelet Indices and Their Kinetics Predict Mortality in Patients of Sepsis.

Platelet indices are inexpensive, easily accessible parameters and potentially useful prognostic indicators in sepsis. In this study we explore the differences in platelet indices and their kinetics between sepsis survivors and non-survivors. A retrospective cohort-study of 97 cases of culture-positive sepsis at a tertiary-care center in North India. Demographics, clinical and laboratory parameters at admission were assessed. Platelet count (PLT), mean-platelet-volume (MPV), platelet-distribution-width (PDW) and plateletcrit (PCT) on admission, and third, fifth and last days of hospitalization were analyzed. Fractional change in platelet indices (ΔMPV72h, ΔPDW72h, ΔPCT72h, and ΔPLT72h) by day-3 were calculated. Unpaired and paired t-tests were used to compare survivors with non-survivors, and to study the change in platelet indices with time. Logistic regression was used for multivariate analysis. ROC-curves and optimum cut-offs to predict mortality were obtained. There were 64 survivors. Non-survivors had significantly higher ΔMPV72h, ΔPDW72h, day-1 MPV and PDW, and lower ΔPLT72h. MPV and PDW increased, and PLT decreased with time among non-survivors. Trends were reversed in survivors. Only MPV and PDW showed significant change by day-3. Both were independent predictors of mortality on multivariate analysis, alongside ΔMPV72h and ΔPLT72h. On ROC analysis, MPV, PDW, ΔMPV72h, ΔPDW72h and ΔPLT72h effectively predicted mortality. Cut-off for MPV was 10.25 fL (sensitivity = 93.9%, specificity = 60.9%), and PDW, 12.6% (sensitivity = 84.8%, specificity = 51.6%). A rise in MPV and a fall in PLT was associated with mortality in this study. MPV and PDW values at admission are effective predictors of mortality and may be used in conjunction with traditional parameters.

38081 A Whole Blood Signature of Neutrophil Expression and Adaptive Immune Downregulation Characterizes Sepsis Mortality

ABSTRACT IMPACT: This work identifies host immune perturbations in sepsis mortality that suggests targets for a precision medicine paradigm in the host response to infection. OBJECTIVES/GOALS: To compare the early whole blood transcriptome during sepsis between 30-day survivors and non-survivors in the Intensive Care Unit (ICU), and to evaluate for pathway enrichment that might explain sepsis lethality. METHODS/STUDY POPULATION: We enrolled 162 sepsis patients in the first 24 hours of ICU admission, particularly targeting individuals requiring vasopressors. Peripheral whole blood was collected in PAXgene vacutainers. Isolated RNA was analyzed with Affymetrix Human Genome ST 2.0 microarray. Differential gene expression was performed with Bioconductor/R/limma using log2 fold-change +/-0.6 as a threshold for differential expression, and a Benjamini-Hochberg adjusted p-value <0.05 to declare significance. Functional gene enrichment was performed using the Gene Ontology (GO) database with PANTHER overrepresentation test (Fisher’s Exact) on all transcripts with adjusted p-value <0.05. Pathways analysis was performed with the Reactome Project using the raw fold change and significance data to identify dysregulated pathways. RESULTS/ANTICIPATED RESULTS: There were 58 non-survivors (36% mortality). We identified 39 genes as differentially expressed between sepsis non-survivors and survivors; 31 were upregulated in non-survivors and 8 had reduced expression. Several of the most overexpressed transcripts are neutrophil-specific, including LCN, MPO, OLF4M4, DEFA3, and DEFA4. A functional gene overrepresentation test further supports this finding, as the most enriched gene ontologies were neutrophil-mediated killing, neutrophil cytotoxicity, neutrophil extravasation, and respiratory burst, all demonstrating higher than 10-fold enrichment and FDR < 0.02. Pathway analysis of the peripheral blood transcriptome was notable for immune response derangement, specifically downregulation of both innate and adaptive immune pathways (FDR < 0.00001). DISCUSSION/SIGNIFICANCE OF FINDINGS: We identified increased expression of neutrophil-related genes in sepsis non-survivors, replicating candidates previously identified in pediatric sepsis mortality and ARDS. These immune perturbations in sepsis mortality may represent key targets for eventually employing precision medicine strategies in sepsis.

Correlation of thyroid hormone profile and acute physiology and chronic health evaluation II (APACHE II) score with the survival in sepsis in a tertiary care centre

Background: Thyroid hormone plays a pivotal role in the adaptation of metabolic function to stress and critical illness like sepsis. Thyroid dysfunction is associated with increased mortality in sepsis. The role of thyroid dysfunction as a prognostic marker in sepsis remains unclear.
 Aims and Objectives: To correlate the baseline thyroid function tests with APACHE II score and mortality in adult patients admitted with sepsis in Intensive Care Unit (ICU).
 Materials and Methods: This was a cross sectional, observational study done for a period of one year from September 2019 to September 2020 in a tertiary care referral hospital. Patients admitted with sepsis to ICU were scored on admission using APACHE II score. Blood was sent for thyroid function tests on admission. Patients were divided into survivors and non-survivors based on the outcome. Statistical analysis was done by calculating mean values, Fisher’s exact test and Pearson’s correlation.
 Results: A total of 52 patients were included. The mean age was 55.65± 18.55 years with a male predominance (M: F=1.4:1). Pneumonia was the commonest cause of sepsis in the study (20 patients,38.5%). Mortality was seen in 20 patients (38.5%) The mean values of thyroid hormones were lower in non-survivors. APACHE II Score was higher among the non-survivors as compared to survivors. (21.7±5.571 vs 19.78 ± 5.939, p value>0.05). Thyroid hormones (T3, T4, FT3, FT4) had a negative correlation with APACHE II score in non-survivors. TSH had significant positive correlation with APACHE II score in non-survivors (p value=0.027).
 Conclusion: Thyroid hormone levels did not correlate significantly with APACHE II score and mortality among the non-survivors of sepsis.

Circulating bioactive adrenomedullin as a marker of sepsis, septic shock and critical illness

BackgroundBiomarkers can be of help to understand critical illness and to identify and stratify sepsis. Adrenomedullin is a vasoactive hormone, with reported prognostic and potentially therapeutic value in sepsis. The primary aim of this study was to investigate the association of circulating bioactive adrenomedullin (bio-ADM) levels at intensive care unit (ICU) admission with mortality in sepsis patients and in a general ICU population. Secondary aims included the association of bio-ADM with organ failure and the ability of bio-ADM to identify sepsis.MethodsIn this retrospective observational study, adult patients admitted to one of four ICUs during 2016 had admission bio-ADM levels analysed. Age-adjusted odds ratios (OR) with 95% CI for log-2 transformed bio-ADM, and Youden’s index derived cut-offs were calculated. The primary outcome was 30-day mortality, and secondary outcomes included the need for organ support and the ability to identify sepsis.ResultsBio-ADM in 1867 consecutive patients were analysed; 632 patients fulfilled the sepsis-3 criteria of whom 267 had septic shock. The median bio-ADM in the entire ICU population was 40 pg/mL, 74 pg/mL in sepsis patients, 107 pg/mL in septic shock and 29 pg/mL in non-septic patients. The association of elevated bio-ADM and mortality in sepsis patients and the ICU population resulted in ORs of 1.23 (95% CI 1.07–1.41) and 1.22 (95% CI 1.12–1.32), respectively. The association with mortality remained after additional adjustment for lactate in sepsis patients. Elevated bio-ADM was associated with an increased need for dialysis with ORs of 2.28 (95% CI 2.01–2.59) and 1.97 (95% CI 1.64–2.36) for the ICU population and sepsis patients, respectively, and with increased need of vasopressors, OR 1.33 (95% CI 1.23–1.42) (95% CI 1.17–1.50) for both populations. Sepsis was identified with an OR of 1.78 (95% CI 1.64–1.94) for bio-ADM, after additional adjustment for severity of disease. A bio-ADM cut-off of 70 pg/mL differentiated between survivors and non-survivors in sepsis, but a Youden’s index derived threshold of 108 pg/mL performed better.ConclusionsAdmission bio-ADM is associated with 30-day mortality and organ failure in sepsis patients as well as in a general ICU population. Bio-ADM may be a morbidity-independent sepsis biomarker.

Inhibitory Immune Checkpoint Molecule Expression in Clinical Sepsis Studies: A Systematic Review.

Checkpoint inhibitors have been proposed for sepsis following reports of increased checkpoint molecule expression in septic patients. To determine whether clinical studies investigating checkpoint molecule expression provide strong evidence supporting trials of checkpoint inhibitors for sepsis. PubMed, EMBASE, Scopus, Web of Science, inception through October 2019. Studies comparing checkpoint molecule expression in septic patients versus healthy controls or critically ill nonseptic patients or in sepsis nonsurvivors versus survivors. Two investigators extracted data and evaluated study quality. Thirty-six studies were retrieved. Across 26 studies, compared with healthy controls, septic patients had significantly (p ≤ 0.05) increased CD4+ lymphocyte programmed death-1 and monocyte programmed death-ligand-1 expression in most studies. Other checkpoint molecule expressions were variable and studied less frequently. Across 11 studies, compared with critically ill nonseptic, septic patients had significantly increased checkpoint molecule expression in three or fewer studies. Septic patients had higher severity of illness scores, comorbidities, and mortality in three studies providing analysis. Across 12 studies, compared with septic survivors, nonsurvivors had significantly increased expression of any checkpoint molecule on any cell type in five or fewer studies. Of all 36 studies, none adjusted for nonseptic covariates reported to increase checkpoint molecule expression. Although sepsis may increase some checkpoint molecule expression compared with healthy controls, the data are limited and inconsistent. Further, data from the more informative patient comparisons are potentially confounded by severity of illness. These clinical checkpoint molecule expression studies do not yet provide a strong rationale for trials of checkpoint inhibitor therapy for sepsis.

Prediction of sepsis mortality using metabolite biomarkers in the blood: a meta-analysis of death-related pathways and prospective validation

BackgroundSepsis is a leading cause of death in intensive care units (ICUs), but outcomes of individual patients are difficult to predict. The recently developed clinical metabolomics has been recognized as a promising tool in the clinical practice of critical illness. The objective of this study was to identify the unique metabolic biomarkers and their pathways in the blood of sepsis nonsurvivors and to assess the prognostic value of these pathways.MethodsWe searched PubMed, EMBASE, Cochrane, Web of Science, CNKI, Wangfang Data, and CQVIP from inception until July 2019. Eligible studies included the metabolomic analysis of blood samples from sepsis patients with the outcome. The metabolic pathway was assigned to each metabolite biomarker. The meta-analysis was performed using the pooled fold changes, area under the receiver operating characteristic curve (AUROC), and vote-counting of metabolic pathways. We also conducted a prospective cohort metabolomic study to validate the findings of our meta-analysis.ResultsThe meta-analysis included 21 cohorts reported in 16 studies with 2509 metabolite comparisons in the blood of 1287 individuals. We found highly limited overlap of the reported metabolite biomarkers across studies. However, these metabolites were enriched in several death-related metabolic pathways (DRMPs) including amino acids, mitochondrial metabolism, eicosanoids, and lysophospholipids. Prediction of sepsis death using DRMPs yielded a pooled AUROC of 0.81 (95% CI 0.76–0.87), which was similar to the combined metabolite biomarkers with a merged AUROC of 0.82 (95% CI 0.78–0.86) (P > 0.05). A prospective metabolomic analysis of 188 sepsis patients (134 survivors and 54 nonsurvivors) using the metabolites from DRMPs produced an AUROC of 0.88 (95% CI 0.78–0.97). The sensitivity and specificity for the prediction of sepsis death were 80.4% (95% CI 66.9–89.4%) and 78.8% (95% CI 62.3–89.3%), respectively.ConclusionsDRMP analysis minimizes the discrepancies of results obtained from different metabolomic methods and is more practical than blood metabolite biomarkers for sepsis mortality prediction.Trial registrationThe meta-analysis was registered on OSF Registries, and the prospective cohort study was registered on the Chinese Clinical Trial Registry (ChiCTR1800015321).

To study the value of hemodynamic parameters in comparison to lactate values and outcome of illness

A prospective, non-intervention study was undertaken after ethical committee approval in the Department of Surgery, Index Medical College Hospital & Research Centre, Indore. Persistent higher LACTATE levels in non-survivors in major trauma and sepsis after 48 hours. And gradually decrease level in survivor. Thus, rising serum lactate levels suggest early prediction of shock and mortality. (p values less than 0.01). Rising serum lactate levels predict mortality in trauma and sepsis irrespective of age of patients. Because results are statistically insignificant (p > 0.01). Organ dysfunction suggest higher mortality in trauma and sepsis patients. Statistically significant (p

Are Lipoprotein Levels and Ratios Able to Predict Mortality due to Sepsis?

To compare lipoprotein levels, and non-HDL to high-density lipoprotein (HDL) ratios of survivors and nonsurvivors of sepsis, and to determine the predictivity levels of specified parameters in mortality. Descriptive study. Department of Internal Medicine, Kirikkale University, School of Medicine, Training and Research Hospital, Kirikkale, Turkey, from December 2017 to December 2018. The study subjects included 37 non-survivors and 32 survivors of sepsis with similar ages, comorbidities, and disease activities. The total lipoprotein levels, and non-HDL to HDL ratios of the participants were compared retrospectively. HDL and non-HDL to HDL ratios were found to be different between the two groups. The cut-off levels of these values were determined as 32 and 3.4, respectively. The cut-off levels found in the study suggest that the low HDL levels and high non-HDL to HDL ratios significantly increase the mortality risk for patients (OR=1.8 and 3.45, respectively). Non-HDL to HDL ratio may be used as a useful tool for predicting sepsis mortality. These values may also be included as a part of scoring systems. Further investigations are needed to clarify the role of lipoproteins in sepsis.

DNA methylation of a NF-\u03baB binding site in the aquaporin 5 promoter impacts on mortality in sepsis

Altered aquaporin 5 (AQP5) expression in immune cells impacts on key mechanisms of inflammation and is associated with sepsis survival. Since epigenetic regulation via DNA methylation might contribute to a differential AQP5 expression in sepsis, we tested the hypotheses that DNA methylation of the AQP5 promotor (1) influences AQP5 expression, (2) is associated with the 30-day survival of septic patients, and (3) alters the nuclear transcription factor NF-κB binding. AQP5 mRNA expression was quantified by real-time PCR in whole blood samples of 135 septic patients. In silico computer analysis of the AQP5 promoter (nt-567 to nt-975) revealed seven putative inflammatory transcription factor binding sites and methylation of these sites was analyzed. Electrophoretic mobility shift assays were performed to assess the binding of nuclear NF-κB to the AQP5 promoter region nt-937. After adjustment for multiple testing, a greater methylation rate was found at cytosine site nt-937 in the AQP5 promoter linked to NF-κB binding in non-survivors compared to survivors (p = 0.002, padj = 0.014). This was associated with greater AQP5 mRNA expression in non-survivors (p = 0.037). Greater (≥16%) promoter methylation at nt-937 was also associated with an independently increased risk of death within 30 days (HR: 3.31; 95% CI: 1.54–6.23; p = 0.002). We detected a functionally important AQP5 promoter cytosine site (nt-937) linked to the binding of the inflammatorily acting nuclear transcription factor NF-κB, with increased methylation in sepsis non-survivors. Thus, nt-937 APQ5 promoter methylation, presumably related to NF-κB binding, is prognostically relevant in sepsis and demonstrates that epigenetic changes impact on sepsis outcome.

Prediction of mortality in adult patients with sepsis using six biomarkers: a systematic review and meta-analysis

BackgroundAngiopoietin-1 (Ang-1) and 2 (Ang-2), high mobility group box 1 (HMGB1), soluble receptor for advanced glycation endproducts (sRAGE), soluble triggering receptor expressed on myeloid cells 1 (sTREM1), and soluble urokinase-type plasminogen activator receptor (suPAR) have shown promising results for predicting all-cause mortality in critical care patients. The aim of our systematic review and meta-analysis was to assess the prognostic value of these biomarkers for mortality in adult patients with sepsis.MethodsA systematic literature search of the MEDLINE, PubMed, EMBASE, and Cochrane Library databases, for articles in English published from 01.01.1990 onwards, was conducted. The systematic review focused exclusively on observational studies of adult patients with sepsis, any randomized trials were excluded. For the meta-analysis, only studies which provide biomarker concentrations within 24 h of admission in sepsis survivors and nonsurvivors were included. Results are presented as pooled mean differences (MD) between nonsurvivors and survivors with 95% confidence interval for each of the six biomarkers. Studies not included in the quantitative analysis were narratively summarized. The risk of bias was assessed in all included studies using the Quality in Prognosis Studies (QUIPS) tool.ResultsThe systematic literature search retrieved 2285 articles. In total, we included 44 studies in the qualitative analysis, of which 28 were included in the meta-analysis. The pooled mean differences in biomarker concentration (nonsurvivors − survivors), measured at onset of sepsis, are listed as follows: (1) Ang-1: − 2.9 ng/ml (95% CI − 4.1 to − 1.7, p < 0.01); (2) Ang-2: 4.9 ng/ml (95% CI 2.6 to 7.1, p < 0.01); (3) HMGB1: 1.2 ng/ml (95% CI 0.0 to 2.4, p = 0.05); (4) sRAGE: 1003 pg/ml (95% CI 628 to 1377, p < 0.01); (5) sTREM-1: 87 pg/ml (95% CI 2 to 171, p = 0.04); (6) suPAR: 5.2 ng/ml (95% CI 4.5 to 6.0, p < 0.01).ConclusionsAng-1, Ang-2, and suPAR provide beneficial prognostic information about mortality in adult patients with sepsis. The further development of standardized assays and the assessment of their performance when included in panels with other biomarkers may be recommended.Trial registration This study was recorded on PROSPERO, prospective register of systematic reviews, under the registration ID: CRD42018081226

Identifying crucial genes for prognosis in septic patients: Gene integration study based on PRISMA guidelines.

Background:Sepsis is a serious clinical condition with a poor prognosis, despite improvements in diagnosis and treatment.Therefore, novel biomarkers are necessary that can help with estimating prognosis and improving clinical outcomes of patients with sepsis.Methods:The gene expression profiles GSE54514 and GSE63042 were downloaded from the GEO database. DEGs were screened by t test after logarithmization of raw data; then, the common DEGs between the 2 gene expression profiles were identified by up-regulation and down-regulation intersection. The DEGs were analyzed using bioinformatics, and a protein-protein interaction (PPI) survival network was constructed using STRING. Survival curves were constructed to explore the relationship between core genes and the prognosis of sepsis patients based on GSE54514 data.Results:A total of 688 common DEGs were identified between survivors and non-survivors of sepsis, and 96 genes were involved in survival networks. The crucial genes Signal transducer and activator of transcription 5A (STAT5A), CCAAT/enhancer-binding protein beta (CEBPB), Myc proto-oncogene protein (MYC), and REL-associated protein (RELA) were identified and showed increased expression in sepsis survivors. These crucial genes had a positive correlation with patients’ survival time according to the survival analysis.Conclusions:Our findings indicate that the genes STAT5A, CEBPB, MYC, and RELA may be important in predicting the prognosis of sepsis patients.

Intravenous fluid resuscitation is associated with septic endothelial glycocalyx degradation

BackgroundIntravenous fluids, an essential component of sepsis resuscitation, may paradoxically worsen outcomes by exacerbating endothelial injury. Preclinical models suggest that fluid resuscitation degrades the endothelial glycocalyx, a heparan sulfate-enriched structure necessary for vascular homeostasis. We hypothesized that endothelial glycocalyx degradation is associated with the volume of intravenous fluids administered during early sepsis resuscitation.MethodsWe used mass spectrometry to measure plasma heparan sulfate (a highly sensitive and specific index of systemic endothelial glycocalyx degradation) after 6 h of intravenous fluids in 56 septic shock patients, at presentation and after 24 h of intravenous fluids in 100 sepsis patients, and in two groups of non-infected patients. We compared plasma heparan sulfate concentrations between sepsis and non-sepsis patients, as well as between sepsis survivors and sepsis non-survivors. We used multivariable linear regression to model the association between volume of intravenous fluids and changes in plasma heparan sulfate.ResultsConsistent with previous studies, median plasma heparan sulfate was elevated in septic shock patients (118 [IQR, 113–341] ng/ml 6 h after presentation) compared to non-infected controls (61 [45–79] ng/ml), as well as in a second cohort of sepsis patients (283 [155–584] ng/ml) at emergency department presentation) compared to controls (177 [144–262] ng/ml). In the larger sepsis cohort, heparan sulfate predicted in-hospital mortality. In both cohorts, multivariable linear regression adjusting for age and severity of illness demonstrated a significant association between volume of intravenous fluids administered during resuscitation and plasma heparan sulfate. In the second cohort, independent of disease severity and age, each 1 l of intravenous fluids administered was associated with a 200 ng/ml increase in circulating heparan sulfate (p = 0.006) at 24 h after enrollment.ConclusionsGlycocalyx degradation occurs in sepsis and septic shock and is associated with in-hospital mortality. The volume of intravenous fluids administered during sepsis resuscitation is independently associated with the degree of glycocalyx degradation. These findings suggest a potential mechanism by which intravenous fluid resuscitation strategies may induce iatrogenic endothelial injury.

TO STUDY THE TIME TREND OF NORMALIZATION OF LACTATE THAT FAVORS SURVIVAL IN MAJOR TRAUMA AND SEPSIS.

Background: &#x0D; A prospective, non-intervention study was undertaken To study the time trend of normalization of lactate that favors survival in major trauma and sepsis in the Department of Surgery, Index Medical College Hospital and Research Centre, Indore, M.P., India for 01 year time duration. A total of 50 patients were included into study.&#x0D; Result: persistent higher LACTATE levels in non-survivors in major trauma and sepsis after 48 hours. And gradually decrease level in survivor. Thus, rising serum lactate levels suggest early prediction of shock and mortality.(p values less than 0.01)&#x0D; Above table suggest that rising serum lactate levels predict mortality in trauma and sepsis irrespective of age of patients. Because results are statistically insignificant (p &gt; 0.01)&#x0D; Conclusion: Lactate values probably need to be followed for longer periods in critical patients even when they have tided over the present crisis. The utility of regular lactate analysis in these patients would depend on factors such as availability and cost of test also. There are no existing studies to support the above premise.&#x0D; Keywords: Normalization, Lactate, Survival, Trauma &amp; Sepsis

Risk Factors for 30-Day Mortality in Neonatal Gram-Negative Bacilli Sepsis.

Multidrug-resistant gram-negative bacilli (MDR-GNB) have emerged globally as a serious threat and with a high case fatality rate (CFR). We performed a case-control study in a Thai neonatal intensive care unit to identify the risk factors for 30-day CFR of GNB sepsis between 1991 and 2017. The CFR was analyzed by Cox's proportional hazards model. For 27 years, the percentage of MDR-GNB from GNB sepsis was 66% (169/257). The medians (interquartile ranges) of gestational age and birth weight of the neonates with GNB sepsis were 33 (29-38) weeks and 1,817 (1,100-2,800) grams, respectively. The 30-day CFRs of the neonates with MDR-GNB and non-MDR-GNB sepsis were 33% (56/169) and 20% (18/88), respectively, (hazard ratio [HR] = 1.74; 95% confidence interval [CI]: 1.03-2.97; p = 0.04). Using Cox's proportional hazards model, nonsurvivors in GNB sepsis were more likely to have septic shock (adjusted HR [aHR] = 6.67; 95% CI: 3.28-13.57; p < 0.001) or no microbiological cure (aHR = 10.65; 95% CI: 4.98-22.76; p < 0.001) than survivors. Neonates suspected of sepsis with septic shock need broad-spectrum empirical antimicrobial therapy until the second successive negative culture, especially in high MDR areas.

A Comparative Study of the Diagnostic and Prognostic Utility of Soluble Urokinase-type Plasminogen Activator Receptor and Procalcitonin in Patients with Sepsis and Systemic Inflammation Response Syndrome.

ABSTRACTIntroductionDifferentiation between sepsis and systemic inflammation response syndrome (SIRS) remains a diagnostic challenge for clinicians as both may have similar clinical presentation. A quick and accurate diagnostic tool that can discriminate between these two conditions would aid in appropriate therapeutic decision-making. This prospective study was conducted to evaluate the diagnostic and prognostic utility of soluble urokinase-type plasminogen activator receptor (suPAR) and procalcitonin (PCT) in sepsis and SIRS patients.Materials and methodsEighty-eight patients were enrolled, of which 29 were SIRS and 59 were sepsis patients. The levels of suPAR and PCT were measured on the day of admission (day 1), day 3, and day 7.ResultsThe levels of suPAR and PCT were significantly higher (p = 0.05 and p < 0.001, respectively) in sepsis group as compared to the SIRS group. The soluble urokinase-type plasminogen activator receptor was a better diagnostic tool in predicting sepsis over PCT [area under curve (AUC) 0.89 vs 0.82] on day 1. The best cutoff for suPAR was 5.58 pg/mL [96% sensitivity and 90% negative predictive value (NPV)] and the best cut-off for PCT was 1.96 ng/mL (93.1% sensitivity and 80% NPV). However, PCT had better prognostic trends (p = 0.006) to identify nonsurvivors in sepsis group.ConclusionOur findings suggest that both suPAR and PCT can be used as potential test tools to differentiate between SIRS and sepsis. Procalcitonin showed significant prognostic trends to identify nonsurvivors. The soluble urokinase-type plasminogen activator receptor showed better diagnostic potential than PCT on day 1.Clinical significanceBoth suPAR and PCT can be used as surrogate biomarkers to distinguish sepsis from SIRS. Procalcitonin showing a significant prognostic trend to identify nonsurvivors can help the clinicians to take relevant clinical decisions. Also, the use of biomarkers like PCT and suPAR could reduce the inappropriate use of antibiotics in noninfective SIRS.How to cite this articleSharma A, Ray S, Mamidipalli R, Kakar A, Chugh P, Jain R, et al. A Comparative Study of the Diagnostic and Prognostic Utility of Soluble Urokinase-type Plasminogen Activator Receptor and Procalcitonin in Patients with Sepsis and Systemic Inflammation Response Syndrome. Indian J Crit Care Med 2020;24(4):245–251.

Evaluating the discriminating capacity of cell death (apoptotic) biomarkers in sepsis

BackgroundSepsis biomarker panels that provide diagnostic and prognostic discrimination in sepsis patients would be transformative to patient care. We assessed the mortality prediction and diagnostic discriminatory accuracy of two biomarkers reflective of cell death (apoptosis), circulating cell-free DNA (cfDNA), and nucleosomes.MethodsThe cfDNA and nucleosome levels were assayed in plasma samples acquired in patients admitted from four emergency departments with suspected sepsis. Subjects with non-infectious systemic inflammatory response syndrome (SIRS) served as controls. Samples were acquired at enrollment (T0) and 24 h later (T24). We assessed diagnostic (differentiating SIRS from sepsis) and prognostic (28-day mortality) predictive power. Models incorporating procalcitonin (diagnostic prediction) and APACHE II scores (mortality prediction) were generated.ResultsTwo hundred three subjects were included (107 provided procalcitonin measurements). Four subjects exhibited uncomplicated sepsis, 127 severe sepsis, 35 septic shock, and 24 had non-infectious SIRS. There were 190-survivors and 13 non-survivors. Mortality prediction models using cfDNA, nucleosomes, or APACHEII yielded AUC values of 0.61, 0.75, and 0.81, respectively. A model combining nucleosomes with the APACHE II score improved the AUC to 0.84. Diagnostic models distinguishing sepsis from SIRS using procalcitonin, cfDNA(T0), or nucleosomes(T0) yielded AUC values of 0.64, 0.65, and 0.63, respectively. The three parameter model yielded an AUC of 0.74.ConclusionsTo our knowledge, this is the first head-to-head comparison of cfDNA and nucleosomes in diagnosing sepsis and predicting sepsis-related mortality. Both cfDNA and nucleosome concentrations demonstrated a modest ability to distinguish sepsis survivors and non-survivors and provided additive diagnostic predictive accuracy in differentiating sepsis from non-infectious SIRS when integrated into a diagnostic prediction model including PCT and APACHE II. A sepsis biomarker strategy incorporating measures of the apoptotic pathway may serve as an important component of a sepsis diagnostic and mortality prediction tool.

Symmetrical (SDMA) and asymmetrical dimethylarginine (ADMA) in sepsis: high plasma levels as combined risk markers for sepsis survival

BackgroundNitric oxide (NO) regulates processes involved in sepsis progression, including vascular and immune function. NO is generated by nitric oxide synthases (NOS) from L-arginine. Cellular L-arginine uptake is inhibited by symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA) is a competitive inhibitor of NOS. Increased inhibitor blood concentrations lead to reduce NO bioavailability. The aim of this study was to determine whether plasma concentrations of SDMA and ADMA are markers for sepsis survival.MethodThis prospective, single center study involved 120 ICU patients with sepsis. Plasma SDMA and ADMA were measured on admission (day 1), day 3 and day 7 by mass spectrometry together with other laboratory markers. The sequential organ failure assessment (SOFA) score was used to evaluate sepsis severity. Survival was documented until day 28. Groups were compared using the Mann-Whitney U test, chi-squared test or non-parametric analysis of variance (ANOVA). Mortality was assessed using Kaplan-Meier curves and compared using the log-rank test. Specific risk groups were identified using a decision tree algorithm.ResultsMedian plasma SDMA and ADMA levels were significantly higher in non-survivors than in survivors of sepsis: SDMA 1.14 vs. 0.82 μmol/L (P = 0.002) and ADMA 0.93 vs. 0.73 μmol/L (P = 0.016). ANOVA showed that increased plasma SDMA and ADMA concentrations were significantly associated with SOFA scores. The 28-day mortality was compared by chi-square test: for SDMA the mortality was 12% in the lower, 25% in the intermediate and 43% in the 75th percentile (P = 0.018); for ADMA the mortality was 18–20% in the lower and intermediate but 48% in the 75th percentile (P = 0.006). The highest mortality (61%) was found in patients with plasma SDMA > 1.34 together with ADMA levels > 0.97 μmol/L.ConclusionsIncreased plasma concentrations of SDMA and ADMA are associated with sepsis severity. Therefore, our findings suggest reduced NO bioavailability in non-survivors of sepsis. One may use individual SDMA and ADMA levels to identify patients at risk. In view of the pathophysiological role of NO we conclude that the vascular system and immune response are most severely affected when SDMA and ADMA levels are high.

Phosphatidylserine expressing platelet microparticle levels at hospital presentation are decreased in sepsis non-survivors and correlate with thrombocytopenia

BackgroundSepsis induced platelet activation releases platelet microparticles (PMPs). PMPs express phosphatidylserine (PS) and can serve as a scaffold for the prothrombinase complex, thereby promoting coagulation. Studies of PMPs in intensive care unit sepsis patients demonstrate mixed results, while the earliest changes and potential effects of clinical interventions remain understudied. We hypothesized PMPs would be associated with patient outcome and dysfunctional coagulation shortly after emergency department presentation with sepsis. MethodsCohort study of patients from a single center enrolled in a previously published randomized control trial comparing two early resuscitation strategies. Adults presenting to the emergency department (ED) with suspected infection, ≥2 SIRS criteria, and either systolic blood pressure <90 mm Hg or lactate >4 mmol/L were eligible. Triple positive platelet microparticles (PMPs) expressing phosphatidylserine and integrin complexes alphaIIb (CD41) and beta3 (CD61) were quantitated using plasma from the time of enrollment. The primary outcome was in-hospital mortality. Secondary outcomes included platelet count, disseminated intravascular coagulation (DIC), and prothrombin time (PT). Results193 patients were enrolled and 184 had samples available. In-hospital mortality was 21%. 10 (5%) patients developed DIC. Median platelet count was 197 (IQR 135, 280) and PT was 13.2 (IQR 11.9, 16.8). Median triple positive PMP counts were 932 per μL (IQR 381, 1872). PMPs were significantly lower in non-survivors (575 vs 1128, p = 0.02) and non-significantly lower in DIC (387 vs 942, p = 0.17). PMPs demonstrated a positive linear association with platelet count (p < 0.001, R2 = 0.21). After adjusting for platelet count, PMPs were no longer significant predictors of mortality (p = 0.28). We observed no association between PMPs and PT. ConclusionSimilar to patients enrolled later in the intensive care unit, PS-expressing PMPs are lower in emergency department sepsis non-survivors. These changes primarily reflect the degree of thrombocytopenia, and an independent prognostic role was not observed. Future studies should control for platelet count in assessment of PMP prognosis in sepsis.