Sepsis-related Death Research Articles

Sepsis surveillance in patients with head-and-neck cancer undergoing chemo-radiation.

The infection rate among patients with head-and-neck cancer (HNC) undergoing chemoradiotherapy (CRT) is approximately 19%, with sepsis-related death ranging from 3-9%. A previous study at our institute found a 12%sepsis-related death rate in HNC patients during CRT. The objective of this study is to investigate the utilization of sepsis surveillance and early intervention in reducing the occurrence of sepsis-related deaths in locally advanced HNC patients receiving CRT. This retrospective analysis examined 54 patients with locally advanced HNC undergoing CRT who underwent sepsis surveillance between January 2018 and December 2021. The study recorded the utilization of oral and intravenous antibiotics, G-CSF, early admissions and their reasons, and the incidence of early mortality. Data analysis was conducted using SPSS v.24 software. Twenty-one (38.9%) patients were prescribed oral antibiotics, and 14 (25.9%) received G-CSF on an outpatient basis. Twenty-nine (54%) patients required hospital admission. Among the admitted patients, 28 (96%) received intravenous antibiotics, and G-CSF was administered in 18 (62%) patients. In 8 cases, antibiotic treatment was intensified due to persistent fever and deteriorating neutropenia. The median time for receiving antibiotics and G-CSF after starting CRT was 5th week (range: 3-8weeks). Five patients required readmission. Only one patient succumbed to sepsis. Among the 54 patients, 48 (89%) completed the scheduled RT, while 14 (25.9%) received all 6 cycles of chemotherapy. Sepsis surveillance and the prompt use of antibiotics and G-CSF, along with early hospitalization, when necessary, reduces the occurrence of sepsis-related early deaths in HNC patients undergoing CRT.

Association Between Measurable Residual Levels and Infection Mortality in Acute Myeloid Leukemia

Abstract Background Acute myeloid leukemia (AML) outcomes have improved over the years. Better AML disease risk classification, achieved by measuring minimal residual disease (MRD) levels, has contributed to improved treatment and survival. Even though the role of MRD in survival is still preliminary, results are promising. However, infections are still a problem to circumvent. In our previous protocol LMA-GATLA 2007 we found a 30% incidence of sepsis related death (SRD), and they were more frequent during or after first induction. The overall survival of that study was 51.4 % (0.38). In this study, we aimed to analyze the mortality rates due to infection; and determine if there is an association of the MRD levels and infection mortality rates; also, we will analyze overall outcomes of AML. Methods Patients were accrued form the National Registry GATLA LMA 2021 protocol. Disease risks were classified based on cytogenetics and molecular abnormalities as standard risk (SR), high risk (HR), and very high risk (VHR). MRD determinations were performed using flow cytometry after 1st induction with mitoxantrone, anthraciclines and etoposide (MAE) protocol, at day 22 and 29 and after 2nd induction with high dose citarabine and mitoxantrone (HAM). We used descriptive statistics (analysis by frequency), compared categorical variables using chi-square or χ2 test and Fisher test, and time to event calculation techniques. Results 95 patients have been accrued, 51.6 % were males. The median age was 9 years of age (IQR 3-13), and 31% were SR, 22% HR, and 47% VHR. MRD levels < 0.1% were seen in 55.5% post first induction, 92% post intensification and 85% post consolidation. Estimated probability of overall survival was 65% (ES 0.6) at 45.7 (2.7) months, (CI 95% 40.3-51,1). 23 pts (24%) died; 11 (48 %) for progression, 7 (30%) for sepsis, for non-sepsis toxicity 3 (13%), other causes 2 pts (9%). Hazard ratio of death with MRD > 0.1% was 2.35 (p=0.06, 95% CI 0.043-1.756). The incidence of SRD was 7.4%, 4 patients had sepsis with MRD < 0.1% (57 %), after HAM /consolidation phase; and 3 patients with > 0.1% (43%) when in relapse (p= 0.028). The SRD episodes were independent from MRD levels, however patients on remission showed SRD as late events, because no patient developed SRD during or after first induction. Conclusion Overall survival results have improved with current protocol. MRD seems a valuable tool to estimate response, levels >0.1 % are associated with increased risk of death. However, better infection prevention and care are required to improve further the outcomes, especially those associated with higher MRD levels.

Utilize proteomic analysis to identify potential therapeutic targets for combating sepsis and sepsis-related death.

Sepsis is an inflammatory disease that leads to severe mortality, highlighting the urgent need to identify new therapeutic strategies for sepsis. Proteomic research serves as a primary source for drug target identification. We employed proteome-wide Mendelian randomization (MR), genetic correlation analysis, and colocalization analysis to identify potential targets for sepsis and sepsis-related death. Genetic data for plasma proteomics were obtained from 35,559 Icelandic individuals and an initial MR analysis was conducted using 13,531 sepsis cases from the FinnGen R10 cohort to identify associations between plasma proteins and sepsis. Subsequently, significant proteins underwent genetic correlation analysis, followed by replication in 54,306 participants from the UK Biobank Pharma Proteomics Project and validation in 11,643 sepsis cases from the UK Biobank. The identified proteins were then subjected to colocalization analysis, enrichment analysis, and protein-protein interaction network analysis. Additionally, we also investigated a MR analysis using plasma proteins on 1,896 sepsis cases with 28-day mortality from the UK Biobank. After FDR correction, MR analysis results showed a significant causal relationship between 113 plasma proteins and sepsis. Genetic correlation analysis revealed that only 8 proteins had genetic correlations with sepsis. In the UKB-PPP replication analysis, only 4 proteins were found to be closely associated with sepsis, while validation in the UK Biobank sepsis cases found overlaps for 21 proteins. In total, 30 proteins were identified in the aforementioned analyses, and colocalization analysis revealed that only 2 of these proteins were closely associated with sepsis. Additionally, in the 28-day mortality MR analysis of sepsis, we also found that only 2 proteins were significant. The identified plasma proteins and their associated metabolic pathways have enhanced our understanding of the complex relationship between proteins and sepsis. This provides new avenues for the development of drug targets and paves the way for further research in this field.

Causal effects of sepsis on structural changes in cerebral cortex: A Mendelian randomization investigation.

Previous research has shown a strong correlation between sepsis and brain structure. However, whether this relationship represents a causality remains elusive. In this study, we employed Mendelian randomization (MR) to probe the associations of genetically predicted sepsis and sepsis-related death with structural changes in specific brain regions. Genome-wide association study (GWAS) data for sepsis phenotypes (sepsis and sepsis-related death) were obtained from the IEU OpenGWAS. Correspondingly, GWAS data for brain structural traits (volume of the subcortical structure, cortical thickness, and surface area) were derived from the ENIGMA consortium. Inverse variance weighted was mainly utilized to assess the causal effects, while weighted median and MR-Egger regression served as complementary methods. Sensitivity analyses were implemented with Cochran Q test, MR-Egger regression, and MR-PRESSO. In addition, a reverse MR analysis was carried out to assess the possibility of reverse causation. We identified that genetic liability to sepsis was normally significantly associated with a reduced surface area of the postcentral gyrus (β = -35.5280, SE = 13.7465, P = .0096). The genetic liability to sepsis-related death showed a suggestive positive correlation with the surface area of fusiform gyrus (β = 11.0920, SE = 3.6412, P = .0023) and posterior cingulate gyrus (β = 3.6530, SE = 1.6684, P = .0286), While it presented a suggestive negative correlation with surface area of the caudal middle frontal gyrus (β = -11.4586, SE = 5.1501, P = .0261) and frontal pole (β = -1.0024, SE = 0.4329, P = .0206). We also indicated a possible bidirectional causal association between genetic liability to sepsis-related death and the thickness of the transverse temporal gyrus. Sensitivity analyses verified the robustness of the above associations. These findings suggested that genetically determined liability to sepsis might influence the specific brain structure in a causal way, offering new perspectives to investigate the mechanism of sepsis-related neuropsychiatric disorders.

Source Control and Antibiotics in Intra-Abdominal Infections.

Intra-abdominal infections (IAIs) account for a major cause of morbidity and mortality, representing the second most common sepsis-related death with a hospital mortality of 23-38%. Prompt identification of sepsis source, appropriate resuscitation, and early treatment with the shortest delay possible are the cornerstones of management of IAIs and are associated with a more favorable clinical outcome. The aim of source control is to reduce microbial load by removing the infection source and it is achievable by using a wide range of procedures, such as definitive surgical removal of anatomic infectious foci, percutaneous drainage and toilette of infected collections, decompression, and debridement of infected and necrotic tissue or device removal, providing for the restoration of anatomy and function. Damage control surgery may be an option in selected septic patients. Intra-abdominal infections can be classified as uncomplicated or complicated causing localized or diffuse peritonitis. Early clinical evaluation is mandatory in order to optimize diagnostic testing and establish a therapeutic plan. Prognostic scores could serve as helpful tools in medical settings for evaluating both the seriousness and future outlook of a condition. The patient's conditions and the potential progression of the disease determine when to initiate source control. Patients can be classified into three groups based on disease severity, the origin of infection, and the patient's overall physical health, as well as any existing comorbidities. In recent decades, antibiotic resistance has become a global health threat caused by inappropriate antibiotic regimens, inadequate control measures, and infection prevention. The sepsis prevention and infection control protocols combined with optimizing antibiotic administration are crucial to improve outcome and should be encouraged in surgical departments. Antibiotic and antifungal regimens in patients with IAIs should be based on the resistance epidemiology, clinical conditions, and risk for multidrug resistance (MDR) and Candida spp. infections. Several challenges still exist regarding the effectiveness, timing, and patient stratification, as well as the procedures for source control. Antibiotic choice, optimal dosing, and duration of therapy are essential to achieve the best treatment. Promoting standard of care in the management of IAIs improves clinical outcomes worldwide. Further trials and stronger evidence are required to achieve optimal management with the least morbidity in the clinical care of critically ill patients with intra-abdominal sepsis.

Circulating micronutrient levels and their association with sepsis susceptibility and severity: a Mendelian randomization study.

Background: Sepsis, a global health challenge, necessitates a nuanced understanding of modifiable factors for effective prevention and intervention. The role of trace micronutrients in sepsis pathogenesis remains unclear, and their potential connection, especially with genetic influences, warrants exploration. Methods: We employed Mendelian randomization (MR) analyses to assess the causal relationship between genetically predicted blood levels of nine micronutrients (calcium, β-carotene, iron, magnesium, phosphorus, vitamin C, vitamin B6, vitamin D, and zinc) and sepsis susceptibility, severity, and subtypes. The instrumental variables for circulating micronutrients were derived from nine published genome-wide association studies (GWAS). In the primary MR analysis, we utilized summary statistics for sepsis from two independent databases (UK Biobank and FinnGen consortium), for initial and replication analyses. Subsequently, a meta-analysis was conducted to merge the results. In secondary MR analyses, we assessed the causal effects of micronutrients on five sepsis-related outcomes (severe sepsis, sepsis-related death within 28days, severe sepsis-related death within 28days, streptococcal septicaemia, and puerperal sepsis), incorporating multiple sensitivity analyses and multivariable MR to address potential heterogeneity and pleiotropy. Results: The study revealed a significant causal link between genetically forecasted zinc levels and reduced risk of severe sepsis-related death within 28days (odds ratio [OR] = 0.450; 95% confidence interval [CI]: 0.263, 0.770; p = 3.58 × 10-3). Additionally, suggestive associations were found for iron (increased risk of sepsis), β-carotene (reduced risk of sepsis death) and vitamin C (decreased risk of puerperal sepsis). No significant connections were observed for other micronutrients. Conclusion: Our study highlighted that zinc may emerges as a potential protective factor against severe sepsis-related death within 28days, providing theoretical support for supplementing zinc in high-risk critically ill sepsis patients. In the future, larger-scale data are needed to validate our findings.

Gut microbiota and sepsis and sepsis-related death: a Mendelian randomization investigation.

It is unclear what the causal relationship is between the gut microbiota and sepsis. Therefore, we employed Mendelian randomization (MR) to determine whether a causal link exists between the two. This study used publicly available genome-wide association studies (GWAS) summary data of gut microbiota, sepsis, sepsis (critical care), and sepsis (28-day death in critical care) to perform a two-sample MR analysis. To ensure the robustness of the results, we also conducted a sensitivity analysis. For sepsis susceptibility, inverse variance weighted (IVW) estimates revealed that Victivallales (OR = 0.86, 95% CI, 0.78-0.94, p = 0.0017) was protective against sepsis, while Lentisphaerae (OR = 0.89, 95% CI, 0.80-0.99), Gammaproteobacteria (OR = 1.37, 95% CI, 1.08-1.73), Clostridiaceae1 (OR = 1.21, 95% CI, 1.04-1.40), RuminococcaceaeUCG011 (OR = 1.10, 95% CI, 1.01-1.20), Dialister (OR = 0.85, 95% CI, 0.74-0.97), and Coprococcus2 (OR = 0.81, 95% CI, 0.69-0.94) presented a suggestive association with the development of sepsis (all p < 0.05). For sepsis (critical care), IVW estimates indicated that Lentisphaerae (OR = 0.70, 95% CI, 0.53-0.93), Victivallales (OR = 0.67, 95% CI, 0.50-0.91), Anaerostipes (OR = 0.49, 95% CI, 0.31-0.76), LachnospiraceaeUCG004 (OR = 0.51, 95% CI, 0.34-0.77), and Coprococcus1 (OR = 0.66, 95% CI, 0.44-0.99) showed a suggestive negative correlation with sepsis (critical care) (all p < 0.05). For sepsis (28-day death in critical care), IVW estimates suggested that four bacterial taxa had a normally significant negative correlation with the risk of sepsis-related death, including Victivallales (OR = 0.54, 95% CI, 0.30-0.95), Coprococcus2 (OR = 0.34, 95% CI, 0.14-0.83), Ruminiclostridium6 (OR = 0.43, 95% CI, 0.22-0.83), and Coprococcus1 (OR = 0.45, 95% CI, 0.21-0.97), while two bacterial taxa were normally significantly positively linked to the risk of sepsis-related death, namely, Mollicutes (OR = 2.03, 95% CI, 1.01-4.08) and Bacteroidales (OR = 2.65, 95% CI, 1.18-5.96) (all p < 0.05). The robustness of the above correlations was verified by additional sensitivity analyses. This MR research found that several gut microbiota taxa were causally linked to the risk of sepsis, sepsis in critical care, and sepsis-related 28-day mortality in critical care.

Causal effects of gut microbiota on sepsis and sepsis-related death: insights from genome-wide Mendelian randomization, single-cell RNA, bulk RNA sequencing, and network pharmacology

BackgroundGut microbiota alterations have been implicated in sepsis and related infectious diseases, but the causal relationship and underlying mechanisms remain unclear.MethodsWe evaluated the association between gut microbiota composition and sepsis using two-sample Mendelian randomization (MR) analysis based on published genome-wide association study (GWAS) summary statistics. Sensitivity analyses were conducted to validate the robustness of the results. Reverse MR analysis and integration of GWAS and expression quantitative trait loci (eQTL) data were performed to identify potential genes and therapeutic targets.ResultsOur analysis identified 11 causal bacterial taxa associated with sepsis, with increased abundance of six taxa showing positive causal relationships. Ten taxa had causal effects on the 28-day survival outcome of septic patients, with increased abundance of six taxa showing positive associations. Sensitivity analyses confirmed the robustness of these associations. Reverse MR analysis did not provide evidence of reverse causality. Integration of GWAS and eQTL data revealed 76 genes passing the summary data-based Mendelian randomization (SMR) test. Differential expression of these genes was observed between sepsis patients and healthy individuals. These genes represent potential therapeutic targets for sepsis. Molecular docking analysis predicted potential drug-target interactions, further supporting their therapeutic potential.ConclusionOur study provides insights for the development of personalized treatment strategies for sepsis and offers preliminary candidate targets and drugs for future drug development.

Analysis of pathogenic factors on the death rate of sepsis patients

Background The Surviving Sepsis Campaign (SSC) believed that early identification of septic shock, aggressive fluid resuscitation and maintenance of effective perfusion pressure should be carried out. However, some of the current research focused on a single death factor for sepsis patients, based on a limited sample, and the research results of the relationship between comorbidities and sepsis related death also have some controversies. Method Therefore, our study used data from a large sample of 9,544 sepsis patients aged 18–85 obtained from the MIMIC-IV database, to explore the risk factors of death in patients with sepsis. We used the general clinical information, organ dysfunction scores, and comorbidities to analyze the independent risk factors for death of these patients. Results The death group had significantly higher organ dysfunction scores, lower BMI, lower body temperature, faster heart rate and lower urine-output. Among the comorbidities, patients suffering from congestive heart failure and liver disease had a higher mortality rate. Conclusion This study helps to identify sepsis early, based on a comprehensive evaluation of a patient’s basic information, organ dysfunction scores and comorbidities, and this methodology could be used for actual clinical diagnosis in hospitals.

Machine learning for the prediction of sepsis-related death: a systematic review and meta-analysis

Background and objectivesSepsis is accompanied by a considerably high risk of mortality in the short term, despite the availability of recommended mortality risk assessment tools. However, these risk assessment tools seem to have limited predictive value. With the gradual integration of machine learning into clinical practice, some researchers have attempted to employ machine learning for early mortality risk prediction in sepsis patients. Nevertheless, there is a lack of comprehensive understanding regarding the construction of predictive variables using machine learning and the value of various machine learning methods. Thus, we carried out this systematic review and meta-analysis to explore the predictive value of machine learning for sepsis-related death at different time points.MethodsPubMed, Embase, Cochrane, and Web of Science databases were searched until August 9th, 2022. The risk of bias in predictive models was assessed using the Prediction model Risk of Bias Assessment Tool (PROBAST). We also performed subgroup analysis according to time of death and type of model and summarized current predictive variables used to construct models for sepsis death prediction.ResultsFifty original studies were included, covering 104 models. The combined Concordance index (C-index), sensitivity, and specificity of machine learning models were 0.799, 0.81, and 0.80 in the training set, and 0.774, 0.71, and 0.68 in the validation set, respectively. Machine learning outperformed conventional clinical scoring tools and showed excellent C-index, sensitivity, and specificity in different subgroups. Random Forest (RF) and eXtreme Gradient Boosting (XGBoost) are the preferred machine learning models because they showed more favorable accuracy with similar modeling variables. This study found that lactate was the most frequent predictor but was seriously ignored by current clinical scoring tools.ConclusionMachine learning methods demonstrate relatively favorable accuracy in predicting the mortality risk in sepsis patients. Given the limitations in accuracy and applicability of existing prediction scoring systems, there is an opportunity to explore updates based on existing machine learning approaches. Specifically, it is essential to develop or update more suitable mortality risk assessment tools based on the specific contexts of use, such as emergency departments, general wards, and intensive care units.

Sepsis induced cardiotoxicity by promoting cardiomyocyte cuproptosis

BackgroundCurrently, sepsis induced cardiotoxicity is among the major causes of sepsis-related death. The specific molecular mechanisms of sepsis induced cardiotoxicity are currently unknown. Therefore, the purpose of this paper is to identify the key molecule mechanisms for sepsis induced cardiotoxicity. MethodsOriginal data of sepsis induced cardiotoxicity was derived from Gene Expression Omnibus (GEO; GSE63920; GSE44363; GSE159309) dataset. Functional enrichment analysis was used to analysis sepsis induced cardiotoxicity related signaling pathways. Our findings also have explored the relationship of cuproptosis and N6-Methyladenosine (m6A) in sepsis induced cardiotoxicity.Mice are randomly assigned to 3 groups: saline treatment control group, LPS group administered a single 5 mg/kg dose of LPS for 24 h, LPS + CD274 inhibitor group administered 10 mg/kg CD274 inhibitor for 24 h. ResultsOverall, expression of cuproptosis-related genes (CRGs) CD274, Ceruloplasmin (CP), Vascular endothelial growth factor A (VEGFA), Copper chaperone for cytochrome c oxidase 11 (COX11), chemokine C–C motif ligand 8 (CCL8), Mitogen-activated protein kinase kinase 1(MAP2K1), Amine oxidase 3 (AOC3) were significantly altered in sepsis induced cardiotoxicity. The results of spearman correlation analysis was significant relationship between differentially regulated genes (DEGs) of CRGs and the expression level of m6A methylation genes. GO and KEGG showed that these genes were enriched in response to interferon-beta, MHC class I peptide loading complex, proteasome core complex, chemokine receptor binding, TAP binding, chemokine activity, cytokine activity and many more. These findings suggest that cuproptosis is strongly associated with sepsis induced cardiotoxicity. ConclusionIn the present study, we found that cuproptosis were associated with sepsis induced cardiotoxicity. The CD274, CP, VEGFA, COX11, CCL8, MAP2K1, AOC3 genes are showing a significant difference expression in sepsis induced cardiotoxicity. Our studies have found significant correlations between CRGs and m6A methylation related genes in sepsis induced cardiotoxicity. These results provide insight into mechanism for sepsis induced cardiotoxicity.

Most patients with an increased risk for sepsis-related morbidity or death do not recognize sepsis as a medical emergency: results of a survey study using case vignettes

BackgroundSepsis is a medical emergency with potentially life-threatening consequences. Patients play a crucial role in preventing and recognizing sepsis at an early stage. The understanding of risk groups’ sepsis knowledge and their ability to use this knowledge to recognize sepsis as an emergency is incomplete.MethodsWe conducted a cross-sectional survey in Germany and included a sample of 740 persons stratified by age (< 60 years, ≥ 60 years), specific chronic diseases (e.g. diabetes, chronic diseases, cancer), and region (Berlin/Brandenburg vs. other federal states of Germany). Standardized questionnaires were administered by a market research institute through online, telephone, or face-to-face methods. We assessed sepsis knowledge through a series of questions and the ability to recognize sepsis as an emergency through five case vignettes. To identify predictors of sepsis knowledge and the ability to recognize sepsis as a medical emergency, we conducted multiple linear regressions.ResultsOf the 36 items on sepsis knowledge, participants answered less than 50 per cent correctly (mean 44.1%; standard deviation (SD) 20.1). Most patients knew that sepsis is a defensive host response to infection (75.9%), but only 30.8% knew that vaccination can prevent infections that lead to sepsis. Across the five vignettes, participants identified sepsis as an emergency in only 1.33 of all cases on average (SD = 1.27). Sepsis knowledge was higher among participants who were older, female, and more highly educated and who reported more extensive health information seeking behaviour. The ability to recognize sepsis as an emergency was higher among younger participants, participants without chronic diseases, and participants with higher health literacy, but it was not significantly associated with sepsis knowledge.ConclusionsRisk groups showed low levels of knowledge regarding the preventive importance of vaccination and a low ability to recognize sepsis as a medical emergency. Higher levels of sepsis knowledge alone were not sufficient to improve the ability to identify sepsis as a medical emergency. It is crucial to develop effective educational strategies—especially for persons with lower education levels and infrequent health information seeking behaviour—that not only transfer but also facilitate the choice of appropriate actions, such as seeking timely emergency care.Trial registration: DRKS00024561. Registered 9 March 2021.

Low levels of small HDL particles predict but do not influence risk of sepsis

BackgroundLow levels of high-density lipoprotein (HDL) cholesterol have been associated with higher rates and severity of infection. Alterations in inflammatory mediators and infection are associated with alterations in HDL cholesterol. It is unknown whether the association between HDL and infection is present for all particle sizes, and whether the observed associations are confounded by IL-6 signalling.MethodsIn the UK Biobank, ~ 270,000 individuals have data on HDL subclasses derived from nuclear magnetic resonance analysis. We estimated the association of particle count of total HDL and HDL subclasses (small, medium, large, and extra-large HDL) with sepsis, sepsis-related death, and critical care admission in a Cox regression model. We subsequently utilised genetic data from UK Biobank and FinnGen to perform Mendelian randomisation (MR) of each HDL subclass and sepsis to test for a causal relationship. Finally, we explored the role of IL-6 signalling as a potential causal driver of changes in HDL subclasses.ResultsIn observational analyses, higher particle count of small HDL was associated with protection from sepsis (Hazard ratio, HR 0.80; 95% CI 0.74–0.86, p = 4 × 10–9 comparing Quartile 4, highest quartile of HDL to Quartile 1, lowest quartile of HDL), sepsis-related death (HR 0.80; 95% CI 0.74–0.86, p = 2 × 10–4), and critical care admission with sepsis (HR 0.72 95% CI 0.60–0.85, p = 2 × 10–4). Parallel associations with other HDL subclasses were likely driven by changes in the small HDL compartment. MR analyses did not strongly support causality of small HDL particle count on sepsis incidence (Odds ratio, OR 0.98; 95% CI 0.89–1.07, p = 0.6) or death (OR 0.94, 95% CI 0.75–1.17, p = 0.56), although the estimate on critical care admission with sepsis supported protection (OR 0.73, 95% CI 0.57–0.95, p = 0.02). Bidirectional MR analyses suggested that increased IL-6 signalling was associated with reductions in both small (beta on small HDL particle count − 0.16, 95% CI − 0.10 to − 0.21 per natural log change in SD-scaled CRP, p = 9 × 10–8).and total HDL particle count (beta − 0.13, 95% CI − 0.09 to − 0.17, p = 7 × 10–10), but that the reverse effect of HDL on IL-6 signalling was largely null.ConclusionsLow number of small HDL particles are associated with increased hazard of sepsis, sepsis-related death, and sepsis-related critical care admission. However, genetic analyses did not strongly support this as causal. Instead, we demonstrate that increased IL-6 signalling, which is known to alter infection risk, could confound associations with reduced HDL particle count, and suggest this may explain part of the observed association between (small) HDL particle count and sepsis.

Perioperative Death within 24 Hours: An Analysis of 2,000 Incident Reports of the Perioperative and Anesthetic Adverse Events in Thailand (PAAd Thai) Study

Background: Perioperative death is one of the indicators of anesthetic patient safety. The perioperative death rate has dramatically declined with the modern anesthetic techniques and perioperative medicine. Objective: To study contributing factors, factors minimizing incidents, and suggested corrective strategies. Materials and Methods: The present study was part of the Perioperative and Anesthetic Adverse Events in Thailand (PAAd Thai) Study, focusing on the incidents of perioperative death within 24 hours. The perioperative incidents from 22 tertiary hospitals across Thailand were gathered monthly. Two senior anesthesiologists reviewed the reports. Any discrepancy was solved by discussion for a consensus. Results: Of the first 2,000 incident reports in the PAAd Thai Study, there were 404 (20.2%) incident reports of 24 hours perioperative death. Extreme age of less than one year in 6.2% and more than 80 years in 8.2%, with ASA physical status of 3 or more in 97% while 51.2% occurred in the age group between 20 to 64 years. General anesthesia was the main anesthetic technique among fatal cases in 94.1% of the cases. Ninety-one cases (22.5%) occurred in the operating theatre with anesthesiology team witness. The high-risk surgeries with fatal outcomes were general surgery in 46.2%, cardiac surgery in 12.5%, neurological surgery in 11.6%, and endoscopic procedure in 3.2%. Exsanguination in 52.7%, particularly after traffic accident was the major cause of death followed by cardiac factors in 27.2%, and sepsis in 23%. Intraoperative death had higher proportion of exsanguination at 72.5% than postoperative death at 43% (p&lt;0.001). Postoperative death had higher proportion of sepsis-related death and brain death than intraoperative death at 27.5% versus 7.7% (p&lt;0.001), and 20.8% versus 5.5% (p=0.001), respectively. The factor-related death included Patient in 97.8%, Surgical in 42.3%, Anesthetic in 19.3%, and Systematic factors in 31.4%. Fatal causes were considered as preventable in 28.7%, particularly by surgical safety checklist in 18.1%. Conclusion: The multicenter study revealed a high proportion of 24 hours. perioperative death was commonly caused by exsanguination. Postoperative death was related to patient condition. Suggested corrective strategies were quality assurance activity, improved supervision, additional training, ICU availability, and more guidelines and compliance to guidelines including surgical safety checklists. Keywords: Mortality; Perioperative death; Incident report; Surgical safety checklists; Adverse event; Incident report

The value of right ventricular ultrasound assessment and cardiac biomarkers in the prognosis of sepsis.

The aim of this study was to explore the risk factors affecting the prognosis of patients with sepsis using a prospective design. From January 2022 to March 2023, a prospective study was conducted in the Intensive Care Unit (ICU) of Cangzhou Central Hospital, including 58 patients who met the diagnostic criteria for sepsis. Patients were divided into a survival group (39 cases) and a death group (19 cases) based on outcome. Within 24 hours, the following indicators were collected: gender, age, underlying diseases, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, Sequential Organ Failure Assessment (SOFA) score, cardiac troponin I (cTnI), B-type natriuretic peptide (BNP), lactate, procalcitonin, ejection fraction (EF), tricuspid annular plane systolic excursion (TAPSE), systolic velocity (S'), and global longitudinal strain/strain rate (GLS/GLSr) and global circumferential strain/strain rate (GCS/GCSr) by speckle tracking. Logistic regression analysis was used to evaluate the risk factors for mortality in septic patients, and receiver operating characteristic (ROC) curves were used to evaluate the predictive value of various risk factors for sepsis-related death. There was no significant difference in gender, age, underlying diseases, BNP, procalcitonin, EF, TAPSE, S', GLSr, GCS, or GCSr between the two groups (p>0.05). There were statistically significant differences in APACHE II score, SOFA score, cTnI, lactate, and GLS between the two groups (p<0.05). Logistic regression analysis showed that SOFA score (OR=2.32, 95% CI: 1.067-5.289, p<0.05), cTnI (OR=1.19, 95% CI: 1.001-1.312, p<0.05), and GLS (OR=1.58, 95% CI: 1.012-2.721, p<0.05) were risk factors for sepsis-related death (p<0.05). The areas under the ROC curves for SOFA score, cTnI, and GLS were 0.769, 0.757, and 0.846, respectively. SOFA score, cTnI, and GLS are independent risk factors for mortality in patients with sepsis. Among these factors, GLS has the highest predictive value for patient prognosis. Therefore, when predicting the prognosis of patients with sepsis, the assessment of right ventricular ultrasound can be used in clinical practice.

Mendelian Randomization Analysis Reveals Causal Associations of Polyunsaturated Fatty Acids with Sepsis and Mortality Risk.

Despite numerous observational studies reporting a positive correlation between polyunsaturated fatty acids (PUFAs) and the risk of sepsis and mortality, the causation of such an association has yet to be firmly established. Thus, our study aimed to undertake the Mendelian randomization (MR) approach to scrutinize the potential causalities of PUFAs with sepsis and mortality risk. We conducted the MR investigation using genome-wide association study (GWAS) summary statistics of PUFAs [including omega-3 fatty acids (omega-3), omega-6 fatty acids (omega-6), the ratio of omega-6 to omega-3 fatty acids (omega-6:3), docosahexaenoic acid (DHA), linoleic acid (LA)], sepsis, and sepsis mortality. We utilized the GWAS summary data from the UK Biobank. To establish reliable causality, we employed the inverse-variance weighted (IVW) method as the primary analytical approach, together with four additional MR methods. In addition, we performed heterogeneity and horizontal pleiotropy assessments using Cochrane's Qtest and MR-Egger intercept test, respectively. Finally, we performed a series of sensitivity analyses to enhance the precision and veracity of our findings. The IVW method showed that genetically predicted omega-3 [odd ratio (OR) 0.914, 95% confidence interval (CI) 0.845-0.987, P = 0.023] and DHA (OR 0.893, 95%CI 0.815-0.979, P = 0.015) were suggestively linked to a decreased risk of sepsis. Furthermore, genetically predicted DHA (OR 0.819, 95%CI 0.681-0.986, P = 0.035) was suggestively associated with a reduced risk of sepsis-related death. Conversely, the omega-6:3 ratio (OR 1.177, 95%CI 1.011-1.371, P = 0.036) was suggestively linked to an increased risk of sepsis-induced mortality. On the basis of the MR-Egger intercept assessment, it appears that our MR examination was not influenced by any horizontal pleiotropy (all P > 0.05). Moreover, the reliability of the estimated causal association was confirmed by the sensitivity analyses. Our study supported the casual effect between PUFAs and susceptibility to sepsis and sepsis-related death. Our findings underline the importance of specific PUFAs levels, particularly for individuals with a genetic susceptibility to sepsis. Further research is needed to confirm these findings and investigate the underlying mechanisms.

Patient characteristics in sepsis-related deaths: prevalence of advanced frailty, comorbidity, and age in a Norwegian hospital trust

ObjectiveTo examine the prevalence of advanced frailty, comorbidity, and age among sepsis-related deaths in an adult hospital population.MethodsRetrospective chart reviews of deceased adults within a Norwegian hospital trust, with a diagnosis of infection, over 2 years (2018–2019). The likelihood of sepsis-related death was evaluated by clinicians as sepsis-related, possibly sepsis-related, or not sepsis-related.ResultsOf 633 hospital deaths, 179 (28%) were sepsis-related, and 136 (21%) were possibly sepsis-related. Among these 315 patients whose deaths were sepsis-related or possibly sepsis-related, close to three in four patients (73%) were either 85 years or older, living with severe frailty (Clinical Frailty Scale, CFS, score of 7 or more), or an end-stage condition prior to the admission. Among the remaining 27%, 15% were either 80–84 years old, living with frailty corresponding to a CFS score of 6, or severe comorbidity, defined as 5 points or more on the Charlson Comorbidity Index (CCI). The last 12% constituted the presumably healthiest cluster, but in this group as well, the majority died with limitations of care due to their premorbid functional status and/ or comorbidity. Findings remained stable if the population was limited to sepsis-related deaths on clinicians’ reviews or those fulfilling the Sepsis-3 criteria.ConclusionsAdvanced frailty, comorbidity, and age were predominant in hospital fatalities where infection contributed to death, with or without sepsis. This is of importance when considering sepsis-related mortality in similar populations, the applicability of study results to everyday clinical work, and future study designs.

Therapeutic potential of IL6R blockade for the treatment of sepsis and sepsis-related death: A Mendelian randomisation study.

Sepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin 6 (IL-6). Genetic variants in IL6R known to down-regulate IL-6 signalling are associated with improved Coronavirus Disease 2019 (COVID-19) outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RAs). We hypothesised that blockade of IL6R could also improve outcomes in sepsis. We performed a Mendelian randomisation (MR) analysis using single nucleotide polymorphisms (SNPs) in and near IL6R to evaluate the likely causal effects of IL6R blockade on sepsis (primary outcome), sepsis severity, other infections, and COVID-19 (secondary outcomes). We weighted SNPs by their effect on CRP and combined results across them in inverse variance weighted meta-analysis, proxying the effect of IL6RA. Our outcomes were measured in UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative (HGI), and the GenOSept and GainS consortium. We performed several sensitivity analyses to test assumptions of our methods, including utilising variants around CRP and gp130 in a similar analysis. In the UK Biobank cohort (N = 486,484, including 11,643 with sepsis), IL6R blockade was associated with a decreased risk of our primary outcome, sepsis (odds ratio (OR) = 0.80; 95% confidence interval (CI) 0.66 to 0.96, per unit of natural log-transformed CRP decrease). The size of this effect increased with severity, with larger effects on 28-day sepsis mortality (OR = 0.74; 95% CI 0.47 to 1.15); critical care admission with sepsis (OR = 0.48, 95% CI 0.30 to 0.78) and critical care death with sepsis (OR = 0.37, 95% CI 0.14 to 0.98). Similar associations were seen with severe respiratory infection: OR for pneumonia in critical care 0.69 (95% CI 0.49 to 0.97) and for sepsis survival in critical care (OR = 0.22; 95% CI 0.04 to 1.31) in the GainS and GenOSept consortium, although this result had a large degree of imprecision. We also confirm the previously reported protective effect of IL6R blockade on severe COVID-19 (OR = 0.69, 95% CI 0.57 to 0.84) in the COVID-19 HGI, which was of similar magnitude to that seen in sepsis. Sensitivity analyses did not alter our primary results. These results are subject to the limitations and assumptions of MR, which in this case reflects interpretation of these SNP effects as causally acting through blockade of IL6R, and reflect lifetime exposure to IL6R blockade, rather than the effect of therapeutic IL6R blockade. IL6R blockade is causally associated with reduced incidence of sepsis. Similar but imprecisely estimated results supported a causal effect also on sepsis related mortality and critical care admission with sepsis. These effects are comparable in size to the effect seen in severe COVID-19, where IL-6 receptor antagonists were shown to improve survival. These data suggest that a randomised trial of IL-6 receptor antagonists in sepsis should be considered.

Sars-Cov-2 Vaccination Response Monitoring in Lymphoma and Multiple Myeloma Patients Following Standard Versus High-Dose Chemotherapy and Autologous Stem Cell Transplantation

Introduction: According to international guidelines the vaccination schedule for hematological patients is mainly recommended prior to treatment start, three to six months after chemotherapy and following both allogeneic and autologous transplantation due to weakened immune response with variable response efficacy. As for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus several studies have demonstrated high risk of severe infections in patients with hematological malignancies and prolonged virus persistence. Methods: Our prospective study purpose was to evaluate the level of COVID-19 immunity prior to antineoplastic treatment and monitor it until 12 months after transplantation (ASCT group) or 6 months following standard chemotherapy treatment (Chemo group) in previously vaccinated patients with confirmed immune response. All lymphoma and multiple myeloma (MM) patients aged 18 or above that underwent mRNA vaccination against COVID-19, with a confirmed humoral anti-COVID-19 antibody response (targeted antibody titer greater than 17.8 BAU/ml), and were treated with either standard or high-dose chemotherapy and ASCT were eligible. Patients were allowed to receive the second or third vaccination dose in course of study, if they did not receive it previously, and eventual SARS-CoV-2 infections were registered along with the outcome. The study was approved by the independent ethics committee and patients provided written informed consent. Results: Twenty patients in the ASCT group were monitored with a median follow-up of 6 months (range 1-12) and most of them (80%) were in first line of treatment. Eleven patients had myeloma, with four of them undergoing tandem ASCT, and were, therefore, monitored twice, while four patients were affected by lymphoma. Patient characteristics, vaccination status and median anti-Covid-19 values prior to ASCT, one- and three-months following transplantation are described in table 1. Three patients had COVID-19 infection following ASCT and all of them were paucisymptomatic, with anti-COVID-19 antibody value of 150 BAU/ml, 102 BAU/ml and 50 BAU/ml each. Three patients received the third dose following ASCT, and only in one of them slight increase of anti-COVID-19 antibodies was evidenced. Two patients passed away, one due to disease progression and the second patient had pneumonia-related death not associated to SARS-CoV-2. Thirty-one patients in the Chemo group had a median follow-up of 4 months (range 0-12), twenty-five suffering from lymphoma (80%), and nineteen of them received rituximab as part of their treatment, while the rest had MM. Table 1 describes in detail the second group, like the ASCT group. Two patients had COVID-19 positivity alone in course of treatment, while one patient had paucisymptomatic infection and had out-hospital treatment, with anti-COVID-19 antibody value of 292 BAU/ml, 60 BAU/ml and 189 BAU/ml each. Five patients received further vaccination dose in course of treatment, without specific humoral response. Three patients passed away, two of them due to disease progression, while one suffered from sepsis-related death in neutropenic patient negative for SARS-CoV-2. There was no statistical difference according to age, baseline disease, treatment line, number of vaccination doses and rituximab treatment prior to treatment start in the study cohort (p>0.05), using Wilcoxon-Mann-Whitney test. Difference between Chemo and ASCT group anti-COVID-19 values, on the other hand, was statistically different one month following treatment start (p=0.05), unlike baseline and after three months (p>0.05). Lymphoma patients from Chemo group were also more likely to have higher values of anti-COVID-19 antibodies at baseline (p=0.03) and one month (p=0.02) following treatment start compared to MM patients, unlike the ASCT group (p>0.05). Conclusions: The impact of both standard- and high-dose chemotherapy followed by ASCT on anti-COVID-19 humoral response is described in our study and confirms the immunity loss in treated patients. Furthermore, vaccination in course of therapy or following ASCT showed limited benefit in regaining anti-virus immunity. Therefore, the importance of re-vaccination in patients undergoing induction or consolidation treatment remains doubtful. Further studies with larger patient cohorts and longer follow-up are needed in order to analyze and confirm the abovementioned data. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Association between blood urea nitrogen to serum albumin ratio and in-hospital mortality of patients with sepsis in intensive care: A retrospective analysis of the fourth-generation Medical Information Mart for Intensive Care database.

This study aimed to investigate the relationship between the blood urea nitrogen to serum albumin ratio (BAR) and in-hospital mortality in patients with sepsis. This is a retrospective cohort study. All septic patient data for the study were obtained from the intensive care unit of Beth Israel Deaconess Medical Center. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using multivariable Cox regression analyses. Survival curves were plotted and subgroup analyses were stratified by relevant covariates. Among 23,901 patients, 13,464 with sepsis were included. The overall in-hospital mortality rate was 18.9% (2550/13464). After adjustment for confounding factors, patients in the highest BAR quartile had an increased risk of sepsis death than those in the lowest BAR quartile (HR: 1.42, 95% CI: 1.3-1.55), using BAR as a categorical variable. When BAR was presented as a continuous variable, the prevalence of in-hospital sepsis-related death increased by 8% (adjusted HR: 1.08, 95% CI: 1.07-1.1, P < 0.001) for each 5-unit increase in BAR, irrespective of confounders. Stratified analyses indicated age interactions (P < 0.001), and the correlation between BAR and the probability of dying due to sepsis was stable. BAR was significantly associated with in-hospital mortality in intensive care patients with sepsis. A higher BAR in patients with sepsis is associated with a worse prognosis in the ICU in the USA. However, further research is required to confirm this finding.