Sepsis-related Deaths Research Articles

The infection post flexible UreteroreNoscopy (I-FUN) predictive model based on machine learning: a new clinical tool to assess the risk of sepsis post retrograde intrarenal surgery for kidney stone disease.

To create a machine-learning model for estimating the likelihood of post-retrograde intrarenal surgery (RIRS) sepsis. All consecutive patients with kidney stone(s) only undergoing RIRS in 16 centers were prospectively included (January 2022-August 2023). adult, renal stone(s) only, CT scan (within three months), mid-stream urine culture (within 10 days). concomitant ureteral stone, bilateral procedures. In case of symptomatic infection/asymptomatic bacteriuria, patients were given six days of antibiotics according to susceptibility profiles. All patients had antibiotics prophylaxis. Variables selected for the model: age, gender, age-adjusted Charlson Comorbidity Index, stone volume, indwelling preoperative bladder catheter, urine culture, single/multiple stones, indwelling preoperative stent/nephrostomy, ureteric access sheath, surgical time. Analysis was conducted using Python programming language, with Pandas library and machine learning models implemented using the Scikit-learn library. Machine learning algorithms tested: Decision Tree, Random Forest, Gradient Boosting. Overall performance was accurately estimated by K-Fold cross-validation with three folds. 1552 patients were included. There were 20 (1.3%) sepsis cases, 16 (1.0%) septic shock cases, and three more cases (0.2%) of sepsis-related deaths. Random Forest model showed the best performance (precision = 1.00; recall = 0.86; F1 score = 0.92; accuracy = 0.92). A web-based interface of the predictive model was built and is available at https://emabal.pythonanywhere.com/ CONCLUSIONS: Our model can predict post-RIRS sepsis with high accuracy and might facilitate patient selection for day-surgery procedures and identify patients at higher risk of sepsis who deserve extreme attention for prompt identification and treatment.

COVID-19 and sepsis-related excess mortality in the US during the first three years: A national-wide time series study.

The COVID-19 pandemic's global impact has been devastating, causing millions of deaths. Our study investigates excess sepsis-related mortality trends over three years during the pandemic. Using CDC's National Vital Statistics System data from January 2018 to March 2023, we projected sepsis-related deaths during the pandemic using a Poisson log-linear regression model. We compared observed versus predicted deaths and analyzed temporal trends by demographics and regions. Among the 753,160 deaths documented between March 2020 and March 2023, a significant downward trend was noted in sepsis-related mortality rates from March 2022 to March 2023, coinciding with the surge of the Omicron variant. The excess mortality rates were 170.6 per million persons (95% CI: 168.2-172.6), 167.5 per million persons (95% CI: 163.6-170.9), and 73.3 per million persons (95% CI: 69.4-76.6) in the first, second, and third years, respectively. Increased sepsis-related mortality was observed across all age subgroups, with the greatest increase noted in those aged 85 years and above compared to middle- and young-aged decedents. Disparities were also observed across racial/ethnic, sex/gender subgroups, and geographic regions. This study highlights the effectiveness of current policies and prevention measures in response to the long-term circulating of SARS-CoV-2 in the community.

Factors related to sepsis in critical care setting in Rwanda selected referral hospital

BACKGROUND Sepsis is described as potentially fatal organ failure induced by an unbalanced host response to infection. Annual estimates put the number of sepsis cases at over 19 million. The number of sepsis-related deaths is estimated to reach 5 million, with the vast majority happening in LMICs. However, such information is required to increase awareness of sepsis's global impact, especially in developing countries like Rwanda. The study aimed to evaluate the factors related to sepsis in a critical care setting in Rwanda's selected referral hospital. METHODOLOGY A cross-sectional study design with a quantitative approach was conducted and simple random sampling was used. Files of 191 study participants and a structured questionnaire were used in data collection, bivariate and multivariate logistic regression in SPSS version 21 was used in data analysis, and results were presented in tables. RESULTS The prevalence of sepsis was 40.3%. By plotting bivariate analysis the results showed that sepsis was significantly associated with the following variables; self-employed as an occupation with (OR=0.216, 95%CI:0.047-0.987) p 0.48 taking reference for unemployed; pneumonia with sepsis at (OR=1.993, 95%CI:0.657-6.043) p 0.023, systemic infection (OR=0.329, 95%CI:0.104-1.044) p 0.059; other procedure with (OR=4.735,95%CI:1.509- 14.855); procedure timeframe not mentioned with (OR=0.123,95%CI:0.027-0.553) p 0.032; hospitalized 15 days and more with OR=6.697 (95%CI:0.809-59.863) and p 0.032. CONCLUSION The prevalence of sepsis was 40.3% and factors related to sepsis include; occupation, having pneumonia, systemic infection, timeframe for carrying out the procedure, and patient being hospitalized for 15 days and more.

The burden of sepsis in Italy: an analysis of treatable mortality trends

Abstract Background The burden of sepsis, a life-threatening condition triggered by the body’s extreme response to infection, remains a critical global healthcare concern. Sepsis-related deaths often result from delayed recognition, insufficient treatment, or gaps in healthcare delivery. The study aims to analyze treatable mortality for sepsis in Italy and its regions. Methods A retrospective study was conducted on data of treatable mortality for sepsis in Italy and its regions. According to joint OECD/Eurostat list, we included sepsis deaths with the ICD-10 codes A40 (excl. A40.3 [sepsis due to Streptococcus pneumoniae]) and A41 (excl. A41.3 [sepsis due to Hemophilus influenzae]) from 2006 to 2019. Through data on the resident population two-year age-standardized rates by region were calculated. Results From 2006/7 to 2018/9 an overall increase was observed in Italy, from 1.6 to 2.2 age-standardized mortality rates with a maximum peak in 2014/5 (+46.7%). This trend was confirmed for Lombardy (+47.8%), Veneto (+48.8%), Emilia-Romagna (+49.3%), Tuscany (52.0%), Marche (+58.4%%), Abruzzo (39.4%), Molise (26.7%), Apulia (+57.0%), Sicily (+57.2%), and Sardinia (+46.8%). Aosta Valley (+72,5%) had a maximum peak in 2010/1, while Piedmont (+42.5%), Autonomous Province (A.P.) of Bolzano (+27.8%), A.P. of Trento (+45.0%), Friuli-Venezia Giulia (+23.3%) in 2012/3, Calabria (+46.4%) in 2016/7 and lastly Campania (+52.9%) and Basilicata (+73.0%) in 2018/9. Liguria (+49.8%), Latium (47.2%) and Umbria (49.3%) showed two maximum values, one in the 2012/3 and the other in the 2014/5. Conclusions We observed an overall increase in age-standardized mortality rates throughout Italy, with a peak in 2014/5. This trend was resumed in ten regions, while three regions showed multiple peaks, indicating fluctuations in mortality rates. These findings underline the importance of targeted health interventions and policy initiatives to address region-specific health challenges. Key messages • Regional disparities in mortality rates highlight the necessity for customized health interventions and policy measures between Italian regions. • Recognizing fluctuating mortality trends in specific regions is crucial to effectively address various health challenges.

Opportunities and Challenges of Application of Cytosorb Therapy in Sepsis Management

Sepsis is a life-threatening organ dysfunction due to a dysregulated host response to infection. In 2017, an estimated 48·9 million incident cases of sepsis were recorded worldwide, and 11·0 million sepsis-related deaths were reported, representing 19·7% of all global deaths.1 Though overall data related to sepsis is poor but it is also a major health care challenge for resource limited countries. Severe sepsis is a significant & common health problem in ICU patients of Bangladesh2. A continuum of severity from sepsis to septic shock and multi-organ dysfunction syndrome (MODS) exists. MODS is a clinical syndrome characterized by the development of progressive and potentially reversible physiologic dysfunction in 2 or more organs or organ systems that is induced by a variety of acute insults, including sepsis. Sepsis leads to malignant intravascular inflammation, coagulopathy, circulatory derangement, tissue hypoxia, cytotoxicity and apoptosis. As a result, dysfunction of vital organ systems occur. Host response and other factors influenc outcome. Patients with sepsis must be treated with-timely, appropriate antibiotics, intravenousfluids, vasopressor and inotropic support & oxygen therapy.3 Other additional treatments including extracorporeal blood purification techniques (BPT). These techniques include hemofiltration, hemoperfusion, intermittent or continuous high-volume hemofiltration (HVHF), plasmapheresis or adsorption.4 The rationale behind such an approach is to achieve “immune homeostasis” which theoretically reduces the potential damage caused by dysregulation of the host response to infection. Given the pivotal role of cytokine production in sepsis, it follows that removal of these substances, through such BPT, may attenuate the response particularly in the early phase of sepsis.5 Indications include 1) Rhabdomyolysis resulting from Reperfusion syndrome, Trauma, Malignant Hyperthermia. 2) External injuries including Sepsis/Septic shock, Hemorrhagic shock, Trauma, Ruptured aortic aneurysm, Post-Cardiac Arrest Syndrome, Cardio-pulmonary resuscitation, Extensive surgery, Organ transplantation, Cardiosurgical intervention, Severe skin and soft tissue damage, Burns, Necrotizing fasciitis, Post-Cardiotomy Syndrome, Acute Respiratory Distress Syndrome. 3) Diseases: Pancreatitis, Liver insufficiency, Renal insufficiency, Stroke, Myocardial infarction, Cardiogenic shock/Heart failure, Tumor Lysis Syndrome, Hemophagocytosis Syndrome. Liver failure/Hyperbilirubinemia bridging to transplant or to recovery, Life-threatening bleeding under Direct Oral Anticoagulants (DOAC)6. Bangladesh Crit Care J September 2024; 12 (2): 79-80

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.

B-137 Sepsis risk prediction using machine learning (ML) and routine blood markers up to 1 week before emergency admission

Abstract Background Sepsis is a major global health concern, responsible for approximately 50 million cases and 11 million deaths annually, representing 20% of global mortality. It is the leading cause of hospital readmissions and deaths, with associated costs exceeding $38 billion per year. Alarmingly, 80% of sepsis cases occur outside the hospital, and 70% of patients visit an outpatient facility within a week of admission. Early diagnosis and appropriate treatment could prevent 80% of sepsis-related deaths. Our study demonstrates that machine learning models hold significant promise in identifying sepsis risks using routine blood tests up to 1 week before admission. Methods For our study, we utilized a dataset of over 25,000 patient records, including both sepsis and non-sepsis cases, sourced from MIMIC-IV (version 2.2), a comprehensive electronic health record dataset from Beth Israel Deaconess Medical Center, Boston, MA. We employed a gradient boosted model with 300 trees, a maximal depth of 30 layers, and gain ratio as the criterion for attribute selection. The model's performance was evaluated using 10-fold cross-validation, demonstrating optimal performance. Input parameters included age, gender, and results of routine blood markers such as complete blood counts, differential counts, comprehensive metabolic panels, and lipid panels recorded up to 1 week before sepsis diagnosis. Results Our model achieved remarkable predictive accuracy for sepsis risk, with an area under the receiver operating characteristic curve (AUC) of 0.99 and accuracy of 0.99. Notably, the model achieved 1.0 sensitivity, 0.99 specificity, 0.99 positive predictive value, 1.0 negative predictive value, 0.99 F measure, and 0.99 Youden index. Calcium, protein, liver enzymes, hematocrit, white blood cells, and cholesterol were identified as key contributors to sepsis risk prediction. Importantly, prediction accuracy remained consistent up to 1 week prior to diagnosis. Conclusions In conclusion, dysregulated intracellular calcium handling during sepsis is associated with an intensified inflammatory response, cellular death, and subsequent organ dysfunction. Low serum protein levels, particularly albumin, are linked to poor outcomes in sepsis. Recent studies have identified liver dysfunction as an early event in sepsis, underscoring its significance in the disease process. Elevated bilirubin levels are associated with an increased risk of mortality. Low hematocrit (HCT) levels are linked to higher 30-day mortality and serve as an independent prognostic biomarker in sepsis. Monocytes play a significant role in sepsis pathophysiology, undergoing various changes including preserved phagocytic activity, increased reactive oxygen species and nitric oxide generation, and decreased production of inflammatory cytokines such as IL-6 and TNF-alpha. Septic patients often exhibit lymphopenia, affecting CD4 and CD8 T cells, B cells, and natural killer (NK) cells. Hypocholesterolemia is common in sepsis and serves as an important early prognostic factor, with low plasma concentrations associated with poor outcomes. Since every hour of delayed treatment increases the risk of death by 4%-9%, changes in routine blood markers detected by machine learning models can provide early indications of impending sepsis up to 1 week before diagnosis.

Released bacterial ATP shapes local and systemic inflammation during abdominal sepsis

Sepsis causes millions of deaths per year worldwide and is a current global health priority declared by the WHO. Sepsis-related deaths are a result of dysregulated inflammatory immune responses indicating the need to develop strategies to target inflammation. An important mediator of inflammation is extracellular adenosine triphosphate (ATP) that is released by inflamed host cells and tissues, and also by bacteria in a strain-specific and growth-dependent manner. Here, we investigated the mechanisms by which bacteria release ATP. Using genetic mutant strains of Escherichia coli (E. coli), we demonstrate that ATP release is dependent on ATP synthase within the inner bacterial membrane. In addition, impaired integrity of the outer bacterial membrane notably contributes to ATP release and is associated with bacterial death. In a mouse model of abdominal sepsis, local effects of bacterial ATP were analyzed using a transformed E. coli bearing an arabinose-inducible periplasmic apyrase hydrolyzing ATP to be released. Abrogating bacterial ATP release shows that bacterial ATP suppresses local immune responses, resulting in reduced neutrophil counts and impaired survival. In addition, bacterial ATP has systemic effects via its transport in outer membrane vesicles (OMV). ATP-loaded OMV are quickly distributed throughout the body and upregulated expression of genes activating degranulation in neutrophils, potentially contributing to the exacerbation of sepsis severity. This study reveals mechanisms of bacterial ATP release and its local and systemic roles in sepsis pathogenesis.

Released bacterial ATP shapes local and systemic inflammation during abdominal sepsis.

Sepsis causes millions of deaths per year worldwide and is a current global health priority declared by the WHO. Sepsis-related deaths are a result of dysregulated inflammatory immune responses indicating the need to develop strategies to target inflammation. An important mediator of inflammation is extracellular adenosine triphosphate (ATP) that is released by inflamed host cells and tissues, and also by bacteria in a strain-specific and growth-dependent manner. Here, we investigated the mechanisms by which bacteria release ATP. Using genetic mutant strains of Escherichia coli (E. coli), we demonstrate that ATP release is dependent on ATP synthase within the inner bacterial membrane. In addition, impaired integrity of the outer bacterial membrane notably contributes to ATP release and is associated with bacterial death. In a mouse model of abdominal sepsis, local effects of bacterial ATP were analyzed using a transformed E. coli bearing an arabinose-inducible periplasmic apyrase hydrolyzing ATP to be released. Abrogating bacterial ATP release shows that bacterial ATP suppresses local immune responses, resulting in reduced neutrophil counts and impaired survival. In addition, bacterial ATP has systemic effects via its transport in outer membrane vesicles (OMV). ATP-loaded OMV are quickly distributed throughout the body and upregulated expression of genes activating degranulation in neutrophils, potentially contributing to the exacerbation of sepsis severity. This study reveals mechanisms of bacterial ATP release and its local and systemic roles in sepsis pathogenesis.

Serum Vitamin D level in sepsis patients and its correlation with clinical outcome

Background: Serum Vitamin D plays an important role in sepsis; lack of Vitamin D has been linked to a higher risk for the progression of infections, as it signifies an immune system mediator. Aims and Objectives: In this study, our aim is to evaluate the correlation between serum levels of Vitamin D and clinical outcome in sepsis patients. Materials and Methods: The present prospective cohort study was performed on patients over 18 years of age suspected of sepsis presenting to an emergency department during 1 year. For all eligible patients, the blood sample was drawn for the measurement of serum level of Vitamin D3, and its correlation with outcomes such as mortality, renal failure, and liver failure was assessed. Results: One hundred and sixty patients with a mean age of 48.5±20.587 years were studied (60.0% males). The mean serum level of Vitamin D3 in the studied patients was 32.0±12.54 ng/mL. By considering 30–100 ng/mL as the normal range of Vitamin D, 70% of the patients had Vitamin D deficiency. Only age (r=−0.261, P=0.037) and mortality (r=−0.426, P=0.025) showed a significant correlation with mean Vitamin D. Conclusion: Based on the result of this study, out of 160 patients, 61.25% of patients with sepsis are Vitamin D deficient. There is a significant and inverse relationship between mortality and advanced age which were associated with serum Vitamin D3 levels. Hence, supplementing with Vitamin D appears to have potential benefits in reducing infection rates, sepsis-related deaths, and infection prevalence, particularly in the elderly.

Predictive Accuracy of Infant Clinical Sign Algorithms for Mortality in Young Infants Aged 0 to 59 Days: A Systematic Review.

Clinical sign algorithms are a key strategy to identify young infants at risk of mortality. Synthesize the evidence on the accuracy of clinical sign algorithms to predict all-cause mortality in young infants 0-59 days. MEDLINE, Embase, CINAHL, Global Index Medicus, and Cochrane CENTRAL Registry of Trials. Studies evaluating the accuracy of infant clinical sign algorithms to predict mortality. We used Cochrane methods for study screening, data extraction, and risk of bias assessment. We determined certainty of evidence using Grading of Recommendations Assessment Development and Evaluation. We included 11 studies examining 26 algorithms. Three studies from non-hospital/community settings examined sign-based checklists (n = 13). Eight hospital-based studies validated regression models (n = 13), which were administered as weighted scores (n = 8), regression formulas (n = 4), and a nomogram (n = 1). One checklist from India had a sensitivity of 98% (95% CI: 88%-100%) and specificity of 94% (93%-95%) for predicting sepsis-related deaths. However, external validation in Bangladesh showed very low sensitivity of 3% (0%-10%) with specificity of 99% (99%-99%) for all-cause mortality (ages 0-9 days). For hospital-based prediction models, area under the curve (AUC) ranged from 0.76-0.93 (n = 13). The Score for Essential Neonatal Symptoms and Signs had an AUC of 0.89 (0.84-0.93) in the derivation cohort for mortality, and external validation showed an AUC of 0.83 (0.83-0.84). Heterogeneity of algorithms and lack of external validation limited the evidence. Clinical sign algorithms may help identify at-risk young infants, particularly in hospital settings; however, overall certainty of evidence is low with limited external validation.

Role of Kynurenine and Its Derivatives in the Neuroimmune System.

In recent years, there has been a growing realization of intricate interactions between the nervous and immune systems, characterized by shared humoral factors and receptors. This interplay forms the basis of the neuroimmune system, the understanding of which will provide insights into the pathogenesis of neurological diseases, in which the involvement of the immune system has been overlooked. Kynurenine and its derivatives derived from tryptophan have long been implicated in the pathogenesis of various neurological diseases. Recent studies have revealed their close association not only with neurological disorders but also with sepsis-related deaths. This review provides an overview of the biochemistry of kynurenine and its derivatives, followed by a discussion of their role via the modulation of the neuroimmune system in various diseases.

Trajectories of State-Level Sepsis-Related Mortality by Race and Ethnicity Group in the United States.

Background: Recent reports on the national temporal trends of sepsis-related mortality in the United States (US) suggested improvement of outcomes in several race and ethnicity groups. However, it is unknown whether national data reflect state-level trajectories. Methods: We used the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research Multiple Cause of Death data set to identify all decedents with sepsis in the US during 2010-2019. Negative binomial regression models were fit to estimate national and state-level trends of age-adjusted sepsis-related mortality rates within race and ethnicity groups. Results: There were 1,852,610 sepsis-related deaths in the US during 2010-2019. Nationally, sepsis-related mortality rates decreased among Blacks and Asians, were unchanged among Hispanics and Native Americans, and rose among Whites. The percent of states with similar trends were 30.0% among Blacks, 32.1% among Asians, 74.3% among Hispanics, 75.0% among Native Americans, and 66.7%% among Whites, while trending in opposite direction from 3.6% among Asians to 15.0% among Blacks. Conclusions: National trends in sepsis-related mortality in the US did not represent state-level trajectories in race ethnicity groups. Gains in sepsis outcomes among race and ethnicity groups at the national level were not shared equitably at the state level.

Sepsis-related mortality: long-term trends in Northeastern Italy, including pandemic years

Background Global estimates of sepsis mortality are based on multiple causes of death (MCOD, any mention of the condition on death certificates); however, MCOD data are sparse and mainly referring to the pre-pandemic period. Objectives To investigate recent trends in sepsis-related mortality, associated sites of infection, and comorbidities in Veneto (Northeastern Italy). Methods Mortality records from 2008 to 2022 were extracted, and sepsis-related mortality was assessed based both on the underlying cause of death (UCOD) and on MCOD. The average annual percent change in age-standardised rates was estimated by join point regression through the whole study period. MCOD records were investigated to retrieve infection sites and comorbidities. Results Sepsis was mentioned in 63,479 death certificates, growing from 4.9% out of all deaths in 2008 to 12.9% in 2022. Age-standardised mortality rates increased yearly by 8.2% (95%CI 2.1–14.7%) based on the UCOD and by 5.9% (95%CI 5.3–6.5%) based on MCOD. Sharp peaks in monthly mortality were observed in correspondence with flu epidemics, COVID-19 pandemic waves, and periods of extreme heat. The percentage of sepsis-related deaths associated to urinary tract infections, and with mention of neurodegenerative disorders and chronic kidney disease increased over time. Conclusion Raised awareness of physicians, ageing of the population, spread of antimicrobial resistance further fuelled by the COVID-19 pandemic are among reasons of increasing sepsis-related mortality in Italy. Continuous monitoring of sepsis by means of MCOD data and other surveillance tools is warranted.

Impact of Exercise Training on Survival Rate and Neural Cell Death in Sepsis Through the Maintenance of Redox Equilibrium.

Sepsis-related deaths occur during both the early proinflammatory and the late immunosuppressive phases of the condition. The balance of pro- and anti-inflammatory responses is influenced by damaged cells that die via either proinflammatory necroptosis or anti-inflammatory apoptosis. Both forms of cell death may be mediated by reactive oxygen species (ROS) generated during the proinflammatory response. Recent evidence suggests that exercise training boosts antioxidative capacity and could offer protection against sepsis. Given these findings, we aimed to examine the impact of exercise training on neural cell death in the context of sepsis. We assessed the effectiveness of exercise in reducing ROS production and the inflammatory response using a cecal ligation and puncture (CLP)-induced sepsis model. Forty C57BL/6N male mice were randomly divided into 2 groups: control (CLP-Con; n=20) and experimental (CLP-Ex; n=20). Before the induction of sepsis by CLP, the CLP-Ex mice underwent interval training on a treadmill 3 days per week for 8 weeks. Each day involved 10 cycles of 2 minutes at 8 m/min and 2 minutes at 15 m/min. After the CLP procedure, we monitored the survival of 10 mice from each group over a 30-hour period. The findings indicated that exercise training increased the survival rate among mice with CLP-induced sepsis by enhancing antioxidative capacity and delaying the transition from a hyperdynamic to an immunosuppressive state. Exercise training may delay the progression from the hyperdynamic state to the hypodynamic phase of sepsis by increasing antioxidant capacity and reducing apoptotic cell death.

Sustaining the Continued Effectiveness of an Antimicrobial Stewardship Program in Preterm Infants.

There are wide variations in antibiotic use in neonatal intensive care units (NICUs). Limited data are available on antimicrobial stewardship (AS) programs and long-term maintenance of AS interventions in preterm very-low-birth-weight (VLBW) infants. We extended a single-centre observational study carried out in an Italian NICU. Three periods were compared: I. "baseline" (2011-2012), II. "intervention" (2016-2017), and III. "maintenance" (2020-2021). Intensive training of medical and nursing staff on AS occurred between periods I and II. AS protocols and algorithms were maintained and implemented between periods II and III. There were 111, 119, and 100 VLBW infants in periods I, II, and III, respectively. In the "intervention period", there was a reduction in antibiotic use, reported as days of antibiotic therapy per 1000 patient days (215 vs. 302, p < 0.01). In the "maintenance period", the number of culture-proven sepsis increased. Nevertheless, antibiotic exposure of uninfected VLBW infants was lower, while no sepsis-related deaths occurred. Our restriction was mostly directed at shortening antibiotic regimens with a policy of 48 h rule-out sepsis (median days of early empiric antibiotics: 6 vs. 3 vs. 2 in periods I, II, and III, respectively, p < 0.001). Moreover, antibiotics administered for so-called culture-negative sepsis were reduced (22% vs. 11% vs. 6%, p = 0.002), especially in infants with a birth weight between 1000 and 1499 g. AS is feasible in preterm VLBW infants, and antibiotic use can be safely reduced. AS interventions, namely, the shortening of antibiotic courses in uninfected infants, can be sustained over time with periodic clinical audits and daily discussion of antimicrobial therapies among staff members.

Call for a Singapore National Action Plan for Sepsis (SNAPS): Stop sepsis, save lives.

Sepsis is a life-threatening organ dysfunction syndrome caused by a dysregulated host response to an infection.1 It affects up to 48.9 million people globally every year and causes 11 million sepsis-related deaths, accounting for 1 in every 5 deaths worldwide.2 The huge disease burden leads to significant consumption of healthcare resources due to longer hospitalisation and the need for intensive care.3 The resultant economic impact is tremendous; for instance, the 1-year incremental costs of sepsis to the healthcare system in Ontario, Canada approximates CAD 1 billion.3 In addition to the complexity of care required for sepsis, the higher healthcare costs incurred may be explained by the post-sepsis syndrome. Sequelae of sepsis include physical, psychological and medical complications.4

Rab26 alleviates sepsis-induced immunosuppression as a master regulator of macrophage ferroptosis and polarization shift

Macrophage dysfunction is a significant contributor to more than 70 % of sepsis-related deaths, specifically secondary bacterial infections, during the immunosuppression stage of sepsis. Nevertheless, the role of Rab26 in this context remains unclear. In this study, we observed a substantial decrease in Rab26 expression in macrophages during the immunosuppressive phase of sepsis, which was also found to be suppressed by high extracellular levels of HMGB1. During the progression of sepsis, Rab26 deficiency promotes a polarization shift from the M1 to the M2-like phenotype in macrophages, rendering them susceptible to ferroptosis. Subsequent experimentation has revealed that Rab26 deficiency facilitates the degradation of GPX4, thereby aggravating macrophage ferroptosis through the upregulation of levels of lipid ROS, MDA, and ferrous iron induced by RSL3, a ferroptosis inducer. Additionally, Rab26-deficient mice in the immunosuppressed phase of sepsis exhibit heightened susceptibility to secondary infections, leading to exacerbated lung tissue damage and increased mortality rate. Overall, these findings indicate that Rab26 plays a crucial role in sepsis-induced macrophage immunosuppression by regulating macrophage ferroptosis and polarization. Hence, it represents a potential novel target for sepsis therapy.

Preventable deaths involving sepsis in England and Wales, 2013-2022: a systematic case series of coroners' reports.

Coroners' Prevention of Future Death (PFDs) reports are an under-utilized resource to learn about preventable deaths in England and Wales. We aimed to identify sepsis-related PFDs and explore the causes and concerns in this subset of preventable sepsis deaths. Four thousand three hundred five reports were acquired from the Courts and Tribunals Judiciary website between July 2013 and November 2022, which were screened for sepsis. Demographic information, coroners concerns and responses to these reports were extracted and analyzed, including a detailed paediatric subgroup analysis. Two hundred sixty-five reports (6% of total PFDs) involved sepsis-related deaths. The most common cause of death in these reports was "sepsis without septic shock" (42%) and the most common site of infection was the respiratory system (18%) followed by gastrointestinal (16%) and skin (13%) infections. Specific pathogens were named in few reports (27%). Many deaths involved multimorbid patients (49%) or those with recent surgery (26%). Coroners named 773 individual concerns, the most frequent were: a failure to keep accurate records or notes (28%), failure in communication or handover (27%) or failure to recognize risk factors or comorbidities (20%). Paediatric cases frequently reported issues with sepsis screening tools (26%). Sepsis PFDs resulted in 421 individual reports being sent, of which 45% received no response. Most organisations who did respond acknowledged concerns and initiated a new change (74%). Sepsis-related PFDs provide valuable insights into preventable causes of sepsis and identify important sources of improvement in sepsis care. Wider dissemination of findings is vital to learn from these reports.

Flat Dose Intravenous Immunoglobulin Primary Infection Prophylaxis in Multiple Myeloma Patients on Bispecific Antibody Therapy: Vanderbilt Experience

BACKGROUND Bispecific antibodies (BsAbs) are novel immunotherapeutic agents with prolific anti-multiple myeloma (MM) efficacy in highly relapsed/refractory disease (RRMM). They have been associated with profound and prolonged hypogammaglobinemia which represents a unique challenge regarding increased risk of serious (sometimes fatal) infections. Though IVIG has historically been dosed at 0.4g/kg for secondary prophylaxis, there is still uncertainty in optimal timing, schedule and frequency of supplementation in MM patients. At Vanderbilt University Medical Center, we have adopted a flat dose 10g IVIG prophylaxis schedule, which on average delivers ~36% of historical, weight-based dosing. At present, expert recommendations advise IVIG replacement every 4 weeks in recipients of BsAb starting the second month of therapy and continuing until the end of therapy or until serum IgG levels reach &amp;gt; 400 mg/dL, whichever is longer ( Mohan M et al. Br J Haematol.2023;00:1-11). Considering that MM BsAbs are currently used with continued dosing schedule, adoption and anticipated new BsAb approvals are increasing, IVIG has previously been on national/global shortage (occasionally unavailable), IVIG replacement during hypogammaglobulinemia represents a crucial aspect of adequate infection prophylaxis in MM, we explored the impact of our institutional 10g IVIG prophylaxis on infection rates in RRMM patients receiving BsAbs. Prior studies with comparable BsAbs reported Grade (G) ≥3 infection rate of 32-45% and 18%, in anti-BCMA and anti-GPRC5D BsAbs, respectively. In these trials, overall, 14-53% of patients received IVIG prophylaxis. METHODS We performed a retrospective review using electronic medical record of RRMM patients receiving anti-BCMA or anti-GPRC5D BsAbs from Jan 2019 to Dec 2022, either on clinical trials or as a standard of care at our institution. The inclusion criteria were minimum of two months of BsAb therapy, and the use of at least one month of monthly IVIG prophylaxis for serum IgG &amp;lt; 400 mg/dL. All patients were also on baseline valacyclovir, trimethoprim-sulfamethoxazole and levofloxacin prophylaxis. Routine disease and treatment specifics as well as infection rates and grades were collected. Infections were defined as mild (infections treated outpatient), moderate (required hospital admission) or severe (hospital admission with intensive care unit level of care), next to also being graded by CTCAE v5 with the rest of hematologic and non-hematologic adverse events (AEs). RESULTS A total of 30 patients with RRMM were identified. Table 1 illustrates the demographic and disease specifics: 79% received a median (range) of 4 (2-7) lines of prior therapy, over half were penta-class exposed, 27% were triple and quad refractory, 67% received a prior autologous stem cell transplant and 17% underwent prior treatment with BCMA targeting CAR-T therapy. All except 2 patients received BsAb therapy on clinical trials. Anti-GPRC5D BsAb was used to treat 60% of patients, while the rest (40%) received anti-BCMA BsAb, all of which were given for a median of 27 (12-45) months (Table 1). Overall, 30% of patients had one infectious episode, while 43% had ≥2. Viral infections (57%) were twice as common as bacterial (30%) (Table 2). Infections were mild in 60%, moderate in 23%, and severe in 6.6% of patients. We observed 27% rate of G ≥3 infectious complications. Patients had a median (range) IgG at diagnosis of 1284(196-5431), and 499(210-2246) at the time of onset of first infection (IgG values at the start of BsAb therapy, at first and at ≥2 infections are outlined in Table 2). The rate of G ≥3 neutropenia and lymphopenia was 6.6% and 30% respectively. There were 2 (6.6%) sepsis related deaths, one each with anti-BCMA and anti-GPRC5D BsAbs. Table 2 also describes severity and the rates of cytokine release syndrome and neurotoxicity. CONCLUSIONS We observed relatively lower rate of severe or ≥ G3 infectious events with 10g flat IVIG dosing schedule. While our results represent a small, single-institutional cohort of predominantly anti-GPRC5D treated RRMM patients and require prospective validation in a randomized (IVIG 10g vs 0.4g/kg body weight) fashion, they demonstrate feasibility of reduced level dosing of a critical resource such as IVIG, in the fast expanding, national/global BsAb-based MM armamentarium.