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Sepsis-induced acute lung injury (ALI), characterized by widespread lung dysfunction, is associated with significant morbidity and mortality due to the lack of effective pharmacological treatments available clinically. Small-molecule compounds derived from natural products represent an innovative source and have demonstrated therapeutic potential against sepsis-induced ALI. These natural small molecules may provide a promising alternative treatment option for sepsis-induced ALI. This review aims to summarize the pathogenesis of sepsis and potential therapeutic targets. It assembles critical updates (from 2014 to 2024) on natural small molecules with therapeutic potential against sepsis-induced ALI, detailing their sources, structures, effects, and mechanisms of action. [ABSTRACT FROM AUTHOR]

Sepsis-induced acute lung injury (ALI), characterized by widespread lung dysfunction, is associated with significant morbidity and mortality due to the lack of effective pharmacological treatments available clinically. Small-molecule compounds derived from natural products represent an innovative source and have demonstrated therapeutic potential against sepsis-induced ALI. These natural small molecules may provide a promising alternative treatment option for sepsis-induced ALI. This review aims to summarize the pathogenesis of sepsis and potential therapeutic targets. It assembles critical updates (from 2014 to 2024) on natural small molecules with therapeutic potential against sepsis-induced ALI, detailing their sources, structures, effects, and mechanisms of action.

Background: Sepsis is a syndrome that occurs following an infection and marked by severe inflammatory responses, and if not treated in time, it can lead to multi-organ failure syndrome and death. This study examines the effects of a novel combination therapy using azithromycin and mesenchymal stem cell-derived extracellular vesicles (EVs) on a cecal ligation and puncture (CLP) model of sepsis., Methods: Human Wharton's jelly-mesenchymal stem cells were cultured, characterized, and used to extract EVs. The CLP sepsis model was induced in mice, followed by treatments: saline, AZM, EVs, and combination therapy (A+E). Clinical sepsis scores were recorded 24 h post-treatment. Serum, peritoneal fluid, and organ tissues (kidney, liver, lung) were collected and analyzed for biochemical parameters (AST ALT, and creatinine), inflammatory markers, bacterial load, and histopathological changes., Results: The A+E combined treatment improved the clinical scores of septic mice. The administration of A+E reduced bacterial loads in the peritoneum of septic mice, contributing to effective control of infection. Inflammatory markers of neutrophils-to-lymphocytes ratio (NLR) and TNF-α serum levels were significantly lower in the combinational therapy group, indicating significant anti-inflammatory effect of this combination. Additionally, combination of AZM and EVs alleviated organ damage mainly within liver, kidneys and lungs. Based on histopathological assessments and biochemical parameters, there was diminished tissue damage as well as reduced inflammation, which is correlated with improved functions of these vital organs., Conclusion: The combined use of azithromycin and EVs offers a promising therapeutic approach for sepsis by effectively controlling infection and modulating the inflammatory response., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Mesenchymal Stromal Cells (MSCs) are the preferred candidates for therapeutics as they possess multi-directional differentiation potential, exhibit potent immunomodulatory activity, are anti-inflammatory, and can function like antimicrobials. These capabilities have therefore encouraged scientists to undertake numerous preclinical as well as a few clinical trials to access the translational potential of MSCs in disease therapeutics. In spite of these efforts, the efficacy of MSCs has not been consistent-as is reflected in the large variation in the values of outcome measures like survival rates. Survival rate is a resultant of complex cascading interactions that not only depends upon upstream experimental factors like dosage, time of infusion, type of transplant, etc.; but is also dictated, post-infusion, by intrinsic host specific attributes like inflammatory microniche including proinflammatory cytokines and alarmins released by the damaged host cells. These complex interdependencies make a researcher's task of designing MSC transfusion experiments challenging., Methods: In order to identify the rules and associated attributes that influence the final outcome (survival rates) of MSC transfusion experiments, we decided to apply machine learning techniques on manually curated data collected from available literature. As sepsis is a multi-faceted condition that involves highly dysregulated immune response, inflammatory environment and microbial invasion, sepsis can be an efficient model to verify the therapeutic effects of MSCs. We therefore decided to implement rule-based classification models on data obtained from studies involving interventions of MSCs in sepsis preclinical models., Results: The rules from the generated graph models indicated that survival rates, post-MSC-infusion, are influenced by factors like source, dosage, time of infusion, pre-Interleukin-6 (IL-6)/ Tumour Necrosis Factor- alpha (TNF-α levels, etc. CONCLUSION: This approach provides important information for optimization of MSCs based treatment strategies that may help the researchers design their experiments., (© 2024. The Author(s).)

Objectives: It is suggested that sepsis may be classified into four clinical phenotypes, using an algorithm employing 29 admission parameters. We applied a simplified phenotyping algorithm among patients with bacterial sepsis and severe COVID-19 and assessed characteristics and outcomes of the derived phenotypes., Design: Retrospective analysis of data from prospective clinical studies., Setting: Greek ICUs and Internal Medicine departments., Patients and Interventions: We analyzed 1498 patients, 620 with bacterial sepsis and 878 with severe COVID-19. We implemented a six-parameter algorithm (creatinine, lactate, aspartate transaminase, bilirubin, C-reactive protein, and international normalized ratio) to classify patients with bacterial sepsis intro previously defined phenotypes. Patients with severe COVID-19, included in two open-label immunotherapy trials were subsequently classified. Heterogeneity of treatment effect of anakinra was assessed. The primary outcome was 28-day mortality., Measurements and Main Results: The algorithm validated the presence of the four phenotypes across the cohort of bacterial sepsis and the individual studies included in this cohort. Phenotype α represented younger patients with low risk of death, β was associated with high comorbidity burden, and δ with the highest mortality. Phenotype assignment was independently associated with outcome, even after adjustment for Charlson Comorbidity Index. Phenotype distribution and outcomes in severe COVID-19 followed a similar pattern., Conclusions: A simplified algorithm successfully identified previously derived phenotypes of bacterial sepsis, which were predictive of outcome. This classification may apply to patients with severe COVID-19 with prognostic implications., Competing Interests: Dr. Karakike has received funding by the Horizon2020 Marie Skłodowska-Curie International Training Network “the European Sepsis Academy” (grant number 676129- granted to the National and Kapodistrian University of Athens). Dr. Poulakou reports receiving grant funding and/or speaker’s honoraria from Gilead, Menarini, Merck Sharp & Dohme (MSD), Pfizer, Roche, and Sobi. Dr. Panagopoulos has received honoraria from GILEAD Sciences, Janssen, and MSD. Dr. Milionis reports receiving honoraria, consulting fees, and nonfinancial support from healthcare companies, including Amgen, Angelini, Bayer, Mylan, MSD, Pfizer, and Servier. Dr. Dalekos has acted as advisor/lecturer for Abbvie, Bristol-Myers Squibb, Gilead, Novartis, Roche, Amgen, MSD, Janssen, Ipsen, Genkyotex, Sobi, and Pfizer; he has received grant support from Bristol-Myers Squib, Gilead, Roche, Janssen, Abbvie, and Bayer; and he was or is currently principal investigator in national and international protocols sponsored by Abbvie, Bristol-Myers Squibb, Novartis, Gilead, Novo Nordisk, Genkyotex, Regulus Therapeutics, Tiziana Life Sciences, Bayer, Astellas, Ipsen, Pfizer, Amyndas Pharamaceuticals, CymaBay Therapeutics, and Roche. Dr. Giamarellos-Bourboulis has received honoraria from Abbott Products Operations, bioMérieux, Brahms GmbH, GlaxoSmithKline, InflaRx GmbH, Pfizer, and Swedish Orphan BioVitrum; he received independent educational grants from Abbott Products Operations, bioMérieux, Johnson & Johnson, MSD, Union Chimique Belge, and Swedish Orphan BioVitrum; and he received funding from the Horizon 2020 European grants ImmunoSep and Optimal use of hospital resources and intervention using suPAR for improving prognosis and care for patients with COVID-19 and the Horizon Health grant Equine Polyclonal antibodies Immunotherapy against COVID-19/SARS-CoV2–VOC (granted to the Hellenic Institute for the Study of Sepsis). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: The potential adverse effects associated with invasive mechanical ventilation (MV) can lead to delayed decisions on starting MV. We aimed to explore the association between the timing of MV and the clinical outcomes in patients with sepsis ventilated in intensive care unit (ICU)., Methods: We analyzed data of adult patients with sepsis between September 2019 and December 2021. Data was collected through the Korean Sepsis Alliance from 20 hospitals in Korea. Patients who were admitted to ICU and received MV were included in the study. Patients were divided into 'early MV' and 'delayed MV' groups based on whether they were on MV on the first day of ICU admission or later. Propensity score matching was applied, and patients in the two groups were compared on a 1:1 ratio to overcome bias between the groups. Outcomes including ICU mortality, hospital mortality, length of hospital and ICU stay, and organ failure at ICU discharge were compared., Results: Out of 2440 patients on MV during ICU stay, 2119 'early MV' and 321 'delayed MV' cases were analyzed. The propensity score matching identified 295 patients in each group with similar baseline characteristics. ICU mortality was lower in 'early MV' group than 'delayed MV' group (36.3% vs. 46.4%; odds ratio, 0.66; 95% confidence interval, 0.47-0.93; p = 0.015). 'Early MV' group had lower in-hospital mortality, shorter ICU stay, and required tracheostomy less frequently than 'delayed MV' group. Multivariable logistic regression model identified 'early MV' as associated with lower ICU mortality (odds ratio, 0.38; 95% confidence interval, 0.29-0.50; p < 0.001)., Conclusion: In patients with sepsis ventilated in ICU, earlier start (first day of ICU admission) of MV may be associated with lower mortality., (© 2024. The Author(s).)

Background: For patients with sepsis receiving non-invasive ventilation (NIV), early rehabilitation is crucial. The Sitting Baduanjin (SBE) is an efficient early rehabilitation exercise suitable for bed patients. There is no consensus about the effect of SBE on the early rehabilitation of septic patients with NIV. This study focused on how the SBE affected the early rehabilitation of sepsis patients with NIV., Methods: 96 sepsis patients with NIV were randomly assigned to either an Baduanjin group that received the SBE based on the routine rehabilitation exercise (n = 48) or a control group (n = 48) that received routine rehabilitation exercise. The primary outcome was the Medical Research Council(MRC)score, and the Barthel Index score, the duration of NIV, length of ICU stay, length of total stay, hospitalization expense as secondary outcomes., Results: A total of 245 sepsis patients were screened, with 96 randomly assigned. The study was completed by 90 patients out of the 96 participants.Results revealed that the MRC score increased in both groups, but the improvement of muscle strength in Baduanjin group was more obvious, with statistical significance (p < 0.001).There was statistically significantly difference between the two groups in Barthel Index at the day of transfer out of ICU(P = 0.028).The patients in the Baduanjin group had an average reduction of 24.09 h in the duration of NIV and 3.35 days in total length of hospital stay compared with the control group (p < 0.05).Of note, the Baduanjin group had significantly reduction the total hospitalization expense. No serious adverse events occurred during the intervention period., Conclusions: In patients with sepsis, the SBE appears to improve muscle strength and activities of daily living (ADL), and lowed the duration of NIV, the length of the total stay, and the hospitalization expense., Trial Registration: The study registered on the Chinese Clinical Trial Registry ( www.chictr.org.cn ), Clinical Trials identifier ChiCTR1800015011 (28/02/2018)., (© 2024. The Author(s).)

Background: Sepsis is a heterogeneous syndrome, and enrollment of more homogeneous patients is essential to improve the efficiency of clinical trials. Artificial intelligence (AI) has facilitated the identification of homogeneous subgroups, but how to estimate the uncertainty of the model outputs when applying AI to clinical decision-making remains unknown., Objective: We aimed to design an AI-based model for purposeful patient enrollment, ensuring that a patient with sepsis recruited into a trial would still be persistently ill by the time the proposed therapy could impact patient outcome. We also expected that the model could provide interpretable factors and estimate the uncertainty of the model outputs at a customized confidence level., Methods: In this retrospective study, 9135 patients with sepsis requiring vasopressor treatment within 24 hours after sepsis onset were enrolled from Beth Israel Deaconess Medical Center. This cohort was used for model development, and 10-fold cross-validation with 50 repeats was used for internal validation. In total, 3743 patients with sepsis from the eICU Collaborative Research Database were used as the external validation cohort. All included patients with sepsis were stratified based on disease progression trajectories: rapid death, recovery, and persistent ill. A total of 148 variables were selected for predicting the 3 trajectories. Four machine learning algorithms with 3 different setups were used. We estimated the uncertainty of the model outputs using conformal prediction (CP). The Shapley Additive Explanations method was used to explain the model., Results: The multiclass gradient boosting machine was identified as the best-performing model with good discrimination and calibration performance in both validation cohorts. The mean area under the receiver operating characteristic curve with SD was 0.906 (0.018) for rapid death, 0.843 (0.008) for recovery, and 0.807 (0.010) for persistent ill in the internal validation cohort. In the external validation cohort, the mean area under the receiver operating characteristic curve (SD) was 0.878 (0.003) for rapid death, 0.764 (0.008) for recovery, and 0.696 (0.007) for persistent ill. The maximum norepinephrine equivalence, total urine output, Acute Physiology Score III, mean systolic blood pressure, and the coefficient of variation of oxygen saturation contributed the most. Compared to the model without CP, using the model with CP at a mixed confidence approach reduced overall prediction errors by 27.6% (n=62) and 30.7% (n=412) in the internal and external validation cohorts, respectively, as well as enabled the identification of more potentially persistent ill patients., Conclusions: The implementation of our model has the potential to reduce heterogeneity and enroll more homogeneous patients in sepsis clinical trials. The use of CP for estimating the uncertainty of the model outputs allows for a more comprehensive understanding of the model's reliability and assists in making informed decisions based on the predicted outcomes., (©Meicheng Yang, Jinqiang Zhuang, Wenhan Hu, Jianqing Li, Yu Wang, Zhongheng Zhang, Chengyu Liu, Hui Chen. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 04.09.2024.)

Importance: Intravenous fluids are an essential part of treatment in sepsis, but there remains clinical equipoise on which type of crystalloid fluids to use in sepsis. A previously reported sepsis subphenotype (ie, group D) has demonstrated a substantial mortality benefit from balanced crystalloids compared with normal saline., Objective: To test the hypothesis that targeting balanced crystalloids to patients with group D sepsis through an electronic health record (EHR) alert will reduce 30-day inpatient mortality., Design, Setting, and Participants: The Precision Resuscitation With Crystalloids in Sepsis (PRECISE) trial is a parallel-group, multihospital, single-blind, pragmatic randomized clinical trial to be conducted at 6 hospitals in the Emory Healthcare system. Patients with suspicion of group D infection in whom a clinician initiates an order for normal saline in the emergency department (ED) or intensive care unit (ICU) will be randomized to usual care and intervention arms., Intervention: An EHR alert that appears in the ED and ICUs to nudge clinicians to use balanced crystalloids instead of normal saline., Main Outcomes and Measures: The primary outcome is 30-day inpatient mortality. Secondary outcomes are ICU admission, in-hospital mortality, receipt of vasoactive drugs, receipt of new kidney replacement therapy, and receipt of mechanical ventilation (vasoactive drugs, kidney replacement therapy, and mechanical ventilation are counted if they occur after randomization and within the 30-day study period). Intention-to-treat analysis will be conducted., Discussion: The PRECISE trial may be one of the first precision medicine trials of crystalloid fluids in sepsis. Using routine vital signs (temperature, heart rate, respiratory rate, and blood pressure), available even in low-resource settings, a validated machine learning algorithm will prospectively identify and enroll patients with group D sepsis who may have a substantial mortality reduction from used of balanced crystalloids compared with normal saline., Results: On finalizing participant enrollment and analyzing the data, the study's findings will be shared with the public through publication in a peer-reviewed journal., Conclusions: With use of a validated machine learning algorithm, precision resuscitation in sepsis could fundamentally redefine international standards for intravenous fluid resuscitation., Trial Registration: ClinicalTrials.gov Identifier: NCT06253585.

Sepsis is a severe medical condition characterized by a systemic inflammatory response, often culminating in multiple organ dysfunction and high mortality rates. In recent years, there has been a growing recognition of the pivotal role played by mitochondrial damage in driving the progression of sepsis. Various factors contribute to mitochondrial impairment during sepsis, encompassing mechanisms such as reactive nitrogen/oxygen species generation, mitophagy inhibition, mitochondrial dynamics change, and mitochondrial membrane permeabilization. Damaged mitochondria actively participate in shaping the inflammatory milieu by triggering key signaling pathways, including those mediated by Toll-like receptors, NOD-like receptors, and cyclic GMP-AMP synthase. Consequently, there has been a surge of interest in developing therapeutic strategies targeting mitochondria to mitigate septic pathogenesis. This review aims to delve into the intricate mechanisms underpinning mitochondrial dysfunction during sepsis and its significant impact on immune dysregulation. Moreover, we spotlight promising mitochondria-targeted interventions that have demonstrated therapeutic efficacy in preclinical sepsis models., (© 2024. The Author(s).)

Background: Sepsis is a complex condition with high morbidity and mortality. Prompt treatment can improve survival, but for survivors the risk of deterioration and readmission remains high. Little is known about the association between discharge setting and readmission among sepsis survivors., Objective: To examine 30-day hospital readmission rates in adult sepsis survivors by the type of setting to which patients were discharged., Methods: The Medical Information Mart for Intensive Care database was used to identify adult sepsis survivors and evaluate 30-day readmission by discharge setting. A χ2 contingency analysis was used with each factor and presence/absence of readmission. The Kruskal-Wallis test was used to compare readmissions across discharge settings., Results: From our sample (N = 7107; mean age 66.5 years; 46.2% women), 23.6% (n = 1674) were readmitted within 30 days and of those readmitted, 30% were readmitted between 1 and 3 times. Discharge setting (P < .001) and age (P = .02) were significantly associated with readmission, but sex, ethnicity, and insurance type were not. High numbers of readmissions were seen in patients discharged to skilled nursing facilities (29.6%), home health care (26.9%), and home (15.0%). Similar high comorbidity burden and acuteness of illness were seen in patients discharged to these settings., Conclusions: Sepsis survivors discharged to skilled nursing facilities, home health care, and home are at high risk for 30-day readmission. The rates of readmission from home health care and home settings were alarming. Often patients are discharged to inappropriate settings, placing them at risk for residual sepsis and readmission. Future research should focus on appropriate timing of hospital discharge and transition to the most appropriate discharge setting., (©2024 American Association of Critical-Care Nurses.)

Sepsis is a major contributor to poor child health outcomes around the world. The high morbidity, mortality, and societal cost associated with paediatric sepsis render it a global health priority, as summarised in Paper 1 of this Series. Sepsis is characterised by a dysregulated host response to infection that manifests as organ failure, and children are uniquely susceptible to sepsis, as discussed in Paper 2. The focus of this third Series paper is quality improvement in paediatric sepsis. The 2017 WHO resolution on sepsis outlined key aims to reduce the burden of sepsis. As of 2024, only a small number of countries have implemented systematic, paediatric-focused quality improvement programmes to raise sepsis awareness, enhance recognition of sepsis, promote timely treatment, and provide long-term support for paediatric sepsis survivors. We examine programme successes and systematic barriers to quality improvement targeting paediatric sepsis. We highlight the need for programme design to consider the entire patient journey, starting with prevention, caregiver awareness, recognition at home, education of the health-care workforce, development of health-care systems, and establishment of long-term family and survivor support extending beyond the intensive care unit. Building on lessons learnt from existing quality improvement programmes, we outline implementation strategies and measures to enable benchmarking. Ultimately, quality improvement on a global scale can only be accelerated through a global learning platform focusing on paediatric sepsis., Competing Interests: Declaration of interests LJS received grants from the Swiss Personalized Health Network, Australian National Health and Medical Research Council, Medical Research Future Fund, and US National Institutes of Health (R01HD105939). All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Sepsis is the second leading cause of pregnancy-related mortality in the United States. Early recognition, treatment, and escalation of care for the obstetric patient affected by sepsis mitigate the risk of mortality and improve patient outcomes. In this article, we provide an overview of maternal sepsis and address topics of maternal pathophysiology, early warning signs, diagnostic criteria, early goal-directed therapy, and contemporary critical care practices. We also present an overview of common etiologies of maternal sepsis and suggested treatment approaches., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The South Korean government implemented a multidisciplinary nutritional support team (NST) system to focus on the proper evaluation and supply of nutritional status in hospitalized patients who are at a higher risk of malnutrition., Methods: This nationwide population-based cohort study included patients diagnosed with sepsis who were admitted to hospitals from 2016 to 2020. The NST should consist of four professional personnel (physicians, full-time nurses, full-time pharmacists, and full-time clinical dietitians). The NST group included patients with sepsis admitted to a hospital with an NST system, whereas the non-NST group included patients with sepsis admitted to a hospital without an NST system., Results: A total of 323,841 patients with sepsis were included in the final analysis, and 120,274 (37.1%) admitted to a hospital with an NST system were included in the NST group. In the multivariable Cox regression analysis, the NST group showed a 15% lower 90-day mortality than the non-NST group (hazard ratio [HR]:0.85, 95% confidence interval [CI]:0.83, 0.86; P < 0.001). The NST group shows 11% lower 1-year all-cause mortality than the non-NST group (HR:0.89, 95% CI:0.87, 0.90; P < 0.001). In subgroup analyses, a more evident association of the NST group with lower 90-day mortality was shown in the intensive care unit admission group and age ≥65 years old group., Conclusions: Multidisciplinary NST intervention is associated with improved survival outcomes in patients with sepsis. Moreover, this association was more evident in patients with sepsis aged ≥65 years old who were admitted to the ICU., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The digitisation of health care is offering the promise of transforming the management of paediatric sepsis, which is a major source of morbidity and mortality in children worldwide. Digital technology is already making an impact in paediatric sepsis, but is almost exclusively benefiting patients in high-resource health-care settings. However, digital tools can be highly scalable and cost-effective, and-with the right planning-have the potential to reduce global health disparities. Novel digital solutions, from wearable devices and mobile apps, to electronic health record-embedded decision support tools, have an unprecedented opportunity to transform paediatric sepsis research and care. In this Series paper, we describe the current state of digital solutions in paediatric sepsis around the world, the advances in digital technology that are enabling the development of novel applications, and the potential effect of advances in artificial intelligence in paediatric sepsis research and clinical care., Competing Interests: Declaration of interests RSW served on the data safety monitoring board of the GRACE trial (granulocyte-macrophage colony-stimulating factor for reversal of immunoparalysis in pediatric sepsis-induced multiple organ dysfunction syndrome), chairs the data safety monitoring board of the PRECISE study (personalized immunomodulation in pediatric sepsis-induced multiple organ dysfunction syndrome), and is a co-investigator on the SHIPSS trial (stress hydrocortisone for pediatric septic shock; R01HD096901). LNS-P has stock options in Celldom, Saccharo, Allyx Therapeutics, and InnoSIGN, which are companies focused on diagnostic and therapeutic approaches to cancer and Alzheimer's disease, not sepsis. HS has received support for travel to meetings related to sepsis quality improvement from the Children's Hospital Association, and travel support from the Society of Critical Care Medicine. RSW declares travel support from the Society of Critical Care Medicine, and is co-chair (unpaid) of the Pediatric Sepsis Definitions Task Force for the Society of Critical Care Medicine. LNS-P, HS, LJS, and TDB are members (unpaid) of the Pediatric Sepsis Definitions Task Force for the Society of Critical Care Medicine. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license.)

Sepsis disproportionally affects children across all health-care settings and is one of the leading causes of morbidity and mortality in neonatal and paediatric age groups. As shown in the first paper in this Series, the age-specific incidence of sepsis is highest during the first years of life, before approaching adult incidence rates during adolescence. In the second paper in this Series, we focus on the unique susceptibility of paediatric patients to sepsis and how the underlying dysregulated host response relates to developmental aspects of children's immune system, genetic, perinatal, and environmental factors, and comorbidities and socioeconomic determinants of health, which often differ between children and adults. State-of-the-art clinical management of paediatric sepsis is organised around three treatment pillars-diagnosis, early resuscitation, and titration of advanced care-and we examine available treatment guidelines and the limitations of their supporting evidence. Serious evidence gaps remain in key areas of paediatric sepsis care, especially surrounding recognition, common interventions, and survivor support, and to this end we offer a research roadmap for the next decade that could accelerate targeted diagnostics and personalised use of immunomodulation. However, improving outcomes for children with sepsis relies fundamentally on systematic quality improvement in both recognition and treatment, which is the theme of the third paper in this Series. Digital health, as shown in the fourth and final paper of this Series, holds promising potential in breaking down the barriers that hinder progress in paediatric sepsis care and, ultimately, global child health., Competing Interests: Declaration of interests LJS declares grants from the Swiss Personalized Health Network, National Health and Medical Research Council (Australia), Medical Research Future Fund (Australia), and US National Institutes of Health (R01HD105939). RSW declares grants from the US National Institutes of Health as co-investigator on the Novel Pediatric Sepsis Criteria and Clinical Decision Support Tools project (R01 HD105939-01) and is a data safety and monitoring board member (unpaid) for the GRACE trial (granulocyte-macrophage colony-stimulating factor for reversal of immunoparalysis in pediatric sepsis-induced multiple organ dysfunction syndrome). All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objective: The objective of this study was to verify whether any parameter among those used as the target for haemodynamic optimisation (e.g., mean arterial pressure, central venous oxygen saturation, systolic or diastolic dysfunction, CO 2 gap, lactates, right ventricular dysfunction, and PvaCO 2 /CavO 2 ratio) is correlated with mortality in an undifferentiated population with sepsis or septic shock., Methods: An umbrella review, searching MEDLINE, the Cochrane Database of Systematic Reviews, Health Technology Assessment Database, and the JBI Database of Systematic Reviews and Implementation Reports, was performed. We included systematic reviews and meta-analyses enrolling a population of unselected patients with sepsis or septic shock. The main outcome was mortality. Two authors conducted data extraction and risk-of-bias assessments independently. We used a random-effects model to pool binary and continuous data and summarised estimates of effect using equivalent odds ratios (eORs). We used the ROBIS tool to assess risk of bias and the assessment of multiple systematic reviews 2 score to assess global quality., Data Synthesis: 17 systematic reviews and meta-analyses (15 828 patients) were included in the quantitative analysis. Diastolic dysfunction (eOR: 1.42; 95% confidence interval [CI]: 1.14-1.76), PvaCO 2 /CavO 2 ratio (eOR: 2.15; 95% CI: 1.37-3.37), and CO 2 gap (eOR: 1.86; 95% CI: 1.07-3.25) showed a significant correlation with mortality. Lactates were the parameter with highest inconsistency (I 2  = 92%). Central venous oxygen saturation and right ventricle dysfunction showed significant statistical excess test of significance (p-value = 0.009 and 0.005, respectively). None of the considered parameters showed statistically significant publication bias., Conclusions: According to this umbrella review, diastolic dysfunction is the haemodynamic variable that is most closely linked to the prognosis of septic patients. The PvaCO 2 /CavO 2 ratio and the CO 2 gap are significantly related to the mortality of septic patients, but the poor quality of evidence or the low number of cases, studied so far, limit their clinical applicability., Clinical Trial Registration: PROSPERO: International prospective register of systematic reviews, 2023, CRD42023432813 (Available from: https://www.crd.york.ac.uk/prospero/display&#95;record.php?ID=CRD42023432813)., (Copyright © 2024 Australian College of Critical Care Nurses Ltd. Published by Elsevier Ltd. All rights reserved.)

Objective: This study aims to assess compliance with medical protocols and outcomes, as well as determine the consistency in clinical practice across different Pediatric Emergency Departments (PED) in public sector hospitals of a low-middle income country., Methods: A retrospective analysis was conducted on patients presenting to PEDs of five public sector hospitals, namely Civil Hospital Karachi (PED 1), National Institute of Child Health (PED 2), Abbasi Shaheed Hospital (PED 3), Sheikh Zayed Hospital Larkana (PED 4), and Ghulam Muhammad Mahar College Hospital Sukkur (PED 5). The analysis covered a three-month period from February 1, 2023, to April 30, 2023. Patients diagnosed with Acute asthma, Sepsis, and Septic Shock during the study duration were included. Outcomes for each disease were evaluated based on compliance with standardized protocols.The statistical significance of data was measured by adding the p values., Results: 110,450 patients visited PED during the study period and mortality rate was 2% (n=2193). 12% (13,240) were diagnosed with the three diseases during the study period. Sepsis was on top (74%, n=9,751), followed by Septic Shock (14%, n=1898), and Acute Asthma (12%, n=1591). The overall compliance rate for the three diseases was 77% (n = 10,240). Adherence to standard protocols were 98% (n = 1561) for acute asthma, 85% (n = 8240) for Sepsis, and 23% (n = 439) for Septic Shock across the five emergency departments. Of the patients who were managed according to standard protocol, 31% (n = 3135) were discharged, 30% (n- 3094) were admitted, 11% (n = 1151) were referred, 15% (n = 1501) left against medical advice and 13% (n = 1359) did not survive. On the other hand, in patients where there was noncompliance to standard protocols, 27% (n = 805) did not survive, 27% (n = 807) were discharged, 24% (n = 710) were admitted, 8% (n = 260) were referred and 14% (n = 418) left against medical advice. The differences in adherence rates among the three diseases were statistically significant (p < 0.001)., Conclusion: The overall mortality rate was 2% in these five emergency departments and the medical protocol was followed in every third patient out of fourth in those three diseases. The survival rate till ED disposition was doubled in those patients for whom medical protocols were followed as compared to those for non-compliant. The majority of PED demonstrated good compliance with standardized practices. However, this study identified areas that require attention and further training, especially early recognition and management of septic shock where compliances seem alarmingly low. Our data analysis indicates that adherence to guidelines has resulted in uniformity in clinical practice and the provision of early evidence-based quality care. Nevertheless, there is still room for improvement in ensuring consistent adherence to medical protocols in pediatric emergency settings and thus improving patient outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The post-discharge prognosis of patients with sepsis remains a crucial issue; however, few studies have investigated the relationship between pre-sepsis health status and subsequent prognosis in a large population. This study aimed to examine the effect of the pre-sepsis care needs level on changes in care needs and mortality in patients with sepsis 1 year post-discharge., Methods: This was a population-based retrospective cohort study including twelve municipalities in Japan that participated in the Longevity Improvement & Fair Evidence study between April 2014 and March 2022, with a total of 1,491,608 persons. The pre-hospitalization levels of care needs (baseline) were classified from low to high, as no care needs, support level and care needs level 1, care needs levels 2-3, and care needs levels 4-5 (fully dependent). The outcomes were changes in care needs level and mortality 1 year post-discharge, assessed by baseline care needs level using Cox proportional hazard models., Results: The care needs levels of 17,648 patients analyzed at baseline were as follows: no care needs, 7982 (45.2%); support level and care needs level 1, 3736 (21.2%); care needs levels 2-3, 3089 (17.5%); and care needs levels 4-5, 2841 (16.1%). At 1 year post-discharge, the distribution of care needs were as follows: no care needs, 4791 (27.1%); support level and care needs level 1, 2390 (13.5%); care needs levels 2-3, 2629 (14.9%); care needs levels 4-5, 3373 (19.1%); and death, 4465 (25.3%). Patients with higher levels of care needs exhibited an increased association of all-cause mortality 1 year post-discharge after adjusting for confounders [hazard ratios and 95% confidence intervals: support level and care needs level 1, 1.05 (0.96, 1.15); care needs levels 2-3, 1.46 (1.33, 1.60); and care needs levels 4-5, 1.92 (1.75, 2.10); P for trend < 0.001]., Conclusions: Elevated care needs and mortality were observed in patients with sepsis within 1 year post-discharge. Older patients with sepsis and higher baseline levels of care needs had a high association of all-cause mortality 1 year post-discharge., (© 2024. The Author(s).)

Background: Sepsis survivors experience high morbidity and mortality. Though recommended best practices have been established to address the transition and early post hospital needs and promote recovery for sepsis survivors, few patients receive recommended post-sepsis care. Our team developed the Sepsis Transition and Recovery (STAR) program, a multicomponent transition intervention that leverages virtually-connected nurses to coordinate the application of evidence-based recommendations for post-sepsis care with additional clinical support from hospitalist and primary care physicians. In this paper, we present findings from a qualitative pre-implementation study, guided by the Consolidated Framework for Implementation Research (CFIR), of factors to inform successful STAR implementation at a large learning health system prior to effectiveness testing as part of a Type I Hybrid trial., Methods: We conducted semi-structured qualitative interviews (n = 16) with 8 administrative leaders and 8 clinicians. Interviews were transcribed and analyzed in ATLAS.ti using a combination deductive/inductive strategy based on CFIR domains and constructs and the Constant Comparison Method., Results: Six facilitators and five implementation barriers were identified spanning all five CFIR domains (Intervention Characteristics, Outer Setting, Inner Setting, Characteristics of Individuals and Process). Facilitators of STAR included alignment with health system goals, fostering stakeholder engagement, sharing STAR outcomes data, good communication between STAR navigators and patient care teams/PCPs, clinician promotion of STAR with patients, and good rapport and effective communication between STAR navigators and patients, caregivers, and family members. Barriers of STAR included competing demands for staff time and resources, insufficient communication and education of STAR's value and effectiveness, underlying informational and technology gaps among patients, lack of patient access to community resources, and patient distrust of the program and/or health care., Conclusions: CFIR proved to be a robust framework for examining facilitators and barriers for pre-implementation planning of post-sepsis care programs within diverse hospital and community settings in a large LHS. Conducting a structured pre-implementation evaluation helps researchers design with implementation in mind prior to effectiveness studies and should be considered a key component of Type I hybrid trials when feasible., Trial Registration: Clinicaltrials.gov, NCT04495946 . Registered August 3, 2020., (© 2024. The Author(s).)

Background/purpose: Sepsis is a leading cause of morbidity, mortality and healthcare utilisation for children worldwide, particularly in resource-limited regions. In Kumasi, Ghana, organ system failure and mortality in children who present to the emergency department (ED) with symptoms of sepsis are often due to late presentation and lack of recognition and implementation of time-critical evidence-based interventions. The purpose of this study was to assess the barriers and facilitators for families in seeking healthcare for their septic children; and to understand the barriers and facilitators for ED providers in Kumasi to recognise and implement sepsis bundle interventions., Design: Single-centre qualitative interviews of 39 caregivers and 35 ED providers in a teaching hospital in Kumasi, Ghana., Results: Thematic analysis of data from caregivers about barriers included: fear of hospital, finances, transportation, delay from referring hospital, cultural/spiritual differences, limited autonomy and concerns with privacy and confidentiality. Negative impacts on family life included financial strain and neglect of other children. ED providers reported barriers included: lack of training, poor work environment and accessibility of equipment. Facilitators from caregivers and providers included some support from the National Health Insurance. Caregivers reported having positive experiences with frontline clinicians, which encouraged them to return to seek health services., Implications: Qualitative structured interviews identified facilitator and critical barrier themes about seeking healthcare, and sepsis identification/management in the paediatric population arriving for care in our centre in Kumasi, Ghana. This study highlights significant deficiencies in healthcare systems that make sepsis management challenging in these settings., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Owing to a lack of data, this study aimed to explore the effect of cardiac preload on myocardial strain in patients with sepsis., Methods: A total of 70 patients with sepsis in intensive care unit (ICU) of a tertiary teaching hospital in China from January 2018 to July 2019 and underwent transthoracic echocardiography were enrolled. Echocardiographic data were recorded at ICU admission and 24 h later. Patients were assigned to low left ventricular end-diastolic volume index (LVEDVI) and normal LVEDVI groups. We assessed the impact of preload on myocardial strain between the groups and analyzed the correlation of echocardiographic parameters under different preload conditions., Results: Thirty-seven patients (53%) had a low LVEDVI and 33 (47%) a normal LVEDVI. Those in the low LVEDVI group had a faster heart rate (121.7 vs. 95.3, p < 0.001) and required a greater degree of fluid infusion (3.67 L vs. 2.62 L, P = 0.019). The left ventricular global strain (LVGLS) (-8.60% vs. -10.80%, p = 0.001), left ventricular global circumferential strain (LVGCS) (-13.83% vs. -18.26%, p = 0.006), and right ventricular global longitudinal strain (RVGLS) (-6.9% vs. -10.60%, p = 0.001) showed significant improvements in the low LVEDVI group after fluid resuscitation. However, fluid resuscitation resulted in a significantly increased cardiac afterload value (1172.00 vs. 1487.00, p = 0.009) only in the normal LVEDVI group. Multivariate backward linear regression showed that LVEDVI changes were independently associated with myocardial strain-related improvements during fluid resuscitation. The baseline LVEDVI was significantly negatively correlated with the LVGLS and RVGLS (r = -0.44 and - 0.39, respectively) but not LVGCS. LVEDVI increases during fluid resuscitation were associated with improvements in the myocardial strain degree., Conclusions: Myocardial strain alterations were significantly influenced by the cardiac preload during fluid resuscitation in sepsis., (© 2024. The Author(s).)

Introduction: Sepsis often leads to acute kidney injury (AKI), presenting significant challenges in fluid management. This study explores the potential of analyzing intrarenal venous flow (IRVF) patterns to guide tailored fluid therapy, aiming to improve patient outcomes., Patient Concerns: A patient was admitted to the intensive care unit with symptoms of septic shock, including fever, severe hypotension, and altered mental status, secondary to a perforated ascending colon adenocarcinoma., Diagnosis: The patient was diagnosed with perforated ascending colon adenocarcinoma, septic shock, and AKI. Clinical findings included elevated inflammatory markers and impaired renal function., Interventions: The primary therapeutic interventions included surgical resection of the perforated colon, administration of broad-spectrum antibiotics, and fluid resuscitation. Fluid management was guided by continuous monitoring of IRVF, which facilitated precise adjustments to optimize fluid balance and renal perfusion., Outcomes: By utilizing IRVF patterns to guide fluid therapy, the patient's circulatory status and renal function significantly improved. The individualized fluid management approach contributed to better stabilization of the patient's condition., Lessons: This case underscores the potential utility of IRVF patterns in guiding fluid management strategies for patients with sepsis and AKI. The main is the benefit of IRVF-guided fluid therapy in improving patient outcomes. Further research is warranted to validate the efficacy and safety of this approach, with the aim of enhancing clinical outcomes in critically ill patients., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

High volume hemofiltration (HVHF) could remove from plasma inflammatory mediators involved in sepsis-associated acute kidney injury (SA-AKI). The IVOIRE trial did not show improvements of outcome and organ dysfunction using HVHF. The aim of this study was to evaluate in vitro the biological effects of plasma of patients treated by HVHF or standard volume hemofiltration (SVHF). We evaluated leukocyte adhesion, apoptosis and functional alterations of endothelial cells (EC) and tubular epithelial cells (TEC). In vitro data were correlated with plasma levels of TNF-α, Fas-Ligand (FasL), CD40-Ligand (CD40L), von Willebrand Factor (vWF) and endothelial-derived microparticles. An experimental model of in vitro hemofiltration using LPS-activated blood was established to assess cytokine mass adsorption during HVHF or SVHF. Plasma concentrations of TNF-ɑ, FasL, CD40L and von Willebrand Factor (vWF) were elevated at the start (d1h0) of both HVHF and SVHF, significantly decreased after 6 h (d1h6), remained stable after 12 h (d1h12) and then newly increased at 48 h (d3h0). Plasma levels of all these molecules were similar between HVHF- and SVHF-treated patients at all time points considered. In addition, the levels of endothelial microparticles remained always elevated, suggesting the presence of a persistent microvascular injury. Plasma from septic patients induced leukocyte adhesion on EC and TEC through up-regulation of adhesion receptors. Moreover, on EC, septic plasma induced a cytotoxic and anti-angiogenic effect. On TEC, septic plasma exerted a direct pro-apoptotic effect via Fas up-regulation and caspase activation, loss of polarity, altered expression of megalin and tight junction molecules with an impaired ability to internalize albumin. The inhibition of plasma-induced cell injury was concomitant to the decrease of TNF-α, Fas-Ligand and CD40-Ligand levels. The protective effect of both HVHF and SVHF was time-limited, since a further increase of circulating mediators and plasma-induced cell injury was observed after 48 h (d3h0). No significant difference of EC/TEC damage were observed using HVHF- or SVHF-treated plasma. The in vitro hemofiltration model confirmed the absence of a significant modulation of cytokine adsorption between HVHF and SVHF. In comparison to SVHF, HVHF did not increase inflammatory cytokine clearance and did not reverse the detrimental effects of septic plasma-induced EC and TEC injury. Further studies using adsorptive membranes are needed to evaluate the potential role of high dose convective therapies in the limitation of the harmful activity of plasma soluble factors involved in SA-AKI.Trial registration IVOIRE randomized clinical trial; ClinicalTrials.gov (NCT00241228) (18/10/2005)., (© 2024. The Author(s).)

Background: This study aimed to compare the effect of two methods of maintenance intravenous fluid therapy on hyponatremia in hospitalized infants with sepsis., Methods: In a double-blinded randomized clinical trial, 60 term infants with sepsis were enrolled. Blood samples were taken to determine sodium, potassium, Creatinine, and BUN levels before the initiation of treatment. Urine samples were taken to assess specific gravity and urinary output. Infants in the intervention group received half saline in 10% dextrose and infants in the control group were assigned to receive the conventional solution as maintenance. The above indicators were re-evaluated 24 and 48 h after the initiation of treatment. Two groups were compared concerning the incidence of hyponatremia, and other criteria such as urinary output and urinary specific gravity, blood urea nitrogen (BUN), and creatinine levels., Results: Hyponatremia was more common in the control group. Sodium levels were significantly higher in half saline recipients 24 h (137.83 ± 2.86 vs. 134.37 ± 1.91 mmol/L), and 48 h (138.10 ± 2.41 vs. 133.66 ± 1.98 mmol/L) after treatment (P < 0.001). Although BUN in the intervention group was significantly higher in comparison to the control group, the difference in urinary output, urine specific gravity, potassium, and Creatinine levels were not significant in the two groups., Conclusions: The use of a half-saline solution as maintenance fluid reduces the risk of hyponatremia after 48 h when compared to 0.18%NaCl., Trial Registration: This has been registered at Iranian Registry of Clinical Trials (Retrospectively registered, Registration date: 2017-10-12, identifier: IRCT2017053034223N1, https://irct.behdasht.gov.ir/trial/26204 )., (© 2024. The Author(s).)

Early diagnosis and prompt management are essential to enhance the outcomes of patients with sepsis and septic shock. Over the past two decades, evidence-based guidelines have guided appropriate treatment and recommended the implementation of a bundle strategy to deliver fundamental treatments within the initial hours of care. Shortly after its introduction, the implementation of a bundle strategy has led to a substantial decrease in mortality rates across various health care settings. The primary advantage of these bundles is their universality, making them applicable to all patients with sepsis. However, this same quality also represents their primary disadvantage as it fails to account for the significant heterogeneity within the septic patient population. Recently, the individualization of treatments included in the bundle has been suggested as a potential strategy for further improving the prognosis of patients with sepsis. New strategies for the early identification of microorganisms and their resistance patterns, advanced knowledge of antibiotic kinetics in critically ill patients, more conservative fluid therapy in specific patient populations, and early use of alternative vasopressors to catecholamines, as well as tailored source control based on patient conditions and site of infection, are potential approaches to personalize initial care for specific subgroups of patients. These innovative methodologies have the potential to improve the management of septic shock. However, their implementation in clinical practice should be guided by solid evidence. Therefore, it is imperative that future research evaluate the safety, efficacy, and cost-effectiveness of these strategies., Competing Interests: M.G. has received honoraria for speaking at conferences and advisory services from Biomerieux, Thermofischer, Pfizer, MSD, Gilead, Shionogi, AOP Pharma, and Viatris related to the topic of this study. The other authors declare that they have no conflict of interest related to the topic of this study., (Thieme. All rights reserved.)

Leaving university I started working for the Belgian National Radio as a journalist. I used to travel a lot and produce radio features about life abroad and how people all over the world dealt with the different challenges in society. A privileged job that I enjoyed doing for many years. In the meantime, I got married and became a mother of two sons. Nothing to worry about, so it seemed, until January 30, 2009. I had been fighting the symptoms of flu for some days. Instead of recovering, I began to feel worse and worse: I had a high fever, was asleep most of the time, could barely eat or drink, and had to cough a lot. The general practitioner sent me to hospital. A few hours later, I had to be reanimated. It was a close call: I was infected by the Streptococcus pyogenes bacteria. My blood started thickening, my organs stopped functioning, and I went into a septic shock, followed by a cardiac arrest. I was successfully reanimated, but still not stable. For 10 days, I was fighting to survive at the intensive care unit (ICU), with several cardiac arrests and reanimations, some of which were long-lasting. The Head of the ICU informed my husband that there was less than 5% chance to survive and if so, he could not predict what kind of damage there would be: the amount of drugs that I had been given, including noradrenaline, was so extremely high, that it became very unclear how my body would respond to it. And if, as by miracle, I would survive: what kind of damage would there be? Physical? Mental? Physical and mental? No specialist could answer those questions. But both the health care professionals and my family fought to keep me alive., Competing Interests: None declared., (Thieme. All rights reserved.)

Recovery from sepsis is a key global health issue, impacting 38 million sepsis survivors worldwide per year. Sepsis survivors face a wide range of physical, cognitive, and psychosocial sequelae. Readmissions to hospital following sepsis are an important driver of global healthcare utilization and cost. Family members of sepsis survivors also experience significant stressors related to their role as informal caregivers. Increasing recognition of the burdens of sepsis survivorship has led to the development of postsepsis recovery programs to better support survivors and their families, although optimal models of care remain uncertain. The goal of this article is to perform a narrative review of recovery from sepsis from the perspective of patients, families, and health systems., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: To inform World Health Organization guidelines for the management of serious bacterial infection (SBI) (suspected or confirmed sepsis, pneumonia, or meningitis) in infants aged 0-59 days., Objective: To conduct an "overview of systematic reviews" to: (1) understand which systematic reviews have examined diagnosis and management of SBI in infants aged 0-59 days in the last 5 years; and (2) assess if the reviews examined PICOs (population, intervention, comparator, outcomes) and regimens currently being recommended in low and middle income countries (LMICs) by the World Health Organization., Data Sources: MEDLINE; Embase; Cochrane Library; Epistemonikos; PROSPERO., Study Selection: Systematic reviews of randomized controlled trials or observational studies of infants aged 0-59 days examining diagnostic accuracy and antibiotic regimens for SBI from January 1, 2018 to November 3, 2023., Data Extraction: Dual independent extraction of study characteristics, PICOs, and methodological quality., Results: Nine systematic reviews met our criteria. Two reviews examined diagnostic accuracy for sepsis, and no reviews examined pneumonia or meningitis. Five reviews examined antibiotic effectiveness (sepsis [n = 4]; pneumonia [n = 1]), and no reviews examined meningitis. One review examined antibiotic duration for sepsis and one for meningitis, and no reviews for pneumonia. Only 4 of the 9 systematic reviews met criteria for high-quality., Limitations: Our review was limited to the last 5 years to inform current guideline updates., Conclusions: Few studies have examined antibiotic regimens currently being used in LMICs and quality is of concern in many studies. More high-quality data are needed to inform management of SBI in newborns, especially in LMICs.

Precision and personalized medicine remain an elusive but illustrious goal in the realm of critical care, particularly in the areas of trauma and sepsis. These aims specifically refer to data gathering, interpretation, and treatment application on an individualized basis in the clinical care of patients. Until now, personalized medicine has mainly remained focused on genetics and epigenetic phenomena and has propelled clinical care forward, especially in the field of oncology. Advances in technology and methodology continue to proliferate in early-phase research, and some of these advancements are well poised to break into the clinical sphere of critical care. Here, we describe 2 topics at the forefront of investigation with potent and imminent potential for clinical application., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: To perform a post-hoc reanalysis of the Standard versus Accelerated Initiation of Renal-Replacement Therapy in Acute Kidney Injury (STARRT-AKI) and the Intensity of Continuous Renal-Replacement Therapy in Critically Ill Patients (RENAL) trials through hierarchical composite endpoint analysis using win ratio (WR)., Material and Methods: All patients with complete information from the STARRT-AKI (which compared accelerated versus standard approaches for renal replacement therapy - RRT initiation) and RENAL (which compared two different RRT doses in critically ill patients) trials were selected. WR was defined as a hierarchical composite endpoint using 90-day mortality, RRT dependency at 90-days, intensive care unit (ICU) length-of-stay (LOS), and hospital LOS (primary analysis); values above the unit represent a benefit of the intervention for the hierarchical composite endpoint. A secondary analysis replacing LOS by days alive and free of RRT was performed. Stratified analyses were performed according to illness severity score, surgical status, and the presence of sepsis., Results: The WR analysis produced 2,141,830 pairs for the STARRT-AKI trial and 536,446 pairs for the RENAL trial, respectively. The WR results for STARRT-AKI and RENAL were 1.04 (95% confidence interval [CI] 0.96-1.13; p = 0.33) and 1.02 (95% CI; 0.90-1.15; p = 0.75) for the primary analysis, and 0.88 (95% CI; 0.79-0.99; p = 0.03) and 1.02 (95% CI; 0.87-1.21; p = 0.77) for the secondary analysis, respectively. The stratified analysis of the primary suggested possible benefit of the accelerated-strategy in the STARRT-AKI trial for non-surgical patients with sepsis, while the secondary analysis suggested possible harm of the accelerated-strategy for surgical patients without sepsis. There was no evidence of heterogeneity in treatment effects in stratified analyses in the RENAL trial., Conclusion: WR approach using a hierarchical composite endpoint is feasible for trials in critical care nephrology. The primary re-analyses of the STARRT-AKI and RENAL trials both yielded neutral results; however, there was suggestion of heterogeneity in treatment effect in stratified analyses of the STARRT-AKI trial by surgical status and sepsis. Selection of the endpoints and hierarchical ordering before trial design using the WR approach can have important implications for trial interpretation., Trial Registry: ClinicalTrials.gov number NCT02568722 (STARRT-AKI) and NCT00076219 (RENAL)., Competing Interests: Declaration of competing interest FGZ has received grants for investigator-initiated trials from Bactiguard (Sweden), and Ionis Pharmaceuticals (USA), unrelated to the topic of this study. RB has received honoraria and grants from Baxter. SMB has received fees from Baxter for scientific advisory and speaking; fees from BioPorto, Novartis, Sea Star Medical and SphingoTec for scientific advisory., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Sepsis refers to a potentially life-threatening situation where the immune system of the human body has an extreme response to an infection. In the presence of underlying comorbidities, the situation can become even worse and result in death. Employing unsupervised machine learning techniques, such as clustering, can assist in providing a better understanding of patient phenotypes by unveiling subgroups characterized by distinct sepsis progression and treatment patterns. More concretely, this study introduces M-ClustEHR, a clustering approach that utilizes medical data of multiple modalities by employing a multimodal autoencoder for learning comprehensive sepsis patient representations. M-ClustEHR consistently outperforms traditional clustering approaches in terms of several internal clustering performance metrics, as well as cluster stability in identifying phenotypes in the sepsis cohort. The unveiled patterns, supported by existing medical literature and clinicians, highlight the importance of multimodal clustering for advancing personalized sepsis care., Competing Interests: Declaration of competing interest We declare no Conflict of Interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Sepsis is a life-threatening disorder with no definitive cure. Preclinical studies suggest that extracellular vesicles derived from mesenchymal stromal cells (EV-MSCs) can mitigate inflammatory conditions, potentially leading to increased survival and reduced organ dysfunction during sepsis. Our aim to conduct this systematic review and meta-analysis is assessing the EV-MSCs therapeutic efficacy in sepsis., Methods: PubMed, Embase, Scopus, WOS and ProQuest databases and also Google Scholar search engine were searched for published articles. We used hazard ratio (HR) and standardized mean difference (SMD) as effect sizes to evaluate the therapeutic effect of EV-MSCs on survival rate and determine their effect on reducing organ dysfunction, respectively. Finally, we employed GRADE tool for preclinical animal studies to evaluate certainty of the evidence., Results: 30 studies met the inclusion criteria for our article. Our meta-analysis results demonstrate that animals treated with MSC-EVs have better survival rate than untreated animals (HR = 0.33; 95% CI: 0.27-0.41). Our meta-analysis suggests that EV-MSCs can reduce organ dysfunctions in sepsis, such as the lung, kidney, and liver. Additionally, EV-MSCs decrease pro-inflammatory mediators like TNF-α, IL-1β, and IL-6., Conclusion: Our results indicate that EV-MSCs can be as promising therapy for sepsis management in animal models and leading to increased survival rate and reduced organ dysfunction. Furthermore, our study introduces a novel tool for risk of bias assessment and provides recommendations based on various analysis. Future studies with aiming to guide clinical translation can utilize the results of this article to establish stronger evidence for EV-MSC effectiveness., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Sepsis manifests as a dysregulated immune response to an infection, leading to tissue damage, organ failure, and potentially death or long-term health issues. Sepsis remains a major health challenge globally, causing approximately 50 million cases and 11 million deaths annually. Early management of sepsis focuses on source control, antimicrobial treatment, and supporting vital organ function. Subsequent care includes metabolic, nutritional, and immune therapies to address the complex needs of septic patients. Metabolic management is based on obtaining moderate glucose targets. Nutritional support aims to mitigate hypercatabolism and muscle wasting, but aggressive early nutrition does not improve outcomes and could even be harmful. Immune modulation is crucial due to the dual nature of sepsis-induced immune responses. Corticosteroids have shown benefits in shock and organ dysfunction reversal and in mortality reduction with current guidelines recommending them in vasopressor therapy-dependent patients. In conclusion, sepsis management beyond the initial hours requires a multifaceted approach, focusing on metabolic, nutritional, and immune system support tailored to individual patient needs to enhance survival and recovery., Competing Interests: None declared., (Thieme. All rights reserved.)

Introduction: The global provision of essential healthcare stands as a critical concern. Consequently, healthcare policies play a pivotal role in determining the allocation of resources. However, the optimal indicators for prioritizing such policies remain uncertain. This study proposes that employing the concept of treatable mortality in a stepwise manner could serve as a viable approach to setting healthcare policy priorities. Furthermore, it aims to demonstrate this concept through the application of real-world data., Methods: A model was developed to assess treatable mortality at a national level focusing on severe emergency conditions. We established stepwise targets, encompassing short-term, mid-term, and long-term goals to reduce mortality rates and enhance healthcare efficiency. The short-term target consists of directing attention to regions exhibiting in-hospital mortality rates surpassing the national average within a specific disease category and reducing them to the national average. The mid-term objective entails decreasing the in-hospital mortality rate of the specific disease group to match that of the region with the lowest rate nationwide. As for long-term target, it aligns the in-hospital mortality rate with that of OECD countries possessing average or lowest rates. The model was applied using data from South Korea's National Emergency Department Information System, specifically analyzing acute myocardial infarction (AMI), stroke, and sepsis., Results: Reaching the short-term target resulted in the treatable deaths for AMI numbered 191, for stroke 249, and for sepsis 546. Meeting the mid-term target led to treatable deaths for AMI at 749, for stroke at 958, and for sepsis at 1552. Finally, achieving the long-term target yielded the treatable deaths for AMI at 2606, for stroke at 1642, and for sepsis at 2619. Consequently, a reallocation of more healthcare resources to sepsis over AMI or stroke is recommended., Conclusions: This study proposes the utilization of treatable mortality as a metric for establishing healthcare policies. The stepwise approach provides valuable insights for policymaking at various levels. Despite limitations, the model offers a foundation for resource allocation and international mortality rate comparisons, aiming for achievable rates worldwide., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Sepsis results when a severe infection overwhelms the normal regulatory mechanisms of the immune system, resulting in a dysregulated host response characterized by new-onset organ failure. A wide range of infectious challenges can induce sepsis, resulting in an even wider range of maladaptive immune responses. This makes sepsis a syndromic diagnosis without a unifying, underlying molecular mechanism. The next step toward personalized medicine for sepsis is to resolve the heterogeneity across the universe of septic patients in order to establish pathobiologically homogenous sepsis "endotypes" that have uniformly defined changes in physiology and immunology. Defining the mechanisms of immune dysfunction within these endotypes will provide a roadmap for the application of immunomodulatory therapies for sepsis. This approach can drive in a paradigm shift in sepsis treatment, moving beyond supportive care and toward active efforts to restore normal immune function., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Prior studies have shown that maternal deaths due to sepsis occur due to delays in recognition, treatment, and escalation of care through medical chart reviews. This study was conducted to obtain the patient perspective for near-miss and maternal mortality cases due to sepsis., Objective: To identify quality improvement opportunities for improving maternal sepsis through patient and support person experiences., Study Design: Twenty semi-structured interviews and three follow-up focus groups with patients who experienced critical illness from maternal sepsis in the United States and their support persons (when available) were conducted from May 23, 2022, through October 14, 2022. In this qualitative study, data were analyzed using inductive thematic analysis., Results: In this qualitative study of patients with maternal sepsis and their support persons, four main quality improvement themes were identified. The themes were the following: (1) participants reported a lack of awareness of pregnancy-related warning signs and symptoms of when to seek care, (2) many of the presenting symptoms participants experienced were not typical of expected warning signs of maternal sepsis, such as severe pain, overwhelming tiredness, and lack of fever (3) participant concerns were met with dismissal leading to delays in diagnosis, (4) participants experienced long-term sequelae but had difficulty receiving screening and referrals for treatment., Conclusions: The findings of this study suggest that standardized patient education about the warning signs of maternal sepsis and provider education about the presentation of maternal sepsis, improved listening to patients, and follow-up for sequalae of sepsis are needed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Exosome-derived microRNAs (miRNAs) are emerging as pivotal players in the pathophysiology of sepsis, representing a new frontier in both the diagnosis and treatment of this complex condition. Sepsis, a severe systemic response to infection, involves intricate immune and nonimmune mechanisms, where exosome-mediated communication can significantly influence disease progression and outcomes. During the progress of sepsis, the miRNA profile of exosomes undergoes notable alterations, is reflecting, and may affect the progression of the disease. This review comprehensively explores the biology of exosome-derived miRNAs, which originate from both immune cells (such as macrophages and dendritic cells) and nonimmune cells (such as endothelial and epithelial cells) and play a dynamic role in modulating pathways that affect the course of sepsis, including those related to inflammation, immune response, cell survival, and apoptosis. Taking into account these dynamic changes, we further discuss the potential of exosome-derived miRNAs as biomarkers for the early detection and prognosis of sepsis and advantages over traditional biomarkers due to their stability and specificity. Furthermore, this review evaluates exosome-based therapeutic miRNA delivery systems in sepsis, which may pave the way for targeted modulation of the septic response and personalized treatment options., Competing Interests: The authors declare that there is no conflict of interest with respect to the publication of this article., (Copyright © 2024 Yujie Xiao et al.)

Background: Fluid resuscitation is an essential component for sepsis treatment. Although several studies demonstrated that dynamic variables were more accurate than static variables for prediction of fluid responsiveness, fluid resuscitation guidance by dynamic variables is not standard for treatment. The objectives were to determine the effects of dynamic inferior vena cava (IVC)-guided versus (vs.) static central venous pressure (CVP)-guided fluid resuscitation in septic patients on mortality; and others, i.e., resuscitation targets, shock duration, fluid and vasopressor amount, invasive respiratory support, length of stay and adverse events., Methods: A single-blind randomized controlled trial was conducted at Thammasat University Hospital between August 2016 and April 2020. Septic patients were stratified by acute physiologic and chronic health evaluation II (APACHE II) <25 or ≥25 and randomized by blocks of 2 and 4 to fluid resuscitation guidance by dynamic IVC or static CVP., Results: Of 124 patients enrolled, 62 were randomized to each group, and one of each was excluded from mortality analysis. Baseline characteristics were comparable. The 30-day mortality rates between dynamic IVC vs. static CVP groups were not different (34.4% vs. 45.9%, p=0.196). Relative risk for 30-day mortality of dynamic IVC group was 0.8 (95%CI=0.5-1.2, p=0.201). Different outcomes were median (interquartile range) of shock duration (0.8 (0.4-1.6) vs. 1.5 (1.1-3.1) days, p=0.001) and norepinephrine (NE) dose (6.8 (3.9-17.8) vs. 16.1 (7.6-53.6) milligrams, p=0.008 and 0.1 (0.1-0.3) vs. 0.3 (0.1-0.8) milligram⋅kilogram -1 , p=0.017). Others were not different., Conclusions: Dynamic IVC-guided fluid resuscitation does not affect mortality of septic patients. However, this may reduce shock duration and NE dose, compared with static CVP guidance., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Sricharoenchai T and Saisirivechakun P.)

In a previous study, sepsis was noted as a diagnosis on the home health record only 4% of the time for 165,000 sepsis survivors transitioning from hospital to home health care in America. If sepsis and other conditions are not clearly documented in the transitional care record this can lead to unpreparedness, missed, care, and poor patient outcomes. Our implementation science study discovered a source of this problem regarding the sepsis documentation in 16 hospitals referring to five home care agencies. Together, researchers, hospital, and home care personnel developed and implemented two information technology solutions to address this deficit in seven hospitals. The automated method was more readily adopted and effective in improving information transfer between hospital and home health care.

The use of healthcare information technology (HIT) is vital for storing and exchanging health information during patient transitions, playing a significant role in care coordination for sepsis survivors. The critical role of HIT was evident during the pre-implementation phase of a study to implement an evidence-based protocol supporting the timely transition of sepsis survivors to home health and outpatient care. Through 61 semi-structured interviews involving 91 stakeholders, over half of the 33 identified themes were related to HIT. Notably, electronic health record (EHR) alert systems led to over-capture and alarm fatigue. Efficient information transfer during HHC referral highlighted the need for improved EHR access. The study underscores HIT's importance and potential while emphasizing the need for collaborative policy and interface development to promote effective transitions in care.

Patients with acquired immune deficiency syndrome (AIDS) are susceptible to numerous complications, such as sepsis and acute kidney injury (AKI), leading to adverse outcomes. Continuous renal replacement therapy (CRRT) is becoming increasingly popular for treating sepsis and AKI. This study aimed to verify the effectiveness of CRRT in the treatment of patients with AIDS with sepsis and AKI to provide new directions for the treatment of severe AIDS. Data of 74 people with AIDS, sepsis, and AKI were collected. The patients were divided into CRRT and non-CRRT groups. There was no difference in the indicators between the two groups at admission. Vital signs, pH, serum potassium level, renal function, blood lactate level, acute physiology and chronic health evaluation II score, and sequential organ failure assessment score in the CRRT group demonstrated significant improvements over those in the non-CRRT group at both 24 and 72 h after admission (P < 0.05). The levels of interleukin 6 and procalcitonin declined more significantly in the CRRT group at 72 h after admission (P < 0.05). The CRRT group had a higher 28-day survival rate than the non-CRRT group (P < 0.05). CRRT improves the clinical indicators and increases the short-term survival rate of patients with AIDS, sepsis, and AKI.

The endothelial glycocalyx, a gel-like layer that lines the luminal surface of blood vessels, is composed of proteoglycans, glycoproteins, and glycosaminoglycans. The endothelial glycocalyx plays an essential role in vascular homeostasis, and its degradation in trauma and sepsis can lead to microvascular dysfunction and organ injury. While there are no proven therapies for preventing or treating endothelial glycocalyx degradation, some initial literature suggests that plasma may have a therapeutic role in trauma and sepsis patients. Overall, the literature suggesting the use of plasma as a therapy for endothelial glycocalyx degradation is non-clinical basic science or exploratory. Plasma is an established therapy in the resuscitation of patients with hemorrhage for restoration of coagulation factors. However, plasma also contains other bioactive components, including sphingosine-1 phosphate, antithrombin, and adiponectin, which may protect and restore the endothelial glycocalyx, thereby helping to maintain or restore vascular homeostasis. This narrative review begins by describing the endothelial glycocalyx in health and disease: we discuss the overlapping disease mechanisms in trauma and sepsis that lead to its damage and introduce plasma transfusion as a potential therapy for prevention and treatment of endothelial glycocalyx degradation. Second, we review the literature on plasma as an exploratory therapy for endothelial glycocalyx degradation in trauma and sepsis. Third, we discuss the safety of plasma transfusion by reviewing the adverse events associated with plasma and other blood product transfusions, and we examine modern transfusion precautions that have enhanced the safety of plasma transfusion. We conclude that the literature proposes that plasma may have the potential to prevent and treat endothelial glycocalyx degradation in trauma and sepsis, indicating the need for further research., (© 2024. The Author(s).)

In recent years, gene therapy has been made possible with the success of nucleic acid drugs against sepsis and its related organ dysfunction. Therapeutics based on nucleic acids such as small interfering RNAs (siRNAs), microRNAs (miRNAs), messenger RNAs (mRNAs), and plasmid DNAs (pDNAs) guarantee to treat previously undruggable diseases. The advantage of nucleic acid-based therapy against sepsis lies in the development of nanocarriers, achieving targeted and controlled gene delivery for improved efficacy with minimal adverse effects. Entrapment into nanocarriers also ameliorates the poor cellular uptake of naked nucleic acids. In this study, we discuss the current state of the art in nanoparticles for nucleic acid delivery to treat hyperinflammation and apoptosis associated with sepsis. The optimized design of the nanoparticles through physicochemical property modification and ligand conjugation can target specific organs-such as lung, heart, kidney, and liver-to mitigate multiple sepsis-associated organ injuries. This review highlights the nanomaterials designed for fabricating the anti-sepsis nanosystems, their physicochemical characterization, the mechanisms of nucleic acid-based therapy in working against sepsis, and the potential for promoting the therapeutic efficiency of the nucleic acids. The current investigations associated with nanoparticulate nucleic acid application in sepsis management are summarized in this paper. Noteworthily, the potential application of nanotherapeutic nucleic acids allows for a novel strategy to treat sepsis. Further clinical studies are required to confirm the findings in cell- and animal-based experiments. The capability of large-scale production and reproducibility of nanoparticle products are also critical for commercialization. It is expected that numerous anti-sepsis possibilities will be investigated for nucleic acid-based nanotherapeutics in the future., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.