The pathophysiology of sepsis and precision-medicine-based immunotherapy.

Sepsis remains a major cause of morbidity and mortality in both low- and high-income countries. Antibiotic therapy and supportive care have significantly improved survival following sepsis in the twentieth century, but further progress has been challenging. Immunotherapy trials for sepsis, mainly aimed at suppressing the immune response, from the 1990s and 2000s, have largely failed, in part owing to unresolved patient heterogeneity in the underlying immune disbalance. The past decade has brought the promise to break this blockade through technological developments based on omics-based technologies and systems medicine that can provide a much larger data space to describe in greater detail the immune endotypes in sepsis. Patient stratification opens new avenues towards precision medicine approaches that aim to apply immunotherapies to sepsis, on the basis of precise biomarkers and molecular mechanisms defining specific immune endotypes. This approach has the potential to lead to the establishment of immunotherapy as a successful pillar in the treatment of sepsis for future generations.

Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension.

BACKGROUND: Intravenous fluids and vasopressor agents are commonly used in early resuscitation of patients with sepsis, but comparative data for prioritizing their delivery are limited. METHODS: In an unblinded superiority trial conducted at 60 U.S. centers, we randomly assigned patients to either a restrictive fluid strategy (prioritizing vasopressors and lower intravenous fluid volumes) or a liberal fluid strategy (prioritizing higher volumes of intravenous fluids before vasopressor use) for a 24-hour period. Randomization occurred within 4 hours after a patient met the criteria for sepsis-induced hypotension refractory to initial treatment with 1 to 3 liters of intravenous fluid. We hypothesized that all-cause mortality before discharge home by day 90 (primary outcome) would be lower with a restrictive fluid strategy than with a liberal fluid strategy. Safety was also assessed. RESULTS: A total of 1563 patients were enrolled, with 782 assigned to the restrictive fluid group and 781 to the liberal fluid group. Resuscitation therapies that were administered during the 24-hour protocol period differed between the two groups; less intravenous fluid was administered in the restrictive fluid group than in the liberal fluid group (difference of medians, -2134 ml; 95% confidence interval [CI], -2318 to -1949), whereas the restrictive fluid group had earlier, more prevalent, and longer duration of vasopressor use. Death from any cause before discharge home by day 90 occurred in 109 patients (14.0%) in the restrictive fluid group and in 116 patients (14.9%) in the liberal fluid group (estimated difference, -0.9 percentage points; 95% CI, -4.4 to 2.6; P = 0.61); 5 patients in the restrictive fluid group and 4 patients in the liberal fluid group had their data censored (lost to follow-up). The number of reported serious adverse events was similar in the two groups. CONCLUSIONS: Among patients with sepsis-induced hypotension, the restrictive fluid strategy that was used in this trial did not result in significantly lower (or higher) mortality before discharge home by day 90 than the liberal fluid strategy. (Funded by the National Heart, Lung, and Blood Institute; CLOVERS ClinicalTrials.gov number, NCT03434028.).

Sepsis-Induced Immunosuppression.

Sepsis is expected to have a substantial impact on public health and cost as its prevalence increases. Factors contributing to increased prevalence include a progressively aging population, advances in the use of immunomodulatory agents to treat a rising number of diseases, and immune-suppressing therapies in organ transplant recipients and cancer patients. It is now recognized that sepsis is associated with profound and sustained immunosuppression, which has been implicated as a predisposing factor in the increased susceptibility of patients to secondary infections and mortality. In this review, we discuss mechanisms of sepsis-induced immunosuppression and biomarkers that identify a state of impaired immunity. We also highlight immune-enhancing strategies that have been evaluated in patients with sepsis, as well as therapeutics under current investigation. Finally, we describe future challenges and the need for a new treatment paradigm, integrating predictive enrichment with patient factors that may guide the future selection of tailored immunotherapy.

ASC-expressing pyroptotic extracellular vesicles alleviate sepsis by protecting B cells.

Pyroptosis is an inflammatory programmed cell death process characterized by membrane rupture. Interestingly, pyroptotic cells can generate plenty of nanosized vesicles. Non-inflammatory apoptotic cell death-derived apoptotic vesicles (apoVs) were systemically characterized and displayed multiple physiological functions and therapeutic potentials. However, the characteristics of pyroptotic cell-generated extracellular vesicles (EVs) are largely unknown. Here, we identified a group of pyroptotic EVs (pyroEVs) from in vitro cultured pyroptotic mesenchymal stem cells (MSCs), as well as from septic mouse blood. Compared with apoVs, pyroEVs express similar levels of annexin V, calreticulin, and common EV markers, but express a decreased level of apoptotic marker cleave caspase-3. PyroEVs, but not apoVs and exosomes, specifically express pyroptotic maker apoptosis-associated speck-like protein containing CARD (ASC). More importantly, MSC-derived pyroEVs protect B cells in the spleen and bone marrow to relieve inflammatory responses and enhance the survival rate of the septic mice. Mechanistically, pyroEV membrane-expressed ASC binds to B cells to repress cell death by repressing Toll-like receptor 4. This study uncovered the characteristics of pyroEVs and their therapeutic role in sepsis and B cell-mediated immune response.

Geo-economic Influence on the Effect of Fluid Volume for Sepsis Resuscitation: A Meta-Analysis.

Rationale: Sepsis management relies on fluid resuscitation avoiding fluid overload and its related organ congestion. Objectives: To explore the influence of country income group on risk-benefit balance of fluid management strategies in sepsis. Methods: We searched e-databases for all randomized controlled trials on fluid resuscitation in patients with sepsis or septic shock up to January 2023, excluding studies on hypertonic fluids, colloids, and depletion-based interventions. The effect of fluid strategies (higher versus lower volumes) on mortality was analyzed per income group (i.e., low- and middle-income countries [LMICs] or high-income countries [HICs]). Measurements and Main Results: Twenty-nine studies (11,798 patients) were included in the meta-analysis. There was a numerically higher mortality in studies of LMICs as compared with those of HICs: median, 37% (interquartile range [IQR]: 26-41) versus 29% (IQR: 17-38; P = 0.06). Income group significantly interacted with the effect of fluid volume on mortality: Higher fluid volume was associated with higher mortality in LMICs but not in HICs: odds ratio (OR), 1.47; 95% confidence interval (95% CI): 1.14-1.90 versus 1.00 (95% CI: 0.87-1.16), P = 0.01 for subgroup differences. Higher fluid volume was associated with increased need for mechanical ventilation in LMICs (OR, 1.24 [95% CI: 1.08-1.43]) but not in HICs (OR, 1.02 [95% CI: 0.80-1.29]). Self-reported access to mechanical ventilation also significantly influenced the effect of fluid volume on mortality, which increased with higher volumes only in settings with limited access to mechanical ventilation (OR: 1.45 [95% CI: 1.09-1.93] vs. 1.09 [95% CI: 0.93-1.28], P = 0.02 for subgroup differences). Conclusions: In sepsis trials, the effect of fluid resuscitation approach differed by setting, with higher volume of fluid resuscitation associated with increased mortality in LMICs and in settings with restricted access to mechanical ventilation. The precise reason for these differences is unclear and may be attributable in part to resource constraints, participant variation between trials, or other unmeasured factors.

Heterogeneity of Benefit from Earlier Time-to-Antibiotics for Sepsis.

Rationale: Shorter time-to-antibiotics improves survival from sepsis, particularly among patients in shock. There may be other subgroups for whom faster antibiotics are particularly beneficial.Objectives: Identify patient characteristics associated with greater benefit from shorter time-to-antibiotics.Methods: Observational cohort study of patients hospitalized with community-onset sepsis at 173 hospitals and treated with antimicrobials within 12 hours. We used three approaches to evaluate heterogeneity of benefit from shorter time-to-antibiotics: 1) conditional average treatment effects of shorter (⩽3 h) versus longer (>3-12 h) time-to-antibiotics on 30-day mortality using multivariable Poisson regression; 2) causal forest to identify characteristics associated with greatest benefit from shorter time-to-antibiotics; and 3) logistic regression with time-to-antibiotics modeled as a spline.Measurements and Main Results: Among 273,255 patients with community-onset sepsis, 131,094 (48.0%) received antibiotics within 3 hours. In Poisson models, shorter time-to-antibiotics was associated with greater absolute mortality reduction among patients with metastatic cancer (5.0% [95% confidence interval; CI: 4.3-5.7] vs. 0.4% [95% CI: 0.2-0.6] for patients without cancer, P < 0.001); patients with shock (7.0% [95% CI: 5.8-8.2%] vs. 2.8% [95% CI: 2.7-3.5%] for patients without shock, P = 0.005); and patients with more acute organ dysfunctions (4.8% [95% CI: 3.9-5.6%] for three or more dysfunctions vs. 0.5% [95% CI: 0.3-0.8] for one dysfunction, P < 0.001). In causal forest, metastatic cancer and shock were associated with greatest benefit from shorter time-to-antibiotics. Spline analysis confirmed differential nonlinear associations of time-to-antibiotics with mortality in patients with metastatic cancer and shock.Conclusions: In patients with community-onset sepsis, the mortality benefit of shorter time-to-antibiotics varied by patient characteristics. These findings suggest that shorter time-to-antibiotics for sepsis is particularly important among patients with cancer and/or shock.

Dexmedetomidine or Propofol for Sedation in Mechanically Ventilated Adults with Sepsis.

BACKGROUND: Guidelines currently recommend targeting light sedation with dexmedetomidine or propofol for adults receiving mechanical ventilation. Differences exist between these sedatives in arousability, immunity, and inflammation. Whether they affect outcomes differentially in mechanically ventilated adults with sepsis undergoing light sedation is unknown. METHODS: In a multicenter, double-blind trial, we randomly assigned mechanically ventilated adults with sepsis to receive dexmedetomidine (0.2 to 1.5 µg per kilogram of body weight per hour) or propofol (5 to 50 µg per kilogram per minute), with doses adjusted by bedside nurses to achieve target sedation goals set by clinicians according to the Richmond Agitation-Sedation Scale (RASS, on which scores range from -5 [unresponsive] to +4 [combative]). The primary end point was days alive without delirium or coma during the 14-day intervention period. Secondary end points were ventilator-free days at 28 days, death at 90 days, and age-adjusted total score on the Telephone Interview for Cognitive Status questionnaire (TICS-T; scores range from 0 to 100, with a mean of 50±10 and lower scores indicating worse cognition) at 6 months. RESULTS: Of 432 patients who underwent randomization, 422 were assigned to receive a trial drug and were included in the analyses - 214 patients received dexmedetomidine at a median dose of 0.27 µg per kilogram per hour, and 208 received propofol at a median dose of 10.21 µg per kilogram per minute. The median duration of receipt of the trial drugs was 3.0 days (interquartile range, 2.0 to 6.0), and the median RASS score was -2.0 (interquartile range, -3.0 to -1.0). We found no difference between dexmedetomidine and propofol in the number of days alive without delirium or coma (adjusted median, 10.7 vs. 10.8 days; odds ratio, 0.96; 95% confidence interval [CI], 0.74 to 1.26), ventilator-free days (adjusted median, 23.7 vs. 24.0 days; odds ratio, 0.98; 95% CI, 0.63 to 1.51), death at 90 days (38% vs. 39%; hazard ratio, 1.06; 95% CI, 0.74 to 1.52), or TICS-T score at 6 months (adjusted median score, 40.9 vs. 41.4; odds ratio, 0.94; 95% CI, 0.66 to 1.33). Safety end points were similar in the two groups. CONCLUSIONS: Among mechanically ventilated adults with sepsis who were being treated with recommended light-sedation approaches, outcomes in patients who received dexmedetomidine did not differ from outcomes in those who received propofol. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01739933.).

Application of Cardiovascular Physiology to the Critically Ill Patient.

OBJECTIVES: To use the ventricular pressure-volume relationship and time-varying elastance model to provide a foundation for understanding cardiovascular physiology and pathophysiology, interpreting advanced hemodynamic monitoring, and for illustrating the physiologic basis and hemodynamic effects of therapeutic interventions. We will build on this foundation by using a cardiovascular simulator to illustrate the application of these principles in the care of patients with severe sepsis, cardiogenic shock, and acute mechanical circulatory support. DATA SOURCES: Publications relevant to the discussion of the time-varying elastance model, cardiogenic shock, and sepsis were retrieved from MEDLINE. Supporting evidence was also retrieved from MEDLINE when indicated. STUDY SELECTION, DATA EXTRACTION, AND SYNTHESIS: Data from relevant publications were reviewed and applied as indicated. CONCLUSIONS: The ventricular pressure-volume relationship and time-varying elastance model provide a foundation for understanding cardiovascular physiology and pathophysiology. We have built on this foundation by using a cardiovascular simulator to illustrate the application of these important principles and have demonstrated how complex pathophysiologic abnormalities alter clinical parameters used by the clinician at the bedside.

Echocardiography Does not Reduce Mortality in Sepsis: A Re-Evaluation Using the Medical Information Mart for Intensive Care IV Dataset.

OBJECTIVES: Echocardiography is commonly used for hemodynamic assessment in sepsis, but data regarding its association with outcome are conflicting. The aim of this study was to evaluate the association between echocardiography and outcomes in patients with septic shock using the Medical Information Mart for Intensive Care IV database. DESIGN: Retrospective cohort study comparing patients who did or did not undergo transthoracic echocardiography within the first 5 days of admission for the primary outcome of 28-day mortality. SETTING: Admissions to the Beth Israel Deaconess Medical Center intensive care from 2008 to 2019. PATIENTS: Adults 16 years old or older with septic shock requiring vasopressor support within 48 hours of admission. Readmissions and patients admitted to the coronary care unit or cardiovascular intensive care were excluded, as well as patients with ST-elevation myocardial infarction or cardiac arrest. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Echocardiography was performed in 1,515 (27%) of 5,697 eligible admissions. The primary outcome was analyzed using a marginal structural model and rolling entry matching to adjust for baseline and time-varying confounders. Patients who underwent echocardiography showed no significant difference in 28-day mortality (adjusted hazard ratio 1.09; 95% CI, 0.95-1.25; p = 0.24). This was consistent across multiple sensitivity analyses. Secondary outcomes were changes in management instituted within 4 hours of imaging. Treatment changes occurred in 493 patients (33%) compared with 431 matched controls (29%), with the most common intervention being the administration of a fluid bolus. CONCLUSIONS: Echocardiography in sepsis was not associated with a reduction in 28-day mortality based on observational data. These findings do not negate the utility of echo in cases of diagnostic uncertainty or inadequate response to initial treatment.

Identifying Sources of Inter-Hospital Variation in Episode Spending for Sepsis Care.

OBJECTIVE: To evaluate inter-hospital variation in 90-day total episode spending for sepsis, estimate the relative contributions of each component of spending, and identify drivers of spending across the distribution of episode spending on sepsis care. DATA SOURCES/STUDY SETTING: Medicare fee-for-service claims for beneficiaries (n=324,694) discharged from acute care hospitals for sepsis, defined by MS-DRG, between October 2014 and September 2018. RESEARCH DESIGN: Multiple linear regression with hospital-level fixed effects was used to identify average hospital differences in 90-day episode spending. Separate multiple linear regression and quantile regression models were used to evaluate drivers of spending across the episode spending distribution. RESULTS: The mean total episode spending among hospitals in the most expensive quartile was $30,500 compared with $23,150 for the least expensive hospitals ( P <0.001). Postacute care spending among the most expensive hospitals was almost double that of least expensive hospitals ($7,045 vs. $3,742), accounting for 51% of the total difference in episode spending between the most expensive and least expensive hospitals. Female patients, patients with more comorbidities, urban hospitals, and BPCI-A-participating hospitals were associated with significantly increased episode spending, with the effect increasing at the right tail of the spending distribution. CONCLUSION: Inter-hospital variation in 90-day episode spending on sepsis care is driven primarily by differences in post-acute care spending.

Revolution in sepsis: a symptoms-based to a systems-based approach?

Severe infection and sepsis are medical emergencies. High morbidity and mortality are linked to CNS dysfunction, excessive inflammation, immune compromise, coagulopathy and multiple organ dysfunction. Males appear to have a higher risk of mortality than females. Currently, there are few or no effective drug therapies to protect the brain, maintain the blood brain barrier, resolve excessive inflammation and reduce secondary injury in other vital organs. We propose a major reason for lack of progress is a consequence of the treat-as-you-go, single-nodal target approach, rather than a more integrated, systems-based approach. A new revolution is required to better understand how the body responds to an infection, identify new markers to detect its progression and discover new system-acting drugs to treat it. In this review, we present a brief history of sepsis followed by its pathophysiology from a systems' perspective and future opportunities. We argue that targeting the body's early immune-driven CNS-response may improve patient outcomes. If the barrage of PAMPs and DAMPs can be reduced early, we propose the multiple CNS-organ circuits (or axes) will be preserved and secondary injury will be reduced. We have been developing a systems-based, small-volume, fluid therapy comprising adenosine, lidocaine and magnesium (ALM) to treat sepsis and endotoxemia. Our early studies indicate that ALM therapy shifts the CNS from sympathetic to parasympathetic dominance, maintains cardiovascular-endothelial glycocalyx coupling, reduces inflammation, corrects coagulopathy, and maintains tissue O2 supply. Future research will investigate the potential translation to humans.

A time series driven model for early sepsis prediction based on transformer module.

Sepsis remains a critical concern in intensive care units due to its high mortality rate. Early identification and intervention are paramount to improving patient outcomes. In this study, we have proposed predictive models for early sepsis prediction based on time-series data, utilizing both CNN-Transformer and LSTM-Transformer architectures. By collecting time-series data from patients at 4, 8, and 12 h prior to sepsis diagnosis and subjecting it to various network models for analysis and comparison. In contrast to traditional recurrent neural networks, our model exhibited a substantial improvement of approximately 20%. On average, our model demonstrated an accuracy of 0.964 (± 0.018), a precision of 0.956 (± 0.012), a recall of 0.967 (± 0.012), and an F1 score of 0.959 (± 0.014). Furthermore, by adjusting the time window, it was observed that the Transformer-based model demonstrated exceptional predictive capabilities, particularly within the earlier time window (i.e., 12 h before onset), thus holding significant promise for early clinical diagnosis and intervention. Besides, we employed the SHAP algorithm to visualize the weight distribution of different features, enhancing the interpretability of our model and facilitating early clinical diagnosis and intervention.

Pediatric Sepsis in General Emergency Departments: Association Between Pediatric Sepsis Case Volume, Care Quality, and Outcome.

STUDY OBJECTIVE: To assess whether a general emergency department's (ED) annual pediatric sepsis volume increases the odds of delivering care concordant with Surviving Sepsis pediatric guidelines. METHODS: A retrospective cohort study of children <18 years with sepsis presenting to 29 general EDs. Emergency department and hospital data were abstracted from the medical records of 2 large health care systems, including all hospitals to which children were transferred. Guideline-concordant care was defined as intravenous antibiotics within 3 hours, intravenous fluid bolus within 3 hours, and lactate measured. The association between annual ED pediatric sepsis encounters and the probability of receiving guideline-concordant care was assessed. RESULTS: We included 1,527 ED encounters between January 1, 2015, and September 30, 2021. Three hundred and one (19%) occurred in 25 EDs with <10 pediatric sepsis encounters annually, 466 (31%) in 3 EDs with 11 to 100 pediatric sepsis encounters annually, and 760 (50%) in an ED with more than 100 pediatric sepsis encounters annually. Care was concordant in 627 (41.1%) encounters. In multivariable analysis, annual pediatric sepsis volume was minimally associated with the probability of guideline-concordant care (odds ratio 1.002 [95% confidence interval 1.001 to 1.00]). Care concordance increased from 23.1% in 2015 to 52.8% in 2021. CONCLUSION: Guideline-concordant sepsis care was delivered in 41% of pediatric sepsis cases in general EDs, and annual ED pediatric sepsis encounters had minimal association with the odds of concordant care. Care concordance improved over time. This study suggests that factors other than pediatric sepsis volume are important in driving care quality and identifying drivers of improvement is important for children first treated in general EDs.

A potential approach toward the management of sepsis: The extracorporeal cytokine hemadsorption therapy.

Infectious diseases are among the most common cause of morbidity and mortality among hospitalized patients while systemic inflammatory response syndrome is primarily attributed to the imbalance between pro-inflammatory and anti-inflammatory cytokines. Despite the improvements in the antibiotherapy alternatives and diagnostic modalities, the morbidity and mortality rates of sepsis and septic shock are relatively high among patients admitted to the intensive care units. Extracorporeal cytokine hemadsorption therapies are therapeutic approaches for such patient group with promising early results that especially have grown during COVID-19 pandemic. In this narrative review, our aim is to evaluate the current pre-clinical and clinical knowledge regarding the use of cytokine filtration systems among patients with septic shock.

Viral Delivery of IL-7 Is a Potent Immunotherapy Stimulating Innate and Adaptive Immunity and Confers Survival in Sepsis Models.

Persistence of an immunosuppressive state plays a role in septic patient morbidity and late mortality. Both innate and adaptive pathways are impaired, pointing toward the need for immune interventions targeting both arms of the immune system. We developed a virotherapy using the nonpropagative modified vaccinia virus Ankara (MVA), which harbors the intrinsic capacity to stimulate innate immunity, to deliver IL-7, a potent activator of adaptive immunity. The rMVA-human IL-7 (hIL-7)-Fc encoding the hIL-7 fused to the human IgG2-Fc was engineered and shown to express a dimeric, glycosylated, and biologically active cytokine. Following a single i.v. injection in naive mice, the MVA-hIL-7-Fc increased the number of total and activated B, T, and NK cells but also myeloid subpopulations (Ly6Chigh, Ly6Cint, and Ly6Cneg cells) in both lung and spleen. It triggered differentiation of T cells in central memory, effector memory, and acute effector phenotypes and enhanced polyfunctionality of T cells, notably the number of IFN-γ-producing cells. The MVA vector contributed significantly to immune cell activation, particularly of NK cells. The MVA-hIL-7-Fc conferred a significant survival advantage in the cecal ligation and puncture (CLP) and Candida albicans sepsis models. It significantly increased cell numbers and activation in both spleen and lung of CLP mice. Comparatively, in naive and CLP mice, the rhIL-7-Fc soluble counterpart overall induced less vigorous, shorter lasting, and narrower immune activities than did the MVA-hIL-7-Fc and favored TNF-α-producing cells. The MVA-hIL-7-Fc represents a novel class of immunotherapeutic with clinical potential for treatment of septic patients.

A scoping review of machine learning for sepsis prediction- feature engineering strategies and model performance: a step towards explainability.

BACKGROUND: Sepsis, an acute and potentially fatal systemic response to infection, significantly impacts global health by affecting millions annually. Prompt identification of sepsis is vital, as treatment delays lead to increased fatalities through progressive organ dysfunction. While recent studies have delved into leveraging Machine Learning (ML) for predicting sepsis, focusing on aspects such as prognosis, diagnosis, and clinical application, there remains a notable deficiency in the discourse regarding feature engineering. Specifically, the role of feature selection and extraction in enhancing model accuracy has been underexplored. OBJECTIVES: This scoping review aims to fulfill two primary objectives: To identify pivotal features for predicting sepsis across a variety of ML models, providing valuable insights for future model development, and To assess model efficacy through performance metrics including AUROC, sensitivity, and specificity. RESULTS: The analysis included 29 studies across diverse clinical settings such as Intensive Care Units (ICU), Emergency Departments, and others, encompassing 1,147,202 patients. The review highlighted the diversity in prediction strategies and timeframes. It was found that feature extraction techniques notably outperformed others in terms of sensitivity and AUROC values, thus indicating their critical role in improving sepsis prediction models. CONCLUSION: Key dynamic indicators, including vital signs and critical laboratory values, are instrumental in the early detection of sepsis. Applying feature selection methods significantly boosts model precision, with models like Random Forest and XG Boost showing promising results. Furthermore, Deep Learning models (DL) reveal unique insights, spotlighting the pivotal role of feature engineering in sepsis prediction, which could greatly benefit clinical practice.

Influence of therapeutic plasma exchange treatment on short-term mortality of critically ill adult patients with sepsis-induced organ dysfunction: a systematic review and meta-analysis.

INTRODUCTION: The impact of therapeutic plasma exchange (TPE) on short-term mortality in adult patients with sepsis-induced organ dysfunction remains uncertain. The objective of the study is to assess the effect of adjunct TPE in this setting through a comprehensive literature review. METHODS: The National Library of Medicine's Medline, Ovid (Embase), the Cochrane Library database and clinicaltrial.gov from January 01, 1966, until October 01, 2022, were searched for terms: therapeutic plasma exchange, plasmapheresis, sepsis, and septic shock. We reviewed, selected and extracted data from relevant randomized clinical trials (RCTs) and matched cohort studies (MCSs) comparing short-term mortality in critically ill adult septic patients treated with standard therapy versus those receiving adjunct TPE. Risk of bias was assessed in the RCTs using Cochrane Collaboration tool and in MCSs using ROBINS-I tool. Summary statistics, risk ratios (RRs), and confidence intervals (CIs) were calculated using random effects model. RESULTS: This systematic review included 937 adult critically ill septic patients from five RCTs (n = 367) and fifteen MCSs (n = 570). Of these total, 543 received treatment with TPE in addition to standard care. The meta-analysis includes all five RCTs and only six MCSs (n = 627). The adjunct TPE treatment (n = 300) showed a significant reduction in short-term mortality (RR 0.59, 95% CI 0.47-0.74, I2 3%) compared to standard therapy alone (n = 327). The systematic review of all 20 trials revealed that adding TPE to the standard therapy of critically ill septic patients resulted in faster clinical and/or laboratory recovery. CONCLUSIONS: Our comprehensive and up-to-date review demonstrates that adjunct TPE may provide potential survival benefits when compared to standard care for critically ill adult patients with sepsis-induced organ dysfunction. While results of this meta-analysis are encouraging, large well-designed randomized trials are required to identify the optimal patient population and TPE procedure characteristics prior to widespread adoption into practice.

Sepsis-associated acute kidney injury: recent advances in enrichment strategies, sub-phenotyping and clinical trials.

Acute kidney injury (AKI) often complicates sepsis and is associated with high morbidity and mortality. In recent years, several important clinical trials have improved our understanding of sepsis-associated AKI (SA-AKI) and impacted clinical care. Advances in sub-phenotyping of sepsis and AKI and clinical trial design offer unprecedented opportunities to fill gaps in knowledge and generate better evidence for improving the outcome of critically ill patients with SA-AKI. In this manuscript, we review the recent literature of clinical trials in sepsis with focus on studies that explore SA-AKI as a primary or secondary outcome. We discuss lessons learned and potential opportunities to improve the design of clinical trials and generate actionable evidence in future research. We specifically discuss the role of enrichment strategies to target populations that are most likely to derive benefit and the importance of patient-centered clinical trial endpoints and appropriate trial designs with the aim to provide guidance in designing future trials.

Towards personalized medicine: a scoping review of immunotherapy in sepsis.

Despite significant progress in our understanding of the pathophysiology of sepsis and extensive clinical research, there are few proven therapies addressing the underlying immune dysregulation of this life-threatening condition. The aim of this scoping review is to describe the literature evaluating immunotherapy in adult patients with sepsis, emphasizing on methods providing a "personalized immunotherapy" approach, which was defined as the classification of patients into a distinct subgroup or subphenotype, in which a patient's immune profile is used to guide treatment. Subgroups are subsets of sepsis patients, based on any cut-off in a variable. Subphenotypes are subgroups that can be reliably discriminated from other subgroup based on data-driven assessments. Included studies were randomized controlled trials and cohort studies investigating immunomodulatory therapies in adults with sepsis. Studies were identified by searching PubMed, Embase, Cochrane CENTRAL and ClinicalTrials.gov, from the first paper available until January 29th, 2024. The search resulted in 15,853 studies. Title and abstract screening resulted in 1409 studies (9%), assessed for eligibility; 771 studies were included, of which 282 (37%) were observational and 489 (63%) interventional. Treatment groups included were treatments targeting the innate immune response, the complement system, coagulation and endothelial dysfunction, non-pharmalogical treatment, pleiotropic drugs, immunonutrition, concomitant treatments, Traditional Chinese Medicine, immunostimulatory cytokines and growth factors, intravenous immunoglobulins, mesenchymal stem cells and immune-checkpoint inhibitors. A personalized approach was incorporated in 70 studies (9%). Enrichment was applied using cut-offs in temperature, laboratory, biomarker or genetic variables. Trials often showed conflicting results, possibly due to the lack of patient stratification or the potential influence of severity and timing on immunomodulatory therapy results. When a personalized approach was applied, trends of clinical benefit for several interventions emerged, which hold promise for future clinical trials using personalized immunotherapy.

Albumin versus saline infusion for sepsis-related peripheral tissue hypoperfusion: a proof-of-concept prospective study.

BACKGROUND: Albumin has potential endothelial protective effects through antioxidant and anti-inflammatory properties. However, the effect of albumin on peripheral tissue perfusion in human sepsis remains poorly known. METHODS: Bi-centric prospective study included patients with sepsis with or without shock and prolonged CRT > 3 s despite initial resuscitation. Clinicians in charge of the patients were free to infuse either saline 500 mL or human serum albumin 20% 100 mL over 15 min. Global hemodynamic parameters as well as peripheral tissue perfusion were analyzed after 1 (H1) and 4 h (H4). The primary endpoint was CRT normalization (< 3 s) at H1. RESULTS: 62 patients were screened, and 50 patients (13 sepsis and 37 septic shock) were included, 21 in the saline group and 29 in the albumin group. SOFA score was 8 [5-11], and SAPS II was 53 [45-70]. Median age was 68 [60-76] years with a higher proportion of men (74%). The primary sources of infection were respiratory (54%) and abdominal (24%). At baseline, comorbidities, clinical and biological characteristics were similar between groups. At H1, CRT normalization (< 3 s) was more frequent in patients receiving albumin as compared to patients treated by saline (63 vs 29%, P = 0.02). The decrease in fingertip CRT was more important in the albumin group when compared to saline group (- 1.0 [- 0.3; - 1.5] vs - 0.2 [- 0.1; - 1.1] seconds, P = 0.04) as well as decrease in mottling score. At H4, beneficial effects of albumin on peripheral tissue perfusion were maintained and urinary output trended to be higher in the albumin group (1.1 [0.5-1.8] vs 0.7 [0.5-0.9] ml/kg/h, P = 0.08). Finally, arterial lactate level did not significantly change between H0 and H4 in the saline group but significantly decreased in the albumin group (P = 0.03). CONCLUSION: In patients with resuscitated sepsis, albumin infusion might lead to greater improvement of tissue hypoperfusion compared to saline. CLINICALTRIALS: gov Identifier: NCT05094856.