Sepsis, a dysregulated host response to infection, is a leading cause of morbidity and mortality in critically ill patients, despite advancements in antimicrobial therapies. Recent innovations in extracorporeal blood purification therapies, such as the Selective Cytopheretic Device (SCD), Polymyxin B Hemoperfusion Cartridge (PMX-HP), and Seraph 100 Microbind Affinity Blood Filter (Seraph), have demonstrated promising potential as adjuncts to conventional therapies. The SCD targets activated white blood cells, while PMX-HP binds endotoxins in Gram-negative sepsis. The Seraph targets a broad range of pathogens, including viruses, bacteria and fungi. Evidence from several clinical trials and observational studies indicate that these therapies can improve organ function, and potentially improve survival in patients with sepsis. Despite the strong pathophysiological rationale for using these devices in sepsis, conclusive evidence of their effectiveness remains limited. Multicenter randomized controlled trials are currently underway with each of these devices to establish their role in improving patient outcomes. Further research is needed to establish optimal protocols for their initiation, duration, and integration into standard sepsis management.

Delayed administration of polymyxin B hemoperfusion (PMX-HP) for septic shock could diminish its efficacy in real-world clinical settings.

BEAT-SHOCK (BEst Available Treatment for septic SHOCK) registry is a prospective registry consisting of 309 adult patients with septic shock requiring high-dose norepinephrine (≥ 0.2 μg/kg/min). This predetermined analysis included 82 patients treated with PMX-HP. They were grouped according to the median time from intensive care unit (ICU) admission to administration of PMX-HP: the early administration group (n = 40) and the late administration group (n = 42). The primary outcome was short-term hemodynamic status, including mean arterial pressure and vasoactive-inotropic score (VIS; calculated from doses of dopamine, dobutamine, norepinephrine, epinephrine, vasopressin, milrinone, and levosimendan) within 48 h after ICU admission.

The median time from ICU admission to administration of PMX-HP was 265 min (interquartile range [IQR]: 113-480). The median ages were 70 (IQR: 59-81) and 72 (IQR: 64-80) years (P = 0.77), and 21/40 (53%) and 25/42 (60%) patients were male (P = 0.52) in the early and late administration groups, respectively. The dose of norepinephrine at ICU admission was 0.33 (IQR: 0.24-0.47) and 0.30 (IQR: 0.22-0.34) μg/kg/min in the early and late administration groups, respectively (P = 0.17). Within 48 h after ICU admission, mean arterial pressure was significantly higher at 6 h and 8 h, and VIS was significantly lower at 8 h and thereafter in the early administration group. Within a 28-day period, there were 23 (IQR: 21-25) and 21 (IQR: 0-24) vasopressor/inotrope-free days (P = 0.027), and 18 (IQR: 1-23) and 14 (IQR: 0-19) ICU-free days (P = 0.025) in the early and late administration groups, respectively. The cumulative mortality at 90 days was 15.3% in the early administration group and 31.3% in the late administration group (adjusted hazard ratio 0.38; 95% confidence interval 0.13-1.09).

In patients with septic shock, early administration of PMX-HP was associated with higher mean arterial pressure and lower VIS within 48 h after ICU admission. Additionally, it may be associated with an improved clinical course, represented by more ICU-free and vasopressor/inotrope-free days. Trial registration UMIN Clinical Trial Registry on 1 November 2019 (registration no. UMIN000038302).

The pathogenesis of sepsis is thought to be linked to a dysregulated immune response, particularly that involving neutrophils. We have developed a granulocyte adsorption column as a "decoy organ," which relocates the massive inflammation in organs in the body to a blood purification column. This study was conducted to assess the safety and experimental effectiveness of granulocyte monocyte adsorption apheresis-direct hemoperfusion (G1-DHP) in the treatment of patients with sepsis, using a prospective, multicenter design.

The study included patients diagnosed with sepsis and with an APACHE II score ranging from 17 to 34. A total of five G1-DHP were performed within 3 days of patient enrollment. The primary endpoint was the change in sequential organ failure assessment (SOFA) score from enrollment to 7 days, and the safety endpoints were adverse events and mortality at 28 days.

G1-DHP was performed on 82 patients. The median (interquartile range) SOFA score decreased from 10 (8-11) to 4 (3-7) after 7 days (n = 70; p < 0.01). Granulocytes, mainly neutrophils, were adsorbed, and the neutrophil-to-lymphocyte ratio significantly improved (p < 0.01). Notable improvements were observed in the SOFA scores for circulation and renal function. The acute physiology and chronic health evaluation II score of the 77 patients evaluated for mortality was 27, and the 28-day mortality rate was 7.8%.

This study confirmed that G1-DHP can be safely used as an adjunct to standard sepsis treatment regimens. Although further investigations are required, G1-DHP is a promising supplemental therapy for sepsis.

jRCT1080225183 (Japan Registry of Clinical Trials identifier).

Pediatric sepsis presents a unique clinical challenge due to the distinct characteristics of the developing immune system. The immune response in children differs significantly from that in adults, exhibiting a unique combination of resistance, disease tolerance, and resilience. These factors influence the clinical presentation and prognosis of pediatric patients with sepsis. Over the past few years, various studies have explored the role of immunomodulatory therapies in managing sepsis, including the use of immunoglobulins, corticosteroids, monoclonal antibodies, and immunostimulatory treatments. However, the heterogeneity of the clinical presentations and individual responses makes it difficult to identify universally effective treatments. Recent research has highlighted the importance of a personalized approach based on specific biomarkers and patient phenotyping. Extracorporeal blood purification techniques have emerged as promising strategies for the modulation of hyperinflammation. However, strong evidence supporting their routine use in pediatric sepsis is lacking. This review provides a comprehensive overview of the current knowledge of the immune response in pediatric sepsis and discusses the main immunomodulatory strategies and future perspectives for personalized therapy. A deeper understanding of the immunological differences between children and adults could improve the prognosis and treatment efficacy, paving the way for new approaches to pediatric sepsis management.

Hemoadsorption is a promising therapeutic modality for sepsis, however, the most effective approach is unknown. This meta-analysis aimed to compare the efficacy of different adsorptive blood purification (ABP) modalities in patients with sepsis.

Randomized controlled trials (RCTs) investigating the clinical efficacy of ABP modalities in patients with sepsis were retrieved from English databases from inception up to October 14, 2024. The data were analyzed using Stata15 and R software. Quality assessment and publication bias were assessed using the Cochrane Risk of Bias Assessment Tool and funnel plots, respectively. The outcomes of the meta-analysis were hospital mortality, oxygenation index, ICU stay days, and blood lactate concentration.

A total of 47 RCTs were identified, comprising 9 ABP modalities. In terms of cumulative ranking probability, the HA330 modality achieved the highest reduction in hospital mortality (99.5 %) and ICU stay days (97.2 %), whereas CPFA showed the highest reduction in oxygenation index (94.9 %) and oXiris had the highest reduction in lactate (95.7 %).

HA330 and PMX showed superior overall efficacy in sepsis patients compared with other modalities, although there was potential heterogeneity. However, further RCTs with large samples are advocated to test new approaches of hemosorption and validate the present findings.

While a dysregulated immune response is at the center of the sepsis definition, standard care is still solely focussed on prompt administration of antimicrobial therapy, source control, resuscitation and organ supportive therapies. Extracorporeal blood purification therapies, such as haemoadsorption, have been proposed as a possible adjunctive therapy to standard care in sepsis. These adsorption devices aim to rebalance the dysregulated immune response by removal of excessive amounts of circulating inflammatory mediators, including cytokines and endotoxins. Thus far, the effects of haemoadsorption on clinical outcomes have been insufficiently studied and although its routine use is not justified based on the current evidence, multiple centers use these devices in patients with severe septic shock. This narrative review describes the most well-studied adsorption devices as well as a novel selective adsorption device called the 'IL-6-Sieve', including in vitro data showing its capturing potential. Finally, it addresses important considerations for future trials on haemoadsorption in septic patients.

We sought to delineate the mortality outcome time frames reported in septic shock randomized control trials (RCTs).

Systematic review of PubMed, EMBASE, and the Cochrane Database of Systematic Reviews.

Intensive care units.

Studies that included adult patients with septic shock.

Any type of intervention.

Information about the study, specific patient population, type of study intervention, specific intervention, and number of patients. Mortality time frames were analyzed for geographical differences and changes over time.

The search yielded 2660 unique citations. After screening, 132 eligible studies were identified. A total of 234 mortality time frames were collected from the included studies, of which 15 timeframes were unique. The most frequently reported time frame was 28-day mortality (n = 98, 74% of trials), followed by hospital mortality (n = 35, 27%), ICU mortality (n = 30, 23%), and 90-day mortality (n = 29, 22%). The most reported mortality time frame was 28 days in studies from every continent except Africa. The studies published between 2008 and 2013 (25%) more frequently reported hospital and ICU mortality combination than studies published between 2014 and 2019 (11.4%) (P = 0.043).

There was considerable variability in the mortality time frames reported in ICU-based septic shock trials. This variability may lead to under or overestimation of the problem, overlooking the effectiveness of the interventions studied, and further limiting the application of trials and their pooling in meta-analyses. A consensus regarding time frame reporting in septic shock trials is long overdue.

The 2024 revised edition of the Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock (J-SSCG 2024) is published by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine. This is the fourth revision since the first edition was published in 2012. The purpose of the guidelines is to assist healthcare providers in making appropriate decisions in the treatment of sepsis and septic shock, leading to improved patient outcomes. We aimed to create guidelines that are easy to understand and use for physicians who recognize sepsis and provide initial management, specialized physicians who take over the treatment, and multidisciplinary healthcare providers, including nurses, physical therapists, clinical engineers, and pharmacists. The J-SSCG 2024 covers the following nine areas: diagnosis of sepsis and source control, antimicrobial therapy, initial resuscitation, blood purification, disseminated intravascular coagulation, adjunctive therapy, post-intensive care syndrome, patient and family care, and pediatrics. In these areas, we extracted 78 important clinical issues. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members. As a result, 42 GRADE-based recommendations, 7 good practice statements, and 22 information-to-background questions were created as responses to clinical questions. We also described 12 future research questions.

Polymyxin B haemoperfusion is commonly used to adsorb endotoxins in septic shock caused by Gram-negative bacterial infections. Polymyxin B haemoperfusion has been reported to improve hypotension in Gram-positive bacterial infections; however, its efficacy and mechanism in treating such cases are unclear. We hypothesised that polymyxin B haemoperfusion would be equally effective in improving haemodynamics during Gram-positive bacterial infections as in Gram-negative bacterial infections. We conducted a retrospective study that included patients with septic shock admitted to the intensive care unit. The patients were divided into two groups according to bacterial culture results: Gram-negative rod (GNR) and Gram-positive coccus (GPC). We calculated the vasoactive inotropic score (VIS) before (0 h) and 2, 6, 12 and 24 h after polymyxin B haemoperfusion therapy. Data were analysed using two-way analysis of variance and post hoc tests for the associations between infection type and treatment time. Overall, 157 patients with septic shock were enrolled in the study: 81 and 76 patients were treated or not treated with extracorporeal haemoperfusion therapy, respectively. Although there was no significant difference in the VIS in polymyxin B haemoperfusion between patients with GNR and GPC infections, there was a significant decrease in the VIS over time, even when GPC was the causative organism. In addition, the degree of reduction in the VIS was significantly different in both the GNR and GPC groups compared with that in the non-extracorporeally treated group. Thus, polymyxin B haemoperfusion for septic shock caused by GNR reduced the VIS and could be effective even in cases of GPC infection.

In critical illness, all elements of gut function are perturbed. Dysbiosis develops as the gut microbial community loses taxonomic diversity and new virulence factors appear. Intestinal permeability increases, allowing for translocation of bacteria and/or bacterial products. Epithelial function is altered at a cellular level and homeostasis of the epithelial monolayer is compromised by increased intestinal epithelial cell death and decreased proliferation. Gut immunity is impaired with simultaneous activation of maladaptive pro- and anti-inflammatory signals leading to both tissue damage and susceptibility to infections. Additionally, splanchnic vasoconstriction leads to decreased blood flow with local ischemic changes. Together, these interrelated elements of gastrointestinal dysfunction drive and then perpetuate multi-organ dysfunction syndrome. Despite the clear importance of maintaining gut homeostasis, there are very few reliable measures of gut function in critical illness. Further, while multiple therapeutic strategies have been proposed, most have not been shown to conclusively demonstrate benefit, and care is still largely supportive. The key role of the gut in critical illness was the subject of the tenth Perioperative Quality Initiative meeting, a conference to summarize the current state of the literature and identify key knowledge gaps for future study. This review is the product of that conference.

Polymyxin-B direct hemoperfusion (PMX-DHP) is an endotoxin adsorption column-based blood purification therapy. Since one of the most potent effects of PMX-DHP is blood pressure elevations, it may be the most effective when it is introduced at the time when the need for vasopressors is the greatest, which, in turn, may reduce mortality.

A multicenter retrospective study was conducted at 24 ICUs in Japan. In each ICU, the 20 most recent consecutive cases of septic shock treated with PMX-DHP were analyzed. The duration between the time of the peak vasopressive agent dose, expressed as the noradrenaline equivalent dose (NEq), and the time of PMX initiation was evaluated. The primary outcome was 28-day mortality, and a multivariable analysis was performed to investigate factors associated with mortality.

A total of 480 septic shock patients were included in the analysis. Among all patients, the 28-day mortality group was older, more severely ill, and had a higher body mass index. The NEq peak and NEq on PMX-DHP initiation were both higher in deceased patients. Regarding the timing of PMX-DHP initiation from the NEq peak, -4 << 4 h had more survivors (229/304, 75.3%) than ≤-4 h (50/75, 66.7%) and ≥4 h (66/101, 65.4%) (p = 0.085). When -4 << 4 h was assigned as a reference, the timing of PMX-DHP initiation from the NEq peak of ≤-4 h had an odds ratio of 1.96 (1.07-3.58), p = 0.029, while ≥4 h had an odds ratio of 1.64 (0.94-2.87), p = 0.082 for 28-day mortality, in the multivariable regression analysis. A spline curve of the relationship between the probability of death and the timing of PMX-DHP initiation from the NEq peak showed a downward convex curve with a nadir at timing = 0. The odds ratios of the timing of PMX-DHP initiation other than -4 << 4 h were significantly higher in an older age, male sex, lower BMI, more severe illness, and higher oxygenation.

The induction of PMX-DHP at the time of the peak vasopressor dose correlated with lower mortality. PMX-DHP is one of the options available for elevating blood pressure in septic shock, and its initiation either too early or late for shock peak may not improve the outcome.

The 2012 Kidney Disease Improving Global Outcomes guidelines clearly define emergent indications for kidney replacement therapy; however, whether dialysis should be initiated in critically ill patients without these indications remains unclear. This review briefly summarizes the results of recent landmark trials and discusses their limitations originating from a criteria-based approach at a single time point. Moreover, a personalized approach based on each patient's demand-capacity balance and its future benefits as a platform for kidney support therapy in critically ill patients are discussed.

Eligibility criteria for randomized clinical trials (RCTs) are designed to select clinically relevant patient populations. However, not all eligibility criteria are strongly justified, potentially excluding marginalized groups, and limiting the generalizability of trial findings.

To summarize and evaluate the justification of exclusion criteria in published RCTs in critical care medicine.

A systematic sampling review of parallel-group RCTs published in the top 5 general internal medicine journals by impact factor (The Lancet, New England Journal of Medicine, Journal of the American Medical Association, British Medical Journal, and Annals of Internal Medicine) between January 1, 2018, and February 23, 2023, was conducted. RCTs enrolling adults in intensive care units (ICUs) and RCTs enrolling critically ill patients who required life-sustaining interventions typically initiated in the ICU were included. All study exclusion criteria were categorized as either poorly justified, potentially justified, or strongly justified, adapting previously established criteria, independently and in duplicate.

In total, 225 studies were identified, 75 of which were included. The median (IQR) number of exclusion criteria per trial was 19 (14-24), with 1455 total exclusion criteria. Common exclusion criteria were related to the risk of adverse reaction to interventions (302 criteria [20.8%]), followed by inability to obtain consent (120 criteria [8.2%]), and treatment limitation decisions (97 criteria [6.7%]). Most exclusion criteria were either strongly justified (1080 criteria [74.2%]) or potentially justified (297 criteria [20.4%]), whereas 5.4% (78 criteria) were poorly justified. Of the 78 poorly justified exclusion criteria, the most common were pregnancy (19 criteria [24.4%]), communication barriers (11 criteria [14.1%]), lactation (10 criteria [12.8%]), and lack of health insurance (10 criteria [12.8%]). Overall, 45 of 75 studies (60.0%) had at least 1 poorly justified exclusion criteria.

Most exclusion criteria in critical care medicine RCTs were strongly justifiable. Across poorly justified criteria, the most common exclusions were pregnant or lactating persons, those with communication barriers, and individuals without health insurance. This highlights the need to carefully consider exclusion criteria when designing trials to minimize the inappropriate exclusion of participants and enhance generalizability.

The 2024 revised edition of the Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock (J-SSCG 2024) is published by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine. This is the fourth revision since the first edition was published in 2012. The purpose of the guidelines is to assist healthcare providers in making appropriate decisions in the treatment of sepsis and septic shock, leading to improved patient outcomes. We aimed to create guidelines that are easy to understand and use for physicians who recognize sepsis and provide initial management, specialized physicians who take over the treatment, and multidisciplinary healthcare providers, including nurses, physical therapists, clinical engineers, and pharmacists. The J-SSCG 2024 covers the following nine areas: diagnosis of sepsis and source control, antimicrobial therapy, initial resuscitation, blood purification, disseminated intravascular coagulation, adjunctive therapy, post-intensive care syndrome, patient and family care, and pediatrics. In these areas, we extracted 78 important clinical issues. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members. As a result, 42 GRADE-based recommendations, 7 good practice statements, and 22 information-to-background questions were created as responses to clinical questions. We also described 12 future research questions.

Sepsis is the result of a dysregulated immune response to infection and is associated with acute organ dysfunction. The syndrome's complexity is contingent upon the underlying pathology and individual patient characteristics, including their immune response. The involvement of multiple organs and physiological functions adds complexity, with "organ cross-talk" emerging as a pivotal pathophysiological and clinical aspect. This narrative review to evaluate the rationale and available clinical evidence supporting the use of extracorporeal blood purification therapies as adjunctive therapy in patients with sepsis and septic shock.

A search of the PubMed, Embase, Web of Science and Scopus databases for relevant literature from August 2002 to May 2024 has been conducted. The search was performed using the terms: 1) "blood purification" or "hemadsorption" or "plasma exchange" AND 2) "sepsis" or "septic shock". Therefore the authors have focused our discussion on several key areas such as conducting well-designed trials, developing more personalized protocols, ensuring optimal management and monitoring.

Given the heterogeneity of patients with sepsis, conducting traditional randomized clinical trials in this domain can be a daunting task. However, statistical techniques such as Bayesian methods, propensity score analysis, and emulated clinical trials using clinical databases hold promise for enhancing comparability between the study groups. Indeed, to comprehend the clinical efficacy of extracorporeal blood purification techniques in patients with sepsis, it is imperative to assemble homogeneous groups of patients receiving uniform treatments. Clinical strategies should be individualized, signaling the end of the "one size fits all" approach in sepsis therapy and the need for personalized treatments.

Background: Renal replacement therapy with an oXiris hemofilter may be helpful for patients with acute kidney injury in conjunction with sepsis and septic shock. The aim of this study was to assess the impact of an oXiris membrane on septic shock patients. Methods: All renal replacement therapies with oXiris (Baxter, Deerfield, IL, USA) performed between January 2018 and August 2021 were retrospectively analyzed. CRRT was initiated in continuous venovenous hemodiafiltration (CVVHDF) mode using Prismaflex System (Baxter). Demographic data, starting point of infection, source control, etiology, and course of treatment were analyzed. Results: A total of 32 patients were included in the study. Most patients treated with oXiris had acute kidney injury (AKI) and required CRRT. One patient had KDIGO 1 AKI (3.1%), three patients (9.4%) had KDIGO 2 AKI, and 28 patients (87.5%) had KDIGO 3 AKI. A statistically significant decrease in vasopressin dosage was required to achieve adequate MAP after 24 and 72 h, and a statistically significant decrease in norepinephrine dosage after 72 h was observed, with no SOFA score change on days 2 and 3. Procalcitonin and lactate levels did not change after 24 and 72 h. No beneficial effect on mortality was observed. Conclusions: Treatment with an oXiris membrane can positively impact vasopressors' requirement but not influence SOFA score, procalcitonin or lactate levels, or mortality in septic shock patients.

Sepsis represents a significant global health and hygiene challenge. Excessive activation of macrophages in sepsis can result in certain patients displaying characteristics akin to those observed in Macrophage Activation Syndrome (MAS). MAS represents a grave immune system disorder characterized by persistent and severe inflammation within the body. In the context of sepsis, MAS presents atypically, leading some researchers to refer to it as Macrophage Activation-Like Syndrome (MALS). However, there are currently no effective treatment measures for this situation. The purpose of this article is to explore potential treatment methods for sepsis-associated MALS.

The objective of this review is to synthesize the specific pathophysiological mechanisms and treatment strategies of MAS to investigate potential therapeutic approaches for sepsis-associated MALS.

We searched major databases (including PubMed, Web of Science, and Google Scholar etc.) for literature encompassing macrophage activation syndrome and sepsis up to Mar 2024 and combined with studies found in the reference lists of the included studies.

We have synthesized the underlying pathophysiological mechanism of MALS in sepsis, and then summarized the diagnostic criteria and the effects of various treatment modalities utilized in patients with MAS or MALS. In both scenarios, heterogeneous treatment responses resulting from identical treatment approaches were observed. The determination of whether the patient is genuinely experiencing MALS significantly impacts the ultimate outcomes of therapeutic efficacy. In order to tackle this concern, additional clinical trials and research endeavors are imperative.