Daily Sepsis Research Analysis

RATIONALE: Fluid therapy is one of the main interventions provided for critically ill patients, although there is no consensus regarding the type of solution that should be used. There are two main types: colloid and crystalloid. The most commonly administered crystalloid solution is 0.9% saline. Buffered solutions may offer some theoretical advantages (e.g. less metabolic acidosis, less electrolyte disturbance), but the clinical relevance of these remains unknown. This is an update of a review published in 2019. OBJECTIVES: To assess the effects of buffered solutions versus 0.9% saline for resuscitation or maintenance in critically ill adults and children. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, and four trial registers in July 2023. We checked references, conducted backward and forward citation searches for relevant articles, and contacted study authors to identify additional studies. Although we updated our search in June 2025, the results have not yet been fully incorporated into the review. ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs) with parallel or cross-over design that examined buffered solutions versus 0.9% saline in a critical care setting (resuscitation or maintenance). We included studies with participants who required intravenous fluid therapy due to critical illness (including trauma and burns) or undergoing emergency surgery during critical illness. We included studies of adults or children (or both). We excluded studies of people undergoing elective surgery and studies with multiple interventions in the same arm. OUTCOMES: Our critical outcomes were overall (in-hospital) mortality and acute renal injury. Our important outcomes were organ system dysfunction, need for renal replacement therapy, days without organ support, electrolyte disturbances, blood loss or transfusion, coagulation disorders, total resuscitation fluid volume, quality of life, and cost. To populate a table summarising the findings of our review, we selected key outcomes for decision-makers, which were our two critical outcomes and two of our important outcomes (organ system dysfunction and electrolyte disturbances).

BACKGROUND AND PURPOSE: Sepsis induces immunosuppression, contributing to high mortality. Plasmablasts, including an IL-10-producing regulatory subset, expand during sepsis to exert immunosuppressive functions. This study examined how depleting plasmablasts can improve the prognosis of sepsis, and investigated the underlying mechanisms by focusing on neutrophil function. EXPERIMENTAL APPROACH: Plasmablasts were depleted in vivo in CD138-diphtheria toxin receptor (DTR) transgenic mice subjected to caecal ligation and puncture (CLP)-induced sepsis. The effects of plasmablast depletion on animal survival, bacterial load, inflammatory mediators, and neutrophil number and function were assessed. The proteasome inhibitor bortezomib (BTZ) was evaluated for its ability to suppress plasmablasts, and its therapeutic efficacy in wild-type mice with sepsis. KEY RESULTS: Plasmablast depletion in CD138-DTR mice was associated with an increase in the number and antibacterial function of neutrophils, including increased production of reactive oxygen species (ROS) and phagocytic capacity. In vitro co-culture experiments demonstrated that plasmablasts suppressed neutrophil activity, an effect mediated by adenosine and IL-10 signalling. Treatment of wildtype septic mice with BTZ effectively reduced plasmablast abundance and CD39 expression. BTZ 0.05 mg·kg CONCLUSION AND IMPLICATIONS: Plasmablasts contribute to sepsis immunosuppression by affecting neutrophil function. The clinically-available drug bortezomib can target this population, positioning plasmablast inhibition as a novel and translatable therapeutic strategy to improve bacterial clearance and survival in sepsis.

Sepsis is a leading cause of death for which host-directed therapies are urgently needed. We performed high-dimensional flow cytometry, measurement of soluble biomarkers, and lipopolysaccharide (LPS) stimulation of neutrophils to characterize neutrophil heterogeneity and function in patients with sepsis. We observed that in sepsis patients, low-density neutrophils (LDNs) are elevated and phenotypically diverse populations of innate immune cells with varying degrees of maturity and myeloperoxidase expression. Spleen tyrosine kinase (SYK) expression was found to be higher in whole blood neutrophils and LDNs of sepsis patients compared to healthy donors. Importantly, SYK+LDNs associated with increased levels of intracellular myeloperoxidase (MPO) and soluble biomarkers. Furthermore, SYK+LDNs correlated with clinical outcomes of sepsis disease severity including sequential organ failure assessment (SOFA) score, mechanical ventilation, and vasopressors. Functionally, the SYK inhibitor R406 suppressed changes in neutrophil features of activation from normal-density neutrophils and LDNs including the SYK+ and SYK- neutrophil subsets and MPO release from LDNs following LPS stimulation of sepsis neutrophils. Combined, these results establish LDNs as a heterogenous population of neutrophils that express high levels of SYK and support SYK inhibition as a novel therapeutic target aimed at suppressing overactive neutrophils in sepsis.