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LPS triggers the priming step of NLRP3 inflammasome via the TLR4/NF-κB pathway, accompanied by the increased expression of pro-IL-1β, pro-IL-18, pro-caspase-1 and NLRP3. Hypercapnia promotes NLRP3 inflammasome activation by upregulating P2X7R expression and extracellular ATP levels, leading to the maturation and release of IL-1β and IL-18, a process that is dependent on the priming step induced by LPS. [Display omitted] • LPS triggers the priming step of NLRP3 inflammasome via the TLR4/NF-κB pathway. • Hypercapnia could hardly enhance NLRP3 inflammasome activation without the priming step activation induced by LPS. • Hypercapnia activates the NLRP3 inflammasome in SAE mouse microglia via P2X7R upregulation and ATP release. Sepsis is an uncontrolled inflammatory response to infection and is closely associated with the occurrence of acute respiratory distress syndrome (ARDS). Low tidal volume lung ventilation and permissive hypercapnia is a recognized therapy for ARDS. However, whether permissive hypercapnia aggravates sepsis-associated encephalopathy (SAE) remains unclear. The present study investigated whether hypercapnia contributed to the development of SAE through the purinergic 2X7 receptor (P2X7R) by activating the Nod-like receptor protein 3 (NLRP3) inflammasome in sepsis. The SAE model was established by intracranial injection of lipopolysaccharide (LPS) (1 μg/ml, 5 μl) in C57BL/6 mice. Hypercapnia was induced by mechanical ventilation with a high concentration of CO 2 (5 % CO 2 , 21 % O 2 and 74 % N 2) in vivo. Toll-like receptor 4 (TLR4) and P2X7R knockout (KO) mice were employed in the study, while in vitro , BV2 microglial cells were treated with LPS or a high concentration of CO 2 (15 % CO 2 + 20 % O 2). Immunofluorescence and western blot analysis were used to assess the expression levels of TLR4, NF-κB, phosphorylated (p)-NF-κB, P2X7R, pro-caspase-1, caspase-1, pro-IL-1β, IL-1β, pro-IL-18 and IL-18. ATP levels in the cell culture medium were detected by fluorometric assay. The results revealed that, compared with the sham group, the expression levels of TLR4, p-NF-κB, pro-IL-1β, pro-IL-18 and NLRP3 were significantly upregulated in the LPS and LPS + hypercapnia groups, but not in the hypercapnia group. Although the expression levels of caspase-1, IL-1β and IL-18 were increased slightly in the LPS group, their upregulation was more pronounced in the LPS + hypercapnia group, and it was suppressed when TLR4 was knocked out. Furthermore, P2X7R expression and ATP levels in the cell culture medium remained unchanged in the LPS group compared with the sham group but were remarkably increased both in the hypercapnia and LPS + hypercapnia groups. Additionally, P2X7R KO restrained the caspase-1, IL-1β and IL-18 increased induced by LPS injected intracranially and hypercapnia. In conclusion, LPS induced the priming step of NLRP3 inflammasome activation, but had little effect on the activation step, while hypercapnia played an important role in the activation step through P2X7R, depending on the priming step stimulated by LPS. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to evaluate the efficacy of intraoperative intravenous lidocaine administration in the management of sepsis-associated encephalopathy (SAE)., Methods: This retrospective cohort analysis included 165 patients diagnosed with SAE, who were categorized into two groups: the lidocaine group ( n  = 55) and the control group ( n  = 110). The lidocaine group received an intravenous injection of lidocaine at 1.5 mg/kg following anesthesia induction, and then received a continuous infusion at 1.5 mg/kg/h until the completion of surgery. The control group did not receive lidocaine during surgery. Data collected included patient demographics, medical history, infection site, Acute Physiology and Chronic Health Evaluation (APACHE) II score, Sequential Organ Failure Assessment (SOFA) score, Glasgow Coma Scale (GCS) score, laboratory results, anesthetic agents used, surgery duration, and length of stay in the intensive care unit (ICU). The primary outcome was the in-hospital prognosis of SAE., Results: Patients in the lidocaine group had a significantly shorter ICU stay and a significantly higher rate of favorable prognosis compared with the control group ( p  < 0.05). Multivariate logistic regression analysis identified age and surgery duration as risk factors for SAE prognosis, whereas intraoperative intravenous lidocaine, GCS score, and intravenous dexmedetomidine emerged as protective factors., Conclusion: Intraoperative intravenous administration of lidocaine significantly enhanced the prognosis of SAE patients.