Risk factors associated with intraoperative persistent hypotension in pancreaticoduodenectomy.

BACKGROUND: Intraoperative persistent hypotension (IPH) during pancreaticoduodenectomy (PD) is linked to adverse postoperative outcomes, yet its risk factors remain unclear. AIM: To clarify the risk factors associated with IPH during PD, ensuring patient safety in the perioperative period. METHODS: A retrospective analysis of patient records from January 2018 to December 2022 at the First Affiliated Hospital of Nanjing Medical University identified factors associated with IPH in PD. These factors included age, gender, body mass index, American Society of Anesthesiologists classification, comorbidities, medication history, operation duration, fluid balance, blood loss, urine output, and blood gas parameters. IPH was defined as sustained mean arterial pressure < 65 mmHg, requiring prolonged deoxyepinephrine infusion for > 30 min despite additional deoxyepinephrine and fluid treatments. RESULTS: Among 1596 PD patients, 661 (41.42%) experienced IPH. Multivariate logistic regression identified key risk factors: increased age [odds ratio (OR): 1.20 per decade, 95% confidence interval (CI): 1.08-1.33] (P < 0.001), longer surgery duration (OR: 1.15 per additional hour, 95%CI: 1.05-1.26) (P < 0.01), and greater blood loss (OR: 1.18 per 250-mL increment, 95%CI: 1.06-1.32) (P < 0.01). A novel finding was the association of arterial blood Ca2+ < 1.05 mmol/L with IPH (OR: 2.03, 95%CI: 1.65-2.50) (P < 0.001). CONCLUSION: IPH during PD is independently associated with older age, prolonged surgery, increased blood loss, and lower plasma Ca2+.

System biology approaches to identify hub genes linked with ECM organization and inflammatory signaling pathways in schizophrenia pathogenesis.

Schizophrenia (SZ) is a chronic and devastating mental illness that affects around 20 million individuals worldwide. Cognitive deficits and structural and functional changes of the brain, abnormalities of brain ECM components, chronic neuroinflammation, and devastating clinical manifestation during SZ are likely etiological factors shown by affected individuals. However, the pathophysiological events associated with multiple regulatory pathways involved in the brain of this complex disorder are still unclear. This study aimed to develop a pipeline based on bioinformatics and systems biology approaches for identifying potential therapeutic targets involving possible biological mechanisms from SZ patients and healthy volunteers. About 420 overlapping differentially expressed genes (DEGs) from three RNA-seq datasets were identified. Gene ontology (GO), and pathways analysis showed several biological mechanisms enriched by the commonly shared DEGs, including extracellular matrix organization (ECM) organization, collagen fibril organization, integrin signaling pathway, inflammation mediated by chemokines and cytokines signaling pathway, and GABA-B receptor II and IL4 mediated signaling. Besides, 15 hub genes (FN1, COL1A1, COL3A1, COL1A2, COL5A1, COL2A1, COL6A2, COL6A3, MMP2, THBS1, DCN, LUM, HLA-A, HLA-C, and FBN1) were discovered by comprehensive analysis, which was mainly involved in the ECM organization and inflammatory signaling pathway. Furthermore, the miRNA target of the hub genes was analyzed with the random-forest-based approach software miRTarBase. In addition, the transcriptional factors and protein kinases regulating overlapping DEGs in SZ, namely, SUZ12, EZH2, TRIM28, TP53, EGR1, CSNK2A1, GSK3B, CDK1, and MAPK14, were also identified. The results point to a new understanding that the hub genes (fibronectin 1, collagen, matrix metalloproteinase-2, and lumican) in the ECM organization and inflammatory signaling pathways may be involved in the SZ occurrence and pathogenesis.

Enhanced meningeal lymphatic drainage ameliorates lipopolysaccharide-induced brain injury in aged mice.

BACKGROUND: Sepsis-associated encephalopathy (SAE) is an acute cerebral dysfunction caused by sepsis. Neuroinflammation induced by sepsis is considered a potential mechanism of SAE; however, very little is known about the role of the meningeal lymphatic system in SAE. METHODS: Sepsis was established in male C57BL/6J mice by intraperitoneal injection of 5 mg/kg lipopolysaccharide, and the function of meningeal lymphatic drainage was assessed. Adeno-associated virus 1-vascular endothelial growth factor C (AAV1-VEGF-C) was injected into the cisterna magna to induce meningeal lymphangiogenesis. Ligation of deep cervical lymph nodes (dCLNs) was performed to induce pre-existing meningeal lymphatic dysfunction. Cognitive function was evaluated by a fear conditioning test, and inflammatory factors were detected by enzyme-linked immunosorbent assay. RESULTS: The aged mice with SAE showed a significant decrease in the drainage of OVA-647 into the dCLNs and the coverage of the Lyve-1 in the meningeal lymphatic, indicating that sepsis impaired meningeal lymphatic drainage and morphology. The meningeal lymphatic function of aged mice was more vulnerable to sepsis in comparison to young mice. Sepsis also decreased the protein levels of caspase-3 and PSD95, which was accompanied by reductions in the activity of hippocampal neurons. Microglia were significantly activated in the hippocampus of SAE mice, which was accompanied by an increase in neuroinflammation, as indicated by increases in interleukin-1 beta, interleukin-6 and Iba1 expression. Cognitive function was impaired in aged mice with SAE. However, the injection of AAV1-VEGF-C significantly increased coverage in the lymphatic system and tracer dye uptake in dCLNs, suggesting that AAV1-VEGF-C promotes meningeal lymphangiogenesis and drainage. Furthermore, AAV1-VEGF-C reduced microglial activation and neuroinflammation and improved cognitive dysfunction. Improvement of meningeal lymphatics also reduced sepsis-induced expression of disease-associated genes in aged mice. Pre-existing lymphatic dysfunction by ligating bilateral dCLNs aggravated sepsis-induced neuroinflammation and cognitive impairment. CONCLUSION: The meningeal lymphatic drainage is damaged in sepsis, and pre-existing defects in this drainage system exacerbate SAE-induced neuroinflammation and cognitive dysfunction. Promoting meningeal lymphatic drainage improves SAE. Manipulation of meningeal lymphangiogenesis could be a new strategy for the treatment of SAE.

Peripheral surgery triggers mast cells activation: Focusing on neuroinflammation.

Peripheral surgery can lead to a systemic aseptic inflammatory response comprising several mediators aiming at restoring tissue homeostasis. It induces inflammatory mechanisms through neuroimmune interaction between the periphery and to brain which also plays a critical role in causing cognitive impairments. Accumulating scientific evidence revealed that acute neuroinflammation of the brain triggered by peripheral surgery that causes peripheral inflammation leads to transmitting signals into the brain through immune cells. Mast cells (MCs) play an important role in the acute neuroinflammation induced by peripheral surgical trauma. After peripheral surgery, brain-resident MCs can be rapidly activated followed by releasing histamine, tryptase, and other inflammatory mediators. These mediators then interact with other immune cells in the peripheral and amplify the signal into the brain by disrupting BBB and activating principle innate immune cells of brain including microglia, astrocytes, and vascular endothelial cells, which release abundant inflammatory mediators and in turn accelerate the activation of brain MCs, amplify the cascade effect of neuroinflammatory response. Surgical stress may induce HPA axis activation by releasing corticotropin-releasing hormone (CRH) subsequently influence the activation of brain MCs, thus resulting in impaired synaptic plasticity. Herein, we discuss the better understating of MCs mediated neuroinflammation mechanisms after peripheral surgery and potential therapeutic targets for controlling inflammatory cascades.

Predictive value of NoSAS questionnaire combined with the modified Mallampati grade for hypoxemia during routine sedation for gastrointestinal endoscopy.

BACKGROUND: The incidence of hypoxemia during painless gastrointestinal endoscopy remains a matter of concem. To date, there is no recognized simple method to predict hypoxemia in digestive endoscopic anesthesia. The NoSAS (neck circumference, obesity, snoring, age, sex) questionnaire, an objective and simple assessment scale used to assess obstructive sleep apnea (OSA), combined with the modified Mallampati grade (MMP), may have certain screening value. This combination may allow anesthesiologists to anticipate, manage, and consequently decrease the occurrence of hypoxemia. METHODS: This study was a prospective observational trial. The primary endpoint was the incidence of hypoxaemia defined as pulse oxygen saturation (SpO2) < 95% for 10 s. A total of 2207 patients admitted to our hospital for painless gastrointestinal endoscopy were studied. All patients were measured for age, height, weight, body mass index, neck circumference, snoring, MMP, and other parameters. Patients were divided into hypoxemic and non-hypoxemic groups based on the SpO2. The ROC curve was plotted to evaluate the screening value of the NoSAS questionnaire separately and combined with MMP for hypoxemia. The total NoSAS score was evaluated at cut-off points of 8 and 9. RESULTS: With a NoSAS score ≥ 8 as the critical value for analysis, the sensitivity for hypoxemia was 58.3%, the specificity was 88.4%, and the area under the ROC was 0.734 (P < 0.001, 95% CI: 0.708-0.759). With a NoSAS score ≥ 9 as a critical value, the sensitivity for hypoxemia was 36.50%, the specificity rose to 96.16%, and the area under the ROC was 0.663 (P < 0.001, 95% CI: 0.639-0.688). With the NoSAS Score combined with MMP for analysis, the sensitivity was 78.4%, the specificity was 84%, and the area under the ROC was 0.859 (P < 0.001, 95%CI:0.834-0.883). CONCLUSIONS: As a new screening tool, the NoSAS questionnaire is simple, convenient, and useful for screening hypoxemia. This questionnaire, when paired withMMP, is likely to be helpful for the screening of hypoxemia.

Prophylactic intra-arterial injection of lidocaine: a novel strategy to prevent endovascular embolization-induced trigeminocardiac reflex.

BACKGROUND: Trigeminocardiac reflex (TCR) is a brainstem reflex that can lead to hemodynamic instability manifested as bradycardia, decrease/increase of mean arterial pressure (MAP) and, in the worst case scenario, asystole during surgery. The effective intraoperative management of recurrent and profound TCR has yet to be established. This randomized paired study was performed to identify the effect of a prophylactic intra-arterial injection of lidocaine to prevent TCR caused by Onyx embolization during cerebrovascular intervention surgery. METHODS: A total of 136 patients who received Onyx embolization under general anesthesia were assigned to a control group pretreated with intra-arterial saline injection or a lidocaine group pretreated with an intra-arterial injection of 20 mg lidocaine. Heart rate (HR) and MAP were closely monitored during the embolization procedures and the incidence of TCR, mainly characterized by a decrease in HR of ≥20%, and perioperative adverse events was recorded. RESULTS: During dimethyl sulfoxide (DMSO)/Onyx injection, HR was much slower in the control group than in the lidocaine group (p<0.05). TCR occurred in 12 patients (17.6%) in the control group (cardiac arrest in 3 patients) with decreased (7 cases) or increased (5 cases) MAP, whereas no TCR was observed in the lidocaine group. Notably, most TCR episodes occurred in patients with dural arteriovenous fistula and middle meningeal artery being affected. The composite adverse events were significantly higher in the control group than in the lidocaine group (p<0.05). CONCLUSION: This prospective study shows that a prophylactic intra-arterial injection of 20 mg lidocaine could be recommended as a novel strategy to effectively and safely prevent TCR during endovascular embolization.

Prognostic factors for trigeminocardiac reflex during cerebrovascular intervention operation.

Introduction: Trigeminocardiac reflex (TCR) is a brainstem reflexive response of hemodynamic instability during surgery. Identification of risk factors relevant to TCR during cerebrovascular intervention procedures is helpful to efficiently prevent and treat its occurrence. The purpose of this study was to demonstrate the risk factors for Onyx embolization during cerebrovascular intervention operation so as to optimize perioperative management strategies on TCR. Methods: We performed a retrospective study on the patients with Onyx embolization under general anaesthesia over 6-years period from 2013 to 2018. 354 patients were finally eligible for inclusion, and then divided into TCR group (group T) and control group (group N). Patient characteristics, clinical diagnosis, comorbidities, lesion sites, hemodynamics changes, and complications were compared between two groups. Several multivariable regression models were applied to analyze the risk factors associated with TCR. Results: TCR occurred in 59 patients (16.7%) among 354 patients. There was no significant difference in patient characteristics between two groups (P > 0.05). During DMSO/Onyx injection, HR and MAP were much lower in group T than group N (P < 0.01). Notably, univariable analysis revealed that the patients with dural arteriovenous fistula (DAVF) and middle meningeal artery being affected were associated with a higher incidence of TCR (P < 0.01). Furthermore, multivariable analysis showed that there was a close link of TCR with DAVF [OR = 4.12; 95% CI (1.83-10.65)] and middle meningeal artery embolization [OR = 3.90; 95% CI (1.58-9.63)]. Further stratified analysis of patients with TCR found that patients with middle meningeal artery embolization were more likely to experience hypotension during TCR episode (P < 0.05). Finally, more incidence of postoperative adverse events was observed when TCR episode (P < 0.05). Conclusion: We found that DAVF and middle meningeal artery embolization were independent risk factors for TCR episodes during Onyx endovascular embolization, highly likely leading to intraoperative hemodynamics fluctuations and postoperative adverse events.

Network Biology Approaches to Uncover Therapeutic Targets Associated with Molecular Signaling Pathways from circRNA in Postoperative Cognitive Dysfunction Pathogenesis.

Postoperative cognitive dysfunction (POCD) is a cognitive deterioration and dementia that arise after a surgical procedure, affecting up to 40% of surgery patients over the age of 60. The precise etiology and molecular mechanisms underlying POCD remain uncovered. These reasons led us to employ integrative bioinformatics and machine learning methodologies to identify several biological signaling pathways involved and molecular signatures to better understand the pathophysiology of POCD. A total of 223 differentially expressed genes (DEGs) comprising 156 upregulated and 67 downregulated genes were identified from the circRNA microarray dataset by comparing POCD and non-POCD samples. Gene ontology (GO) analyses of DEGs were significantly involved in neurogenesis, autophagy regulation, translation in the postsynapse, modulating synaptic transmission, regulation of the cellular catabolic process, macromolecule modification, and chromatin remodeling. Pathway enrichment analysis indicated some key molecular pathways, including mTOR signaling pathway, AKT phosphorylation of cytosolic targets, MAPK and NF-κB signaling pathway, PI3K/AKT signaling pathway, nitric oxide signaling pathway, chaperones that modulate interferon signaling pathway, apoptosis signaling pathway, VEGF signaling pathway, cellular senescence, RANKL/RARK signaling pathway, and AGE/RAGE pathway. Furthermore, seven hub genes were identified from the PPI network and also determined transcription factors and protein kinases. Finally, we identified a new predictive drug for the treatment of SCZ using the LINCS L1000, GCP, and P100 databases. Together, our results bring a new era of the pathogenesis of a deeper understanding of POCD, identified novel therapeutic targets, and predicted drug inhibitors in POCD.

Laparotomy-Induced Peripheral Inflammation Activates NR2B Receptors on the Brain Mast Cells and Results in Neuroinflammation in a Vagus Nerve-Dependent Manner.

Background: The pathophysiological mechanisms underlying postoperative cognitive dysfunction (POCD) remain unclear over the years. Neuroinflammation caused by surgery has been recognized as an important element in the development of POCD. Many studies also suggest that the vagus nerve plays an important role in transmitting peripheral injury signals to the central nervous system (CNS) and the resultant neuroinflammation. Previously, we have demonstrated that brain mast cells (BMCs), as the "first responders", play a vital role in neuroinflammation and POCD. However, how the vagus nerve communicates with BMCs in POCD has not yet been clarified. Methods: In the current study, we highlighted the role of the vagus nerve as a conduction highway in surgery-induced neuroinflammation for the first time. In our model, we tested if mice underwent unilateral cervical vagotomy (VGX) had less neuroinflammation compared to the shams after laparotomy (LP) at an early stage. To further investigate the roles of mast cells and glutamate in the process, we employed KitW-sh mice and primary bone marrow-derived MCs to verify the glutamate-NR2B axis on MCs once again. Results: Our results demonstrated that there were higher levels of glutamate and BMCs activation as early as 4 h after LP. Meanwhile, vagotomy could partially block the increases and reduce neuroinflammation caused by peripheral inflammation during the acute phase. Excitingly, inhibition of NR2B receptor and knockout of mast cells can attenuateneuroinflammation induced by glutamate. Conclusion: Taken together, our findings indicate that the vagus is a high-speed pathway in the transmission of peripheral inflammation to the CNS. Activation of BMCs triggered a neuroinflammatory cascade. Inhibition of NR2B receptor on BMCs can reduce glutamate-induced BMCs activation, neuroinflammation, and memory impairment, suggesting a novel treatment strategy for POCD.

The effect of anesthesia depth on radiofrequency catheter ablation of ventricular tachycardia: a retrospective study.

BACKGROUND: Radiofrequency catheter ablation (RFCA) as a safe and effective method has been widely used in ventricular tachycardia (VT) patients, and with which anesthesiologists frequently manage their perioperative care. The aim of this study was to investigate the effects of different anesthetic depths on perioperative RFCA and recurrence in patients who with intractable VT and could not tolerate an awake procedure. METHODS: We reviewed electronic medical records of patients with VT who underwent RFCA by general anesthesia from January 2014 to March 2019. According to intraoperative VT induction, they were divided into two groups: non-inducible group (group N) and inducible group (group I). We constructed several multivariable regression models, in which covariates included patient characteristics, comorbidities, protopathy and bispectral index (BIS) value. RESULTS: One hundred one patients were analyzed. Twenty-nine patients (28.7%) experienced VT no induction, and 26 patients (25.7%) relapsed within 1 year. Compared with group I, the proportion of patients with arrhythmogenic right ventricular cardiomyopathy in group N were higher (P < 0.05), and the recurrence rate of VT was significantly higher (51.7% vs 15.3%) (P < 0.05). The BIS value in group N was significantly lower (P < 0.01), in addition, the BIS < 40 was associated with elevated odds of VT no induction compared with a BIS > 50 (odds ratio, 6.92; 95% confidence interval, 1.47-32.56; P = 0.01). VT no induction was an independent predictor of recurrence after RFCA (odds ratio, 5.01; 95% confidence interval, 1.88-13.83; P < 0.01). CONCLUSION: Lower BIS value during VT induction in RFCA operation was associated with high risk of VT no induction, which affects postoperative outcomes. We proposed that appropriate depth of anesthesia should be maintained during the process of VT induction.

Prophylactic Intra-Arterial Injection of Lidocaine Prevents Trigeminocardiac Reflex During Endovascular Embolization for Dural Arteriovenous Fistula: A Report of 2 Cases.

BACKGROUND Trigeminocardiac reflex (TCR) is a unique brain stem reflex that manifests as the sudden onset of hemodynamic perturbation in heart rate and blood pressure as a result of stimulation of any branches of the trigeminal nerve. Onyx™ embolization in cerebrovascular interventional surgery can trigger TCR, leading to severe hemodynamic fluctuations and even cardiac arrest. Appropriate prophylactic approaches to prevent Onyx™ embolization-induced TCR are still lacking. CASE REPORT We report the cases of 2 patients with recurrent and profound bradycardia due to TCR during endovascular Onyx™ embolization for a dural arteriovenous fistula. Prophylactic intra-arterial injection of lidocaine (10-20 mg) effectively and safely blocked the recurrence and potential occurrence of TCR. These 2 patients had reduced heart rate with either hypotension or hypertension during their TCR episodes, suggesting that stimulating a distinct cerebral artery (occipital artery versus vertebral artery branch) can initiate TCR by provoking the vagus nerve via the common neuronal pathway while simultaneously inhibiting or exciting the sympathetic pathway. CONCLUSIONS Intra-arterial injection of lidocaine during endovascular procedures can be recommended as an effective prophylactic approach for use in the treatment of the cerebrovascular disorder where there is high risk of embolization-induced TCR.

Exosomal miR-409-3p secreted from activated mast cells promotes microglial migration, activation and neuroinflammation by targeting Nr4a2 to activate the NF-κB pathway.

OBJECTIVE: Neuroinflammation plays a critical role in central nervous system diseases. Exosomal miRNAs released from various cells are implicated in cell-to-cell communication. Prior studies have placed substantial emphasis on the role of cytokines in mast cell-microglia interactions during neuroinflammation. However, it has never been clearly determined whether exosomal miRNAs participate in the interaction between mast cells and microglia and thus mediate neuroinflammation. METHODS: The characteristics of exosomes isolated from cell culture supernatants were confirmed by transmission electron microscopy (TEM), nanoparticle-tracking analysis (NTA) and Western blot. The transfer of PKH67-labelled exosomes and Cy3-labelled miR-409-3p was observed by fluorescence microscopy. Migration and activation of murine BV-2 microglial cells were evaluated through Transwell assays and immunofluorescence staining for Iba1 and CD68. CD86, IL-1ß, IL-6 and TNF-α were assessed via qRT-PCR and ELISA. MiR-409-3p was detected by qRT-PCR. Nr4a2 and NF-κB levels were measured by western blot. Regulatory effects were identified by luciferase reporter assays. RESULTS: Lipopolysaccharide (LPS)-stimulated murine P815 mast cells secreted exosomes that were efficiently taken up by murine BV-2 cells, which promoted murine BV-2 cell migration and activation. LPS-P815 exosomes increased the CD86, IL-1ß, IL-6 and TNF-α levels in murine BV-2 microglia. Furthermore, activated mast cells delivered exosomal miR-409-3p to murine BV-2 microglia. Upregulated miR-409-3p promoted murine BV-2 microglial migration, activation and neuroinflammation by targeting Nr4a2 to activate the NF-κB pathway. CONCLUSION: Exosomal miR-409-3p secreted from activated mast cells promotes microglial migration, activation and neuroinflammation by targeting Nr4a2 to activate the NF-κB pathway, which provides evidence that not only cytokines but also exosomal miRNAs participate in neuroinflammation. In the future, targeting exosomal miRNAs may provide new insights into neuroinflammation.