Daily Anesthesiology Research Analysis

IMPORTANCE: The apolipoprotein E (APOE) gene ε4 allele leads to increased Alzheimer disease risk and neuroinflammation and is also believed to play a role in postoperative delirium. However, the safety and feasibility of modulating apoE protein signaling to reduce postoperative neuroinflammation and delirium in older adults are unclear. OBJECTIVE: To assess the safety and feasibility of the apoE mimetic peptide CN-105 for reducing delirium incidence and severity and neuroinflammation after noncardiac or nonintracranial surgery in older adults. DESIGN, SETTING, AND PARTICIPANTS: This triple-blind, escalating dose, phase 2 randomized clinical trial enrolled patients from April 17, 2019, to December 28, 2022, at a tertiary academic medical center. Included patients were 60 years or older and scheduled for a noncardiac or nonintracranial surgery. Exclusion criteria were incarceration, planned chemotherapy within 6 weeks after surgery, or inability to undergo lumbar punctures. Data analyses were based on a modified intention-to-treat approach and were performed from August 14, 2023, to August 22, 2025. INTERVENTIONS: Patients were randomly assigned 3:1 to the CN-105 group or placebo group. The CN-105 group received intravenous CN-105 doses of 0.1, 0.5, or 1 mg/kg starting within 1 hour before surgery and administered every 6 hours afterward until hospital discharge or 13 doses were received. Patients in the placebo group followed the same administration schedule. MAIN OUTCOMES AND MEASURES: The primary outcome was safety-the incidence and number of postoperative adverse events (AEs). Secondary outcomes included feasibility (rate of drug doses administered within 90 minutes of schedule), postoperative delirium incidence and severity, and postoperative changes in cerebrospinal fluid (CSF) cytokine levels (interleukin [IL] 6, granulocyte-colony stimulating factor [G-CSF], monocyte chemoattractant protein-1 [MCP-1], and IL-8). RESULTS: Among 203 enrolled patients, 186 (mean [SD] age, 68.7 [5.2] years; 119 males [64.0%]) were randomized (137 to the CN-105 group, 49 to the placebo group) and underwent surgery. The rates of grade 2 or higher AEs among patients in the CN-105 and placebo groups were 76.6% and 87.8% (relative risk [RR], 0.87; 95% CI, 0.76-1.00; P = .10). The CN-105 vs placebo group had fewer grade 2 or higher AEs per patient (median [IQR], 1 [1-3] vs 2 [1-5]; P = .03). The percentage of CN-105 doses administered within the time window was 94.6% (860 of 909; 95% CI, 92.9%-96.0%) in the CN-105 group and 93.8% (346 of 369; 95% CI, 90.8%-96.0%) in the placebo group. Among patients in the CN-105 vs placebo group, the postoperative delirium incidence was 19.3% vs 26.5% (odds ratio [OR], 0.66; 95% CI, 0.31-1.42; P = .29); the median (IQR) postoperative delirium severity scores were 1 (1-2) vs 2 (1-2) (P = .19); and the median difference in preoperative to 24-hour postoperative CSF cytokine-level changes were as follows: -0.39 pg/mL (95% CI, -0.93 to 0.14 pg/mL, P = .12) for IL-6, -0.84 pg/mL (95% CI, -3.06 to 1.40 pg/mL; P = .18) for G-CSF,-23.32 pg/mL (95% CI, -94.36 to 44.93 pg/mL; P = .57) for IL-8, and -2.36 pg/mL (95% CI, -58.57 to 58.62 pg/mL; P = .50). CONCLUSIONS AND RELEVANCE: In this phase 2 randomized clinical trial of older surgical patients, CN-105 (vs placebo) administration was feasible and did not increase AEs. A phase 3 trial is warranted to further evaluate the efficacy of CN-105 for reducing postoperative AEs and to more precisely determine its effects on postoperative delirium incidence and severity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03802396.

Postoperative delirium (POD) accelerates the transition from mild cognitive impairment (MCI) to Alzheimer's disease (AD) in elderly patients. Microglial metabolic reprogramming, a pivotal aspect of the immune-inflammatory response, modulates microglia-neuron interactions and postoperative cognitive function through microenvironmental alterations. Aberrant overexpression of RUVBL2 disrupts metabolic homeostasis, leading to stress granule (SG) aggregation and fibrosis. This study investigated the role of RUVBL2 in regulating metabolic reprogramming to mediate SG formation, with the aim of identifying novel prognostic targets for inhibiting glycolysis and mitigating POD-induced MCI progression. A POD model was established in aged MCI rats using 3% sevoflurane anesthesia for 3 h, combined with open reduction and internal fixation (ORIF). Multimodal magnetic resonance imaging (MRI) was employed to assess postoperative cognitive function. Glycolytic and oxidative phosphorylation (OXPHOS) activities in primary hippocampal microglia were quantified by extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). Lentiviral-mediated RUVBL2 expression modulation was performed to verify its role in microglial metabolic reprogramming. Postoperative hippocampal microglia underwent metabolic reprogramming from OXPHOS to glycolysis, with RUVBL2 expression correlating positively with POD progression. Elevated RUVBL2 expression drove metabolic reprogramming, while RUVBL2 knockdown inhibited this process, alleviated pro-inflammatory microglia-induced neuroinflammation and SG aggregation, and improved spontaneous neural activity and hippocampus-dependent cognitive deficits. In primary hippocampal microglia, RUVBL2 knockdown enhanced OXPHOS-related OCR and reduced glycolysis-associated ECAR, producing a synergistic neuroprotective effect. These findings reveal the critical role of RUVBL2 in regulating POD, highlight metabolic reprogramming as a novel therapeutic target, and suggest RUVBL2 as a promising intervention strategy for POD.

BACKGROUND: Patients undergoing foot and ankle surgery often experience severe postoperative pain. This study aimed to assess the efficacy of liposomal bupivacaine for popliteal sciatic and saphenous nerve blocks in managing pain after foot and ankle surgery. METHODS: The study was registered with the Chinese Clinical Trial Registry (ChiCTR2400088305) and received ethical approval from the Institutional Review Board of Xuzhou Renci Hospital (XZRCLL-KT-202407003). In this randomized trial, 142 patients undergoing elective foot/ankle surgery received popliteal-sciatic and saphenous nerve blocks with either 50 mg ropivacaine (R group) or 133 mg liposomal bupivacaine (L group). Primary outcome was postoperative sufentanil consumption; secondary outcomes included analgesia duration, motor blockade, recovery quality, sleep quality, and adverse events. RESULTS: Compared with Group R, Group L demonstrated significantly lower sufentanil consumption at 12 h, 24 h, 48 h, and 72 h postoperatively (all CONCLUSION: The administration of liposomal bupivacaine for popliteal sciatic and saphenous nerve blocks significantly reduces postoperative opioid consumption and extends nerve block duration, providing a safe and effective technique for postoperative analgesia in patients undergoing foot and ankle surgery. Preoperative sleep quality, surgical type, and Pain Catastrophizing Scale score are independent predictors of the pain trajectory that can identify patients more likely to benefit from liposomal bupivacaine. CLINICAL TRIAL REGISTRATION: https://www.chictr.org.cn, Identifier ChiCTR2400088305.