A proof-of-concept study of ultrasound-guided continuous parasacral ischial plane block for postoperative pain control in patients undergoing total knee arthroplasty.

BACKGROUND: Continuous peripheral nerve blocks are widely used for anesthesia and postoperative analgesia in lower limb surgeries. The authors aimed to develop a novel continuous sacral plexus block procedure for analgesia during total knee arthroplasty. METHODS: The study comprised two stages. In Stage I, the authors built upon previous theories and technological innovations to develop a novel continuous sacral plexus block method, ultrasound-guided continuous parasacral ischial plane block (UGCPIPB) and subsequently conducted a proof-of-concept study to assess its effectiveness and feasibility. Stage II involved a historical control study to compare clinical outcomes between patients undergoing this new procedure and those receiving the conventional procedure. RESULTS: The study observed a 90% success rate in catheter placement. On postoperative day (POD) 1, POD2, and POD3, the median visual analog scale (VAS) scores were 3 (range, 1.5-3.5), 2.5 (1.6-3.2), and 2.7 (1.3-3.4), respectively. Furthermore, 96.3% of the catheters remained in place until POD3, as confirmed by ultrasound. The study revealed a significant increase in skin temperature and peak systolic velocity of the anterior tibial artery on the blocked side compared with those on the non-blocked side. Complications included catheter clogging in one patient and leakage at the insertion site in two patients. In Stage II, the novel technique was found to be more successful than conventional techniques, with a lower catheter displacement rate than the conventional procedure for continuous sciatic nerve block. CONCLUSION: UGCPIPB proved to be an effective procedure and safe for analgesia in total knee arthroplasty. CHINESE CLINICAL TRIAL REGISTRY NUMBER: ChiCTR2300068902.

Fish oil omega-3 Fatty Acids Alleviate Postoperative delirium-like Behavior in aged mice by Attenuating Neuroinflammation and Oxidative Stress.

Postoperative delirium (POD) is a common and serious neuropsychiatric syndrome among older patients, and lacks effective therapies. Omega-3 fatty acids, possessing anti-inflammatory and antioxidant properties, have shown potent neuroprotective effects in several diseases. The present study investigated whether omega-3 fatty acids could exert a neuroprotective role against POD in aged mice. A mouse model of POD was established to explore the role of omega-3 fatty acids in laparotomy-induced delirium-like behavior by evaluating systemic inflammatory changes, neuroinflammation, oxidative stress, and behavior at different time points in aged mice. Oral gavage with omega-3 fatty acids (300 mg/kg) for 3 weeks before surgery significantly attenuated anesthesia/surgery-induced POD-like behavior and the accumulation of proinflammatory cytokines from the peripheral blood in aged mice. Moreover, it also remarkably mitigated neuroinflammation and the oxidative stress response (malondialdehyde [MDA] and superoxide dismutase [SOD]) in the prefrontal cortex and hippocampus of surgical mice. Our findings provided evidence that pretreatment with omega-3 fatty acids may play a vital role in the treatment of POD through mechanisms involving its anti-inflammatory and antioxidant effects, which may be a promising prevention strategy for POD in aged patients.

Dexmedetomidine alleviates cognitive impairment by promoting hippocampal neurogenesis via BDNF/TrkB/CREB signaling pathway in hypoxic-ischemic neonatal rats.

AIMS: Dexmedetomidine (DEX) has been reported to alleviate hypoxic-ischemic brain damage (HIBD) in neonates. This study aimed to investigate whether DEX improves cognitive impairment by promoting hippocampal neurogenesis via the BDNF/TrkB/CREB signaling pathway in neonatal rats with HIBD. METHODS: HIBD was induced in postnatal day 7 rats using the Rice-Vannucci method, and DEX (25 µg/kg) was administered intraperitoneally immediately after the HIBD induction. The BDNF/TrkB/CREB pathway was regulated by administering the TrkB receptor antagonist ANA-12 through intraperitoneal injection or by delivering adeno-associated virus (AAV)-shRNA-BDNF via intrahippocampal injection. Western blot was performed to measure the levels of BDNF, TrkB, and CREB. Immunofluorescence staining was utilized to identify the polarization of astrocytes and evaluate the levels of neurogenesis in the dentate gyrus of the hippocampus. Nissl and TTC staining were performed to evaluate the extent of neuronal damage. The MWM test was conducted to evaluate spatial learning and memory ability. RESULTS: The levels of BDNF and neurogenesis exhibited a notable decrease in the hippocampus of neonatal rats after HIBD, as determined by RNA-sequencing technology. Our results demonstrated that treatment with DEX effectively increased the protein expression of BDNF and the phosphorylation of TrkB and CREB, promoting neurogenesis in the dentate gyrus of the hippocampus in neonatal rats with HIBD. Specifically, DEX treatment significantly augmented the expression of BDNF in hippocampal astrocytes, while decreasing the proportion of detrimental A1 astrocytes and increasing the proportion of beneficial A2 astrocytes in neonatal rats with HIBD. Furthermore, inhibiting the BDNF/TrkB/CREB pathway using either ANA-12 or AAV-shRNA-BDNF significantly counteracted the advantageous outcomes of DEX on hippocampal neurogenesis, neuronal survival, and cognitive improvement. CONCLUSIONS: DEX promoted neurogenesis in the hippocampus by activating the BDNF/TrkB/CREB pathway through the induction of polarization of A1 astrocytes toward A2 astrocytes, subsequently mitigating neuronal damage and cognitive impairment in neonates with HIBD.

Research and application of a teaching platform for combined spinal-epidural anesthesia based on virtual reality and haptic feedback technology.

BACKGROUND: Intraspinal anesthesia poses significant teaching challenges and inadequate teaching resources, which ultimately limit students' opportunities for practice. To address this issue, we aimed to develop a virtual platform for combined spinal-epidural anesthesia that merges virtual reality technology with haptic feedback technology, while assessing its educational impact and learning outcomes. METHODS: We utilized MIMICS, 3Ds MAX, and UNITY 3D software to perform 3D reconstruction based on lumbar CT/MRI data from a standard male volunteer. The haptic coefficients were configured on each layer by 20 experienced anesthesiologists in accordance with the Geomagic Touch X force feedback device. A total of 20 anesthesiology interns completed 30 virtual puncture training sessions. Two experienced anesthetists evaluated the efficacy of the platform and the level of mastery achieved using the Global Rating Scale (GRS) and a Checklist score, respectively. Finally, a questionnaire survey was conducted to gather feedback on the virtual platform. RESULTS: After the 10th session, the puncture time stabilized at 2.4 min. As the number of sessions increased, the Global Rating Scale (GRS) score stabilized by the 8th session, and the Checklist scores tended to stabilize by the 10th session. Results from questionnaires indicated that over half of the anesthesiology interns (70%) believed that the platform, which exhibited strong repeatability, improved their anatomical recognition and provided a strong sense of breakthrough in identifying the ligamentum flavum. The majority of them (80%) expressed satisfaction with the virtual platform. CONCLUSIONS: The platform effectively facilitated the acquisition of basic and accurate puncture skills on a virtual patient.

Activation of the CD200/CD200R1 axis attenuates neuroinflammation and improves postoperative cognitive dysfunction via the PI3K/Akt/NF-κB signaling pathway in aged mice.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a neurological complication occurring after anesthesia and surgery. Neuroinflammation plays a critical role in the pathogenesis of POCD, and the activation of the cluster of differentiation 200 (CD200)/CD200R1 axis improves neurological recovery in various neurological disorders by modulating inflammation. The aim of this study was to investigate the impact and underlying mechanism of CD200/CD200R1 axis on POCD in aged mice. METHODS: The model of POCD was established in aged mice. To assess the learning and memory abilities of model mice, the Morris water maze test was implemented. CD200Fc (CD200 fusion protein), CD200R1 Ab (anti-CD200R1 antibody), and 740Y-P (a specific PI3K activator) were used to evaluate the effects of the CD200/CD200R1/PI3K/Akt/NF-κB signaling pathway on hippocampal microglial polarization, neuroinflammation, synaptic activity, and cognition in mice. RESULTS: It was observed that anesthesia/surgery induced cognitive decline in aged mice, increased the levels of tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-1 ß and decreased the levels of postsynaptic density protein 95 (PSD-95), synaptophysin (SYN) in the hippocampus. Moreover, CD200Fc and 740Y-P attenuated neuroinflammation and synaptic deficits and reversed cognitive impairment via the phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (Akt)/nuclear factor-kappa B (NF-κB) signaling pathway, whereas CD200R1 Ab administration exerted the opposite effects. Our results further show that the CD200/CD200R1 axis modulates M1/M2 polarization in hippocampal microglia via the PI3K/Akt/NF-κB signaling pathway. CONCLUSIONS: Our findings indicate that the activation of the CD200/CD200R1 axis reduces neuroinflammation, synaptic deficits, and cognitive impairment in the hippocampus of aged mice by regulating microglial M1/M2 polarization via the PI3K/Akt/NF-κB signaling pathway.

Recognition and management of hemorrhaging in combination with emerging enterogenic sepsis during a hepatectomy: a case report.

BACKGROUND: Patients with hemorrhagic shock may develop emerging enterogenic sepsis due to damage to the intestinal mucosal barrier and translocation of intestinal bacteria and endotoxins caused by ischemic injury. Because of the dual effects of anesthesia state and hemorrhagic shock, perioperative emerging enterogenic sepsis is even more rare and insidious. CASE PRESENTATION: We reported a case of 56-year-old man who underwent right hepatectomy for intrahepatic bile duct stones. Severe hemorrhage occurred during the procedure and the hemodynamics neither improved nor worsened after rehydration therapy and vasoactive drug administration. Based on the patient's history and clinical presentation, a possible enterogenic sepsis was considered. After anti-infective treatment and hormone supplementation, the patient's circulation improved significantly and he had an uneventful recovery. CONCLUSION: The possibility of emerging enterogenic sepsis in hemorrhagic shock must always be taken into consideration. Familiarity with the risk factors and pathophysiological alterations of enterogenic sepsis is a prerequisite for early recognition and sound clinical decision making.

Dexmedetomidine Regulates Autophagy via the AMPK/mTOR Pathway to Improve SH-SY5Y-APP Cell Damage Induced by High Glucose.

Neurodegenerative diseases and postoperative cognitive dysfunction involve the accumulation of ß-amyloid peptide (Aß). High glucose can inhibit autophagy, which facilitates intracellular Aß clearance. The α2-adrenoreceptor agonist dexmedetomidine (DEX) can provide neuroprotection against several neurological diseases; however, the mechanism remains unclear. This study investigated whether DEX regulated autophagy via the AMPK/mTOR pathway to improve high glucose-induced neurotoxicity in SH-SY5Y/APP695 cells. SH-SY5Y/APP695 cells were cultured with high glucose with/without DEX. To examine the role of autophagy, the autophagy activator rapamycin (RAPA) and autophagy inhibitor 3-methyladenine (3-MA) were used. The selective AMPK inhibitor compound C was used to investigate the involvement of the AMPK pathway. Cell viability and apoptosis were examined by CCK-8 and annexin V-FITC/PI flow cytometric assays, respectively. Autophagy was analyzed by monodansylcadaverine staining of autophagic vacuoles. Autophagy- and apoptosis-related protein expression and the phosphorylation levels of AMPK/mTOR pathway molecules were quantified by western blotting. DEX pretreatment significantly suppressed high glucose-induced neurotoxicity in SH-SY5Y/APP695 cells, as evidenced by the enhanced viability, restoration of cellular morphology, and reduction in apoptotic cells. Furthermore, RAPA had a protective effect similar to that of DEX, but 3-MA eliminated the protective effect of DEX by promoting mTOR activation. Moreover, the AMPK/mTOR pathway was involved in DEX-mediated autophagy. Compound C significantly suppressed autophagy and reversed the protective effect of DEX against high glucose in SH-SY5Y/APP695 cells. Our findings demonstrated that DEX protected SH-SY5Y/APP695 cells against high glucose-induced neurotoxicity by upregulating autophagy through the AMPK/mTOR pathway, suggesting a role of DEX in treating POCD in diabetic patients.

Dexmedetomidine alleviates olfactory cognitive dysfunction by promoting neurogenesis in the subventricular zone of hypoxic-ischemic neonatal rats.

Background: Hypoxic-ischemic brain damage (HIBD) is the main cause of neurological dysfunction in neonates. Olfactory cognitive function is important for feeding, the ability to detect hazardous situations and social relationships. However, only a few studies have investigated olfactory cognitive dysfunction in neonates with HIBD; furthermore, the specific mechanisms involved are yet to be elucidated. It has been reported that neurogenesis in the subventricular zone (SVZ) is linked to olfactory cognitive function. Recently, dexmedetomidine (DEX) has been shown to provide neuroprotection in neonates following HIBD. In the present study, we investigated whether DEX could improve olfactory cognitive dysfunction in neonatal rats following HIBD and attempted to determine the underlying mechanisms. Methods: We induced HIBD in rats using the Rice-Vannucci model, and DEX (25 µg/kg, i.p.) was administered immediately after the induction of HIBD. Next, we used triphenyl tetrazolium chloride (TTC) staining and the Zea-longa score to assess the success of modelling. The levels of BDNF, TNF-α, IL-1ß and IL-6 were determined by western blotting. Immunofluorescence staining was used to detect microglial activation and microglial M1/M2 polarization as well as to evaluate the extent of neurogenesis in the SVZ. To evaluate the olfactory cognitive function, the rats in each group were raised until post-natal days 28-35; then, we performed the buried food test and the olfactory memory test. Results: Analysis showed that HIBD induced significant brain infarction, neurological deficits, and olfactory cognitive dysfunction. Furthermore, we found that DEX treatment significantly improved olfactory cognitive dysfunction in rat pups with HIBD. DEX treatment also increased the number of newly formed neuroblasts (BrdU/DCX) and neurons (BrdU/NeuN) in the SVZ by increasing the expression of BDNF in rat pups with HIBD. Furthermore, analysis showed that the neurogenic effects of DEX were possibly related to the inhibition of inflammation and the promotion of M1 to M2 conversion in the microglia. Conclusion: Based on the present findings, DEX treatment could improve olfactory cognitive dysfunction in neonatal rats with HIBD by promoting neurogenesis in the SVZ and enhancing the expression of BDNF in the microglia. It was possible associated that DEX inhibited neuroinflammation and promoted M1 to M2 conversion in the microglia.

Effect of Ultrasound-Guided Fascia Iliac Compartment Block with Nalbuphine and Ropivacaine on Preoperative Pain in Older Patients with Hip Fractures: A Multicenter, Triple-Blinded, Randomized, Controlled Trial.

INTRODUCTION: Pain management for older patients with hip fractures is challenging. This study aimed to investigate the effect of ultrasound-guided fascia iliac compartment block (UGFICB) using different doses of nalbuphine in combination with ropivacaine on preoperative analgesia in older patients with hip fractures. METHODS: In this multicenter randomized controlled trial, 280 elderly patients with hip fracture were randomly allocated into four UGFICB groups (n = 70 in each group): a ropivacaine group (30 mL 0.1% ropivacaine + 0.9% normal saline) and three ropivacaine plus nalbuphine groups (5, 10, and 20 mg nalbuphine, respectively). The primary outcomes were the duration of analgesia at rest and on passive movement. Secondary outcomes included sensory block area, side effects, and vital signs. The doses of rescue analgesia with parecoxib sodium were also analyzed. RESULTS: The addition of nalbuphine dose-dependently increased the duration of analgesia at rest and on passive movement (P < 0.05) and expanded the area of sensory block (P < 0.05). Compared with the ropivacaine group, the pain scores at rest and on movement at 6 and 8 h after the block were lower in three ropivacaine plus nalbuphine groups (P < 0.05), without between-group differences at 2, 4, and 12 h. The four groups had comparable side effects (nausea and vomiting) and vital signs (P > 0.05). CONCLUSIONS: UGFICB with 5, 10, and 20 mg nalbuphine added to ropivacaine prolonged the analgesia duration, increased sensory block area, reduced pain, and decreased the doses of rescue parecoxib sodium for older patients after hip fracture, without obvious side effects. Among these three doses, nalbuphine 20 mg in combination with ropivacaine provided the longest duration of analgesia and the largest sensory block area. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2000029934).

Regional Analgesia in Video-Assisted Thoracic Surgery: A Bayesian Network Meta-Analysis.

Background: A variety of regional analgesia methods are used during video-assisted thoracic surgery (VATS). Our network meta-analysis (NMA) sought to evaluate the advantages of various methods of localized postoperative pain management in VATS patients. Methods: PubMed, the Cochrane Library, and EMBASE were searched from their date of inception to May 2021 for randomized controlled trials (RCTs) comparing two or more types of locoregional analgesia in adults using any standardized clinical criteria. This was done using Bayesian NMA. Results: A total of 3,563 studies were initially identified, and 16 RCTs with a total of 1,144 participants were ultimately included. These studies, which spanned the years 2014 to 2021 and included data from eight different countries, presented new information. There were a variety of regional analgesia techniques used, and in terms of analgesic effect, thoracic epidural anesthesia (TEA) [SMD (standard mean difference) = 1.12, CrI (Credible interval): (-0.08 to -2.33)], thoracic paravertebral block (TPVB) (SMD = 0.67, CrI: (-0.25 to 1.60) and erector spinae plane block (ESPB) (SMD = 0.34, CrI: (-0.5 to 1.17) were better than other regional analgesia methods. Conclusion: Overall, these findings show that TEA, TPVB and ESPB may be effective forms of regional analgesia in VATS. This research could be a valuable resource for future efforts regarding the use of thoracic regional analgesia and enhanced recovery after surgery. Systematic Review Registration: Identifier [PROSPERO CRD42021253218].

mTOR-mediated autophagy in the hippocampus is involved in perioperative neurocognitive disorders in diabetic rats.

INTRODUCTION: Perioperative neurocognitive disorders (PND) are common neurological complications after surgery. Diabetes mellitus (DM) has been reported to be an independent risk factor for PND, but little is known about its mechanism of action. Mammalian target of rapamycin (mTOR) signaling is crucial for neuronal growth, development, apoptosis, and autophagy, but the dysregulation of mTOR signaling leads to neurological disorders. The present study investigated whether rapamycin can attenuate PND by inhibiting mTOR and activating autophagy in diabetic rats. METHODS: Male diabetic Sprague-Dawley rats underwent tibial fracture surgery under isoflurane anesthesia to establish a PND model. Cognitive functions were examined using the Morris water maze test. The levels of phosphorylated mTOR (p-mTOR), phosphorylated tau (p-tau), autophagy-related proteins (Beclin-1, LC3), and apoptosis-related proteins (Bax, Bcl-2, cleaved caspase-3) in the hippocampus were examined on postoperative days 3, 7, and 14 by Western blot. Hippocampal amyloid ß (Aß) levels were examined by immunohistochemistry. RESULTS: The data showed that surgical trauma and/or DM impaired cognitive function, induced mTOR activation, and decreased Beclin-1 levels and the LC3-II/I ratio. The levels of Aß and p-tau and the hippocampal apoptotic responses were significantly higher in diabetic or surgery-treated rats than in control rats and were further increased in diabetic rats subjected to surgery. Pretreatment of rats with rapamycin inhibited mTOR hyperactivation and restored autophagic function, effectively decreasing tau hyperphosphorylation, Aß deposition, and apoptosis in the hippocampus. Furthermore, surgical trauma-induced neurocognitive disorders were also reversed by pretreatment of diabetic rats with rapamycin. CONCLUSION: The results demonstrate that mTOR hyperactivation regulates autophagy, playing a critical role in the mechanism underlying PND, and reveal that the modulation of mTOR signaling could be a promising therapeutic strategy for PND in patients with diabetes.

S100A9 Upregulation Contributes to Learning and Memory Impairments by Promoting Microglia M1 Polarization in Sepsis Survivor Mice.

Sepsis-associated encephalopathy (SAE) is a clinical syndrome of brain dysfunction secondary to sepsis, which is characterized by long-term neurocognitive deficits such as memory, attention, and executive dysfunction. However, the mechanisms underlying SAE remain unclear. By using transcriptome sequencing approach, we showed that hippocampal S100A9 was significantly increased in sepsis induced by cecal ligation and puncture (CLP) or lipopolysaccharide (LPS) challenge. Thus, we used S100A9 inhibitor Paquinimod to study the role of S100A9 in cognitive impairments in CLP-induced and LPS-induced mice models of SAE. Sepsis survivor mice underwent behavioral tests or the hippocampal tissues subjected to Western blotting, real-time quantitative PCR, and immunohistochemistry. Our results showed that CLP-induced and LPS-induced memory impairments were accompanied with increased expressions of hippocampal microglia Iba1 and CD86 (M1 markers), but reduced expression of Arg1 (M2 marker). Notably, S100A9 inhibition significantly improved the survival rate and learning and memory impairments in sepsis survivors, with a shift from M1 to M2 phenotype. Taken together, our study suggests that S100A9 upregulation might contribute to learning and memory impairments by promoting microglia M1 polarization in sepsis survivors, whereas S100A9 inhibition might provide a potential therapeutic target for SAE.

Amitriptyline Protects Against Lidocaine-induced Neurotoxicity in SH-SY5Y Cells via Inhibition of BDNF-mediated Autophagy.

Amitriptyline (AMI) is a traditional tricyclic antidepressant that has been proven to exhibit neuroprotective effects in various neurological disorders. However, the underlying mechanism by which AMI attenuates lidocaine-induced neurotoxicity remains poorly understood. Brain-derived neurotrophic factor (BDNF) is an essential neurotrophin to neuronal development and survival in the brain, and recent studies have suggested that BDNF plays an important role in mediating lidocaine-induced neurotoxicity. The present study was performed to evaluate the protective effect of AMI against the neurotoxicity induced by lidocaine and to explore the role of BDNF-dependent autophagy in this process. The data showed that AMI pretreatment alleviated lidocaine-induced neurotoxicity, as evidenced by the restoration of cell viability, normalization of cell morphology, and reduction in the cell apoptosis index. In addition, autophagy inhibitor 3-methyladenine (3-MA) had a protective effect similar to that of AMI, but autophagy activator rapamycin eliminated the protective effect of AMI by suppressing mTOR activation. Moreover, at the molecular level, we found that AMI-mediated autophagy was involved in the expression of BDNF. The overexpression of BDNF or application of exogenous recombinant BDNF significantly suppressed autophagy and protected SH-SY5Y cells from apoptosis induced by Lido, whereas the neuroprotection of AMI was abolished by either knockdown of BDNF or use of a tropomyosin-related kinase B (TrkB) inhibitor ANA-12 in SH-SY5Y cells. Overall, our findings demonstrated that the protective effect of AMI against lidocaine-induced neurotoxicity correlated with inhibition of autophagy activity through upregulation of BDNF expression.

Deficiency of Mitochondrial Functions and Peroxidation of Frontoparietal Cortex Enhance Isoflurane Sensitivity in Aging Mice.

Background: Hypersensitivity to general anesthetics may predict poor postoperative outcomes, especially among the older subjects. Therefore, it is essential to elucidate the mechanism underlying hypersensitivity to volatile anesthetics in the aging population. Given the fact that isoflurane sensitivity increases with aging, we hypothesized that deficiencies of mitochondrial function and elevated oxidative levels in the frontoparietal cortex may contribute to the enhanced sensitivity to isoflurane in aging mice. Methods: Isoflurane sensitivity in aging mice was determined by the concentration of isoflurane that is required for loss of righting reflex (LORR). Mitochondrial bioenergetics of the frontoparietal cortex was measured using a Seahorse XFp analyzer. Protein oxidation and lipid oxidation in the frontoparietal cortex were assessed using the Oxyblot protein oxidation detection kit and thiobarbituric acid reactive substance (TBARS) assay, respectively. Contributions of mitochondrial complex II inhibition by malonate and peroxidation by ozone to isoflurane sensitivity were tested in vivo. Besides, effects of antioxidative therapy on mitochondrial function and isoflurane sensitivity in mice were also measured. Results: The mean concentration of isoflurane that is required for LORR in aging mice (14-16 months old) was 0.83% ± 0.13% (mean ± SD, n = 80). Then, the mice were divided into three groups as sensitive group (S group, mean - SD), medium group (M group), and resistant group (R group, mean + SD) based on individual concentrations of isoflurane required for LORR. Activities of mitochondrial complex II and complex IV in mice of the S group were significantly lower than those of the R group, while frontoparietal cortical malondialdehyde (MDA) levels were higher in the mice of S group. Both inhibition of mitochondrial complexes and peroxidation significantly decreased the concentration of isoflurane that is required for LORR in vivo. After treatment with idebenone, the levels of lipid oxidation were alleviated and mitochondrial function was restored in aging mice. The concentration of isoflurane that required for LORR was also elevated after idebenone treatment. Conclusions: Decreased mitochondrial functions and higher oxidative stress levels in the frontoparietal cortex may contribute to the hypersensitivity to isoflurane in aging mice.

Monoacylglycerol Lipase Inactivation by Using URB602 Mitigates Myocardial Damage in a Rat Model of Cardiac Arrest.

OBJECTIVES: Monoacylglycerol lipase participates in organ protection by regulating the hydrolysis of the endocannabinoid 2-arachidonoylglycerol. This study investigated whether blocking monoacylglycerol lipase protects against postresuscitation myocardial injury and improves survival in a rat model of cardiac arrest and cardiopulmonary resuscitation. DESIGN: Prospective randomized laboratory study. SETTING: University research laboratory. SUBJECTS: Male Sprague-Dawley rat (n = 96). INTERVENTIONS: Rats underwent 8-minute asphyxia-based cardiac arrest and resuscitation. Surviving rats were randomly divided into cardiopulmonary resuscitation + URB602 group, cardiopulmonary resuscitation group, and sham group. One minute after successful resuscitation, rats in the cardiopulmonary resuscitation + URB602 group received a single dose of URB602 (5 mg/kg), a small-molecule monoacylglycerol lipase inhibitor, whereas rats in the cardiopulmonary resuscitation group received an equivalent volume of vehicle solution. The sham rats underwent all of the procedures performed on rats in the cardiopulmonary resuscitation and cardiopulmonary resuscitation + URB602 groups minus cardiac arrest and asphyxia. MEASUREMENTS AND MAIN RESULTS: Survival was recorded 168 hours after the return of spontaneous circulation (n = 22 in each group). Compared with vehicle treatment (31.8%), URB602 treatment markedly improved survival (63.6%) 168 hours after cardiopulmonary resuscitation. Next, we used additional surviving rats to evaluate myocardial and mitochondrial injury 6 hours after return of spontaneous circulation, and we found that URB602 significantly reduced myocardial injury and prevented myocardial mitochondrial damage. In addition, URB602 attenuated the dysregulation of endocannabinoid and eicosanoid metabolism 6 hours after return of spontaneous circulation and prevented the acceleration of mitochondrial permeability transition 15 minutes after return of spontaneous circulation. CONCLUSIONS: Monoacylglycerol lipase blockade may reduce myocardial and mitochondrial injury and significantly improve the resuscitation effect after cardiac arrest and cardiopulmonary resuscitation.

Melatonin improves neurological outcomes and preserves hippocampal mitochondrial function in a rat model of cardiac arrest.

Cerebral injury after cardiac arrest (CA)/cardiopulmonary resuscitation (CPR) has been implicated in the poor prognosis of CA survivors. This study was designed to evaluate the impact of melatonin on postresuscitation neurological outcomes and to explore the underlying mechanism. Sprague-Dawley rats were randomly assigned to four groups: sham group, CPR group, melatonin pretreatment group (Pre-M) and posttreatment group (Post-M). For the last 2 groups, daily melatonin gavage was performed for 12 consecutive days before or 24 hours after rat survival from CA/CPR. No statistical differences were observed in heart rate (HR), mean arterial blood pressure (MAP), and end-tidal carbon dioxide (ETCO2) at baseline and after restoration of spontaneous circulation (ROSC) among groups. However, melatonin pretreatment or posttreatment significantly improved neurological deficit score and memory and spatial learning ability after CA/CPR. Further studies demonstrated that the complex I- and complex-II supported mitochondrial respiration were greatly increased under melatonin treatment. In addition, melatonin treatment preserved the mitochondrial-binding hexokinase II (HKII) and ATP levels and suppressed the upregulated protein lysine acetylation in hippocampus after CA/CPR. In conclusion, using a rat asphyxial CA model we have demonstrated that treatment with melatonin either before or after CA/CPR provides a promising neuroprotective effect, and this protection was mediated by increasing mitochondrial HKII expression, suppressing protein acetylation and improving mitochondrial function in hippocampus.

Cognitive impairments induced by severe acute pancreatitis are attenuated by berberine treatment in rats.

Cognitive impairments induced by severe acute pancreatitis (SAP) are severe complications, for which there are a lack of effective pharmacological treatment strategies. Berberine is an isoquinoline alkaloid extracted from the Chinese herb, Coptis rhizome, which exhibits numerous biological effects on gastrointestinal disorders. However, the effects of berberine on SAP­induced cognitive impairments remain unknown. The present study aimed to investigate the effects of berberine on cognitive impairments associated with SAP. Wistar rats were randomly divided into Sham, Sham + berberine, SAP and SAP + berberine groups. Rats were intraperitoneally injected with L­arginine (3 g/kg) to induce SAP. Subsequently, selected rats were intragastrically administered berberine (100 mg/kg) once daily for 6 consecutive days. Disease severities of rats were investigated 48 h post­induction of SAP via determination of serum amylase levels and hematoxylin and eosin staining. Survival rates, performance of behavioral tests (automated rotarod and fear conditioning tests), blood brain barrier (BBB) permeability, and the expression levels of tumor necrosis factor (TNF)­α and interleukin (IL)­1ß in hippocampal tissues were also determined. Proteins associated with apoptosis and necroptosis in the hippocampal tissues of SAP rats, including caspase­3, receptor­interacting protein kinase (RIP)1 and RIP3, were detected via western blotting. The results revealed that treatment with L­arginine induced SAP, which subsequently resulted in increased BBB permeability, mortality rates and cognitive deficits in rats. The expression levels of TNF­α, IL­1ß, caspase­3, RIP1 and RIP3 were significantly increased in the hippocampal tissues of SAP rats, thus suggesting that neuroinflammation, apoptosis and necroptosis may be involved in neurodegeneration associated with the development of SAP. Notably, administration of berberine protected the integrity of the BBB, decreased levels of brain inflammation and mortality rates, and attenuated increased levels of proteins associated with apoptosis and necroptosis and cognitive deficits associated with SAP in rats. The results of the present study demonstrated that daily treatment with berberine may attenuate cognitive deficits and reduce associated mortality via exhibition of anti­neuroinflammatory effects and attenuation of neuronal apoptosis and necroptosis in the hippocampal tissues of SAP rats.

Effect of high-flow nasal cannula oxygen therapy in adults with acute hypoxemic respiratory failure: a meta-analysis of randomized controlled trials.

BACKGROUND: Conflicting recommendations exist on whether high-flow nasal cannula (HFNC) oxygen therapy should be administered to adult patients in critical care with acute hypoxemic respiratory failure. We performed a meta-analysis of randomized controlled trials (RCTs) to evaluate its effect on intubation rates. METHODS: We searched electronic databases from inception to April 2016. We included RCTs that compared HFNC oxygen therapy with usual care (conventional oxygen therapy or noninvasive ventilation) in adults with acute hypoxemic respiratory failure. Because of the different methodologies and variation in clinical outcomes, we conducted 2 subgroup analyses according to oxygen therapy used and disease severity. We pooled data using random-effects models. The primary outcome was the proportion of patients who required endotracheal intubation. RESULTS: We included 6 RCTs (n = 1892). Compared with conventional oxygen therapy, HFNC oxygen therapy was associated with a lower intubation rate (risk ratio [RR] 0.60, 95% confidence interval [CI] 0.38 to 0.94; I2 = 49%). We found no significant difference in the rate between HFNC oxygen therapy and noninvasive ventilation (RR 0.86, 95% CI 0.68 to 1.09; I2 = 2%). In the subgroup analysis by disease severity, no significant differences were found in the intubation rate between HFNC oxygen therapy and either conventional oxygen therapy or noninvasive ventilation (interaction p = 0.3 and 0.4, respectively). INTERPRETATION: The intubation rate with HFNC oxygen therapy was lower than the rate with conventional oxygen therapy and similar to the rate with noninvasive ventilation among patients with acute hypoxemic respiratory failure. Larger, high-quality RCTs are needed to confirm these findings.

Protective effects of dexmedetomidine combined with flurbiprofen axetil on remifentanil-induced hyperalgesia: A randomized controlled trial.

High dosages of intra-operative remifentanil are associated with opioid-induced hyperalgesia (OIH). The aim of the present study was to investigate the effect of combined dexmedetomidine and flurbiprofen axetil treatment on remifentanil-induced hyperalgesia. Patients with an American Society of Anesthesiologists physical status of I-II who were diagnosed with hysteromyoma and scheduled for laparoscopic assisted vaginal hysterectomy (LAVH) were randomly divided into three groups. Group hyperalgesia (Group H, n=29) received intra-operative remifentanil, Group hyperalgesia and dexmedetomidine (Group HD, n=28) received remifentanil and a continuous infusion of dexmedetomidine, and Group hyperalgesia, dexmedetomidine and flurbiprofen axetil (Group HDF, n=29) received remifentanil, flurbiprofen axetil and dexmedetomidine. Mechanical pain thresholds were measured during the preoperative visit and postoperatively at 1, 6 and 24-h time points. Visual analog scale (VAS) scores, time to analgesic requirement, total sufentanil consumption and side effects were assessed postoperatively. Mechanical pain threshold at the incision site was significantly lower in Group H compared with Groups HD and HDF (both P<0.05), and significantly higher in Group HDF than in Group HD (P<0.05). The area of secondary hyperalgesia at the incision site was greater in Group H than in the other two groups (both P<0.05), and significantly smaller in Group HDF compared with Group HD (P<0.05). VAS scores and total sufentanil consumption were significantly higher in Group H compared with the other two groups (both P<0.05), and were significantly lower in Group HDF compared with Group HD (P<0.05). Dexmedetomidine combined with flurbiprofen axetil exhibits synergetic effects in the prevention of remifentanil-induced hyperalgesia in patients undergoing LAVH.