The 90% effective concentration of alfentanil combined with 0.075% ropivacaine for epidural labor analgesia: a single-center, prospective, double-blind sequential allocation biased-coin design.

PURPOSE: More literature studies have reported that alfentanil is safe and effective for labor analgesia. However, there is no unified consensus on the optimal dosage of alfentanil used for epidural analgesia. This study explored the concentration at 90% of minimum effective concentration (EC90) of alfentanil combined with 0.075% ropivacaine in patients undergoing epidural labor analgesia to infer reasonable drug compatibility and provide guidance for clinical practice. METHODS: In this prospective, single-center, double-blind study, a total of 45 singleton term primiparas with vaginal delivery who volunteered for epidural labor analgesia were recruited. The first maternal was administered with 3 µg/mL alfentanil combined with 0.075% ropivacaine with the infusion of 10 mL of the mixture every 50 min at a background dose of 3 mL/h. In the absence of PCEA, a total of 15 mL of the mixture is injected per hour. The subsequent alfentanil concentration was determined on the block efficacy of the previous case, using an up-down sequential allocation with a bias-coin design. 30 min after epidural labor analgesia, the block of patient failed with visual analog score (VAS) > 3, the alfentanil concentration was increased in a 0.5 µg/mL gradient for the next patient, while the block was successful with VAS ≤ 3, the alfentanil concentration was remained or decreased in a gradient according to a randomized response list for the next patient. EC90 and 95% confidence interval were calculated by linear interpolation and prediction model with R statistical software. RESULTS: In this study, the estimated EC90 of alfentanil was 3.85 µg/mL (95% confidence interval, 3.64-4.28 µg/mL). CONCLUSION: When combined with ropivacaine 0.075%, the EC90 of alfentanil for epidural labor analgesia is 3.85 µg/mL in patients undergoing labor analgesia.

An interpretable machine learning model to predict off-pump coronary artery bypass grafting-associated acute kidney injury.

BACKGROUND: Off-pump coronary artery bypass grafting-associated acute kidney injury (OPCAB-AKI) is related to 30-day perioperative mortality. Existing mathematical models cannot be applied to help clinicians make early diagnosis and intervention decisions. OBJECTIVES: This study used an interpretable machine learning method to establish and screen an optimized OPCAB-AKI prediction model. MATERIAL AND METHODS: Clinical data of 1110 patients who underwent OPCAB in the Department of Cardiac Surgery of General Hospital of Northern Theater Command (Shenyang, China) from January 2018 to December 2020 were collected retrospectively. Four machine learning models were used, including logistic regression (LR), decision tree (DT), random forest (RF), and eXtreme Gradient Boosting (XGBoost). The SHapley Additive exPlanation (SHAP) tool was used for explanatory analysis of the black-box model. The mean absolute value of the characteristic SHAP parameter was defined and sorted. The correlation between the characteristic parameters and OPCAB-AKI was determined based on the SHAP value. A quantitative analysis of a single characteristic and an interaction analysis of multiple characteristics were carried out for the main risk factors. RESULTS: The RF prediction model had the best performance, with an area under the curve (AUC) of 0.90, a precision rate of 0.80, an accuracy rate of 0.83, a recall rate of 0.74, and an F1 score of 0.78 for positive samples. The interpretation analysis of the SHAP model results showed that intraoperative urine volume contributed to the greatest extent to the RF model, and other parameters included intraoperative sufentanil dosage, intraoperative dexmedetomidine dosage, cyclic variation coefficient during the induction period, intraoperative hypotension duration, age, preoperative baseline serum creatinine, body mass index (BMI), and Acute Physiology, Age and Chronic Health Evaluation (APACHE) II score. CONCLUSIONS: The model constructed by the RF ensemble learning algorithm predicted OPCAB-AKI, and indicators such as intraoperative urine volume were closely related to OPCAB-AKI.

A role of GABAA receptor α1 subunit in the hippocampus for rapid-acting antidepressant-like effects of ketamine.

Ketamine can produce rapid-acting antidepressant effects in treatment-resistant patients with depression. Although alterations in glutamatergic and GABAergic neurotransmission in the brain play a role in depression, the precise molecular mechanisms in these neurotransmission underlying ketamine's antidepressant actions remain largely unknown. Mice exposed to FSS (forced swimming stress) showed depression-like behavior and decreased levels of GABA (γ-aminobutyric acid), but not glutamate, in the hippocampus. Ketamine increased GABA levels and decreased glutamate levels in the hippocampus of mice exposed to FSS. There was a correlation between GABA levels and depression-like behavior. Furthermore, ketamine increased the levels of enzymes and transporters on the GABAergic neurons (SAT1, GAD67, GAD65, VGAT and GAT1) and astrocytes (EAAT2 and GAT3), without affecting the levels of enzymes and transporters (SAT2, VGluT1 and GABAAR γ2) on glutamatergic neurons. Moreover, ketamine caused a decreased expression of GABAAR α1 subunit, which was specifically expressed on GABAergic neurons and astrocytes, an increased GABA synthesis and metabolism in GABAergic neurons, a plasticity change in astrocytes, and an increase in ATP (adenosine triphosphate) contents. Finally, GABAAR antagonist bicuculline or ATP exerted a rapid antidepressant-like effect whereas pretreatment with GABAAR agonist muscimol blocked the antidepressant-like effects of ketamine. In addition, pharmacological activation and inhibition of GABAAR modulated the synthesis and metabolism of GABA, and the plasticity of astrocytes in the hippocampus. The present data suggest that ketamine could increase GABA synthesis and astrocyte plasticity through downregulation of GABAAR α1, increases in GABA, and conversion of GABA into ATP, resulting in a rapid-acting antidepressant-like action. This article is part of the Special Issue on 'Ketamine and its Metabolites'.

Effects of Different Types of Early Restrictive Fluid Resuscitation on Immune Function and Multiorgan Damage on Hemorrhagic Shock Rat Model in a Hypothermic Environment.

Objective: This study was aimed at investigating the effects of different types of fluid restriction fluid resuscitation on the immune dysfunction and organ injury of hemorrhagic shock rats under a hypothermic environment. Methods: SD rats were divided into sham operation group (SHAM), hemorrhagic shock model group (HS), crystal liquid limited resuscitation group (CRLLR), colloidal liquid limited resuscitation group (COLLR), and nonlimited resuscitation group (NLR); rats in each group were placed in a low-temperature environment of 0-5°C for 30 min, and then, a hemorrhagic shock rat model was prepared. Sodium lactate Ringer's restricted resuscitation solution, hydroxyethyl starch restricted resuscitation solution, and hydroxyethyl starch were used for resuscitation, and hemodynamic examination was performed. The mortality rate, inflammatory factors, oxidative stress factors, and immune function were detected by ELISA. The dysfunction and injury of the intestinal, lung, liver, and kidney were examined by histological methods. Results: Hemorrhagic shock resulted in decreased immune function and activation of inflammation. Unrestricted fluid infusion further activated the inflammatory response. The crystalloid-restricted fluid infusion performed effectively to regulate inflammatory response, promote antioxidative activity, and reduce the immunosuppressive reaction. Rehydration could regulate the coagulation. The hydroxyethyl starch reduced the expression of platelet glycoproteins Ib and IIb/IIIa and blocked the binding of fibrinogen to activated platelets, thereby inhibiting intrinsic coagulation and platelet adhesion and aggregation. Rats in the CRLLR group showed to relieve the injury of the lung, liver, kidney, and intestine from hemorrhagic shock in low-temperature environment. Conclusion: The early application of restrictive crystalloid resuscitation in hemorrhagic shock rats in hypothermic environment showed the best therapy results. Early LR-restrictive fluid replacement promotes the balance of inflammatory response and the recovery of immunosuppressive state, resists oxidative stress, stabilizes the balance of coagulation and fibrinolysis, improves coagulation function, and relieves organ injury.

Comparison of the third-generation streamlined liner of the pharynx airway (SLIPA-3G) with the laryngeal mask airway supreme for laparoscopic cholecystectomy: a randomized prospective study.

BACKGROUND: The third-generation streamlined liner of the pharynx airway (SLIPA-3G) is a new-generation supraglottic airway device (SAD) that is non-cuffed and disposable, with a sealing pressure that varies dynamically with the airway pressure. This study compared the SLIPA-3G with the laryngeal mask airway supreme (LMAS) in patients undergoing laparoscopic cholecystectomy. METHODS: Two hundred and twenty patients scheduled for laparoscopic cholecystectomy were randomly allocated to either the SLIPA-3G group or the LMAS group. Data were collected on the patients' hemodynamic parameters at different time points, ease of insertion, fiberoptic view, oropharyngeal leak pressure (OLP) at different time points and SAD-related complications. RESULTS: The mean OLP immediately after device placement in the LMAS group was significantly higher than that of the SLIPA-3G group (31.34 ± 6.99 cmH2O vs.28.94 ± 6.01 cmH2O, P = 0.008, 95% CI 0.62-4.17). The OLPs of the two groups were not significantly different after the induction of a pneumoperitoneum until the end of surgery. The OLP increased gradually through the course of the operation in the SLIPA-3G group (P value = 0.035) but not in the LMAS group (P value = 0.945). There was no significant difference between the two groups in hemodynamic parameters, insertion time and success rate, fiberoptic view and complication rate. CONCLUSIONS: The SLIPA-3G and LMAS were associated with comparable OLPs, hemodynamic parameters, ease of insertion, fiberoptic views and complication rates when used during laparoscopic cholecystectomy. The SLIPA-3G can be used as an effective alternative to the LMAS in patients undergoing laparoscopic surgeries.

Perioperative intravenous S(+)-ketamine for acute postoperative pain in adults: study protocol for a multicentre, randomised, open-label, positive-controlled, pragmatic clinical trial (SAFE-SK-A trial).

INTRODUCTION: Postoperative pain remains incompletely controlled for decades. Recently, multimodal analgesia is emerging as a potential approach in the management of postoperative pain. Therein, S(+)-ketamine is appealing as an adjuvant drug in multimodal analgesia due to its unique pharmacological advantages. This pragmatic clinical trial (SAFE-SK-A trial) is designed to investigate the analgesic effect and safety of S(+)-ketamine for acute postoperative pain in adults and explore the optimal strategy of perioperative intravenous S(+)-ketamine in a real-world setting. METHODS AND ANALYSIS: This multicentre, randomised, open-label, positive-controlled, pragmatic clinical trial (SAFE-SK-A study) is planned to conduct in 80 centres from China and recruit a total of 12 000 adult participants undergoing a surgical procedure under general anaesthesia. Patient recruitment started in June 2021 and will end in June 2022. Participants will be randomised in a ratio of 2:1 to either receive perioperative intravenous S(+)-ketamine plus conventional anaesthesia or conventional anaesthesia only. Given the pragmatic nature of the study, no specific restriction as to the administration dosage, route, time, synergistic regimen or basic analgesics. Primary endpoints are the area under the broken line of Numerical Rating Scale (NRS) scores for pain intensity and the total opioid consumption within 48 hours postoperative. Secondary endpoints are postoperative NRS scores, the anaesthesia recovery time, time of first rescue analgesia, the incidence of rescue analgesia, the incidence of postoperative delirium, patient questionnaire for effect, changes from baseline in cognitive function and anxiety and depression, as well as the adverse events and pharmacoeconomic outcomes. The general linear model will be used for the primary endpoint, and appropriate methods will be used for the secondary endpoints. ETHICS AND DISSEMINATION: This trial has been approved by the local Institutional Review Board (S2021-026-02) and conducted following the Declaration of Helsinki. Results of this trial will be publicly disclosed and published in scientific journals. TRIAL REGISTRATION NUMBER: NCT04837170; Pre-results.

Reversing Postcardiopulmonary Bypass Associated Cognitive Dysfunction Using k-Opioid Receptor Agonists to Regulate Microglial Polarization via the NLRP3/Caspase-1 Pathway.

Cardiopulmonary bypass (CPB) is mainly used during cardiac surgeries that treat ischemic, valvular, or congenital heart disease and aortic dissections. The disorders of central nervous system (CNS) that occur after cardiopulmonary bypass are attracting considerable interest. Postoperative neurocognitive disorders (PND) have been reported as the leading cause of patients' disability and death following CPB. The k-opioid receptor (KOR) agonists (U50488H) have been suggested to be vital in the treatment of surgically induced CNS neuroinflammatory responses. In this article, the transitions between the M1 and M2 microglial polarization state phenotypes were hypothesized to significantly affect the regulatory mechanisms of KOR agonists on postcardiopulmonary bypass (post-CPB) neuroinflammation. We investigated the effects of U50488H on neuroinflammation and microglia polarization in rats exposed to CPB and explored the method of the NLRP3/caspase-1 pathway. Thirty SD rats were randomly divided into three groups: sham operation group, cardiopulmonary bypass model group, and CPB+ k-opioid receptor agonist (U50488H) group, with ten rats in each group. The Morris water maze was used to evaluate the changes in the cognitive function of CPB rats. Hematoxylin and eosin (HE) staining and TUNEL were performed to assess the rats' hippocampal damage. Enzyme-Linked Immunosorbent Assay (ELISA) was used to detect changes in brain injury markers and inflammatory factors. Furthermore, immunofluorescence was used to observe the expression of microglia polarization and NLRP3 followed by Western blots to detect the expression of the NLRP3/caspase-1 pathway and microglia polarization-related proteins. Rat microglia were cultured in vitro, with LPS stimulation, and treated with U50488H and a caspase-1 antagonist to evaluate the effects and mechanism of action of U50488H. KORs alleviated hippocampal damage caused by CPB and improved PND. CPB activated the NLRP3 inflammasome and upregulated pro-caspase-1 expression which promoted the expression of pro-IL-lß and pro-IL-18 and resulted in increased inflammation. However, KORs also inhibited NLRP3 and transformed microglia from the M1 to the M2 state. Caspase-1 inhibitor treatment reduced the microglial polarization induced by KORs. The κ-opioid receptor agonists inhibited the inflammation mediated by microglia and improved PND through the NLRP3/caspase-1 signaling pathway.

κ­opioid receptor agonist U50488H attenuates postoperative cognitive dysfunction of cardiopulmonary bypass rats through the PI3K/AKT/Nrf2/HO­1 pathway.

Postoperative cognitive dysfunction (POCD) is a common complication following cardiopulmonary bypass (CPB). U50488H, a κ­opioid receptor (KOR) agonist, can specifically activate KORs on hippocampal nerve cells, resulting in neuroprotective effects. The present study established a CPB rat model, observed the protective effect of U50488H on CPB­induced POCD and brain damage and explored the regulatory mechanism of the PI3K/AKT/nuclear factor erythroid 2­related factor 2 (Nrf2)/heme oxygenase (HO)­1 pathway. Sprague­Dawley rats were divided into the following groups: Sham operation (Sham group), CPB (CPB group), KOR agonist (U50488H) + CPB (U50488H group), CPB + U50488H + HO­1 antagonist (ZnPP­IX; ZnPP group) and CPB + U50488H + PI3K antagonist (LY294002; LY294002 group), with 10 rats in each group. Neurological scores and the Morris water maze test were used to evaluate cognitive function; hematoxylin and eosin and terminal deoxynucleotidyl transferase dUTP nick end labeling assays were performed to observe hippocampal neuron damage in rats. Immunofluorescence was used to detect reactive oxygen species, glial fibrillary acidic protein and Nrf2 expression in the hippocampus. Enzyme­linked immunosorbent assays were used to detect inflammatory and oxidative stress factors. Western blotting was used to examine the expression of PI3K/AKT/Nrf2/HO­1­related proteins. It was demonstrated that U50488H significantly reduced the neural function score of rats with POCD induced by CPB, relieved cognitive dysfunction, reduced hippocampal neuron damage, inhibited the rate of apoptosis, repaired oxidative stress injury and protected against brain damage caused by CPB. In addition, U50488H could promote Nrf2 entry into the nucleus and upregulate HO­1 and thioredoxin 1 (Trx1) expression. In CPB rats treated with PI3K inhibitors, less Nrf2 was detected in the nucleus and HO­1 and Trx­1 expression levels were reduced in the nucleus. Therefore, U50488H, a KOR agonist, can activate Nrf2/HO­1 via the PI3K/AKT pathway to improve cognitive function and reduce brain damage in CPB rats.

[Effect of transcutaneous electrical acupoint stimulation on catheter related bladder discomfort after ureteroscopic lithotripsy].

OBJECTIVE: To verify the efficacy of transcutaneous electrical acupoint stimulation (TEAS) on catheter related bladder discomfort after ureteroscopic lithotripsy. METHODS: Sixty male patients with selective ureteroscopic lithotripsy under general anesthesia were randomly divided into a TEAS group (30 cases, one case dropped off) and a sham TEAS group (30 cases, 2 cases dropped off). Before anesthesia induction, the patients in the TEAS group were treated with TEAS at Guanyuan (CV 4), Zhongji (CV 3), Zusanli (ST 36) and Sanyinjiao (SP 6) for 30 min, with disperse-dense wave, frequency of 2 Hz/ 15 Hz and current intensity of 6 to 10 mA. The patients in the sham TEAS group were treated with the same TEAS device at the same acupoints, but no electrical stimulation was given. After 30 min, anesthesia induction started. The total dosages of propofol and remifentanil in the two groups were recorded, and the time of operation and anesthesia, the time of wake-up and the time of stay in postanesthesia care unit (PACU) were recorded. The postoperative recovery was evaluated 5 min (T1) after wake-up, 1 h (T2), 2 h (T3) and 6 h (T4) after the operation, including the severity of urinary tract irritation and visual analogue scale (VAS) score. The occurrence of adverse reactions was observed, such as nausea and vomiting, dizziness and headache. RESULTS: The dosage of remifentanil in the TEAS group was significantly lower than that in the sham TEAS group (P<0.05); but the dosage of propofol had no significant difference between the two groups (P>0.05). Compared with the sham TEAS group, the incidence of more-than-moderate urinary tract irritation symptoms in the TEAS group was reduced (P<0.05), and the VAS scores 1 and 2 h after operation were reduced (P<0.05). CONCLUSION: The 30-min TEAS at Guanyuan (CV 4), Zhongji (CV 3), Zusanli (ST 36) and Sanyinjiao (SP 6) before anesthesia induction could significantly control the severity of postoperative urinary tract irritation in patients with ureteroscopic lithotripsy, reduce the dosage of anesthetic drugs and relieve postoperative pain.

κ-opioid receptor agonists may alleviate intestinal damage in cardiopulmonary bypass rats by inhibiting the NF-κB/HIF-1α pathway.

The aims of the present study were to investigate the protective effect of a κ-opioid receptor (KOR) agonist on intestinal barrier dysfunction in rats during cardiopulmonary bypass (CPB), as well as to examine the role of NF-κB and the transcription factor hypoxia-inducible factor-1α (HIF-1α) signaling pathway in the regulatory mechanism. A total of 50 rats were randomly divided into five groups, with 10 rats in each group: Sham surgery group (group Sham), CPB surgery group (group CPB), KOR agonist + CPB (group K), KOR agonist + specific KOR antagonist + CBP (group NK) and KOR agonist + NF-κB pathway specific inhibitor + CPB (group NF). Intestinal microcirculation was evaluated to determine intestinal barrier dysfunction in rats following CPB surgery. Hematoxylin and eosin (H&E) staining was used to observe intestinal tissue injury in the rats. ELISA was used to detect the inflammatory factors interleukin (IL)-1ß, IL-6, IL10 and tumor necrosis factor-α, and the oxidative stress factors superoxidase dismutase, malondialdehyde and nitric oxide in serum. In addition, ELISA was used to investigate the serum levels of the intestinal damage markers D-lactic acid, diamine oxidase and intestinal fatty acid-binding protein. Western blotting was used to investigate the protein expression levels of tight junction proteins zonula occludens-1 and claudin-1. Furthermore, immunohistochemistry was used to examine intestinal injuries and western blotting was used to detect expression levels of NF-κB/HIF-1α signaling pathway-related proteins. H&E staining results suggested that the KOR agonist alleviated intestinal damage in the CPB model rats. This effect was reversed by the addition of a KOR antagonist. Further investigation of inflammatory and oxidative stress factors using ELISA revealed that the KOR agonist reduced the inflammatory and oxidative stress responses in the intestinal tissues of the CPB model rats. The ELISA results of intestinal damage markers and western blotting results of tight junction protein expression suggested that KOR agonist treatment may alleviate intestinal injury in CPB model rats. In addition, the western blotting and immunohistochemistry results suggested that KOR agonists may decrease the expression levels of NF-κB, p65 and HIF-1α in CPB. Collectively, the present results suggested that KOR agonists are able to ameliorate the intestinal barrier dysfunction in rats undergoing CPB by inhibiting the expression levels of NF-κB/HIF-1α signaling pathway-related proteins.

Kappa opioid receptor agonists improve postoperative cognitive dysfunction in rats via the JAK2/STAT3 signaling pathway.

Postoperative cognitive dysfunction (POCD) is a common and well­known complication following surgery, particularly cardiopulmonary bypass (CPB) surgery. There are currently no suitable treatments for POCD, which is associated with increased illness and mortality rates. The present study aimed to identify a novel treatment for POCD. The protective effect of kappa opioid receptor (KOR) agonists on POCD in rats following CPB was determined and the regulatory mechanism of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway was examined. The rats were randomly divided into five groups: Sham operation (Sham group), CPB operation (CPB group), KOR agonist + CPB (K group), KOR agonist + norbinaltorphimine (nor­BNI) + CPB (NK group), and KOR agonist + JAK2­STAT3 specific pathway inhibitor + CPB (AG group). A water maze test and neurological function scores were used to evaluate POCD. Hematoxylin and eosin staining was used to observe hippocampal neurons. ELISA was used to detect the levels of inflammatory factors, oxidative stress factors and brain injury markers. Immunofluorescence was used to visualize the neurons. TUNEL staining and western blotting were used to detect neuronal apoptosis, and western blotting was also used to detect JAK2/STAT3 pathway­related proteins. The KOR agonists significantly improved POCD. S­100ß and NSE detection revealed that KOR agonists alleviated brain damage in CPB rats, and this result was reversed by KOR antagonists. The KOR agonists led to a significantly reduced inflammatory response and oxidative stress, as determined by ELISA detection, and attenuated hippocampal neuronal apoptosis, as revealed by TUNEL staining and western blotting, compared with the results in the CPB group. Finally, the KOR agonists inhibited the expression levels of phosphorylated (p­)JAK2 and p­STAT3, rather than total JAK2 and STAT3, compared with levels in the CPB group. Taken together, KOR agonists improved POCD in rats with CPB by inhibiting the JAK2/STAT3 signaling pathway.

Hydrogen­rich solution against myocardial injury and aquaporin expression via the PI3K/Akt signaling pathway during cardiopulmonary bypass in rats.

Myocardial ischemia, hypoxia and reperfusion injury are induced by aortic occlusion, cardiac arrest and resuscitation during cardiopulmonary bypass (CPB), which can severely affect cardiac function. The aim of the present study was to investigate the effects of hydrogen­rich solution (HRS) and aquaporin (AQP) on cardiopulmonary bypass (CPB)­induced myocardial injury, and determine the mechanism of the phosphatidylinositol 3­kinase (PI3K)/protein kinase B (Akt) signaling pathway. Sprague Dawley rats were divided into a sham operation group, a CPB surgery group and a HRS group. A CPB model was established, and the hemodynamic parameters were determined at the termination of CPB. The myocardial tissues were observed by hematoxylin and eosin, and Masson staining. The levels of myocardial injury markers [adult cardiac troponin I (cTnI), lactate dehydrogenase (LDH), creatine kinase MB (CK­MB) and brain natriuretic peptide (BNP)], inflammatory factors [interleukin (IL)­1ß, IL­6 and tumor necrosis factor­α (TNF­α)] and oxidative stress indicators [superoxide dismutase (SOD), malondialdehyde (MDA) and myeloperoxidase (MPO)] were determined by ELISA. Furthermore, H9C2 cells were treated with HRS following hypoxia/reoxygenation. Cell viability and cell apoptosis were investigated. The expression of apoptosis regulator Bcl­2 (Bcl­2), apoptosis regulator Bax (Bax), caspase 3, AQP­1, AQP­4, phosphorylated (p)­Akt, heme oxygenase 1 (HO­1) and nuclear factor erythroid 2­related factor 2 (Nrf2) were investigated using western blotting and quantitative­polymerase chain reaction of tissues and cells. Following CPB, myocardial cell arrangement was disordered, myocardial injury markers (cTnI, LDH, CK­MB and BNP), inflammatory cytokines (IL­1ß, IL­6 and TNF­α) and MDA levels were significantly increased compared with the sham group; whereas the SOD levels were significantly downregulated following CPB compared with the sham group. HRS attenuated myocardial injury, reduced the expression levels of cTnI, LDH, CK­MB, BNP, IL­1ß, IL­6, TNF­α, MDA and MPO, and increased SOD release. Levels of Bcl­2, AQP­1, AQP­4, p­Akt, HO­1 and Nrf2 were significantly increased following HRS; whereas Bax and caspase­3 expression levels were significantly reduced following CPB. HRS treatment significantly increased the viability of myocardial cells, reduced the rate of myocardial cell apoptosis and the release of MDA and LDH compared with the CPB group. A PI3K inhibitor (LY294002) was revealed to reverse the protective effect of HRS treatment. HRS was demonstrated to attenuate CPB­induced myocardial injury, suppress AQP­1 and AQP­4 expression following CPB treatment and protect myocardial cells via the PI3K/Akt signaling pathway.

Hydrogen-rich solution attenuates myocardial injury caused by cardiopulmonary bypass in rats via the Janus-activated kinase 2/signal transducer and activator of transcription 3 signaling pathway.

The incidence of complications and mortality following open-heart surgery with cardiopulmonary bypass (CPB) is associated with the severity of the myocardial injury that occurs during surgery. Hydrogen-rich solution (HRS) may prevent antioxidant stress and inhibit apoptosis and inflammation. The present study was designed to investigate the effects of HRS on CPB-induced myocardial injury, and to investigate its potential regulation of the Janus-activated kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway. The HRS treatment resulted in the significant upregulation of malonyl dialdehyde (MDA) and myeloperoxidase (MPO), whilesuperoxide dismutase (SOD) levels were significantly downregulated, compared with the Sham group (P<0.05). Additionally, HRS treatment improved myocardial injury, and decreased the expression levels of cardiac troponins, heart-type fatty acid binding protein, interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α, MDA and MPO, and increased SOD release in CPB rats (P<0.05). Additionally, in the CPB group without the HRS treatment, the expression levels of B-cell lymphoma (Bcl)-2, JAK2, phospho-JAK2 (p-JAK2), STAT3 and phospho-STAT3 (p-STAT3) were significantly decreased, and Bax was significantly increased, compared with the Sham group (P<0.05). By contrast, compared with the CPB group, the expression levels of B-cell lymphoma 2 (Bcl-2), JAK2, phosphorylated (p)-JAK2, STAT3 and p-STAT3 in the HRS group were significantly increased, and Bcl-2-associated X protein expression was significantly decreased (P<0.05). In JAK2 knockdown experiments using siRNA, HRS treatment following hypoxia/reoxygenation also significantly increased the viability of myocardial cells, decreased the rate of myocardial cell apoptosis, elevated the levels of SOD and suppressed the release of MDA and lactate dehydrogenase in the control siRNA and CPB groups (P<0.05). Furthermore, JAK2 siRNA attenuated these protective effects of HRS (P<0.05 vs. control siRNA, HRS and CPB groups). Additionally, the results demonstrated that the HRS treatment significantly increased the expression levels of p-JAK2, p-STAT3 and Bcl-2 in myocardial cells following hypoxia and decreased Bax expression in the control siRNA and CPB groups (P<0.05). In addition, JAK2 siRNA was determined to attenuate these effects of HRS (P<0.05 vs. control siRNA, HRS and CPB groups). Taken together, these results indicated that HRS may alleviate CPB-induced myocardial injury, inhibit myocardial cell apoptosis and protect myocardial cells through regulation of the JAK2/STAT3 signaling pathway.

Activated Α7nachr Improves Postoperative Cognitive Dysfunction and Intestinal Injury Induced by Cardiopulmonary Bypass in Rats: Inhibition of the Proinflammatory Response Through the Th17 Immune Response.

Backgrund/Aims: To investigate the effects of activated α7 nicotinic acetylcholine receptor (α7nAChR) on postoperative cognitive dysfunction (POCD) and intestinal injury induced by cardiopulmonary bypass (CPB) and its relationship with the Th17 response in order to provide a theoretical basis for organ protection and targeted drug therapy during the perioperative period. METHODS: Sprague-Dawley rat models of CPB were established. Rat intestinal and brain injuries were observed after CPB using hematoxylin and eosin staining. Cell apoptosis was determined using terminal deoxynucleotidyl transferase dUTP nick end labeling. Inflammatory factors and markers of brain injury in rat serum were measured using enzyme-linked immunosorbent assay. The expression levels of Bcl-2, Bax, caspase-3, ZO-1, occludin, AQP4, RORγT, and α7nAchR were examined using western blotting. Transcription factor RORγT expression was determined using real-time fluorescent quantitative polymerase chain reaction. Th17 cells in the peripheral blood and spleen were determined using flow cytometry. α7nAchR knockout rats were established. The Th17 response in the peripheral blood and spleen of α7nAchR knockout rats was further verified using flow cytometry. RESULTS: CPB can induce POCD and intestinal injury in rats. α7nAchR activation markedly reduced intestinal injury, POCD, neuronal apoptosis, proinflammatory factor expression, and number of CD4+IL-17+ cells. α7nAchR knockout significantly increased serum D-lactic acid, FABP2, S-100ß, NSE, TNF-α, IL-6, and IL-17 secretion. The number of CD4+IL-17+ cells was also significantly increased. CONCLUSION: α7nAchR activation markedly ameliorates the intestinal injury and POCD induced by CPB. Inhibition of the Th17 immune response can reduce the proinflammatory response, which could provide a new method for clinical perioperative organ protection and targeted drug therapy.

Endotracheal intubation in elective cervical surgery: A randomized, controlled, assessor-blinded study.

BACKGROUND: We compared the effectiveness and safety of endotracheal intubation using the GlideScope (GS) video laryngoscope, CTrach laryngeal mask airway (LMA), or Shikani optical stylet rigid laryngoscope (SOS) during elective cervical surgery. METHODS: Forty-five patients undergoing elective cervical surgery were randomly and equally assigned to endotracheal intubation via GS, LMA, or SOS airway management. RESULTS: Endotracheal intubation was successfully completed in all patients. The mean intubation times of the groups differed significantly (P < .01): GS, 17.9 ±â€Š3.1 s; SOS, 40.4 ±â€Š13.7 s; and LMA, 80.5 ±â€Š22.5 s. The groups had similar heart rates and mean arterial pressures throughout the intubation, except that at 2 minutes after intubation the mean arterial pressure of the GS group (106.1 ±â€Š18.5 mm Hg) was significantly higher than that of the LMA (89.7 ±â€Š18.5 mm Hg) or SOS (89.7 ±â€Š18.5 mm Hg; P < .01). The change in C2-5 Cobb angle from baseline was significantly higher in the GS group (GS, 34.2°â€Š±â€Š7.3°) than the LMA (24.4°â€Š±â€Š5.8°) or SOS (25.5°â€Š±â€Š6.4°); P < .01). CONCLUSIONS: The CTrach LMA and SOS rigid laryngoscope are effective, safe alternatives to the GS video laryngoscope for patients undergoing elective cervical surgery.

Hydrogen-Rich Saline Attenuates Brain Injury Induced by Cardiopulmonary Bypass and Inhibits Microvascular Endothelial Cell Apoptosis Via the PI3K/Akt/GSK3ß Signaling Pathway in Rats.

BACKGROUND/AIMS: Cardiopulmonary bypass (CPB) is prone to inducing brain injury during open heart surgery. A hydrogen-rich solution (HRS) can prevent oxidation and apoptosis, and inhibit inflammation. This study investigated effects of HRS on brain injury induced by CPB and regulatory mechanisms of the PI3K/Akt/GSK3ß signaling pathway. METHODS: A rat CPB model and an in vitro cell hypoxia model were established. After HRS treatment, Rat behavior was measured using neurological deficit score; Evans blue (EB) was used to assess permeability of the blood-brain barrier (BBB); HE staining was used to observe pathological changes; Inflammatory factors and brain injury markers were detected by ELISA; the PI3K/Akt/GSK3ß pathway-related proteins and apoptosis were assessed by western blot, immunohistochemistry and qRT -PCR analyses of brain tissue and neurons. RESULTS: After CPB, brain tissue anatomy was disordered, and cell structure was abnormal. Brain tissue EB content increased. There was an increase in the number of apoptotic cells, an increase in expression of Bax and caspase-3, a decrease in expression of Bcl2, and increases in levels of Akt, GSK3ß, P-Akt, and P-GSK3ß in brain tissue. HRS treatment attenuated the inflammatory reaction ,brain tissue EB content was significantly reduced and significantly decreased expression levels of Bax, caspase-3, Akt, GSK3ß, P-Akt, and P-GSK3ß in the brain. After adding the PI3K signaling pathway inhibitor, LY294002, to rat cerebral microvascular endothelial cells (CMECs), HRS could reduce activated Akt expression and downstream regulatory gene phosphorylation of GSK3ß expression, and inhibit CMEC apoptosis. CONCLUSION: The PI3K/Akt/GSK3ß signaling pathway plays an important role in the mechanism of CPB-induced brain injury. HRS can reduce CPB-induced brain injury and inhibit CMEC apoptosis through the PI3K/Akt/GSK3ß signaling pathway.

α7 nicotinic acetylcholine receptor agonist inhibits the damage of rat hippocampal neurons by TLR4/Myd88/NF­κB signaling pathway during cardiopulmonary bypass.

The present study aimed to investigate the effect of α7 nicotinic acetylcholine receptor (α7nAChR) agonist on the damage of hippocampal neurons and the expression of toll like receptor 4 (TLR4)/myeloid differentiation primary response 88 (Myd88)/nuclear factor (NF)­κB signal pathway­associated factors in cardiopulmonary bypass (CPB). Sprague Dawley rats were randomly divided into five groups: Sham operation (Sham); CPB; CPB + α7nAChR agonist PHA568487 (PHA); CPB + α7nAChR inhibitor MLA (MLA); and CPB + PHA568487 + TLR4 antagonist (CPT). Blood and brain tissue samples were harvested at 12 h following the withdrawal of CPB. Levels of serum inflammatory factors [interleukin (IL)­1ß, IL­6 and tumor necrosis factor (TNF)­α] and brain injury markers [S­100ß and neuron­specific enolase (NSE)] were measured using ELISA. In addition, pathological histology and apoptosis changes were observed using hematoxylin and eosin staining, and Tunnel assays. Quantitative polymerase chain reaction and western blot assays were used to determine the expression of TLR4, Myd88 and NF­κB mRNA, and protein in the hippocampus. The morphology of hippocampal pyramidal cells in the Sham group was observed to be normal. Pyramidal cells in the CPB, MLA and CPT groups were loosely arranged, and the baselines had disappeared, with clear nucleus pyknosis and neuronal apoptosis. Furthermore, the cells in the PHA group were slightly damaged. IL­1ß, IL­6, TNF­α, S­100ß and NSE expression levels in the CPB, MLA, and CPT groups were significantly higher compared with that in the Sham group (P<0.05). Compared with CPB group, the expression of inflammatory cytokines in the PHA group was significantly lower (P<0.05). The expression of TLR4, Myd88 and NF­κB mRNA, and protein in the hippocampus of CPB, MLA and CPT groups were significantly higher compared with that in the Sham group, and the PHA group expression was significantly lower compared with the CPB group (P<0.05). α7nAChRs agonist can inhibit the apoptosis of rat brain neurons induced by CPB, and may protect against brain injury through the TLR4/Myd88/NF­κB signaling pathway.

Penehyclidine hydrochloride attenuates the cerebral injury in a rat model of cardiopulmonary bypass.

This study investigated the effect of penehyclidine hydrochloride (PHC) on regulatory mediators during the neuroinflammatory response and cerebral cell apoptosis following cardiopulmonary bypass (CPB). Forty-eight rats were randomly divided among 4 groups as follows: sham-operation, vehicle, low-dose PHC (0.6 mg·(kg body mass)(-1)), and high-dose PHC (2.0 mg·(kg body mass)(-1)). CPB was performed in the latter 3 groups. The plasma levels of neuron specific enolase (NSE) and S-100B were tested with ELISA. Real-time PCR and Western blotting were used to evaluate the expression levels of matrix metalloproteinase-9 (MMP-9), IL-10, caspase-3, Bcl-2, and p38 in brain tissue. The ultrastructure of hippocampus tissue was examined under an electron microscope. PHC attenuated the increase of plasma NSE and S-100B following CPB. MMP-9, cleaved caspase-3, and phosphorylated p38 expression were substantially increased in the vehicle group compared with the sham-operation group and gradually diminished with increasing doses of PHC. IL-10 and Bcl-2 expression were markedly lower in the vehicle group than in the sham-operation group and gradually recovered with increasing doses of PHC. PHC attenuated the histopathological changes of cerebral injury following CPB. PHC favorably regulates the inflammatory response and reduces markers of neuronal injury following CPB, potentially by reducing p38 and caspase-3 activation.

Injection of ropivacaine into the subarachnoid changes the ultrastructure and proteome of the rat spinal cord.

1. In the present study, we investigated the impact of 1.0% ropivacaine on the ultrastructure and proteome of the rat spinal cord. 2. Rats received three injections (90-min intervals, 0.2 mL/kg) of 0.9% NaCl, 0.5% ropivacaine or 1.0% ropivacaine via an implanted intrathecal catheter. Transmission electron microscopy was performed to exam the ultrastructure of the spinal cord. Two-dimensional electrophoresis followed by mass spectrometry identification were carried out to investigate the proteome. 3. In the rats administered 1.0% ropivacaine, deformed organelles, detached myelinated nerve fiber layer, and incomplete inner and outer shaft membranes were observed in the spinal cord and posterior root shrunken nuclei. Furthermore, in the rat spinal cord 1.0% ropivacaine induced the down-regulation of voltage-dependent anion channel 2 (VDAC2) and mitochondrial pyruvate dehydrogenase subunit alpha (ODPA), the upregulation of myelin basic protein (MBP), the disappearance of myelin transcription factor 1 (MYT1) and the appearance of heat shock protein 25 (HSP25). Little change was observed in the 0.5% ropivacaine or control groups. 4. Our results suggest that 1.0% ropivacaine treatment led to neurotoxicity, as shown by ultrastructural and proteomic changes in the rat spinal cord. Specific proteins were identified that are implicated in 1.0% ropivacaine-induced neurotoxicity.

Penehyclidine hydrochloride preserves the intestinal barrier function in patients undergoing cardiopulmonary bypass.

OBJECTIVE: The study objective was to investigate the protective effect of penehyclidine hydrochloride on intestinal barrier function integrity and its therapeutic potential on endotoxemia and systemic inflammatory response in patients undergoing cardiopulmonary bypass. METHODS: Forty patients undergoing cardiac valve replacement with cardiopulmonary bypass were enrolled in the study. All patients were randomly divided into the penehyclidine hydrochloride or control group (20 patients in each group). Patients in the penehyclidine hydrochloride group received an intravenous injection of 0.05 mg/kg penehyclidine hydrochloride 10 minutes before cardiopulmonary bypass, and those in the control group were given the same volume of saline. Blood samples for blood glucose, lactic acid, intestinal fatty acid binding protein, D-lactate, serum endotoxin (lipopolysaccharide), interleukin-6, and interleukin-10 measurements were collected during the following time points: immediately after anesthesia induction (T0), 10 minutes after the release of aortic-clamping (T1), immediately after weaning from cardiopulmonary bypass (T2), 2 hours postoperatively (T3), 6 hours postoperatively (T4), and 18 hours postoperatively (T5). RESULTS: Blood glucose, lactic acid, intestinal fatty acid binding protein, D-lactate, lipopolysaccharide, interleukin-6, and interleukin-10 were significantly increased at all postoperative time points. At specific postoperative time points, blood glucose, lactic acid, intestinal fatty acid binding protein, D-lactate, lipopolysaccharide, and interleukin-6 were statistically lower in the penehyclidine hydrochloride group than in the control group. Postoperatively, interleukin-10 did not differ between the penehyclidine hydrochloride and control groups. CONCLUSIONS: Penehyclidine hydrochloride preserves intestinal barrier function integrity, attenuates endotoxemia, and inhibits systemic inflammatory response in patients undergoing cardiopulmonary bypass, possibly by improving intestinal microcirculation and depressing stress response.