Dexmedetomidine pretreatment alleviates ropivacaine-induced neurotoxicity via the miR-10b-5p/BDNF axis.

BACKGROUND: Ropivacaine is commonly applied for local anesthesia and may cause neurotoxicity. Dexmedetomidine (DEX) exhibits neuroprotective effects on multiple neurological disorders. This study investigated the mechanism of DEX pretreatment in ropivacaine-induced neurotoxicity. METHODS: Mouse hippocampal neuronal cells (HT22) and human neuroblastoma cells (SH-SY5Y) were treated with 0.5 mM, 1 mM, 2.5 mM, and 5 mM ropivacaine. Then the cells were pretreated with different concentrations of DEX (0.01 µM, 0.1 µM, 1 µM, 10 µM, and 100 µM) before ropivacaine treatment. Proliferative activity of cells, lactate dehydrogenase (LDH) release, and apoptosis rate were measured using CCK-8 assay, LDH detection kit, and flow cytometry, respectively. miR-10b-5p and BDNF expressions were determined using RT-qPCR or Western blot. The binding of miR-10b-5p and BDNF was validated using dual-luciferase assay. Functional rescue experiments were conducted to verify the role of miR-10b-5p and BDNF in the protective mechanism of DEX on ropivacaine-induced neurotoxicity. RESULTS: Treatment of HT22 or SH-SY5Y cells with ropivacaine led to the increased miR-10b-5p expression (about 1.7 times), decreased BDNF expression (about 2.2 times), reduced cell viability (about 2.5 times), elevated intracellular LDH level (about 2.0-2.5 times), and enhanced apoptosis rate (about 3.0-4.0 times). DEX pretreatment relieved ropivacaine-induced neurotoxicity, as evidenced by enhanced cell viability (about 1.7-2.0 times), reduced LDH release (about 1.7-1.8 times), and suppressed apoptosis rate (about 1.8-1.9 times). DEX pretreatment repressed miR-10b-5p expression (about 2.5 times). miR-10b-5p targeted BDNF. miR-10b-5p overexpression or BDNF silencing reversed the protective effect of DEX pretreatment on ropivacaine-induced neurotoxicity, manifested as reduced cell viability (about 1.3-1.6 times), increased intracellular LDH level (about 1.4-1.7 times), and elevated apoptosis rate (about 1.4-1.6 times). CONCLUSIONS: DEX pretreatment elevated BDNF expression by reducing miR-10b-5p expression, thereby alleviating ropivacaine-induced neurotoxicity.

Randomized comparison of sevoflurane versus propofol-remifentanil on the cardioprotective effects in elderly patients with coronary heart disease.

BACKGROUND: It is skeptical about cardioprotective property of sevoflurane in patients undergoing noncardiac surgery, especially in the elderly patients with coronary heart disease. We hypothesized that long duration of sevoflurane inhalation in noncardiac surgery could ameliorate myocardial damage in such patients. METHODS: This was a randomized, prospective study. One hundred twenty-one elderly patients with coronary heart disease were randomly allocated into two groups. Maintenance of anesthesia was achieved by sevoflurane inhalation (Group S) or propofol-remifentanil respectively (Group PR). Serum cardiac troponin I (cTnI) and brain natriuretic peptide (BNP) were measured before anesthesia induction (T0), 8 h (T1) and 24 h (T2) after anesthesia respectively. The perioperative cardiac output, complications and postoperative 3-month follow-up from end of surgery were recorded. RESULTS: Between the two groups, there were no statistical differences in the values of cTnI and BNP during the study. However, The area under the curve of cTnI values over 24 h after operation was less in Group S. Group PR had lower cardiac output and consumed more amount of phenylephrine during the study (P < 0.05). CONCLUSIONS: Compared with the group PR, sevoflurane had no benefit in the myocardial protection for the elderly patients with CHD. However, Sevoflurane showed advantage in maintaining hemodynamic stability during the operative period. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-IPR-16008871 , 21 July 2016.

Impact of intra-operative cell salvage on blood coagulation in high-bleeding-risk patients undergoing cardiac surgery with cardiopulmonary bypass: a prospective randomized and controlled trial.

BACKGROUND: Intra-operative cell salvage (CS) was reported to have no impairment on blood coagulation in low-bleeding-risk cardiac surgery with cardiopulmonary bypass (CPB), but studies in high-bleeding-risk cardiac surgery are limited. The objective of this study is to evaluate the impact of CS on blood coagulation in high-bleeding-risk cardiac surgery with CPB. METHODS: One hundred and ten patients were randomly assigned to either with intra-operative CS group (Group CS) or without intra-operative CS group (Group C). Study endpoints included the incidence of impairment of blood coagulation during perioperative period (peri-op) and the incidence of adverse events during postoperative period (post-op). Peri-op was defined as the period from beginning of anesthesia (anesthesia induction) to 24 h after end of surgery. Post-op was defined as the period from the end of surgery to 24 h after end of surgery. The types of impairment of blood coagulation included heparin residual, coagulopathy due to low PLT, coagulopathy due to low FIB, coagulopathy due to low coagulation factors, hyperfibrinolytic. The sum of above five types was total impairment of blood coagulation. Adverse events included excessive bleeding, resternotomy, etc. RESULTS: The incidence of heparin residual measured both at the end of surgery and during post-op were significantly higher in Group CS than in Group C (15.09 vs 4.00, 13.21 vs 2.00 %; p = 0.024, 0.010, respectively). Similarly, the incidence of total impairment of blood coagulation at the end of surgery and during post-op were significantly higher in Group CS than in Group C (32.08 vs 18.00, 26.42 vs 12.00 %; p = 0.043, 0.040, respectively). The incidence of excessive bleeding during post-op was 32.08 % in Group CS compared with 16.00 % in Group C (p = 0.038). Intriguingly, CS was associated with a significantly increase in the relative risk ratios for heparin residual and excessive bleeding (p = 0.034, 0.049, respectively). CONCLUSIONS: Intra-operative CS could impair blood coagulation in the scenario of high-risk-bleeding cardiac surgery with CPB.

The efficacy, safety and cost-effectiveness of intra-operative cell salvage in high-bleeding-risk cardiac surgery with cardiopulmonary bypass: a prospective randomized and controlled trial.

OBJECTIVE: Intra-operative cell salvage (CS) was reported to be ineffective, safe and not cost-effective in low-bleeding-risk cardiac surgery with cardiopulmonary bypass (CPB), but studies in high-bleeding-risk cardiac surgery are limited. The objective of this study is to evaluate the efficacy, safety and cost-effectiveness of intra-operative CS in high-bleeding-risk cardiac surgery with CPB. METHODS: One hundred and fifty patients were randomly assigned to either with intra-operative CS group (Group CS) or without intra-operative CS group (Group C). Study endpoints were defined as perioperative allogeneic red blood cell (RBC) transfusion, perioperative impairment of blood coagulative function, postoperative adverse events and costs of transfusion-related. RESULTS: Both the proportion and quantity of perioperative allogeneic RBC transfusion were significantly lower in Group CS than that in Group C (p=0.0002, <0.0001, respectively). The incidence of residual heparin and total impairment of blood coagulative function in the 24 hours after surgery, the incidence of postoperative excessive bleeding, were significantly higher in Group CS than that in Group C (p=0.018, 0.042, 0.034, respectively). Cost of both allogeneic RBC transfusion and total allogeneic blood transfusion were significantly lower in Group CS than that in Group C (p<0.001, =0.002, respectively). Cost of total blood transfusion was significantly higher in Group CS than that in Group C (p =0.001). CONCLUSION: Intra-operative CS in high-bleeding-risk cardiac surgery with CPB is effective, generally safe, and cost-effective in developed countries but not in China.

Comparison of dexmedetomidine and propofol for conscious sedation in awake craniotomy: a prospective, double-blind, randomized, and controlled clinical trial.

BACKGROUND: It has been reported that dexmedetomidine (DEX) can be used for conscious sedation in awake craniotomy, but few data exist to compare DEX versus propofol (PRO). OBJECTIVE: To compare the efficacy and safety of DEX versus PRO for conscious sedation in awake craniotomy. METHODS: Thirty patients of American Society of Anesthesiologists grade I-II scheduled for awake craniotomy, were randomized into 2 groups each containing 15 subjects. Group D received DEX and group P received PRO. Two minutes after tracheal intubation (T1), PRO (target plasma concentration) was titrated down to 1 to 4 µg/mL in group P. In group D, PRO was discontinued and DEX was administered 1.0 µg/kg followed by a maintenance dose of 0.2 to 0.7 µg/kg/h. The surgeon preset the anticipated awake point-in-time (T0) preoperatively. Ten minutes before T0 (T3), DEX was titrated down to 0.2 µg/kg/h in group D, PRO was discontinued and normal saline (placebo) 5 mL/h was infused in group P. Arousal time, quality of revival and adverse events during the awake period, degree of satisfaction from surgeons and patients were recorded. RESULTS: Arousal time was significantly shorter in group D than in group P (P < .001). The quality of revival during the awake period in group D was similar to that of group P (P = .68). The degree of satisfaction of surgeons was significantly higher in group D than in group P (P < .001), but no difference was found between the 2 groups with respect to patient satisfaction (P = .80). There was no difference between the 2 groups in the incidence of adverse events during the awake period (P > .05). CONCLUSIONS: Either DEX or PRO can be effectively and safely used for conscious sedation in awake craniotomy. Comparing the two, DEX produced a shorter arousal time and a higher degree of surgeon satisfaction.

[A comparative study on the efficacy and safety of intravenous esmolol, amiodarone and diltiazem for controlling rapid ventricular rate of patients with atrial fibrillation during anesthesia period].

OBJECTIVE: To evaluate the efficacy and safety of intravenous esmolol, amiodarone and diltiazem for controlling rapid ventricular rate in patients with atrial fibrillation (AF) during anesthesia period. METHODS: Ninety AF patients with rapid atrial ventricular rate (≥ 120 beats/min) in anesthesia period were randomly divided into 3 groups (n = 30 each: group I patients were treated with intravenous esmolol (0.5 mg/kg loading dose within 1 minute followed with infusion of 0.05 mg×kg(-1)×min(-1)); group II patients were treated with intravenous amiodarone (loading dose: 3 mg/kg for 10 minutes, followed with intravenous infusion of 1 mg/min); group III patients were treated with intravenous diltiazem (0.25 mg/kg for 5 minutes). The heart rate, blood pressure, rhythm were recorded before treatment, at 5, 10, 15, 30, 60 and 90 min after treatment. The reacting time, side effects including hypotension, bradycardia, nausea, vomiting, dizziness, etc, were analyzed. RESULTS: The mean reacting time was significantly shorter in group I (4.3 ± 2.1) min than in group II (19.2 ± 8.5) min and in group III (8.5 ± 3.4) min (P < 0.05). The mean reacting time in group III was significantly shorter than in group II (P < 0.05). The total effective rate were similar among the groups (86.7%, 90.0% and 83.3% with a mean decrease in heart ventricular rate by 42.4%, 42% and 41.9% of the baseline level in group I, group II and group III, respectively). The incidence of total side effect was significantly lower in group II (10%) than in group I (16.7%) and group III (20%, P < 0.05). CONCLUSIONS: Intravenous esmolol, amiodarone and diltiazem are all equally effective and safe on controlling rapid ventricular rate in patients with atrial fibrillation during the anesthesia period. Esmolol use is associated with the shortest mean reacting time and amiodarone use is associated with the lowest total side effect rate in this patient cohort.

Propofol Reversed Hypoxia-Induced Docetaxel Resistance in Prostate Cancer Cells by Preventing Epithelial-Mesenchymal Transition by Inhibiting Hypoxia-Inducible Factor 1α.

Prostate cancer is the second most frequently diagnosed cancer worldwide. Hypoxia-induced epithelial-mesenchymal transition (EMT), driven by hypoxia-inducible factor 1α (HIF-1α), is involved in cancer progression and metastasis. The present study was designed to explore the role of propofol in hypoxia-induced resistance of prostate cancer cells to docetaxel. We used the Cell Counting Kit-8 and 5-ethynyl-2'-deoxyuridine incorporation assay to measure cell viability and cell proliferation, respectively, in prostate cancer cell lines. Then, we detected HIF-1α, E-cadherin, and vimentin expression using western blotting. Propofol reversed the hypoxia-induced docetaxel resistance in the prostate cancer cell lines. Propofol not only decreased hypoxia-induced HIF-1α expression, but also reversed hypoxia-induced EMT by suppressing HIF-1α. Furthermore, small interfering RNA-mediated silencing of HIF-1α reversed the hypoxia-induced docetaxel resistance, although there was little change in docetaxel sensitivity between the hypoxia group and propofol group. The induction of hypoxia did not affect E-cadherin and vimentin expression, and under the siRNA knockdown conditions, the effects of propofol were obviated. These data support a role for propofol in regulating EMT in prostate cancer cells. Taken together, our findings demonstrate that propofol plays an important role in hypoxia-induced docetaxel sensitivity and EMT in prostate cancer cells and that it is a potential drug for overcoming drug resistance in prostate cancer cells via HIF-1α suppression.

Correlation of MDR1 gene polymorphism with propofol combined with remifentanil anesthesia in pediatric tonsillectomy.

The motive of this study was to investigate the interaction between polymorphisms in the MDR1 gene and anesthetic effects following pediatric tonsillectomy. In total, 240 children undergoing tonsillectomy with preoperative propofol-remifentanil anesthesia were selected. Genomic DNA was extracted from the peripheral blood of children after operation, and the MDR1 gene polymorphisms of 2677 G>T/A, 1236 C>T and 3435 C>T were detected by direct sequencing. We tested mean arterial pressure, diastolic blood pressure, systolic blood pressure, and heart rate at several time-points: T0 (5 mins after the repose), T1 (0 min after tracheal intubation), T2 (5 mins after the tracheal intubation), T3 (0 min after the tonsillectomy), T4 (0 min after removal of the mouth-gag) and T5 (5 min after the extubation). The visual analog scale, the face, legs, activity, cry, and consolability pain assessment, and the Ramsay sedation score were recorded after the patients regained consciousness. Adverse reactions were also recorded. The time of induction, respiration recovery, eye-opening, and extubation of children with the CC genotype were found to be shorter compared to the CT + TT genotype of MDR1 1236C > T (all P <.05). The mean arterial pressure, diastolic blood pressure, systolic blood pressure, and heart rate were significantly reduced at T5 in children with the CC genotype (all P <.05). The visual analog scale at 1, 2, 4, and 8 hours post-operation, and the Ramsay sedation score at 5, 10, and 30 min after the extubation were decreased, while the face, legs, activity, cry, and consolability pain assessment score increased (all P <0.05). There was no statistically significant difference in the adverse reaction of MDR1 mutations (P> 0.05). It could be concluded that anesthetic effect following pediatric tonsillectomy in patients with the MDR1 1236C > T CC genotype was stronger than in those carrying the CT + TT genotype.

Association between MDR1/CYP3A4/OPRM1 gene polymorphisms and the post-caesarean fentanyl analgesic effect on Chinese women.

OBJECTIVE: Our study aimed to evaluate the association between the multidrug resistance 1 (MDR1)/cytochrome P450 3A4 (CYP3A4)/µ-opioid receptor (OPRM1) gene polymorphisms and the post-caesarean analgesic effect of fentanyl on Chinese women. METHODS: We recruited 240 patients who received lower segment caesarean section surgeries. Sanger sequencing was used to analyze the MDR11236C > T/CYP3A4*1G/OPRM1A118G polymorphisms. We evaluated post-operative fentanyl consumption and the effect of intravenous analgesia in patients with different genotypes. RESULTS: 1. Subjects with the TT genotype at the 1236C > T polymorphism in the MDR1 gene consumed significantly more fentanyl than that consumed by subjects with the CC and CT genotypes in the first post-operative 24 h and 48 h (P < 0.05), and the MAP/HR/Cor/Ang-1 levels gradually increased immediately after surgery and in the first post-operative 24 h. 2. Subjects with the CYP3A4*1G/*1G genotype needed less fentanyl to achieve pain control than that needed by subjects carrying the CYP3A4*1/*1 and CYP3A4*1/*1G genotypes in the first post-operative 24 h and 48 h (P < 0.05), and the MAP/HR/Cor/Ang-1 levels gradually decreased immediately after surgery and in the first post-operative 24 h. 3. Subjects with the GG genotype at the A118G polymorphism in the OPRM1 gene consumed significantly more fentanyl than that consumed by subjects with the AA and AG genotypes in the first post-operative 24 h and 48 h (P < 0.05), and the MAP/HR/Cor/Ang-1 levels gradually increased immediately after surgery and in the first post-operative 24 h. 4. There were no significant differences in the adverse reactions to fentanyl in patients with different genotypes (P > 0.05). CONCLUSION: These results indicated that the MDR1/CYP3A4/OPRM1 gene polymorphisms influenced the fentanyl consumption and the physiological effects of intravenous analgesia in the Chinese women who received lower segment caesarean section surgeries. Moreover, the present study provides an important foundation and theoretical evidence for the gene-directed rationalization and individualization of medication before caesarean section surgeries.

Comparison of dexmedetomidine and sufentanil for conscious sedation in patients undergoing awake fibreoptic nasotracheal intubation: a prospective, randomised and controlled clinical trial.

INTRODUCTION: Fibreoptic intubation is a valuable technique for difficult airway management in which conscious sedation is paramount. OBJECTIVES: To investigate the efficacy and safety of dexmedetomidine (DEX) and sufentanil (SUF) for conscious sedation during awake nasotracheal intubation under vision by a fibreoptic bronchoscope. METHODS: Forty patients with anticipated difficult airways of American Society of Anesthesiologists I-II scheduled for awake fibreoptic nasotracheal intubation were randomised into two groups each containing 20 subjects. DEX group received DEX at a dose of 1.0 µg/kg over 10 min followed by a continuous infusion of 0.5 µg/kg per hour, while SUF group received SUF target controlled infusion in which the target plasma concentration was 0.3 ng/mL. The nasotracheal intubation conditions and the tolerance to nasotracheal intubation were observed; the occurrence of adverse events including hypertension, bradycardia and respiratory depression during nasotracheal intubation and post-surgical throat pain and hoarseness, and post-surgical memory score were recorded. RESULTS: Better nasotracheal intubation conditions and higher tolerance to intubation were observed in DEX group than those in SUF group (P < 0.05). The incidence rates of hypertension, respiratory depression during intubation and throat pain after surgery were lower in DEX group than those in SUF group; however, the incidence of bradycardia was higher in DEX group than that in SUF group. CONCLUSIONS: DEX provides better nasotracheal intubation conditions, improves patients' tolerance to intubation and leads to lower occurrence of hypertension, respiratory depression and throat pain and post-surgical memory score for sedation during awake fibreoptic nasotracheal intubation.

Inhibition of aberrant cyclin-dependent kinase 5 activity attenuates isoflurane neurotoxicity in the developing brain.

Aberrant CDK5 activity is implicated in a number of neurodegenerative disorders. Isoflurane exposure leads to neuronal apoptosis, and subsequent learning and memory defects in the developing brain. The present study was designed to examine whether and how CDK5 activity plays a role in developmental isoflurane neurotoxicity. Rat pups and hippocampal neuronal cultures were exposed to 1.5% isoflurane for 4 h. The protein and mRNA levels of CDK5, p35 and p25 were detected by western blot and QReal-Time PCR. CDK5 activity was evaluated in vitro using Histone H1 as a substrate. Roscovitine (an inhibitor of CDK5) was applied before isoflurane treatment, cleaved Caspase-3, Bcl-2, Bax, MEF2 and phospho-MEF2A-Ser-408 expressions were determined. Dominant-Negative CDK5 was transfected before isoflurane treatment. Neuronal apoptosis was evaluated by Flow cytometry (FCM) and TUNEL-staining. Cognitive functions were assessed by Morris water maze. We found that isoflurane treatment led to an aberrant CDK5 activation due to its activator p25 that was cleaved from p35 by calpain. Inhibition of CDK5 activity with Roscovitine enhanced Bcl-2, and decreased cleaved Caspase-3 and Bax expressions. In addition, isoflurane exposure resulted in a decrease of MEF2 and increase of phospho-MEF2A-Ser-408, which were rescued by Roscovitine or Dominant-Negative CDK5 transfection. Dominant-Negative CDK5 transfection also decreased the percentage of TUNEL-positive cells in isoflurane neurotoxicity. Moreover, Roscovitine remarkably alleviated the learning and memory deficits induced by postnatal isoflurane exposure. These results indicated that aberrant CDK5 activity-dependent MEF2 phosphorylation mediates developmental isoflurane neurotoxicity. Inhibition of CDK5 overactivation contributes to the relief of isoflurane neurotoxicity in the developing brain.