Dataset Information

GluN2A-selective positive allosteric modulator-nalmefene-flumazenil reverses ketamine-fentanyl-dexmedetomidine-induced anesthesia and analgesia in rats.

ABSTRACT: Anesthetics are used to produce hypnosis and analgesic effects during surgery, but anesthesia for a long time after the operation is not conducive to the recovery of animals or patients. Therefore, finding appropriate treatments to counter the effects of anesthetics could enhance postoperative recovery. In the current study, we discovered the novel role of a GluN2A-selective positive allosteric modulator (PAM) in ketamine-induced anesthesia and investigated the effects of the PAM combined with nalmefene and flumazenil (PNF) in reversing the actions of an anesthetic combination (ketamine-fentanyl-dexmedetomidine, KFD). PAM treatment dose-dependently decreased the duration of the ketamine-induced loss of righting reflex (LORR). Compared with those in the KFD group, the duration of LORR and the analgesic effect of the KFD?+?PNF group were obviously decreased. Meanwhile, successive administration of PNF and KFD had no adverse effects on the cardiovascular and respiratory systems. Both the KFD group and the KFD?+?PNF group showed no changes in hepatic and renal function or cognitive function in rats. Moreover, the recovery of motor coordination of the KFD?+?PNF group was faster than that of the KFD group. In summary, our results suggest the potential application of the PNF combination as an antagonistic treatment strategy for anesthesia.

SUBMITTER: Li C

PROVIDER: S-EPMC7093419 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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GluN2A-selective positive allosteric modulator-nalmefene-flumazenil reverses ketamine-fentanyl-dexmedetomidine-induced anesthesia and analgesia in rats.

Li Chunzhu C Yan Jia J Tang Dewei D Zhu Jidong J Huang Chen C Sun Yu Y Hu Rong R Wang Hao H Fu Chaoying C Chen Yelin Y Jiang Hong H

Scientific reports 20200324 1

Anesthetics are used to produce hypnosis and analgesic effects during surgery, but anesthesia for a long time after the operation is not conducive to the recovery of animals or patients. Therefore, finding appropriate treatments to counter the effects of anesthetics could enhance postoperative recovery. In the current study, we discovered the novel role of a GluN2A-selective positive allosteric modulator (PAM) in ketamine-induced anesthesia and investigated the effects of the PAM combined with n ...[more]

PMID: 32210319

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Project description:Dexmedetomidine as a sole agent showed limited use for painful procedures due to its insufficient sedative/analgesic effect, pronounced hemodynamic instability and prolonged recovery. The aim of this study was to compare the effects of dexmedetomidine-ketamine (DK) versus dexmedetomidine-midazolam-fentanyl (DMF) combination on the quality of sedation/analgesia and recovery profiles for monitored anesthesia care (MAC).Fifty six patients undergoing chemoport insertion were randomly assigned to group DK or DMF. All patients received 1 μg.kg(-1) dexmedetomidine over 10 min followed by 0.2-1.0 μg.kg(-1)h(-1) in order to maintain 3 or 4 of modified Observer's Assessment of Analgesia and Sedation score checked every 3 min. At the start of dexmedetomidine infusion, patients in group DK or DMF received 0.5 mg.kg(-1) ketamine or 0.05 mg.kg(-1) midazolam + 0.5 μg.kg(-1) fentanyl intravenously, respectively. When required, rescue sedatives (0.5 mg.kg-1 of ketamine or 0.05 mg.kg-1 of midazolam) and analgesics (0.5 mg.kg-1 of ketamine or 0.5 μg.kg-1 of fentanyl) were given to the patients in DK or DMF group, respectively. The primary outcome of this study was the recovery parameters (time to spontaneous eye opening and the length of the recovery room stay). The secondary outcomes were parameters indicating quality of sedation/analgesia, cardiorespiratory variables, and satisfaction scores.There were no significant differences in the onset time, time to spontaneous eye opening, recovery room stay, the incidences of inadequate analgesia, hypotension and bradycardia between the two groups. Despite lower infusion rate of dexmedetomidine, more patients in the DMF group had bispectral index (BIS) < 60 than in the DK group and vice versa for need of rescue sedatives. The satisfaction scores of patients, surgeon, and anesthesiologist in the DMF group were significantly better than the DK group.The DK and DMF groups showed comparable recovery time, onset time, cardiorespiratory variables, and analgesia. However, the DMF group showed a better sedation quality and satisfaction scores despite the lower infusion rate of dexmedetomidine, and a higher incidence of BIS < 60 than the DK group.Clinical Trial Registry of Korea KCT0000951 , registered 12/12/2013.

Project description:Background:The literature on drugs used for combined general anesthesia and epidural analgesia (CGE) in lumbar operations is scarce. The purpose of the study was to compare the addition of either dexmedetomidine or fentanyl to bupivacaine for epidural analgesia in combination with general anesthesia with regard to efficacy and adverse events in such operations. Materials and Methods:This prospective, randomized, double-blinded study was conducted on 80 patients who were scheduled for an elective lumbar disc operation, age 20-65 years, of either sex and American Society of Anesthesiologists physical status I or II. They were randomly allocated into one of the two groups - group bupivacaine-dexmedetomidine (BD) (n = 40): patients who received CGE with 15 mL of bupivacaine 0.20% plus 50 ?g of dexmedetomidine and group bupivacaine-fentanyl (BF) (n = 40): patients who received CGE with 15 mL of bupivacaine 0.20% plus 50 ?g fentanyl. The primary outcome was time to first analgesic requirement, whereas the secondary outcomes were the total opioid consumption and pain scores during the first 24 h. The incidence of adverse postoperative (PO) effects related to the study drugs, such as sedation, nausea and vomiting, pruritus, shivering, and respiratory depression, was also documented. Results:Patients in the BD group experienced a significantly prolonged pain-free period, lower total opioid consumption, and lower pain scores than patients in the BF group (P < 0.001). Patients in the BD group showed a significantly lower intraoperative heart rate and mean blood pressure (P < 0.001). Regarding adverse events, there were greater PO sedation scores (P < 0.001) and less frequent episodes of PO nausea and vomiting in the BD group. In addition, patients in the BD group showed less pruritis and shivering. There were no reported cases of respiratory depression in either group. Conclusion:CGE with bupivacaine plus dexmedetomidine provided better PO pain control than bupivacaine plus fentanyl, with fewer adverse events overall.

Project description:Hemorrhage is a leading cause of preventable battlefield and civilian trauma deaths. Ketamine, fentanyl, and morphine are recommended analgesics for use in the prehospital (i.e., field) setting to reduce pain. However, it is unknown whether any of these analgesics reduce hemorrhagic tolerance in humans. We tested the hypothesis that fentanyl (75 µg) and morphine (5 mg), but not ketamine (20 mg), would reduce tolerance to simulated hemorrhage in conscious humans. Each of the three analgesics was evaluated independently among different cohorts of healthy adults in a randomized, crossover (within drug/placebo comparison), placebo-controlled fashion using doses derived from the Tactical Combat Casualty Care Guidelines for Medical Personnel. One minute after an intravenous infusion of the analgesic or placebo (saline), we employed a pre-syncopal limited progressive lower-body negative pressure (LBNP) protocol to determine hemorrhagic tolerance. Hemorrhagic tolerance was quantified as a cumulative stress index (CSI), which is the sum of products of the LBNP and the duration (e.g., [40 mmHg x 3 min] + [50 mmHg x 3 min] …). Compared with ketamine (p = 0.002 post hoc result) and fentanyl (p = 0.02 post hoc result), morphine reduced the CSI (ketamine (n = 30): 99 [73-139], fentanyl (n = 28): 95 [68-130], morphine (n = 30): 62 [35-85]; values expressed as a % of the respective placebo trial's CSI; median [IQR]; Kruskal-Wallis test p = 0.002). Morphine-induced reductions in tolerance to central hypovolemia were not well explained by a prediction model including biological sex, body mass, and age (R2=0.05, p = 0.74). These experimental data demonstrate that morphine reduces tolerance to simulated hemorrhage while fentanyl and ketamine do not affect tolerance. Thus, these laboratory-based data, captured via simulated hemorrhage, suggest that morphine should not be used for a hemorrhaging individual in the prehospital setting.

Dataset Information

GluN2A-selective positive allosteric modulator-nalmefene-flumazenil reverses ketamine-fentanyl-dexmedetomidine-induced anesthesia and analgesia in rats.

Publications

GluN2A-selective positive allosteric modulator-nalmefene-flumazenil reverses ketamine-fentanyl-dexmedetomidine-induced anesthesia and analgesia in rats.

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