Effect of midazolam and butorphanol premedication on inhalant isoflurane anesthesia in mice

Isoflurane is a representative inhalant anesthesia used in laboratory animals. However, isoflurane mediates respiratory depression and adverse clinical reactions during induction. In the present study, we established a novel balanced anesthesia method in mice that combined isoflurane anesthesia with midazolam and butorphanol (MB). Thirty-four male C57BL/6J mice received either isoflurane alone or isoflurane with an intra-peritoneal MB premedication (3 mg/kg midazolam and 4 mg/kg butorphanol). The minimum alveolar concentration (MAC) in each group was evaluated. Induction time and adverse clinical reactions were recorded in each group. Core body temperature, heart rate, respiratory rate, and oxygen saturation (SPO₂) were assessed before and for 1 h after induction. Premedication with MB achieved a significant reduction in MAC compared with isoflurane monoanesthesia (isoflurane, 1.38 ± 0.15%; isoflurane with MB, 0.78 ± 0.10%; P<0.05). Induction time was significantly shortened with MB premedication, and adverse reactions such as excitement or incontinence were observed less frequently. Furthermore, isoflurane anesthesia with MB premedication caused increase of respiratory rates compared to isoflurane monoanesthesia. No significant decrease of SPO₂ was observed in MBI anesthesia, while a decrease in SPO₂ was apparent with isoflurane monoanesthesia (baseline, 98.3% ± 1.1; 10 min after induction, 91.8 ± 6.4%; P<0.05). In conclusion, premedication with MB was effective for the mitigation of respiratory depression induced by isoflurane in mice, with rapid induction and fewer adverse clinical reactions.     

右美托咪定的临床麻醉应用进展

右美托咪定(dexmedetomidine,Dex)是高选择性α2-肾上腺素受体激动剂,具有镇静、镇痛、抑制交感神经活性、无呼吸抑制等药理性质。多项研究证实:围术期或ICUs住院期间给予患者右美托咪定,可以增加患者机械通气耐受力,减少机械通气时间,改善患者病情恢复,减少呼吸抑制,稳定血流动力学,减少麻醉剂用量及降低麻醉剂不良反应发生率,抑制应激反应,保护肺脏、神经功能、心脏功能,降低谵妄发生率,抗寒颤等作用特点。虽然右美托咪定存在心动过缓及低血压等不良反应,故应控制给药速度、剂量,合理用药在以便循环波动可控范围内。目前,右美托咪定可用于重症监护病房(ICUs)、全身麻醉、区域麻醉、小儿麻醉、日间手术及无痛检查等辅助用药。本文主要对右美托咪定的临床麻醉应用做以下介绍。     

Cholesterol level influences opioid signaling in cell models and analgesia in mice and humans

Cholesterol regulates the signaling of μ-opioid receptor in cell models, but it has not been demonstrated in mice or humans. Whether cholesterol regulates the signaling by mechanisms other than supporting the entirety of lipid raft microdomains is still unknown. By modulating cholesterol-enriched lipid raft microdomains and/or total cellular cholesterol contents in human embryonic kidney cells stably expressing μ-opioid receptor, we concluded that cholesterol stabilized opioid signaling both by supporting the lipid raft's entirety and by facilitating G protein coupling. Similar phenomena were observed in the primary rat hippocampal neurons. In addition, reducing the brain cholesterol level with simvastatin impaired the analgesic effect of opioids in mice, whereas the opioid analgesic effect was enhanced in mice fed a high-cholesterol diet. Furthermore, when the records of patients were analyzed, an inverse correlation between cholesterol levels and fentanyl doses used for anesthesia was identified, which suggested the mechanisms above could also be applicable to humans. Our results identified the interaction between opioids and cholesterol, which should be considered in clinics as a probable route for drug-drug interaction. Our studies also suggested that a low cholesterol level could lead to clinical issues, such as the observed impairment in opioid functions.     

寰枢关节尾向置管建立上胸段硬膜外阻滞大鼠模型

目的为持续上胸段硬膜外阻滞的试验研究提供稳定可靠的动物模型。方法以大鼠为研究对象,经寰枢关节尾向于硬膜外腔置入PE-10导管,采用特殊的固定和管理措施。4周后,大鼠硬膜外腔注入美蓝100μL/kg,尸检鉴定模型成功和药液的分布范围。结果置管后4周的成功率为65%,硬膜外腔的感染率为2.5%。结论本研究证实了经寰枢关节尾向置管建立持续上胸段硬膜外模型和特殊管理的可行性,并具有成功率高,稳定性好的特点。     

Bispectral Index Analysis of Opioid Immobilization of Rocky Mountain Elk

Abstract: We immobilized elk with either isoflurane to produce general anesthesia (control), 0.01 mg/kg carfentanil plus 0.1 mg/kg xylazine, or 0.25 mg/kg butorphanol plus 0.4 mg/kg azaperone plus 0.15 mg/kg medetomidine (BAM) and measured the bispectral index (BIS). The carfentanil-xylazine BIS (70.4 + 1.4) and the BAM BIS (60.2 + 1.5) were higher than the control BIS (47.2 + 4.1; P ≤ 0.001). These data indicate that opioids produce neuroleptanalgesia and not general anesthesia or sedation, which explains observed elk responses to these drugs.     

EFFECTIVE, FIELD-BASED INHALATION ANESTHESIA FOR ICE SEALS

Thirty five adult crabeater seals ( Lobodon carcinophaga ) were anesthetized with combinations of the sedative midazolam and the gaseous anesthetic isoflurane during three research cruises to the Antarctic Peninsula (∼67°S, 67°W) in the austral winters of 2001 and 2002. Modifications were required to gas anesthetic equipment to achieve field portability and sufficient heating to allow operations in temperatures as low as -20°C. Seals were sedated with an average intramuscular dose of midazolam of 0.55 ± 0.14 mg/kg delivered via a pole syringe ( n = 32). One seal was not given midazolam and two seals were injected intravenously. Premedication with midazolam provided moderate sedation, making capture and masking practical and safe. Mean induction time with isoflurane was 8 ± 4.8 min. Mean maintenance concentration over the anesthetic period were 2.3%± 0.9% of isoflurane. Average recovery time was 18.2 ± 8.8 min. No substantial difficulties were experienced and anesthetics were easily managed. This drug combination and the use of modified, heated equipment provide an effective anesthetic procedure for crabeater seals.     

Norepinephrine in Goal-Directed Fluid Therapy During General Anesthesia in Elderly Patients Undergoing Spinal Operation: Determining Effective Infusion Rate to Enhance Postoperative Functions

Background and ObjectiveIntraoperative hypotension is a common complication in general anesthesia that could result in different serious complications particularly in elderly patients. This Randomized Clinical Trial (RCT) aims to determine effective continuous infusion rate of norepinephrine to prevent intraoperative hypotension during spinal surgery under general anesthesia in elderly patients.MethodsThis RCT was conducted on elderly patients (n= 108) undergoing general anesthesia for posterior lumbar spinal fusion. The patients were randomly divided into 0.030, 0.060, and 0.090 μg.kg-1.min-1 groups of norepinephrine infusion rates. The outcomes were assessed at entrance to operation room (T0), 15 mins after anesthesia induction (T1), 60 mins following surgery (T2), and immediately after surgery (T3). The intraoperative and postoperative complications and rehabilitation outcomes were comparatively assessed.ResultsAll three groups significantly reduced the incidence of delayed wound healing (0.030 vs. 0.060 vs. 0.090 μg.kg^-1.min^-1; 33.3% vs. 10% vs. 10%, P=0.024) and wound infection (26.7% vs. 6.7% vs. 6.7%, P=0.031). Intraoperative total fluid volume and colloids volume in the 0.030 group were significantly higher than 0.060 and 0.090 groups (P=0.005, P=0.003, and P=0.01, respectively). The 0.060 and 0.090 groups significantly increased mean-arterial-pressure than the 0.030 group at T2 and T3. Both 0.060 and 0.090 infusion rates significantly reduced intraoperative hypotension than 0.030 dosage (P=0.01 and P=0.003, respectively). The bradycardia incidence in the 0.090 group was significantly higher than the 0.030 (P=0.026) and 0.060 groups (P=0.038). The 0.060 group decreased the first intake by 1.4 hours (P=0.008) and first flatus by 1.1 hours (P=0.004) and postoperative hospital stay by 1 day (P=0.066).ConclusionThe 0.060 µg·kg^-1·min^-1 norepinephrine infusion combined with goal-directed fluid therapy exhibited adequate intraoperative management and postoperative outcomes.Clinical Trial Registration www.chictr.org.cn, identifier ChiCTR-1900021309.     

Anesthesia and post-mortem interval profoundly influence the regulatory serine phosphorylation of glycogen synthase kinase-3 in mouse brain

Glycogen synthase kinase-3 (GSK3) is a crucial enzyme contributing to the regulation of neuronal structure, plasticity and survival, is implicated as a contributory factor in prevalent diseases such as Alzheimer's disease and mood disorders and is regulated by a wide range of signaling systems and pharmacological agents. Therefore, factors regulating GSK3 in vivo are currently of much interest. GSK3 is inhibited by phosphorylation of serine-9 or serine-21 in GSK3beta and GSK3alpha, respectively. This study found that accurate measurements of phospho-Ser-GSK3 in brain are confounded by a rapid post-mortem dephosphorylation, with approximately 90% dephosphorylation of both GSK3 isoforms occurring within 2 min post-mortem. Furthermore, three anesthetics, pentobarbital, halothane and chloral hydrate, each caused large in vivo increases in the serine phosphorylation of both GSK3beta and GSK3alpha in several regions of mouse brain. Thus, studies of the phosphorylation state of GSK3 in brain, and perhaps in other tissues, need to take into account post-mortem changes and the effects of anesthetics and there is a direct correlation between anesthesia and high levels of serine-phosphorylated GSK3.     

A phospholipid sensor controls mechanogating of the K+ channel TREK-1

TREK-1 (KCNK2 or K(2P)2.1) is a mechanosensitive K(2P) channel that is opened by membrane stretch as well as cell swelling. Here, we demonstrate that membrane phospholipids, including PIP(2), control channel gating and transform TREK-1 into a leak K(+) conductance. A carboxy-terminal positively charged cluster is the phospholipid-sensing domain that interacts with the plasma membrane. This region also encompasses the proton sensor E306 that is required for activation of TREK-1 by cytosolic acidosis. Protonation of E306 drastically tightens channel-phospholipid interaction and leads to TREK-1 opening at atmospheric pressure. The TREK-1-phospholipid interaction is critical for channel mechano-, pH(i)- and voltage-dependent gating.     

Phase-transition-driven synaptic exocytosis: a hypothesis and its physiological and evolutionary implications

It is proposed that the plasma membrane in the active zones of synaptic terminals contains self-assembling cooperative domains whose Ca2+-induced solidification may be the driving force of the fast neurotransmitter release in the central synapses. This hypothesis and a qualitative model of the phase-transition-driven exocytosis provide formulation of a unitary approach to a number of general problems in the physiology of animals. It allows answering the following questions, among others: (i) What is the physical reason for the existence of a narrow optimum range of body temperatures in warm-blooded species? (ii) What is the physical reason for the inevitable necessity of regular sleep in animals? (iii) Does there indeed exist any general mechanism of general anesthesia?