Neonatal administration with dexmedetomidine does not impair the rat hippocampal synaptic plasticity later in adulthood

Background and objective: The use of dexmedetomidine (DEX), a selective alpha‐2 agonist, in pediatric practice is expanding as a result of its desirable properties. To clarify the long‐term neurological consequences of neonatal administration of DEX, we investigated the long‐term effects of neonatal administration of DEX on hippocampal synaptic activity. Methods: The rat pups received a bolus intraperitoneal injection of either 5 or 10 μg·kg^?1 DEX, or an equivalent volume of vehicle on postnatal day 7 (P7). Nine weeks after administration, evoked potentials (population spike, PS) and long‐term potentiation (LTP) in the hippocampal CA1 region of rats were studied in vivo. Results: Dexmedetomidine had a considerable sedative effect at these doses with little respiratory depression on P7. Nine weeks after administration of DEX, the amplitude of PS in the two treated groups was similar to that in the control group. DEX‐treated rats showed no impairment in the induction of LTP. Furthermore, the response in PS to the paired stimuli was not impaired by neonatal administration of DEX. Conclusion: These findings demonstrate that a single administration of DEX to rats on P7 preserves hippocampal synaptic plasticity as well as synaptic transmission later in life. In view of the some evidence that have demonstrated the permanent detrimental impact of commonly used anesthetics on neurological outcomes after neonatal exposure, our findings may suggest the relative safety of DEX administered as a sedative agent to neonatal animals with regard to the development of hippocampal synaptic functions.     

右美托咪定在慢性阻塞性肺疾病急性发作患者机械通气镇静中的疗效分析

目的：评估右美托味定在慢性阻塞性肺疾病急性发作（AECOPD）患者机械通气镇静中的疗效及安全性。方法：选择60例AECOPD并发呼吸衰竭在ICU接受有创机械通气的患者,按随机数字表法分成右美托咪定组30例和咪达唑仑组30例,观察两组患者镇静的成功率、机械通气时间、ICU住院时间、谵妄发生率、呼吸机相关性肺炎（VAP）的发生率以及心血管不良事件的发生率。结果：两组患者均能达到良好的镇静效果（93．33％：96．67％,P〉0．05）,但右美托咪定组所需吗啡用量明显少于咪达唑仑组[（1．2±0．3）mg／h：（2．5±0．4）mg／h,P〈0．05];右美托咪定组机械通气时间、谵妄发生率、呼吸机相关性肺炎（VAP）的发生率、ICU住院时间均少于咪达唑仑组[（5．22±2．36）d、10％、16．67％、（4．25±1．25）d：（5．63±2．86）d、（2．58±1．36）h、42％、34％、（6．33±2．74）d,P〈0．osJ;右美托咪定组心动过缓发生率较咪达唑仑组高（12％：4%,P〈0．05）,低血压发生率两者相似（22％：20％,P〉0．05）。结论：右美托咪定在起到较好理想镇静效果的同时,所需吗啡应用剂量小,并可以减少机械通气时间、ICU住院时间,减少谵妄发生率,减少呼吸机相关性肺炎发生。其临床不良反应发生率低,安全性较高,可作为AECOPD行机械通气患者镇静的一线用药。     

Population analysis to assess the influence of age and body weight on pharmacokinetics and pharmacodynamics of dexmedetomidine in New Zealand White rabbits

The purpose of this work was i) to develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model of dexmedetomidine (DEX) in New Zealand White rabbits, ii) to investigate the influence of the age and weight of the animals on the model parameters, and iii) to assess the linearity of DEX PKs in the examined dose range. This was a prospective, crossover study, using a total of 18 New Zealand White rabbits. DEX was administered as a single intravenous bolus injection in the doses from 25 to 300 μg kg⁻¹. Each New Zealand White rabbit was given the same dose of drug in its three developmental stages. To determine the DEX PK, seven blood samples were taken from each animal. The pedal withdrawal reflex was the PD response used to assess the degree of sedation. Nonlinear mixed effects modelling was used for the population PK/PD analysis. The typical value of elimination clearance was 0.061 L min⁻¹ and was 35% higher in younger New Zealand White rabbits compared with older animals. The PK of DEX was linear in the examined concentration range. Age-related changes in sensitivity to DEX were not detected. The results suggest that due to the pharmacokinetics, younger animals will have lower DEX concentrations and a shorter duration of sedation than older animals given the same doses of DEX per kg of body weight.     

右美托咪定对脑外伤所致认知功能和脑组织损伤的保护作用

目的： 研究右美托咪定对脑外伤（traumatic brain injury,TBI）后小鼠认知功能和脑组织损伤的影响,揭示右美托咪定（Dex）治疗脑外伤的可能作用机制。方法： 将60只小鼠随机分为假手术组（Sham组）、模型组（TBI组）和右美托咪定治疗组（Dex+TBI组）。采用神经损伤严重程度评分（NSS）和旋转实验（Rotarod test）评价各组小鼠在TBI后24 d的神经功能;采用行为学实验评估TBI后小鼠运动依赖的学习记忆能力损害;HE染色观察脑组织体积损伤,TUNEL染色分析神经元细胞死亡,蛋白印迹实验分析突触相关蛋白pre-BDNF、BDNF、GAP43、Synaptophysin和Synapsin表达。结果： 与TBI组相比,TBI+Dex组小鼠神经损伤恢复水平和认知能力均提高,差异有统计学意义（P<0.01）;脑组织体积损伤减小（P<0.01）,TUNNEL阳性细胞数量显著增加（P<0.01）;突触相关蛋白表达显著增加（P<0.01）。结论： 右美托咪定对脑外伤后小鼠认知功能和脑组织损伤具有保护作用,其机制可能是增加了突触相关蛋白的表达。     

探讨对接受髋关节置换术治疗的高龄患者应用右美托咪定辅助麻醉及镇静的临床价值

目的:探讨髋关节置换术治疗高龄患者中应用右美托咪定辅助麻醉、镇静的效果。方法:选取某院2017年4月~2019年10月时间段收治98例高龄行髋关节置换术患者,以随机数字表法分组,分为实验组和对照组各49例。实验组通过右美托咪定辅助常规全麻,对照组施行常规全麻,比较两组的麻醉效果。结果:手术前两组血清疼痛介质含量、血清炎症细胞因子含量比较,无统计学差异(P>0.05);手术中,实验组和对照组的上述指标实行比较,差异显著(P<0.05)。结论:高龄髋关节置换术治疗患者中,采用右美托咪定辅助麻醉、镇静的效果较好,主要表现在可减轻患者血清疼痛介质含量和血清炎症细胞因子含量。     

从海马区自噬水平探讨右美托咪定缓解老年患者全身麻醉术后认知功能障碍的作用机制

目的从海马区自噬水平探讨右美托咪定缓解老年患者全身麻醉术后认知功能障碍的作用机制。方法选取2015年1月至2018年12月行全身麻醉手术治疗的80例老年患者,随机分为观察组和对照组,各40例。对照组给予常规的全身静脉麻醉,观察组在手术结束前30 min采用静脉泵给予右美托咪定。比较术后2组患者的镇痛效果、认知功能评分、海马区自噬水平和不良反应发生率等。结果观察组患者在术后6、12、24 h的视觉模拟评分法(VAS)评分均低于对照组(P<0.05)。术后24 h,观察组患者的简易智力状态检查量表(MMSE)评分、蒙特利尔认知评估量表(MoCA)评分和海马区自噬水平LC3-Ⅱ、Beclin-1蛋白水平均高于对照组,组间差异均有统计学意义(P<0.05)。观察组和对照组不良反应发生率分别为15.00%(6/40)和7.50%(3/40)(P>0.05)。结论右美托咪定在老年患者全身麻醉术后镇痛效果良好,能够改善患者术后的认知功能,上调海马区自噬标记蛋白水平,且用药安全性好,其改善患者认知功能可能与抑制海马区自噬有关。     

右美托咪定激活PI3K/Akt通路改善LPS诱导的大鼠急性肺损伤实验研究

目的 考察右美托咪定（Dex）对脂多糖（LPS）诱导的大鼠急性肺损伤（ALI）的影响,并探讨可能与PI3K/Akt信号通路改变的相关机制。方法 将80只SD大鼠根据建模方法随机分为5组：对照组、模型组、Dex低剂量组、Dex高剂量组、Dex+LY294002组,建模24 h时处死并分离肺组织,观察组织病理切片,检查肺水肿程度及微血管通透性,采用Western blotting法检测Akt及其磷酸化蛋白以及线粒体凋亡信号相关蛋白的表达水平,检查线粒体细胞色素C、膜电位及ATP含量,并用电镜观察线粒体形态,采用流式细胞术检测肺组织细胞凋亡情况,采用DCFH-DA探针荧光显微镜法检测细胞内的活性氧（ROS）水平。结果 LPS滴注24 h后,病理切片表现有明显的ALI特征,Dex在50 μg/kg剂量时可明显改善LPS诱导的ALI病理特征;以对照组为参照,p-Akt（Thr308）与p-Akt（Ser473）的相对表达量模型组未发生明显变化,Dex组则均显著增高（P<0.001）,在Dex+LY294002组的表达水平较Dex组显著降低（P<0.001）;模型组的Bax与Bcl-2蛋白较对照组的相对表达量分别显著升高与降低（P<0.001）,Dex组分别降低与升高至接近对照组水平,Dex+LY294002组又分别回升与回降;对照组、模型组、Dex组、Dex+LY294002组的肺组织细胞凋亡率分别为2.4%、19.5%、6.7%、13.1%;各组的ROS水平变化与肺组织细胞凋亡情况一致性良好。结论 Dex可通过激活PI3K/Akt信号通路减轻LPS诱导的肺组织细胞凋亡及线粒体凋亡信号激活,继而改善ALI,发挥肺保护作用。     

右美托咪定对新辅助化疗后乳腺癌患者术后痛觉过敏的影响

目的 探讨右美托咪定对化疗后乳腺癌患者术后痛觉过敏的影响。方法 选择择期行乳腺癌改良根治手术的患者120例,将患者分为3组：对照组（C组,n=40）、新辅助化疗组（N组,n=40）和新辅助化疗术前应用右美托咪定组（D组,n=40）。采用视觉模拟评分（Visual Analogue Scale,VAS）和机械痛阈测定分别于患者术后24 h（T5）、48 h（T6）和72 h（T7）进行痛觉评估。结果 与C组相比,N组患者在T5~T7时间点机械痛阈明显下降（P<0.001,P=0.037,0.023）,VAS评分显著增加（P=0.012,0.002,0.036）;与N组相比,D组患者在术后T5~T7时间点的机械痛阈升高（P=0.021,0.004,0.013）,VAS评分显著降低（P=0.031,0.024,0.032）。D组患者在围术期的心率（heart rate,HR）和平均动脉压（mean arterial pressure,MAP）更加平稳;术后再次镇痛患者比例下降,发生躁动不良反应减少。结论 右美托咪定可安全有效地缓解新辅助化疗后乳腺癌患者术后痛觉敏感性。     

右美托咪定对髋关节置换术后老年患者认知功能障碍的影响

目的评价右美托咪定对髋关节置换术后老年患者认知功能障碍的影响。方法择期行髋关节置换术的老年患者80例,年龄〉60岁,性别不限,体重50～75kg,ASA分级Ⅱ或Ⅲ级,采用随机数字表法分为2组（n=40）：对照组（C组）和右美托咪定组（Dex组）。2组麻醉诱导和维持方法相同。Dex组于麻醉诱导前经静脉输注右美托咪定,负荷量为0．8μg／kg,随后以0．5μg·kg^-1·h^-1的速率静脉输注至术毕,C组给予等容量生理盐水。于麻醉诱导前1天（T1）及术后1天（T2）、2天（T3）和3天（T4）记录患者简易精神状态量表（MMSE）评分,记录术后3天内术后认知功能障碍（POCD）的发生情况。结果与术前1天比较,C组术后1、2天时MMSE评分降低（P〈0．05）;与C组比较,Dex组术后1、2天时MMSE评分较高,POCD发生率较低（P〈0．05）。结论右美托咪定可降低髋关节置换术后老年患者认知功能障碍的发生率。     

Early Goal Directed Sedation, a bridge to better clinical outcomes

Critical care has become a central part of modern medicine and an integral essential to improve the outcomes in acute care.The increasing complexity of surgical procedures,severity of co-morbid diseases,life expectancy and societal expectation is likely to escalate the burden and the global need for critical care resources.While millions of patients are ventilated worldwide every year,projections suggest that the number of ventilated patients is expected to rise by 31% over the following decade.1