右美托咪啶联合咪达唑仑在颅脑创伤中的镇静效果及对神经内分泌的影响

目的:探讨右美托咪啶联合咪达唑仑在颅脑创伤中的镇静效果及对神经内分泌的影响。方法:选择2015年3月至2016年5月我院收治的82例颅脑外伤患者,随机分为对照组(n=41)和观察组(n=41),对照组患者给予丙泊酚联合右美托咪啶镇静治疗,观察组患者则给予右美托咪啶联合咪达唑仑镇静治疗。比较两组患者24 h内镇静效率、镇静1 d医疗费用及用药前后呼吸循环功能变化、血清皮质醇、β-内啡肽水平、外周血白细胞计数以及血糖水平。结果:观察组镇静1 d医疗费用较对照组降低,有统计学差异(P0.05),但两组镇静效率比较无统计学差异(P0.05)。用药后观察组患者平均动脉压(MAP)、心率(HR)和呼吸频率(RR)分别高于对照组,差异具有统计学意义(P0.05),而血氧饱和度(SpO2)、中心静脉压(CVP)比较无统计学差异(P0.05)。用药后两组患者血清皮质醇、β-内啡肽均较用药前降低,观察组血清皮质醇、β-内啡肽均高于对照组,差异具有统计学意义(P0.05)。用药后观察组患者外周血白细胞计数、血糖水平较用药前降低,对照组患者血糖水平较用药前降低,观察组患者外周血白细胞计数显著低于对照组,差异具有统计学意义(P0.05)。结论:右美托咪啶联合咪达唑仑应用于颅脑创伤中的镇静效果显著,可有效控制颅脑创伤后的过度应激反应,降低神经内分泌系统紊乱,减少医疗费用,值得临床推广应用。     

神经节苷脂联合咪达唑仑治疗重症颅脑损伤的临床疗效及对患者血清MMP-9、GFAP、MBP、NSE水平的影响

目的:探讨神经节苷脂联合咪达唑仑治疗重症颅脑损伤的临床疗效及对患者血清基质金属蛋白酶-9(MMP-9)、胶质纤维酸性蛋白(GFAP)、髓鞘碱性蛋白(MBP)、神经元特异性烯醇化酶(NSE)水平的影响。方法:选择2016年3月到2017年9月于我院进行治疗的85例重症颅脑损伤患者,将其按随机数表法分为观察组(n=45)和对照组(n=40),对照组使用神经节苷脂治疗,观察组采用神经节苷脂联合咪达唑仑治疗。比较两组治疗后疗效及血清GFAP、中枢神经特异蛋白(S100β)、NSE、MMP-9、MBP、C反应蛋白(CRP)、白细胞介素-6(IL-6)、肿瘤坏死因子α(TNF-α)水平、格拉斯哥昏迷评分(Glasgow Coma Scale,GCS)评分的变化及不良反应的发生情况。结果:治疗后,观察组临床疗效总有效率(93.33%)显著高于对照组(75.00%,P0.05);两组血清GFAP、S100β、NSE、MMP-9、MBP、CRP、IL-6及TNF-α水平均较治疗前明显下降,且观察组以上指标均显著低于对照组(P0.05);观察组GCS评分明显高于对照组(P0.05),且不良反应发生率明显低于对照组(6.67%vs. 30.00%,P0.05)。结论:神经节苷脂联合咪达唑仑治疗重症颅脑损伤患者的临床效果显著,明显优于单用神经节苷脂治疗,可能与其有效改善患者血清MMP-9、GFAP、MBP、NSE水平及抑制炎症因子的生成有关。     

右美托咪定与咪达唑仑对前列腺电切术患者术后认知功能的影响

目的:分析右美托咪定与咪达唑仑对前列腺电切术(TURP)患者认知功能的影响。方法:选择2013年5月-2015年5月在我院接受TURP治疗的良性前列腺增生患者73例作为研究对象。根据麻醉方法不同,将所选患者分为右美托咪定组和咪达唑仑组,分别采用右美托咪定和咪达唑仑麻醉。观察并比较不同时间点两组患者的心率(HR)及平均动脉压(MAP)的变化情况。应用精神状态量表(MMSE)评估两组患者手术前后的认知功能。结果:两组患者术前HR及MAP比较,差异均无统计学意义(P0.05);两组患者手术不同时间点HR、MAP均显著低于术前,且右美托咪定组低于咪达唑仑组,差异具有统计学意义(P0.05);两组患者术前MMSE评分比较,差异无统计学意义(P0.05);两组患者术后MMSE评分均低于术前,且右美托咪定组低于咪达唑仑组,差异均具有统计学意义(P0.05);右美托咪定组术中寒战发生率显著低于咪达唑仑组,差异具有统计学意义(P0.05)。结论:右美托咪定与咪达唑仑对TURP患者均会造成早期认知功能障碍,但右美托咪定的影响较小,患者生命体征较平稳,值得临床推广应用。     

Chronobiological Study of the Pharmacological Response of Rats to Combination Ketamine–Midazolam

Ketamine is commonly administered in combination with benzodiazepines to achieve surgical anaesthesia in rats. The aim of the present study was to analyze the pharmacological response of the combination ketamine–midazolam injected intraperitoneally at different times of day to rats. The study was conducted in July 2003, during the winter in the Southern hemisphere. Female prepuberal Sprague-Dawley rats synchronized to a 12 h light:12 h dark cycle (light, 07:00–19:00 h) were used as experimental animals. A combination treatment of ketamine (40 mg/kg) and midazolam (2 mg/kg) was administered to five different clock-time groups of rats (n = 7/group). Duration of the latency period, ataxia, loss-of-righting reflex (LRR), post-LRR ataxia, and total pharmacological response were assessed by visual assessment. Significant treatment-time differences were detected in the duration of LRR, post-LRR ataxia, and total pharmacological response duration. The longest pharmacological response occurred in rats injected during the light (rest) phase, and the shortest pharmacological response occurred in rats injected during the dark (activity) phase. Cosinor analysis documented circadian rhythmicity in the duration of post-LRR ataxia. The findings of the study indicate the duration of CNS-depression of the ketamine–midazolam combination exhibits treatment-time-dependent variation in the rat.     

Simultaneous determination of fentanyl and midazolam using high-performance liquid chromatography with ultraviolet detection

When measuring fentanyl and midazolam simultaneously in the same plasma sample with standard high-performance liquid chromatography–ultraviolet (HPLC–UV) detection, overlap of the fentanyl peak by the midazolam peak occurs, which makes fentanyl determination impossible. We tested the hypothesis that by acidifying the methanol mobile phase with 0.02% perchloric acid, 70%, it would be possible to separate both peaks. The UV detector was set at 200 nm. Calibration curves for fentanyl (range 0–2000 pg/ml) and midazolam (range 0–400 ng/ml) were linear (r>0.99). The detection limits were 200 pg/ml (fentanyl) and 10 ng/ml (midazolam). Precision and accuracy for intra- and inter-assay variability as well as in-line validation with quality control samples (QCS) were acceptable (< 15 and 20%, respectively), except for fentanyl QCS of 200 pg/ml (17.8% precision). Although less sensitive than gas chromatography–mass spectrometry (GC–MS), reliable measurements of fentanyl, simultaneously with midazolam, can be performed with this HPLC–UV system.     

Differential effect of Shenmai injection, a herbal preparation, on the cytochrome P450 3A-mediated 1′-hydroxylation and 4-hydroxylation of midazolam

Shenmai injection (SMI), one of the most popular herbal preparations, is widely used for the treatment of coronary atherosclerotic cardiopathy and viral myocarditis. The purpose of this study was to investigate the effect of Shenmai injection (SMI) on the CYP3A-mediated metabolism of midazolam (MDZ). The present study demonstrated that SMI could significantly inhibit MDZ 4-hydroxylation but activate its 1′-hydroxylation in human liver microsomes (HLMs), rat liver microsomes (RLM) and recombinant human CYP3A4 and CYP3A5. The opposing effect of SMI was characterized by the kinetic change of increasing V_max/K_m for MDZ 1′-hydroxylation and decreasing V_max/K_m for MDZ 4-hydroxylation in HLM and RLM. The presence ofSMI enhanced the inhibition of ketoconazole on MDZ 4-hydroxylation but weakened or reversed its inhibition on MDZ 1′-hydroxylation in HLM. After single or multiple pretreatment with SMI, the ratios of AUC_{4-OH MDZ}/AUC_MDZ in rats were significantly decreased, while the ratios of AUC_{1′-OH MDZ}/AUC_MDZ were increased. Among the major components in SMI, total ginsenoside (TG), ophiopogon total saponins (OTS), ophiopogon total flavone (OTF), ginsenoside Rd, ophiopogonin D and ophiopogonone A exhibited significant inhibition on both 4-hydroxylation and 1′-hydroxylation of MDZ in HLM and RLM, while no activation on MDZ metabolism was observed in the presence of these major constituents alone or together. To further explore the responsible components, 3 mL of SMI was loaded on a solid phase extraction (SPE) C₁₈ cartridge and then separated by different concentrations of methanol. The fractions eluted with 60% and 90% methanol both showed significant activation on MDZ 1′-hydroxylation in HLM, but the fraction eluted with 30% methanol had no such effect. The results indicated that the activation of SMI on MDZ 1′-hydroxylation might be mainly resulted from the lipid-soluble components in SMI.     

Biphasic action of midazolam on GABAA receptor-mediated responses in rat sacral dorsal commissural neurons

The effect of the benzodiazepine agonist midazolam on gamma-aminobutyric acid(A) (GABA(A)) receptor-mediated currents was investigated in neurons acutely dissociated from the rat sacral dorsal commissural nucleus (SDCN) using the nystatin-perforated patch-recording configuration under voltage-clamp conditions. Midazolam displayed a biphasic effect on GABA responses. Low concentrations of midazolam (1nM-10 microM) reversibly potentiated GABA (3 microM)-activated Cl(-) currents (I(GABA)) in a bell-shaped manner, with the maximal facilitary effect at 0.1 microM; whereas at higher concentrations (above 10 microM), midazolam had an antagonistic effect on I(GABA). Our further study indicated that midazolam changed GABA(A) receptor affinity to GABA and the effects of midazolam on I(GABA) were voltage-independent. The benzodiazepine receptor antagonist, flumazenil, abolished the facilitary effect of low concentrations of midazolam rather than the antagonism of I(GABA) induced by high doses of midazolam. In addition, activation of protein kinase C prevented the inhibitory effect of midazolam at higher concentrations, but did not influence the effect of midazolam at low concentrations. These results indicate that midazolam interacts with another distinct site other than the central benzodiazepine receptors on GABA(A) receptors as an antagonist at higher concentrations in SDCN neurons.     

Gas chromatographic determination of midazolam in low-volume plasma samples

A gas chromatographic method for the sensitive determination of midazolam in plasma volumes as low as 40 μl was developed, utilizing clinazolam as the internal standard. After liquid-liquid extraction at basic pH into 1-chlorobutane-dichloromethane (96:4) a 2- to 4-μl portion of the reconstituted extract was injected under electronic pressure control onto a 12 m × 0.2 mm I.D. methyl silicone capillary column, and was exposed to a three-step temperature program from 120 to 310°C, to separate the analytes from the plasma constituents. The compound of interest was identified and quantified by means of a mass-selective detector. The assay was linear from 10 to 500 ng/ml using 40 μl of plasma (limit of quantification: 10 ng/ml) and was linear from 0.25 to 100 ng/ml using 500 μl of plasma (limit of quantification: 0.25 ng/ml). The intra-day precision for the 40-μl aliquots varied from 2.2 to 6.6%, the corresponding accuracy from −7.4 to −4.4%; the inter-day precision ranged from 5 to 7.2% and the corresponding accuracy from −7.2 to −5.1%.     

异氟烷单独或联合咪达唑仑对7日龄大鼠大脑caspase-3表达的影响

目的 观察异氟烷单独或联合咪达唑仑对7日龄大鼠大脑caspase-3表达的影响.方法 7日龄SD大鼠39只,随机分为对照组(C组,n=13),异氟烷组(I组,n=13)和咪达唑仑联合异氟烷组(MI组,n=13).C组:腹腔注射0.9%生理盐水10ml/kg,吸入30%O2 6 h;I组:在37℃恒温并通入1.5%异氟烷的麻醉小室内维持麻醉6h ;MI组:腹腔注射咪达唑仑9 mg/kg后,随即置于37℃恒温并通入1.5%异氟烷的麻醉小室内维持麻醉6h.麻醉结束即刻每组取3只大鼠,行动脉血气分析.麻醉结束2h 采用Realtime-PCR方法检测皮质和海马组织Caspase-3 mRNA水平的变化;并用免疫组织化学SABC法检测大脑Active caspase-3阳性神经细胞的分布情况,计数阳性细胞.结果 ⑴ I组和MI组大鼠麻醉结束即刻动脉血气分析结果与C组比较差异无统计学意义(P＞0.05).⑵ Realtime-PCR 结果显示,I组与MI组大鼠皮质和海马区Caspase-3 mRNA与对照组相比表达增多,且MI组与I组比较Caspase-3 mRNA表达增加(P<0.05).⑶免疫组化结果也显示:与对照组相比,I组与MI组大鼠在皮质、海马及丘脑部位Active caspase-3阳性神经细胞数量均明显增多 (P<0.05),而MI组与I组相比,在海马和丘脑部位Active caspase-3阳性神经细胞数量明显增多(P<0.05).结论 异氟烷麻醉能诱导脑发育高峰期大鼠重要脑区Caspase-3表达增加,联合应用咪达唑仑增加更明显;推测Caspase-3表达增加可能引起凋亡级联反应,导致神经细胞凋亡增加.     

丙泊酚与咪达唑仑用于全麻后苏醒室躁动疗效的比较

目的:比较丙泊酚及咪达唑仑用于全麻后苏醒室(post-anesthesia care unit,PACU)躁动的疗效。方法:本研究选取2016年11月至2020年4月全麻术后转入PACU后发生中、重度躁动的患者194例,分为丙泊酚组(P组,n=98)、咪达唑仑组(M组,n=96)。P组静脉注射丙泊酚0.5 mg/kg~1 mg/kg,M组静脉注射咪达唑仑0.03 mg/kg。必要时重复给药,直至患者Riker镇静和躁动评分在4分及以下。记录两组患者给药次数、药物起效时间、给药前后Riker评分、PACU停留时间、给药前、末次给药后生命体征及处理方法。结果:首次给药后,两组患者躁动均可得到缓解,Riker评分差异无统计学意义(P>0.05)。P组48例患者缓解后躁动再次加重,重复给药后38例可渐缓解,另10例仍需制动。M组12例患者躁动缓解后再次加重,重复给药后均可渐缓解。两组患者首次给药后躁动缓解后再次加重的症状差异具有统计学意义(P<0.05),PACU停留时间差异无统计学意义(P>0.05)。其中P组7例患者重复给药后呼吸抑制予托下颌面罩供氧后可快速缓解,M组重复给药后3例患者呼吸抑制需放置口咽通气道。结论:咪达唑仑用于PACU躁动较丙泊酚不易反复发作,但重复给药后引起的呼吸抑制需被重视。