Pharmacokinetics and pharmacodynamics of propofol and fentanyl in patients undergoing abdominal aortic surgery – a study of pharmacodynamic drug–drug interactions

Propofol is routinely combined with opioid analgesics to ensure adequate anesthesia during surgery. The aim of the study was to assess the effect of fentanyl on the hypnotic effect of propofol and the possible clinical implications of this interaction. The pharmacokinetic/pharmacodynamic (PK/PD) data were obtained from 11 patients undergoing abdominal aortic surgery, classified as ASA III. Propofol was administered by a target‐controlled infusion system. Fentanyl 2–3 µg/kg was given whenever insufficient analgesia occurred. The bispectral index (BIS) was used to monitor the depth of anesthesia. A population PK/PD analysis with a non‐linear mixed‐effect model (NONMEM 7.2 software) was conducted. Two‐compartment models satisfactorily described the PK of propofol and fentanyl. The delay of the anesthetic effect in relation to PK was described by the effect compartment. The BIS was linked to propofol and fentanyl effect‐site concentrations through an additive E_max model. Context‐sensitive decrement times (CSDT) determined from the final model were used to assess the influence of fentanyl on the recovery after anesthesia. The population PK/PD model was successfully developed to describe simultaneously the time course and variability of propofol and fentanyl concentrations and BIS. Additive propofol–fentanyl interactions were observed and quantitated. The duration of the fentanyl infusion had minimal effect on CSDT when it was shorter than the duration of the propofol infusion. If the fentanyl infusion was longer than the propofol infusion, an almost two‐fold increase in CSDT occurred. Additional doses of fentanyl administered after the cessation of the propofol infusion result in lower BIS values, and can prolong the time of recovery from anesthesia. Copyright © 2016 John Wiley & Sons, Ltd.     

Influence of demographic factors, basic blood test parameters and opioid type on propofol pharmacokinetics and pharmacodynamics in ASA I-III patients

The aim of the study was to examine population pharmacokinetics (PK) and pharmacodynamics (PD) of propofol (CAS 2078-54-8) during total intravenous anesthesia monitored by spectral frequency index (SFx). Twenty-eight patients of ASA physical status I-III (ASA: American Society of Anesthesiologists) scheduled for laparoscopic cholecystectomy were included. In group I an anesthesia was induced with a bolus of propofol (2 mg/kg) and remifentanil (CAS 132875-61-7) (1.0 microg/kg), followed by a continuous infusion of remifentanil. In group II, an alfentanil (CAS 71195-58-9) (10 microg/kg) bolus dose was followed by a continuous infusion of alfentanil. The general anesthetic technique included propofol, opioid and muscle relaxant. During anesthesia, the propofol infusion rate (3-8 mg/kg/h) was adjusted to the SFx value. Venous blood samples were collected from the patients during 240 min after termination of the infusion. A two compartment model was used to describe propofol PK. A standard effect compartment model was used to describe the delay between the effect and the concentration of propofol. The SFx index was linked to the effect site concentrations through a sigmoidal Emax model. The influence of continuous (body weight, age, blood pressure, heart rate and blood oxygenation, serum protein, the erythrocyte count, hemoglobin and hematocrit, serum creatinine and creatinine clearance) and categorical (gender and the type of opioid) covariates on the pharmacokinetic and pharmacodynamic parameters was investigated. PK/PD analysis was performed using NONMEM. All the screened covariates did not influence propofol PK and PD, except of the opioid type. The central compartment volume of propofol was larger in the presence of remifentanil than in the presence of alfentanil.     

七氟烷与丙泊酚用于腹腔镜胆囊切除术麻醉诱导的比较性研究

目的:研究七氟烷和丙泊酚两种麻醉诱导方法对于血流动力学和脑电双频指数(BIS)的影响。方法:将实施腹腔镜辅助下胆囊切除术60例患者分为两组,A组:吸入末浓度达到并维持2.6～3.5%七氟烷麻醉诱导;B组:血浆浓度2.8μg/ml丙泊酚静脉麻醉诱导。观察期间血液动力学与BIS值的变化。结果:两种方法都可以达到较理想的麻醉深度,但A组血液动力学变化非常明显。结论:在麻醉诱导期间,两种方式都有合适的麻醉深度,但循环抑制均较明显。     

瑞芬太尼和丙泊酚联合闭环靶控的临床应用

目的:探讨以脑电双频指数(BIS)、平均动脉压(MBP)、心率(HR)为闭环反馈指标行丙泊酚和瑞芬太尼联合闭环靶控的可行性。方法:40例年龄18~39a,拟行妇科腹腔镜择期手术病人随机分成2组,靶控组设丙泊酚3mg·L-1,瑞芬太尼4μg·L-1的浓度行诱导和维持;闭环靶控组设同样初始浓度,以BIS值(50~60),MBP(8~12kPa),HR(60~100次·min-1)为反馈指标在诱导和麻醉维持过程中进行靶控浓度的反馈调控,术中监测HR,MBP,BIS等指标。结果:术中BIS最高值靶控组为63.7±s2.8,明显高于闭环靶控组的53.3±2.0(P<0.01),且超出所设上限60。插管期靶控组MBP最低值低于闭环靶控组(P<0.05),且低于8kPa;切皮期靶控组MBP最高值明显高于闭环靶控组(P<0.01),且超过12kPa。切皮期靶控组HR最高值明显高于闭环靶控组(P<0.01)。结论:以BIS,MBP和HR作为反馈指标行丙泊酚和瑞芬太尼联合闭环靶控可以更好地维持血流动力学的稳定及适当的麻醉深度。     

丙泊酚靶控输注对老年患者全身麻醉血流动力学的影响

目的探讨丙泊酚不同用药方法对全身麻醉时老年患者血流动力学的影响。方法选取ASAI。II级择期行腹部手术老年患者40例,随机分为丙泊酚靶控输注（TcI）组与丙泊酚常规微泵恒速输注（P）组。麻醉过程中根据脑电双频指数（BIS）调整丙泊酚输注速度或靶浓度,分别记录麻醉诱导前（T0）、麻醉诱导后插管前（T。）、气管插管完成即刻（T2）、气管插管后5rain（＇r3）、切皮即刻（T4）、切皮后5min（＇r5）、气管拔管即刻（T6）两组患者相应的血流动力学参数,包括心率（HR）、收缩压（SBP）、舒张压（DBP）。同时记录各时刻BIS值、苏醒时间及术后不良反应发生率。结果与T0比较,TCI组在T2一T6各时点血流动力学指标波动较小（P〉0．05）;P组HR、SBP与DBP在T1时显著降低,T2与T6时显著升高（P〈0．05）。P组与TcI组比较,T2时SBP与DBP显著增高（P〈0．05）。TCI组患者术后睁眼、拔管时间及不良反应发生率均明显低于P组（P〈0．05）。结论靶控输注丙泊酚用于老年手术患者,血流动力学更加平稳,术后不良反应少。     

罗哌卡因硬膜外阻滞对丙泊酚TCI时BIS的影响

目的探讨罗哌卡因（ropivacaine,RPC）硬膜外用药后对胃肠肿瘤手术患者全麻诱导期丙泊酚靶控输注（TCI）时脑电双频指数（BIS）的影响及机制。方法40例患者随机分为硬膜外生理盐水组（GG）和硬膜外RPC组（GR）,硬膜外穿刺置管成功后连接BIS,设定丙泊酚TCI的效应室浓度2．5μg／mL维持麻醉,手术开始前15min硬膜外给药,GC组用0．9％的生理盐水,GR组用0．75％的RPC,首次剂量10ml,然后以5ml／h持续硬膜外注射,记录患者麻醉维持时的BIS值。结果清醒状态两组BIS值差异无显著性（P〉0．05）,手术后Gc组30rainBIS值平均85．46、GR组BIS值平均80．33,60minGC组BIS值80．19、GR组BIS值72．51,两组患者BIS值显著降低（P〈0．05）。结论硬膜外RPC阻滞显著降低丙泊酚TCI麻醉时的BIS值,增强了镇静深度,可适度减少丙泊酚的用量,提高手术的安全性。     

脑电双频指数在未插管全身麻醉患者靶控输注丙泊酚麻醉中的应用价值

目的 探讨脑电双频指数（BIS）在未插管全麻中麻醉深度监测的应用价值.方法 选择局麻下手术患者60例,随机均分为Ⅰ、Ⅱ、Ⅲ组,分别靶控输注（TCI）丙泊酚1.0、1.5、2.0μg/ml.分别于手术开始前10 min（T0）、局部阻滞麻醉（T1）、手术开始30 min（T2）、手术开始60 min（T3）及手术结束时（T4）记录心率（HR）、平均动脉压（MAP）、血氧饱和度（SpO2）、脑电双频指数（BIS）值和改良清醒镇静（MOAA/S）评分.结果 BIS值随MOAA/S评分下降而下降 Ⅲ组术中各时点的MOAA/S评分均低于Ⅰ组（均P〈0.05）,但术中3例出现呼吸抑制 Ⅱ、Ⅲ组MAP在MOAA/S评分3～2时下降有统计学意义（P〈0.05）.结论 在未插管全麻中,采用丙泊酚1.0～1.5μg/ml TCI镇静较为合适.     

Pharmacokinetics and pharmacodynamics of propofol in children undergoing different types of surgeries

BackgroundPropofol is a commonly used agent in total intravenous anesthesia (TIVA). However, the link between its pharmacokinetics and pharmacodynamics has not been fully characterized in children yet. Our aim was to determine the quantitative relationship between the venous plasma concentration and bispectral index (BIS) effect in a heterogeneous group of pediatric patients undergoing various surgical procedures (ASA status I–III).MethodsNine male and nine female patients were anesthetized with propofol–fentanyl TIVA. Sparse venous samples for propofol concentrations assay and dense BIS measurements were collected during and after the end of infusion. Nonlinear mixed-effect modeling in NONMEM was used for data analysis.ResultsA three-compartment model was linked with a classical E_max model through a biophase compartment to describe the available data. All clearance and volume terms were allometrically scaled to account for the body mass difference among the patients under study. A typical patient had their PK parameters observed within the range of literature values for children. The pharmacodynamic parameters were highly variable. The EC₅₀ of 2.80 mg/L and the biophase distribution rate constant of 3.33 min⁻¹ were found for a typical patient.ConclusionsThe BIS values in children are highly correlated with the propofol effect compartment concentrations according to the classical E_max concentration–response relationship. Children had slightly lower sensitivity to propofol and slightly higher clearance, as compared with the adult data available in literature. The intra-patient variations in the BIS require the anesthesiologist's attention in using BIS values alone to evaluate the depth of anesthesia in children.     

腹腔镜胆囊切除术中靶控输注依托咪酯和丙泊酚的比较

目的观察依托咪酯靶控输注的麻醉效果和不良反应,并与丙泊酚比较。方法择期行腹腔镜胆囊切除术患者40例(ASAⅠ～Ⅱ),随机分为依托咪酯组(E组)和丙泊酚组(P组),每组20例。E组靶控输注依托咪酯进行麻醉诱导并维持,P组靶控输注丙泊酚,维持脑电双频指数(BIS)40～60。两组术中持续输注瑞芬太尼0.1～0.5μg/(kg.min)。分别记录麻醉诱导前(基础值)、插管前1 min、插管后(1、3、5 min)、切皮、切皮后15 min、手术结束时的SBP、DBP、HR及苏醒时间、拔管时间、合并用药情况及不良反应。结果与基础值比较,插管前1 min及插管后3 min、5 min,两组SBP、DBP均显著降低(P<0.05),插管后3 min、5 min及手术切皮时,P组HR显著下降(P<0.05)。P组麻黄素、阿托品的使用率高于E组,不良发应发生率低于E组。E组苏醒时间显著长于P组(P<0.05)。结论与丙泊酚相比,靶控输注依托咪酯更有利于血流动力学稳定,但苏醒时间延长,临床应根据需要合理选择。     

七氟醚对闭环肌松输注罗库溴铵药效的影响

目的观察七氟醚对闭环肌松输注罗库溴铵药效的影响。方法选择ASAI或II级,年龄40～60岁,择期拟在全麻下行胃癌根治术(手术时间2～3h左右)患者60例,随机分为两组(每组30例):七氟醚组(S组)和丙泊酚组(P组)。两组患者采用咪唑安定、舒芬太尼、丙泊酚TCI、罗库溴铵麻醉诱导,罗库溴铵用闭环肌松注射系统(CLMRIS-I)采用T1模式进行肌松监测并且闭环输注。气管插管后S组停止丙泊酚输注,吸入3%七氟醚;P组继续丙泊酚TCI。根据脑电双频谱指数(BIS),调整七氟醚的吸入浓度和丙泊酚TCI浓度。记录罗库溴铵的第1、2、3次的增药时间、肌松恢复情况及用药总量等指标。结果两组患者罗库溴铵的第1次增药时间及恢复指数差异无统计学意义(P>0.05);与P组相比,S组2、3次增药时间明显延长(P<0.05);与P组相比,S组T125%时间、TOFr25%时间延长(P<0.05);与P组相比,S组用药总量减少(P<0.05)。结论七氟醚对罗库溴铵的肌松作用有增效作用,连续吸入2h七氟醚比丙泊酚全凭静脉麻醉罗库溴铵的用量减少38%,但两组患者的肌松恢复指数无差异。     

脑电双频指数监测靶控输注丙泊酚联合瑞芬太尼在老年人无痛胃镜检查中的应用

目的 探讨用脑电双频指数(BIS)监测靶控输注(TCI)丙泊酚联合瑞芬太尼在老年人无痛胃镜检查中的应用.方法 120例ASA Ⅰ～Ⅱ级接受全麻无痛胃肠镜检查的老年患者,随机分成两组:靶控输注丙泊酚联合瑞芬太尼组(A组60例)和脑电双频指数监测靶控输注丙泊酚联合瑞芬太尼组(B组60例).A组根据患者临床体征(如意识、血压、肢动)调整丙泊酚用量,B组根据BIS值调整丙泊酚和瑞芬太尼TCI血浆靶浓度,维持BIS值在55～60.比较术中血流动力学指标、丙泊酚总量、术后清醒时间和不良反应情况.结果 B组T1、T2时点平均动脉压(MAP)和心率(HR)下降幅度小于A组(P＜0.05);B组丙泊酚用量和苏醒时间均明显小于A组(P＜0.05);B组呛咳、呃逆,术后恶心、呕吐、躁动的发生率与A组差异无统计学意义,但呼吸抑制、心动过缓发生率明显高于A组(P＜0.05).结论 脑电双频指数监测靶控输注丙泊酚联合瑞芬太尼可安全地用于老年患者无痛胃镜检查,可减少丙泊酚用量,苏醒迅速,但需密切观察术中呼吸、循环变化.     

舒芬太尼复合异丙酚靶控输注全凭静脉麻醉用于神经外科手术的临床研究

目的：评价舒芬太尼复合异丙酚靶控输注（TCI）全凭静脉麻醉用于神经外科手术的有效性和安全性,并与静吸复合麻醉作比较。方法：30例择期行开颅神经外科手术患者,随机分为静吸复合组（对照组）和靶控输注组（TCI组）,每组15例。TCI组采用异丙酚血浆靶控浓度3μg／mL、舒芬太尼效应室靶控浓度0．2～0．6ng／mL维持麻醉;对照组采用持续吸入1％～2％异氟醚维持麻醉。连续监测并于麻醉前（T0）、诱导后（T1）、气管插管后（T2）、切头皮（T3）、锯颅骨（T4）、切除肿瘤（T5）、缝头皮（T6）及气管拔管后（T7）记录脑电双频谱指数（BIS）、平均动脉压（MAP）、心率（HR）,记录麻醉苏醒时间、拔管时间、麻醉不良反应、拔管后即刻和拔管后30min的清醒程度（OAAS评分）及伤口疼痛程度（VRS评分）。结果：术中两组患者的BIS值均明显降低,维持在40～60范围,两组间差异无统计学意义（P〉0．05）。对照组MAP、HR出现明显波动,TCI组各时点较平稳,与对照组比较,差异有统计学意义（P〈0．05）。与对照组比较,TCI组苏醒时间及拔管时间明显降低（P〈0．05）,拔管后即刻OAAS评分升高,拔管后30min VRS评分降低,拔管后烦躁及恶心呕吐数减少（均P〈0．05）。结论：舒芬太尼复合异丙酚TCI全凭静脉麻醉用于神经外科手术,具有麻醉效果满意、血液动力学稳定、苏醒及拔管快速、术后平稳、无空气污染等优点。     

活体肾移植术中靶控输注丙泊酚效应室浓度与实测血浆药物浓度的对比分析

目的 探讨终末期肾功能衰竭（ESRD）患者行亲属供肾肾移植术,丙泊酚靶控输注（TCI）效应室浓度与实测血浆药物浓度相关性。方法 选取2016年3~10月安徽省立医院择期活体供肾肾移植受体27例,选择血浆靶控,采用丙泊酚和瑞芬太尼诱导麻醉,维持脑电双频指数（BIS）为45~55。依次记录麻醉诱导后10、20、30及40 min及肾移植术中开放髂血管后10、20、30及40 min各时间点丙泊酚TCI效应室浓度,并采集动脉血3 mL,经高效液相色谱串联质谱法（HPLC/MS/MS）测定人血浆实测丙泊酚浓度。监测计算肾移植手术中丙泊酚TCI的偏象度及精密度。结果 与麻醉前（基础值）比较,麻醉后术中HR减慢、平均动脉压（MAP）及BIS值下降,差异有统计学意义（P<0.05）,SpO₂差异无统计学意义（P>0.05）。与麻醉前（基础值）比较,术中髂血管开放前中心静脉压（CVP）差异均无统计学意义（P>0.05）,术中髂血管开放后CVP较开放前均增高,差异有统计学意义（P<0.05）。髂血管开放前丙泊酚TCI偏离度及精密度分别为9.58%、10.42%,髂血管开放后丙泊酚TCI偏离度及精密度分别为14.17%、14.19%,二者均在临床使用范围（-15%<偏离度<15%,精密度<30%）。髂血管开放前丙泊酚效应室浓度、髂血管开放后丙泊酚效应室浓度与实测血浆药物浓度间均存在显著的相关性（F=2.35,R²=0.58,F=2.95,R²=0.71,P<0.05）。髂血管开放前后丙泊酚效应室浓度与实测血浆药物浓度间浓度差值比较,差异无统计学意义（P>0.05）。结论 TCI丙泊酚用于ESRD患者术中维持,效应室浓度与实测血药浓度存在显著相关关系。肾移植患者术中丙泊酚TCI,其偏离度及精密度均在临床使用范围。髂血管开放后大量补液对麻醉深度影响较小,无需增加丙泊酚效应室浓度。     

单纯丙泊酚及复合瑞芬太尼靶控输注用于无痛人工流产术的比较

目的比较丙泊酚复合瑞芬太尼靶控输注与单纯丙泊酚靶控输注用于无痛人工流产(人流)术的效果,探讨合理的静脉麻醉方法。方法80例美国麻醉医师协会(ASA)Ⅰ级接受无痛人流术的病人,分为两组,单纯丙泊酚靶控输注(TCI)组(P组)和丙泊酚复合瑞芬太尼TCI组(PR组),每组40例。P组:丙泊酚血浆靶浓度为6～7mg/L;PR组:丙泊酚血浆靶浓度为3.5～4mg/L、瑞芬太尼血浆靶浓度为1.8～2μg/L。待病人意识消失(睫毛反射消失、呼之不应)后开始手术,扩张宫颈结束时停止给药。结果①麻醉效果PR组优于P组(P<0.05)。②PR组诱导时间(1.1±0.4)min,明显短于P组(P<0.05),PR组丙泊酚总剂量(1.8±0.4)mg/kg,明显少于P组(P<0.01)。③苏醒期躁动、兴奋多语P组发生率分别为55%、50%,PR组未发生(P<0.01)。④两组麻醉后血压均明显下降(P<0.01),扩宫时最低,停药后很快回升,负压吸引时恢复至麻醉前水平(P>0.05),各时段脑电双频指数(BIS)值明显下降(P<0.01,P<0.05),负压吸引时最低,以后逐渐回升。结论在无痛人流术中,丙泊酚复合瑞芬太尼靶控输注优于单纯丙泊酚靶控输注,麻醉效果好、诱导时间短、显著减少丙泊酚用量、减少不良反应,是一种安全、合理的静脉麻醉方法。     

丙泊酚闭环靶控输注在中老年患者气管插管与拔管反应中的应用

目的探讨丙泊酚闭环靶控输注(Closed-loop target controlled infusion,CL-TCI)技术在中老年患者手术中抑制气管插管与拔管反应的应用价值。方法拟行开腹胃肠手术的患者40例,ASAⅠ~Ⅱ级,年龄55~70岁,男22例,女18例。40例患者随机分为2组,开环组(O组)和闭环组(C组),每组20例。O组采用常规TCI技术进行麻醉诱导与维持,丙泊酚初始浓度设为3μg/mL,C组采用CL-TCI技术,以BIS值45±5为反馈指标在麻醉诱导和维持中进行反馈控制。记录并比较两组术中MAP、HR、诱导时间(诱导开始到BIS值达到45±5)、诱导期和整个手术期间丙泊酚用量、手术时间、拔管时间以及拔管后VAS评分。结果两组患者在诱导前MAP和HR差异无统计学意义(P>0.05),在诱导后BIS值达到45±5时,MAP和HR均显著下降(P<0.05)。C组在插管和拔管后即刻以及之后3 min的MAP和HR稳定性比较中均好于O组(P<0.05)。C组在诱导期和整个手术期间丙泊酚用量及拔管时间均明显少于O组(P<0.05),但诱导时间长于O组(P<0.05),两组术后VAS评分比较差异无统计学意义(P>0.05)。结论在中老年患者开腹手术中,丙泊酚CL-TCI在气管插管和拔管期间循环功能稳定方面优于常规TCI,增加了麻醉的安全性。     

靶控输注丙泊酚-瑞芬太尼清醒镇静镇痛用于老年人结肠镜检查

目的研究靶控输注异丙酚-瑞芬太尼清醒镇静镇痛用于老年人结肠镜检查的有效性、安全性。方法70例美国麻醉医师协会(ASA)Ⅰ￣Ⅲ级行结肠镜检查的老年患者,随机分为麻醉组(T组)和对照组(C组),每组35例。T组:异丙酚血浆靶浓度0.4￣1.0μg/ml、瑞芬太尼血浆靶浓度0.4￣0.9ng/ml同时输注,待患者进入镇静分级评分(Ramsay)2级开始镜检,肠镜抵达回盲部停止给药。C组:未用药。结果Ramsay评分:T组2级86%,C组2级20%(P<0.01)。视觉模拟评分(VAS):T组明显小于C组(P<0.01)。T组入镜时间短于C组(P<0.05)。检查过程中:收缩压(SBP)、舒张压(DBP)、心率(HR)C组明显上升(P<0.05或0.01);脑电双频指数(BIS)T组明显降低(P<0.01);血糖C组升高(P<0.05)。T组检查成功率、操作者和患者的满意率均明显高于C组(P<0.01)。结论靶控输注异丙酚-瑞芬太尼用于老年人结肠镜检查能达到良好的清醒镇静镇痛麻醉效果,有效抑制应激反应,稳定血流动力学,缩短入镜时间,提高检查的成功率、患者的耐受性和依从性,是一种安全、有效、可行的麻醉方法。     

国产丙泊酚注射液用于临床麻醉的有效性和安全性探讨

目的评价国产丙泊酚注射液用于临床麻醉的有效性和安全性。方法 80例全麻下行择期手术的患者随机双盲分为2组:试验组(国产丙泊酚组)和对照组(竟安组)各40例。靶控输注丙泊酚,设定血浆靶浓度3μg/mL,至受试者意识消失,然后静脉注射维库溴铵、芬太尼2 min后进行气管插管。靶控输注丙泊酚靶浓度3μg/mL、瑞芬太尼效应室靶浓度4～8 ng/mL和肌松药维持麻醉。麻醉诱导后每5分钟记录血压、心率、BIS。同时记录意识消失时间、意识消失后血浆丙泊酚靶浓度为3μg/mL时的BIS值、辅助用药的种类和剂量、麻醉维持期是否知晓及不良反应。结果试验期间两组最高心率、最低心率、最低血压的差异均无统计学意义(P>0.05)。两组各时点BIS值、意识消失后血浆3μg/mL时BIS均值比较差异无统计学意义(P>0.05)。两组意识消失时间比较差异无统计学意义(P>0.05)。两组术中知晓率均为0。试验组辅用阿托品或麻黄碱的人数少于对照组(P<0.05),但使用总剂量两组间差异无统计学意义(P>0.05)。注射痛、兴奋多语等不良反应发生率两组间比较差异无统计学意义(P>0.05)。结论国产丙泊酚注射液在麻醉深度、意识消失时间、麻醉知晓率及不良反应等方面与进口丙泊酚注射液(竟安)相当,用于临床麻醉安全有效。     

Population pharmacokinetic/pharmacodynamic modeling of clopidogrel in Korean healthy volunteers and stroke patients

Population pharmacokinetic (PK) and pharmacodynamic (PD) modeling of clopidogrel was developed from pooled data from healthy volunteers (n = 44) and stroke patients (n = 35). The PK modeling used plasma concentrations of the clopidogrel metabolite (SR26334), and the PD modeling used platelet aggregation. The models were developed using NONMEM and evaluated via visual predictive check (VPC). Data were analyzed by 2-compartment modeling with Erlang's absorption and first-order elimination. There was no statistically significant covariate for each model parameter. The typical point estimates of PK were k(tr) (identical transfer rate constant) = 5.97 h(-1), k(e) (elimination rate constant) = 0.126 h(-1), k(d) (distribution rate constant) = 0.212 h(-1), V(2) (volume of central compartment) = 21.0 L, and V(3) (volume of peripheral compartment) = 38.8 L. The typical point estimates of PD were k(in) (input rate) = 27.9 h(-1), E(max) (maximum effect on input rate) = 0.292 h(-1), EC(5) (0) (median effective concentration) = 0.00629 ng/mL, and BASE (predose aggregation) = 66.7%. The final model was used to estimate individual parameters using patient data and showed good predictions using VPC.     

右美托咪定对丙泊酚靶控输注意识消失半数有效浓度的影响

目的探讨右美托咪定对丙泊酚靶控输注(TCI)时患者意识消失的半数有效浓度(EC50)的影响。方法择期全身麻醉手术患者40例(ASAⅠ～Ⅱ级),随机分成两组(n=20):右美托咪定组(D组)和对照组(C组)。D组麻醉诱导前经微量泵泵注右美托咪定负荷量0.4μg/kg(15min)静脉输注完毕,然后以0.4μg/(kg·h)维持输注,C组泵注等量生理盐水。麻醉诱导采用丙泊酚TCI,设定起始血浆靶浓度为2.3μg/ml,按相邻浓度比值为1.18序贯法给药,达到设定的血浆靶浓度后进行镇静/警觉评分(OAA/S),后静脉注射舒芬太尼及顺阿曲库铵,纯氧通气3min后气管插管。记录患者静脉输注右美托咪定或生理盐水前(T0),静脉输注15min后(T1),丙泊酚血浆靶浓度达到设定靶浓度时(T2),诱导后插管前(T3),插管后1min(T4)、3min(T5)、5min(T6)各时点的BIS及其MAP、HR。计算并比较D、C组丙泊酚TCI患者意识消失的EC50。结果 D、C组丙泊酚TCI患者意识消失的EC50分别为2.94μg/ml(95%的可信区间为2.79～3.10μg/ml)和3.67μg/ml(95%的可信区间为3.44～3.90μg/ml),D组低于C组(P<0.05)。T1时D组患者BIS值低于C组(P<0.05);T4时C组HR、MAP较T0时均升高(P<0.05)而D组无变化(P>0.05);T1～T6时D组患者的HR均低于C组(P<0.05)。结论右美托咪定以负荷量0.4μg/kg继以0.4μg/(kg·h)维持静脉输注可以使患者产生明显的镇静作用,降低BIS值,减轻气管插管反应,并能使丙泊酚TCI患者意识消失的EC50降低为2.94μg/ml。     

A two-compartment effect site model describes the bispectral index after different rates of propofol infusion

Different estimates of the rate constant for the effect site distribution (k_e0) of propofol, depending on the rate and duration of administration, have been reported. This analysis aimed at finding a more general pharmacodynamic model that could be used when the rate of administration is changed during the treatment. In a cross-over study, 21 healthy volunteers were randomised to receive a 1 min infusion of 2 mg/kg of propofol at one occasion, and a 1 min infusion of 2 mg/kg of propofol immediately followed by a 29 min infusion of 12 mg kg⁻¹ h⁻¹ of propofol at another occasion. Arterial plasma concentrations of propofol were collected up to 4 h after dosing, and BIS was collected before start of infusion and until the subjects were fully awake. The population pharmacokinetic-pharmacodynamic analysis was performed using NONMEM VI. A four-compartment PK model with time-dependent elimination and distribution described the arterial propofol concentrations, and was used as input to the pharmacodynamic model. A standard effect compartment model could not accurately describe the delay in the effects of propofol for both regimens, whereas a two-compartment effect site model significantly improved the predictions. The two-compartment effect site model included a central and a peripheral effect site compartment, possibly representing a distribution within the brain, where the decrease in BIS was linked to the central effect site compartment concentrations through a sigmoidal E_max model.