全胃肠外营养同时输注对药物体内药动学/药效学的影响及相关不良事件

全胃肠外营养(TPN)同时输注对药物体内药动学/药效学产生影响。在药动学方面,一是TPN通过影响代谢酶功能和活性,进而影响药物在体内的代谢;二是TPN具有高渗透性,同时输注可影响药物在体内的分布。在药效学方面,TPN中的脂肪乳剂可与血浆蛋白竞争性结合,增加某些药物(如丙戊酸钠)的游离浓度;TPN中脂肪乳剂富含维生素K1,可拮抗华法林的抗凝作用。另外,TPN的输注可引起诸多不良反应,如肝损伤、胆汁淤积、肠功能屏障的改变、静脉栓塞及导管相关性感染。因此,TPN同时输注将影响药物在体内的药动学和药效学特性及临床用药安全,对应用TPN的患者应严密监护。     

丙泊酚药物代谢动力学研究概述

丙泊酚（propofol）即2，6-二异丙基苯酚，又名异丙酚，是一速效短效静脉麻醉药。由于其具有起效快、苏醒恢复迅速、持续输注后无蓄积等优点，迅速成为诱导、维持麻醉的首选药，广泛地用于神经外科麻醉、儿科麻醉、监测麻醉和ICU病房的镇静。靶控输注系统（Target-controlled infusion，TCI）以药物代谢动力学为基础，以血浆或效应室的药物浓度为指标，通过计算机程序控制药物输注，以达到按临床需要调节麻醉、镇静和镇痛深度的目的，不但方便而且提高了静脉麻醉的控制水平。近年来，TCI在国内外已成为丙泊酚给药的主要方式，而丙泊酚的药物代谢动力学是TCI的主要理论基础。因此，有必要对近年来国内外丙泊酚药物动力学特点进行研究，以使临床更为精确、安全应用TCI。     

丙泊酚靶控输注准确性的研究进展

靶控输注(Target-controlled infusion,TCI)是一种计算机控制的药物输注技术,是根据药代动力学参数计算维持靶浓度的药物输注速度。丙泊酚TCI广泛用于临床麻醉,可对绝大多数患者进行较为准确的麻醉,但有些情况下TCI系统并不能精准预测实际血药浓度,进而影响医生对实际药物浓度的判断,对患者产生不良影响。结合近年文献,本文就影响丙泊酚TCI准确性的因素做一综合阐述。从药代动力学模型的选择、个体间药代动力学的差异和围术期病理生理改变三个方面阐述对丙泊酚TCI时准确性的影响,以提醒麻醉医生了解到所述情况下患者丙泊酚药代动力学的差异,警惕因TCI给药偏差所带来的不良反应,根据其他监测指标调整丙泊酚用药浓度和用药方案。     

舒芬太尼临床药动学研究及应用

目的 介绍舒芬太尼临床药动学及其在靶控输注中的应用.方法 阐述舒芬太尼血药浓度测定方法,总结近年来舒芬太尼临床药动学研究及其在靶控输注中的应用.结果 舒芬太尼给药后在体内呈一级动力学,常用三室模型描述人体内分布过程.年龄、体重、性别和肝、肾功能对舒芬太尼靶控输注的准确度影响较小.结论 靶控输注系统能精确预测舒芬太尼的血药浓度.     

异丙酚的代谢酶及其肝外代谢概况

异丙酚(Propofol)化学名称为2,6-双异丙基酚,其化学结构与已知任何一类静脉麻醉药均不相同。作为静脉麻醉药,其分布容积大、起效快、可控性好,苏醒迅速而完全,持续输注后无蓄积,为其它静脉麻醉药所无法比拟。现其临床普遍用于麻醉和镇静。通常异丙酚主要在肝脏代谢,但在肝移植无肝期的药动学研究发现其有肝外代谢途径,在无肝期也能维持药动学的稳定[1]。异丙酚的这些优点与其代谢酶在体内的广泛分布及表达密切相关。本文着重将其代谢酶及其肝外代谢情况作一简要综述。1异丙酚的代谢途径异丙酚在体内主要通过2条途径进行代谢[2]:一是经典的…     

新型丙泊酚目标控制输注（TCI）系统性能初步评价

目的建立高效液相色谱电化学法测定血浆丙泊酚浓度,初步评价新型丙泊酚目标控制输注（TCI）系统性能。方法丙泊酚通过装有“Diprifusor’Tc2”系统的Alaris输液泵给药,应用Microsoft Excel 2000软件,分析10例病人血浆丙泊酚浓度的实测值与目标值的相关性。结果63份血浆样品丙泊酚实测浓度与目标浓度执行误差的中位数（MDPE）=-10．75％,执行误差绝对值的中位数（MDAPE）=8．57％,摆动度（MDAPDE）=14．60％。丙泊酚血药实测浓度与目标浓度的相关系数r=0．68。结论HPLC-ECD法测定血浆丙泊酚浓度,方法较简便、准确．灵敏度高．重现性好,适用于临床丙泊酚血药浓度监测及药动学研究。新型丙泊酚目标控制输注（TCI）系统偏离性较小。精密度高。但摆动度偏大．用于国人需优化。     

手术病人丙泊酚的血药浓度测定及靶控输注系统评价

目的:测定全身麻醉手术病人血浆中丙泊酚浓度,分析实测的病人血浆中丙泊酚浓度与靶控输注(target controlled infusion,TCI)系统预测的丙泊酚浓度的相关性,对TCI系统进行评价.方法:选择20例美国麻醉医师协会(ASA)评级为ASA1～ ASA2级的全身麻醉手术病人,TCI系统丙泊酚的诱导浓度为6μg/ml;麻醉维持浓度分别为2.8、3.2、3.5、3.8 μg/ml.HPLC法测定给药后不同时间病人血浆中的丙泊酚浓度.结果:麻醉诱导和维持阶段病人血浆中丙泊酚实测浓度高于靶控输注浓度,停止输注后实测浓度低于靶控输注浓度.TCI系统的偏离度(MDPE)和精密度(MDAPE)分别为6.0％和6.2％.病人脑电双频指数、反应熵和状态熵受麻醉影响明显.结论:TCI系统在麻醉指标监测下,可为临床用药提供参考.     

中药药动学研究现状和研究方向

中药药动学是用来研究中药的活性成分、组分、有效单体及复方体内动态变化过程和规律及体内浓度-时间关系的一门学科，以阐明药物吸收、分布、代谢和排泄过程的动力学特征，并根据数学模型提供重要的药动学参数，为药物的初步筛选、剂型设计、质量评价及给药方案的制订提供依据。临床药动学研究可以指导临床用药。使药物的使用更加安全、有效、经济，同时药动学的研究对复方的组方原理、药物作用机制以及药物相互作用方面都有重要意义。中药药动学研究起步较晚，特别是复方成分复杂，活性成分及其作用机制大多数尚不明确，使药动学研究面临许多困难和问题，促使我们要结合中药作用的特殊性，开创有特色的精密的研究方法，一方面是对药动学研究的丰富；另一方面也为中药作用机制研究提供方法和思路。     

熵指数监测靶控输注丙泊酚麻醉深度的临床应用

根据丙泊酚的药动学特点,以房室模型为基础理论的靶控输注系统已逐渐应用于丙泊酚临床麻醉中。熵指数作为一种新型麻醉深度监测指标,与丙泊酚麻醉深度具有很好的相关性,在临床应用中已受到越来越多的关注。本文简要综述靶控输注及熵指数监测丙泊酚麻醉深度的临床应用。     

败血症对抗菌药物药动学的影响机制及其对个体化用药的指导意义

败血症会改变内环境,从而影响药物药动学行为。本综述从药动学角度出发,总结分析败血症中相关病理生理因素对药物体内吸收,分布,代谢,排泄等药动学环节的影响,并且结合各类抗菌药物自身药动学特点,总结其在败血症患者体内药动学变化及剂量调节相关信息。为败血症治疗中预测抗菌药物药动学行为,合理解释治疗药物监测结果,优化治疗方案提供参考。氨基糖苷类、糖肽类、β-内酰胺类等抗菌药物在败血症患者间或个体内存在较大药动学差异及血药浓度波动,需要个体化剂量调节。万古霉素在败血症无器官衰竭时表观分布容积和清除率增大,需要考虑高于常规给药剂量,具体优化剂量方案尚未定论。     

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。     

Current and future applications of target-controlled infusions

Target-controlled infusions (TCI) aim to provide constant, user-defined blood concentrations of a drug. The infusion device of such a system is controlled by a microprocessor that uses population pharmacokinetic data and the individual patient's weight and age to continuously calculate the required drug infusion rate to replace losses from the blood compartment due to drug distribution and metabolism. This technology has several exciting applications in anesthesia where stable blood concentrations of drugs are of benefit. TCI of propofol for general anesthesia and sedation are now widely used, but the technology is also being extended to the fields of intra- and postoperative analgesia and to patient-maintained sedation and analgesia. Early work on targeting the effect site (brain) is under way and target-controlled propofol infusions are being used in experimental closed-loop anesthesia systems.     

固定或改变目标浓度的普鲁泊福目标控制输注的性能

目的　评价国人应用固定或改变目标血药浓度的普鲁泊福 (异丙酚 )目标控制输注 (TCI)系统的性能。方法　自行编制以药代动力学模型为基础的控制程序 ,使用Marsh的普鲁泊福参数 ,通过佳士比 3 40 0注射泵控制普鲁泊福的静脉给药速度。 2 3例择期手术病人 ,分为A、B两组 ,A组给药过程中固定目标血药浓度 ;B组给药过程中改变目标浓度4次。间断采动脉血 ,HPLC荧光法测定血药浓度。结果　313个血标本的执行误差的中位数 (MDPE) =2 6 % ,执行误差绝对值的中位数 (MDAPE) =2 2 3 % ,分散度 (divergence)= - 1 5 0 %·h-1,摆动度 (wobble) =2 2 5 %。A、B两组间MDPE差异有显著性 (P <0 0 5 )。进一步分析去除血药浓度调高后 5min内的数据 ,则两组MDPE差异无显著性 (P>0 0 5 )。结论　使用Marsh的参数进行普鲁泊福TCI麻醉 ,系统的总体性能较好。给药方案与采血时点对性能分析结果产生影响     

Skeletal muscle kinetics of propofol in anaesthetized sheep: effect of altered muscle blood flow

1. The kinetics of propofol were studied in vivo in a skeletal muscle bed of the hindlimb of the anaesthetized sheep at normal and low rates of blood flow. 2. Propofol kinetics in muscle were determined during and after a 20-min i.v. infusion of propofol (10?mg min^?1) via paired arteriofemoral venous blood sampling. One-and-ahalf hours later, the study was repeated but with a concurrent left femoral artery infusion of adrenaline (0.004?mg min^?1) to lower the muscle blood flow by vasoconstriction. 3. Muscle blood flow in the low flow state was 28% of that in the normal state. The kinetics were poorly described by a single flow-limited compartment model, but were better described by a model with a flow-limited component and a deeper distribution component. There were no significant differences in muscle retention of propofol between normal and low flow states. 4. There was an apparent arteriovenous shunt of ～24% of total muscle blood flow for the low flow state, but not for the normal blood flow state.     

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。     

Use of Target Controlled Infusion to Derive Age and Gender Covariates for Propofol Clearance

BACKGROUND AND OBJECTIVE: Attempts to describe the variability of propofol pharmacokinetics in adults and to derive population covariates have been sparse and limited mainly to experiments based on bolus doses or infusions in healthy volunteers. This study aimed to identify age and gender covariates for propofol when given as an infusion in anaesthetized patients. STUDY DESIGN AND SETTING: One hundred and thirteen patients (American Society of Anesthesiologists class I or II and aged 14-92 years) were anaesthetized for elective surgical procedures with propofol using a target controlled infusion (TCI) system and with alfentanil as a baseline analgesic infusion. Frequent venous blood samples were obtained for measurement of propofol plasma concentrations. PHARMACOKINETIC AND STATISTICAL ANALYSIS: Pharmacokinetic accuracy was determined by the percentage prediction error, bias and precision, as were wobble and divergence. The clearance of propofol from the central compartment was determined for each patient using the computerized record of the infusion profile delivered to each patient, together with relevant blood propofol concentration estimations. For each patient, the nonlinear mixed-effects modelling (NONMEM) objective function was employed to determine the goodness of fit. RESULTS: The population distribution of propofol clearance was subsequently found to have a Gaussian distribution only in the log domain (mean value equivalent to 26.1 mL/kg/min). The distribution in the normal domain was consequently asymmetric, with a slight predominance of patients with high values of clearance (5% and 95% confidence limits 17.7 and 42.1 mL/kg/min, respectively). Using regression analysis, gender and age covariates were derived that optimized the performance of the target controlled infusion system. The clearance (CL) of propofol in male patients changed little with age (CL [mL/kg/min]=26.88-0.029xAge; r2=0.006) whereas that in female patients had a higher initial value but decreased progressively with age (CL [mL/kg/min]=37.87-0.198xAge; r2=0.246). CONCLUSION: We achieved a relatively simple and practical covariate model in which the variability of pharmacokinetics within the study population could be ascribed principally to variability in clearance from the central compartment. Pharmacokinetic simulation predicted an improved performance of the TCI system when employing the derived covariates model, especially in elderly female patients.     

Free and bound propofol concentrations in human cerebrospinal fluid

AIMS: The aim of this study was to define the relationship between unbound propofol concentrations in plasma and total drug concentrations in human cerebrospinal fluid (CSF), and to determine whether propofol exists in the CSF in bound form. METHODS: Forty-three patients (divided into three groups) scheduled for elective intracranial procedures and anaesthetized by propofol target control infusion (TCI) were studied. Blood and CSF samples (taken from the radial artery, and the intraventricular drainage, respectively) from group I (17 patients) were used to investigate the relationship between unbound propofol concentration in plasma and total concentration of the drug in CSF. CSF samples taken from group II (18 patients) were used to confirm the presence of the bound form of propofol in this fluid. The CSF and blood samples taken from group III (eight patients) were used to monitor the course of free and bound CSF propofol concentrations during anaesthesia. RESULTS: For group I patients the mean (and 95% confidence interval) total plasma propofol concentration was 6113 (4971, 7255) ng ml(-1), the mean free propofol concentration in plasma was 63 (42, 84) ng ml(-1), and the mean total propofol concentration in CSF was 96 (76, 116) ng ml(-1) (P < 0.05 for the difference between the last two values). For group II patients the fraction of free propofol in CSF was 31 (26, 37)%. For group III patients the fraction of free propofol in CSF during TCI was almost constant (about 36%). CONCLUSIONS: The unbound propofol concentration in plasma was not equal to its total concentration in CSF and cannot be directly related to the drug concentration in the brain. Binding of propofol to components of the CSF may be an additional mechanism regulating the transport of the drug from blood into CSF.     

Assessing circadian rhythms in propofol PK and PD during prolonged infusion in ICU patients

This study evaluates possible circadian rhythms during prolonged propofol infusion in patients in the intensive care unit. Eleven patients were sedated with a constant propofol infusion. The blood samples for the propofol assay were collected every hour during the second day, the third day, and after the termination of the propofol infusion. Values of electroencephalographic bispectral index (BIS), arterial blood pressure, heart rate, blood oxygen saturation and body temperature were recorded every hour at the blood collection time points. A two-compartment model was used to describe propofol pharmacokinetics. Typical values of the central and peripheral volume of distribution and inter-compartmental clearance were V _C  = 27.7 l, V _T  = 801 l, and CL _D  = 2.73 l/min. The systolic blood pressure (SBP) was found to influence the propofol metabolic clearance according to Cl (l/min) = 2.65·(1 − 0.00714·(SBP − 135)). There was no significant circadian rhythm detected with respect to propofol pharmacokinetics. The BIS score was assessed as a direct effect model with EC ₅₀ equal 1.98 mg/l. There was no significant circadian rhythm detected within the BIS scores. We concluded that the light–dark cycle did not influence propofol pharmacokinetics and pharmacodynamics in intensive care units patients. The lack of night–day differences was also noted for systolic blood pressure, diastolic blood pressure and blood oxygenation. Circadian rhythms were detected for heart rate and body temperature, however they were severely disturbed from the pattern of healthy patients.     

Target-controlled infusion systems: role in anaesthesia and analgesia

Drug delivery by target-controlled infusion (TCI) allows automatic adjustments of the infusion rate of a drug to maintain a desired target concentration. Since drug effect is more closely related to blood concentration than to infusion rate, drug delivery via TCI is capable of creating stable blood concentrations of intravenous anaesthetics and analgesics. In this article the concept and history of TCI are described. The rational administration of TCI requires an appropriate pharmacokinetic data set and knowledge of the concentration-effect relationship; therefore, general pharmacokinetic and pharmacodynamic aspects of intravenous anaesthetics and analgesics are also addressed. Intraoperative investigations have demonstrated that TCI drug delivery allows rapid titration to a desired effect. The use of TCI for postoperative analgesia is still experimental, but TCI can, in part, overcome the disadvantages associated with continuous infusions and patient-controlled analgesia regimens in the postoperative period. Although TCI is capable of creating stable blood concentrations, when the target concentration is changed the resulting effect correlates better with a theoretical effect site concentration. The efficacy of TCI systems that can perform effect-site steering are still to be explored.