理想麻醉药

麻醉医生的梦想：理想麻醉药 许多年以前，我们的先人就在振臂高喊： I HAVE A DREAM- 几百年的努力，理想麻醉药是否已找到？ -GOLY GRAIL? 不管结果如何 Nevertheless, we confidently continues to anaesthetise patients. 1.到目前为止，我们是否已经找到了理想 的麻醉药静脉或者吸入麻醉药？ 2.我们是否仍然在努力寻找 ? 3.理想麻醉药的主要特性是什么 ? 理想麻醉药的主要特征 理想麻醉药的主要特征 Pharmacodynamics Short onset and offset. rapid transfer from plasma to effect-site . Constant context-sensitive half-life, whatever the duration of anaesthesia Minimal inter-individual variability Depth of anesthesia correlated with dose (i.e, effect-site Concentration) Linear relationship between depth of anesthesia and concentration 理想麻醉药的主要特征 理想麻醉药的主要特征 麻醉方法的选择： 全凭静脉麻醉（ TIVA)？ 吸入麻醉？ 静吸复合麻醉？ ？ 谁是主导全身麻醉药的主流？ 吸入麻醉药？ 静脉麻醉药？ combination 千佛山医院 麻醉科 n 麻醉污染 n 麻醉诱导慢、苏醒期烦躁 n 对麻醉医生自身影响生育能力和下一代等 n 循环抑制 n 术后恶心呕吐 n 如无静脉通路，麻醉诱导困难 n 气道刺激 n 恶性高热 n 等等 选静脉！ 几个担心： V I M A olatile nduction a2=a20+(k12*a10)- (k21*a20)*dt; a3=a30+(k13*a10)- (k31*a30)*dt; ct=a1/vc; MAINTENANC E 12 - 10 -8 10 -8 -6 X - Y - Z C3C1C2 Target U=(VC*TARGET*K10)+(VC*TAR GET*K13)-(K31*A30)*(EX*(- K31*T) U=U+(VC*TARGET*K12)- (K21*A20)*(EX*(-K21*T) A1=TARGET*VC A2=(A20*(EX*(- K21*T)+(K12*A1)/K21)*(1-EX*( -K21*T) A3=(A30*(EX*(- K31*T)+(K13*A1)/K31)*(1-EX*( -K31*T) C3C2 DECREASE ? zaa=(k21- alpha)*(k31- alpha)*a10; zaa=zaa/(da*( ke0-alpha); zaa=zaa*(exp (-alpha*t); zab=(k21- beta)*(k31- beta)*a10; zab=zab/(db*( ke0-beta); zab=zab*(exp (-beta*t); zap=(k21- py)*(k31- py)*a10; zap=zap/(d_p *(ke0-py); zap=zap*(exp (-py*t); zak=(k21- ke0)*(k31- ke0)*a10; dk=(alpha- ke0)*(beta- ke0)*(py-ke0); zak=zak/(dk); zak=zak*(exp( -ke0*t); zz1=zaa+zab +zap+zak; /* */ zba=q*(k21- alpha)*(k31- alpha); zba=zba/(- alpha)*(ke0- alpha)*da); xxa=zba; zba=zba*(exp (-alpha*t); zbb=q*(k21- beta)*(k31- beta); zbb=zbb/(- beta)*(ke0- beta)*db); xxb=zbb; zbb=zbb*(exp (-beta*t); zbp=q*(k21- py)*(k31-py); zbp=zbp/(- py)*(ke0- py)*d_p); xxp=zbp; zbp=zbp*(exp (-py*t); zbk=q*(k21- ke0)*(k31- ke0); zbk=zbk/(- ke0)*dk); Target C1 = 1/3 PHARMACOKINETICS ! Conc = C1.e-a.t + C2. e-b.t + C3.e-p.t k10, k12, k13, ke0, k21, k31 a1=a10+(k21*a20)+(k31*a30)+q- (e*a10)*dt; a2=a20+(k12*a10)- (k21*a20)*dt; a3=a30+(k13*a10)- (k31*a30)*dt; ct=a1/vc; PHARMACOKINETICS ! Conc = C1.e-a.t + C2. e-b.t + C3.e-p.t k10, k12, k13, ke0, k21, k31 a1=a10+(k21*a20)+(k31*a30)+q- (e*a10)*dt; a2=a20+(k12*a10)- (k21*a20)*dt; a3=a30+(k13*a10)- (k31*a30)*dt; ct=a1/vc; 1 X MANUAL INFUSION REGIMENS FOR PROPOFOL De Grood et al, 1987 Manara et al, 1991 Herregoods et al, 1988 Parma et al, 1990 Cammardella et al, 1990 Price et al, 1988 Du Cailar et al, 1988 Schttler et al, 1988 Ewalenko et al, 1988 Troilo et al, 1990 Steegers & Foster, 1988 Guit et al, 1991 Roberts et al, 1988 Stokes & Hutton, 1991 Bolus + Infusion 2nd Bolus + Change Infusion Infusion Off Infusion On BOLUS药物分布特性 TCI的应用标志者一个梦想的实现， 同时也要求麻醉科医生观念的转变 对药代 -药效 动力学基本原理的深入理解，从根 据经验性的临床用药转换到 TCI的临床应用，需要临床 医生观念的转换。这种观念的转换代表着一种革命， 类似于在过去 20年中麻醉科医师应用高科技的监护设 备来替代血压计袖带和用手触摸脉搏。 靶控输注 （ Target Controlled Infusion， TCI） 丙泊酚 （ propofol） 及瑞芬太尼 （ remifentanil） 等超 短效的静脉麻醉药或麻醉性镇痛药的出现，大大提高 了静脉麻醉的可控性，促进了靶控输注技术的快速发 展。通过利用靶控输注装置，麻醉医生可以较容易地 随时调整静脉麻醉药的血药浓度，保证相对稳定、可 控的麻醉状态，并能够预测病人停止给药后的苏醒时 间，特别适用于外科日间手术（ day case surgery） 的开展。 靶 控 输 注 Target-controlled Infusion bolus血浆药物浓度 时 间 靶控输注 ， 药代动力学模型 ： 靶控效应室 靶控中央室 靶 控 输 注 Target-controlled Infusion 靶 控 输 注 开环泵注 （ Open-loop Infusion） l 闭环泵注 （ Closed-loop Infusion） 按 “剂量 ”给药改为按 “浓度 ”给药 迅速、准确达到靶浓度 及时调整靶浓度及麻醉深度 用药量小、可控性好 麻醉诱导、维持平稳、苏醒快 可保留自主呼吸 术后并发症少 优势 靶 控 输 注 Target-controlled Infusion 丙泊酚靶控输注技术 Diprifusor 丙泊酚的研发简史丙泊酚的研发简史 1974年合成年合成 1981年改用大豆油乳剂作为赋形剂年改用大豆油乳剂作为赋形剂 1986年在全球正式上市年在全球正式上市 1994年正式在中国上市年正式在中国上市 1996年，得普利麻靶控（年，得普利麻靶控（ Prefilled syringe， PFS） 给药技术在全球上市给药技术在全球上市 1996年，得普利麻抗菌配方在全球上市，并且在全球取得了专利年，得普利麻抗菌配方在全球上市，并且在全球取得了专利 ，使得普利麻在长期静脉输注中的安全性更进一步得到提高，尤其，使得普利麻在长期静脉输注中的安全性更进一步得到提高，尤其 是在是在 ICU和其他的镇静中。和其他的镇静中。 l The first commercially available TCI system l Developed to further enhance the convenience and control of IV anaesthesia with Diprivan (propofol) l Designed to be as convenient to use as a vaporizer l Incorporated in syringe pumps from major manufacturers What is Diprifusor? Target Controlled Infusion (TCI) of Diprivan Pharmacokinetic properties of Diprivan (propofol) Open, three-compartment model Effect compartment Central compartment 1 V1 Elimination k10 k12 k21 Second compartment 2 k13 k31 Third compartment 3 keo Drug equilibrates between and within compartments Intravenous infusion k1e Pharmacokinetic parameters for Diprivan (propofol) Incorporated in Diprifusor TCI Software* V1 Volume of central compartment 228 ml kg1 Elimination rate constant from the central compartment k10 0.119 min1 1 1 1 Intercompartmental distribution rate constants 0.114 min 0.055 min 0.0419 min k12 k21 k13 k31 0.0033 min 1 1 * University of Glasgow ke0 0.26 minElimination rate constant from the effect compartment Basic rationale To enable the anaesthetist to alter the depth of anaesthesia in as simple a manner as using standard volatile anaesthetics delivered via calibrated vaporizers Why TCI? Target Controlled Infusion of IV anaesthetic agent l CATIA Computer Assisted Total Intravenous Anaesthesia l TIAC Titration of Intravenous Agents by Computer l CACI Computer Assisted Continuous Infusion l CCIP Computer Controlled Infusion Pump l TCI Target Controlled Infusion TCI is now used as a broader term for continuous control of blood concentration of infused drug Acronyms for basic concept Pharmacokinetic model + computer to control infusion pump Instead of calculating doses in mg/kg/h . the anaesthetist enters: l Body weight of the patient l Age of the patient l Required blood concentration of drug (= target blood concentration in g/ml) What does TCI involve? Microprocessor (= computer) manages the infusion pump l Pharmacokinetics a validated model with specific parameters for drug l Algorithm(s) to control infusion rate l “Control unit” i.e. software and microprocessors for above l Infusion pump l “Communication” system between “control unit” and infusion pump l User interface for input of patient data and target blood concentration Key components of any TCI system Basic software and hardware TCI is an infusion system which allows the anaesthetist to select the target blood concentration required for a particular effect and then to control depth of anaesthesia by adjusting the requested target concentration TCI is not a system for the complete computer control of anaesthesia Defining TCI When applied to anaesthesia Convenience in use l Simple to operate l Easy to titrate the level of anaesthesia l Displays calculated blood or plasma concentrations l Compensates for interrupted infusion l Avoids the need for time-consuming calculations l Continuous process from induction through to maintenance Benefits of TCI Practical aspects Control of anaesthesia l Good control of depth of anaesthesia l Gives stable anaesthesia l Improved control of cardiovascular and respiratory parameters l Induction phase can be used to predict maintenance effects Benefits of TCI Theoretical aspects Prototype Diprifusor TCI system l University of Glasgow, UK (GNC Kenny and colleagues) Other prototype TCI systems for Diprivan l CACI (computer-assisted continuous infusion, Duke University, USA) l STANPUMP (S Shafer, Stanford, USA) l STELPUMP (JF Coetzee, University of Stellenbosch, South Africa) l J Schttler (Bonn, Germany) l RM Tackley (Bristol, UK) l FHM Engbers (Leiden, Holland) Prototype TCI systems for Diprivan Developed in