靜脈麻醉進展新速效短效藥Newerrapidandshort-actingdrugs丙泊酚、依托咪酯、雷米芬太尼新藥代概念New

pharmocokinetic

concepts多室藥代模型應用于臨床長時間輸注后半衰期效應室新給藥系統New

delivery

systems

-

TCI靜脈麻醉藥的時－量相關半衰期藥代學進展－多室模型應用于臨床實際Maintenance

infusion

rate

= CT

×V1×(

k10

+

k12e-

k21t

+

k13e-

k31t

)TCI模型麻醉藥鎮靜鎮痛肌松蘇芬太尼瑞芬太尼MarshArdenGepts

Minto----愛可松-----Szenohradszky丙泊酚依托咪酯TCI兩大貢獻TCI

自動提供計算的血漿藥物濃度

TCI=Intravenous

VaporizerTCI靶濃度滴定藥物作用的治療窗EC50

=

MAC64208100102030Target

Concentration

(μg/ml)TCI-實時血藥濃度非實際血藥濃度缺乏國人的藥代動力學參數臨床研究證明用于國人是可靠的丙泊酚Marsh模型系統誤差為10%-30%min效應室（生物相）v2v3v1注射k13k31k21k12k1eKeoKeo效應室（生物相）BLOOD

-

EFFECT

DELAY10864200102030Target

Concentration

(μg/ml)實時監測呼氣末丙泊酚濃度On-line

monitoring

of

end-tidal

propofol

concentrationReal-time

monitoring

of

propofol

in

expired

air

inhumans

undergoing

total

intravenous

anesthesiaHornuss

C,

Anesthesiol

2007;106:665-74On-line

monitoring

of

end-tidal

propofolconcentration

in

anesthetized

patientsEvan

D

Kharasch, Anesthesiol

2007;106:652-4Shortly

after

the

clinical

introduction

ofpropofol,

the

aroma

noticeableimmediately

upon

opening

the

bottlesuggested

a

sufficiently

high

vaporpressure

to

portend

pulmonary

propofolelimination,

and

hence

the

possibility

ofdetecting

and

quantifying

propofol

inexpired

gas

by

the

mass

spectrometerthen

in

use

in

the

OR.

A

proposal

to

ourOR’s

mass

spectrometer

manufacturer

toinvestigate

this

possibility

was

notreviewed

favorably,

and

the

idea

wassoon

forgotten.Concentration

of

propofol

in

plasma

(ug/ml)藥效學進展TCI靶濃度滴定藥物作用的治療窗EC50

=

MAC丙泊酚意識消失國人與白種人差異–

a

multicenter

clinical

trial(EC05

–

EC95)(3.1

-

7.3)(2.86

-

4.80)(1.5

-

4.1)Cp(μg/ml)Et(μg/ml)BIS白人國人白人國人白人國人EC505.23.832.82.2370.957.9(1.29

-

3.18)(88.8

-

52.9)(77.2

-

39.6)Kenny

GNC.

BJA

2003;90(2):127Xu

ZP,

et

al.

Anesth

Analg

2009;

108(2):478-83藥效：藥物的相互作用藥效：不同目標點藥物相互作用-EC95281004

6藥物B1.0藥

0.9物

0.8A

0.70.60.50.40.30.20.10.095%

noresponse

toverbal

command95%

no

movement

at

skin

incision95%

no

hemodynamic

responseat

skin

incisionIdealClinical

AnesthesiaPK-PD

Models響應曲面模型的應用各種比例下(B/(A+B),兩種藥的同時效應作為一種新藥。每一條實線代表一種“新藥”的藥效學S曲線，由若干條曲線確定一個曲面，這個曲面就是藥物相互作用的響應曲面PK-PD

Models意識消失EC50-EC95范圍消除傷害刺激EC50-EC95范圍兩藥同時應用，自動根據其相互作用計算和顯示各自新的EC50-EC95范圍awake,awarenesstoodeepanesthesiaadequateanesthesiaawake,awarenesstoodeepanesthesiaawake,awarenesstoodeepanesthesiaadequate

anesthesiaSmartPilot白色圓點：計算得到的當前的麻醉深度白色箭頭：計算得到的15分鐘后的麻醉深度SmartPilot

ViewA：MAC

90B：MAC

50C：MAC

awake

（MAC

awake

50）用于吸入麻藥的二維圖

用于靜脈麻藥的二維圖A：TOL

90B：TOL

50C：TOSS

（TOSS

50）閉環控制麻醉Closed-loop

control

of

anesthesiaClosed-loop

systems自動達到和維持預設的靶目標監測變量-導向-控制-生理學/藥理學功能幫助麻醉醫生滴定最佳的給藥劑量防止給藥過量或不足計算機技術/可靠的藥理學作用測定麻醉深度監測仍是難題給藥指標:吸入-MAC靜脈-TCI反饋指標:

BISNarcotrendTOF

-Watch監測：個體差異過量不足殘余作用肌肉松弛程度可以精確監測Ｔ４消失表明阻滯程度達75%

Ｔ３和Ｔ２消失阻滯程度分別達到80%和90%最后Ｔ１消失，表明阻滯程度達到100%如４次顫搐反應都存在則表明阻滯程度不足

75%方法與TOF-watch比較驗證肌松閉環輸注系統監測肌松的準確性30例自身對照每一例病人均同時進行兩種肌松監測

驗證肌松閉環輸注系統麻醉中的有效性和安全性閉環肌松輸注系統羅庫溴銨輸注參數-誘導量為0.6mg/kg，維持輸注速度為0.12mg/kg/h，增藥速度為2mg/kg/h，反饋條件-計數2系統設定當肌松監測達到反饋條件（計數2)連續3次后開始增藥當肌松監測低于反饋條件（計數2）連續2次后則轉為維持速度臨床滿意麻醉－閾值/底線意識-無知曉鎮痛-無傷害性刺激引起的不良(應激)反應肌肉-松弛reduction

inincidence

ofawareness

withrecall(high

risk

patientsp<0.05)11

cases2

casesNo

BISn=1,238BISn=1,22782%1%0.5%0%Myles

PS,

et

al.

Bispectral

index

monitoring

to

prevent

awareness

during

anaesthesia:The

B-Aware

randomised

controlled

trial. Lancet

2004;

363:1757–63首次BIS預防知曉多中心研究:B-AwareEkman

A,

Lindholm

ML,

et

al.

Acta

Anaesthesiol

Scand

2004,48:20–6.77%2

casesBisgroupn=

4945Historicalgroupn=

7826應用BIS監測知曉率由

0.18%（歷史對照）降至

0.04%Anesthesia

Awarenessandthe

BispectralIndex-

The

B-Unaware

Trial0.200.40.610.8B-UNAwareIncidence

(%)Avidan

MS,

et

al.

N

Engl

J

Med

2008,

358:1097-108ETAG

BISn=974

967ETAG組2例知曉BIS組2例知曉BIS-guided

group

(A)Control

group

(B)61

2

3

4

5

6543

4

421

2

21

1

1

1

1

1

10center

center

center

center

center

center

center

center

center

center

center

center

center7

8

9

10

11

12

13CentersFrequencyawareness

frequency

in

Group

A

awarenessfrequency

in

Group

Bconfirmedawareness4

(0.14%）減少77%15

(0.65%)P=0.002possibleawareness4

(0.14%)6

(0.26%)P=0.485dreaming90

(3.1%)71

(3.1%)P=0.986Zhang

C,

etal.

Bispectral

index

monitoringprevent

awareness

during

total

intravenousanaesthesia:

a

prospective,

randomized,

double-blinded,

multicentre

controlled

trial.CMJ

2011,124:3664-95228

cases

/

13

centers監測傷害性刺激指標評價體動心血管反應內分泌反應心率變異性(HRV)TPI

(Tip

PerfusionIndex)SSI

(Surgery

Stress

Index

)末梢灌注指數(TPI)Masimo脈氧血紅蛋白監測儀血管容積波的波形光傳感器末梢血管內通過的血容量大小轉化為電信號-血管容積波經計算機處理后轉化為0-100的指數Analgesia

/

Nociception

Index

(ANI)Mathieu

JEANNE,

MD,

PhDAnesthesia

&

Intensive

CareCic-It

807

InsermUniversity

HospitalLille,

FrancePhysioDoloris:

a

monitoring

device

forAnalgesia

/

Nociception

balanceevaluation

using

Heart

Rate

Variability

analysisExcessAnesthesiaExcessAnesthesiaExcessAnesthesia預防知曉只需簡單加深麻醉？病人無必要去耐受深麻醉！加深麻醉深度將導致其他并發癥過度鎮靜與術后死亡率高有關

BIS<45（深麻醉）術后一年死亡率明顯增加Sub-study證實死亡率與鎮靜狀態關系的報道來自于針對其他目的前瞻性研究數據的追加分析最初設計目的是評估BIS對知曉發生率的影響B-AwareMyles

PS,

et

al. Lancet

2004,363:1757–63B-UnawareAvidan

MS,etal. NEnglJMed2008,

358:1097-108LindholmEkman

A,Lindholm

ML,

et

al. Acta

AnaesthesiolScand2004,48:20–6The

Effect

of

Bispectral

Index

Monitoring

on

Long-TermSurvival

in

the

B-Aware

Trial4.1-yr隨訪BIS監測組-低BIS與預后的關系（對照組未記錄BIS）BIS

<40

for>5

min與其余BIS監測病人比較

hazard

ratio

for

death1.41(95%

CI:

1.02-1.95;

P

<

0.039)odds

ratios

for

MI1.94

(P

<

0.02)for

stroke

3.23

(P

<

0.01)B-Aware亞研究結論理想BIS組的死亡率和發病率明顯較低Leslie

K,

Myles

PS,

et

al.

Anesth

Analg

2010;110:816–22substudy

of

the

B-Aware

trialn

=

4087,

2

yr

follow

upTBIS

<45預測術后1年和2年死亡率hazard

ratio

=1.13

和1.18The

effect

is

very

weak

in

comparison

withASA

IV

=19.3malignancy

status

=9.3age＞80

=2.93Lindholm’s

subsdutyLindholm

et

al.

Anesth

Analg

2009;108:508-12Association

of

perioperative

risk

factors

and

cumulativeduration

of

low

bispectral

index

with

intermediate-termmortality

after

cardiac

surgery

in

the

B-Unaware