Cisatracurium 2006

Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)

Perché il cisatracurium:Nimbex

Claudio Mellonil.p.

Già Direttore UO Anestesia e Rianimazione Ospedale di Faenza


Problemi di sicurezza dei miorilassanti

Fast onset

Fast offset

No blocco residuoEvita antagonismo

No metaboliti attivi

Mancanza effetti collaterali

Profilodi

sicurezza

Facile conservabilità e

Valutazione rischio/beneficio

No blocco residuo

No metaboliti attivi

No liberazione di istamina;no effetti emodinamici

Evita antagonismo

Facile conservabilità/utilizzo

Indipendenza da organi sicurezza


Dinamica


T1 5% T1 25%

T1 75%

Tempo dalla iniezione


RI,ossia recovery index...:min

0102030405060708090

100

%

T1/TC5

T1/tc25

T1/tc75

T1/TC95

RI 5-25

RI 25-75

RI 5-95


2*ED95 dei principali miorilassanti

farmaco Dose(mg/kg)Succinilcolina 1,0

Rocuronium 0,6

Vecuronium 0,1

Atracurium 0,5

Mivacurium 0,2

Cisatracurium 0,1


onset del cisatracurium

0.00

1.12

2.24

3.36

4.48

6.00

7.12

onset

0.05 mg/kg0.1 mg/kg0.1 mg/kg bambini0.2 mg/kg0.4 mg/kg


Onset(sec) e durate(min) dei principali miorilassantia 2*ED95.

0.0

50.0

100.0

150.0

200.0

250.0

300.0

350.0

onset dur T1 25% R 25-75%

succinilcolinarocuroniumvecuroniumatracuriummivacuriumcisatracurium


Farmacodinamica del cisatracurium(Sorooshian,Anesthesiology 1996)

0

20

40

60

80

100

120

onset T1 25% T1 75% RI 25-75%

2 mg:giov2 mg anzi4 mg giov4 mg anzia6 mg giov6 mg anzia8 mg giov8 mg anzia10 mg giov10 mg anzia

min


Farmacodinamica del cisatracurium

0

20

40

60

80

100

120

140

t125% T195% T4/T1>70% RI25-75% RI5-95%

dati da Belmont(A.,1995,82,1139)

0.1 mg/kg

0.2 mg/kg

0.4 mg/kg

inf cont

min


Dati da Bluestein Bluestein LS,Stinson L W, Lennon R L ,Quessy S N.,Wilson

RM. Evaluation of cisatracurium, a new neuromuscular blocking agent, for tracheal intubation. CAN J ANAESTH 1996 / 43: 9 / pp925-31

0

10

20

30

40

50

60

70

min

t125% RI25-75% onset Tof 0.70 doporeversal

0.1 mg/kg

0.15 mg/kg

0.2 mg/kg

N2O,propofol,fentanyl


Farmacodinamica del cisatracurium nell’anziano(Ornstein et al,Anesthesiology,1996,84,520)

0

10

20

30

40

50

60

70

80

90

onset t1 5% T1 25% T1 75% T1 95% TOF 70

anziani

giovani

*


Imbeault K, Withington DE, Varin F. Pharmacokinetics and pharmacodynamics of a 0.1 mg/kg dose of cisatracurium besylate in children duringN2O/O2/propofol anesthesia.Anesth Analg. 2006 Mar;102(3):738-43

05

101520253035404550

min

onset T1 25% T1 75% RI 25-75%

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tempi di ripresa 25-75%

0

2

4

6

8

10

12

14

16

18

RI 25-75%

cisatr

vecu

rocu

atrac

miva inf


Tempi di ripresa al T1 25% in pazienti anziani dopo 2ED95 di

cisatracurium,vecuronium,rocuronium.da Arain SR,Kern S, Ficke DJ, Ebert TJ. Variability of duration of action of neuromuscular-blocking drugs in elderly patients. Acta Anaesthesiol Scand. 2005 Mar;49(3):312-5.

0

20

40

60

80

100

120

140

160

cis rocu vecu

min

max

min

variabilità mediana

Preop midazolam 1 mginduction 5 mg kg(-1) TPS

+2 microg kg(-1) fent. 0.6 mg kg(-1) rocuronium, 0.1 mg kg(-1) vecuronium

or 0.1 mg kg(-1) cisatracurium. maintenance sevoflurane in O2/N2O

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Cinetica


Tran TV,Fiset P, Varin F.Pharmacokinetics and pharmacodynamics of cisatracurium after a short infusion under propofol anesthesia.Anesth.Analg 1998;57:1158

3.7

118

24

0

20

40

60

80

100

120

Cl ml/kg/minV1Vss ml/kgT 1/2 min


Farmacocinetica del cisatracurium nell’anziano(Ornstein et al,Anesthesiology,1996,84,520)

5 4.6

57.857.2

126

108

25.521.5

0

20

40

60

80

100

120

140

Clp V1 Vss T 1/2 beta

anzianigiovani

*

*


Farmacocinetica del cisatracurium nell’anziano(Sorooshian et al,Anesthesiology,1996)

319319

47.6 4713.39.7

36.328.4

0

50

100

150

200

250

300

350

Clp ml/min V1 lt Vss lt T 1/2 betamin

anzianigiovani


dati farmacocinetici del cisatracurium nel bambino e nell'adulto:dati da Tan e Sorooshian (giovani) per gli adulti e Imbeault per i bambini

0,0

20,0

40,0

60,0

80,0

100,0

120,0

140,0

160,0

bambino adulto Tan adultoSorooshian

Clml/kg/min

V1 ml/kg

Vssml/kg

EC 50 micr/ml

t 1/2

*

*

*


Antagonizzazione


Kirkegaard H,Heier T,Caldwell JE Efficacy of tactile guided reversal from cisatracurium induced neuromuscular block.Anesthesiology 2002;96:45-50

� Anest with fent/prop/N2O� cisatrac 0.15 mg/kg� neostigmine 0.07 mg/kg administered at

reappearance of I,II,III,IV of TOF;tactile vs Meccanomyography contralateral.


Time from neostigmine administration to TOFR 0.70

0.00

5.00

10.00

15.00

20.00

25.00

I twitch II twitch III twitch IV twitch

lowmaxminmediana



0

5

10

15

20

25

30

35


lowmaxminmediana



0

10

20

30

40

50

60

70

80


lowmaxminmediana


Kirkegaard H,Heier T,Caldwell JE Efficacy of tactile guided reversal from cisatracurium induced neuromuscular block.Anesthesiology 2002;96:45-50

� This study shows that achieving a TOFR of 0.90 in <10 min following neostigmine reversal is not a realistic goal;therefore counting the number of tactile responses to tof stimulation cannot be used as a guide for neostigmine admninistration if the end point of reversal is a TOFR of 0.90 or higher within

10 min;but is a good predictor of TOFR 0.70.


MMG magnitude of the first TOF twitch(T1) measured at the reappearance of each of the 4 tactile TOF responses.

0

10

20

30

40

50

60

70

80


T1

%

lowmaxminmediana


Correlazione soggettiva-oggettiva(palpazione-meccanomiografia)

� 1 Twitch= T110%

� 3 twitches=T1 25%


� Poiché è noto fin dagli anni ’70 che un TOF di 0.70 è sufficiente per una ventilazione spontanea,tanto ci basta !

� Nessuno poi deve cessare immediatamente la sorveglianza del paziente….

� Non si fa così anche con la TIVA/TCI???


non cumulatività del cisatracurium Belmont

MR,Lien CA,Quessy S,Abou-Donia MM,Abalos A,Eppich L,Savarese JJ.The clinical neuromuscular pharmacology of 51W89 in patients receiving nitrous oxide/opioid /barbiturate anesthesia.Anesthesiology

1995;82:1139-45.

0

5

10

15

20

25

I II III IV V VI VII VIII IX X

Intervallo in min fra le dosi refratte o velocità medie di infusione per un blocco del 95%

dosi ripinf cont

min

microgr/kg/min


Belmont MR,Lien CA,Quessy S,Abou-Donia MM,Abalos A,Eppich L,Savarese JJ.The clinical neuromuscular pharmacology of 51W89 in patients receiving nitrous oxide/opioid /barbiturate anesthesia.Anesthesiology 1995;82:1139-45.


Belmont et al. The clinical neuromuscular pharmacology of 51W89 in patients receiving nitrous oxide/opioid /barbiturate anesthesia.Anesthesiology 1995;82:1139-45.


Cisatracurium e insufficienze d’organo


De Wolf AM.,Freeman JA, Scott VL,Tullock W,Smith DA,Kisor DF, Kerls S,Cook,DR. Pharmacokinetics and pharmacodynamics of cisatracurium in patients with end-stage liver disease undergoing liver transplantation. Br. J. Anaesth. 1996; 76:624-628

020406080

100120140160180200

Vd ml/kg Clp ml/kg/min T 1/2 min T1 25 RI 25-75 Peaklaudanosine

conc

ng/ml

liver transplnormal


farmacodinamica del rocuronium nei cirrotici(da Boyd et al,Bja,1994,73,262p)

0

20

40

60

80

100

120

140

T110% T125% T175% RI25-75%

Tof70

rocu 0.6 mg/kg,isoflurane 0.6%

sanicirrotici

min

*


Repeated doses of rocuronium in cirrhotic and control patients receiving isoflurane(Servin et al.,Anesthesiology,1996,84,)1092

05

101520253035404550

T1 25%a 75

microgr

T1 25%150

micrg

T1 25%225

micrg

T1 90% TOF70%

RI 25-75%

cirroticinormali

min


Mivacurium e insufficienza epatica

0

10

20

30

40

50

t15% t110% t125% t150% t175% tof70% RI25-75%

dati da Devlin et al.,BJA,1993

normcirrotici


Rocuronium nella insuff renale ed epatica

010

2030

4050

6070

80

t1/tc25% t1/tc50% t1/tc75% t1/tc90% RI25-75% R125-75%

dati da Magorian,Khalil e Szenohradsky

normali

insuff ren

insuff epati

min


Variazioni % dei tempi di ripresa dei miorilassanti nella insuff.epatica dati medi da diverse ref:bibliografiche

0

10

20

30

40

50

60

aum

ento

%

T 1 25 T1 90 RI 25-75

rocu ins epatrocu cirrosivecuatraccisatracmivac


Cisatracurium in ICU


Ripresa neuromuscolare dopo infusione prolungata in ICU:da Prielipp et al.

cisatracurium vecuronium

Recovery time after discontinuation:min to tof 0.70

68 +/- 13 min. 387 +/- 163 min,

Prolonged paralysis:patients

2 13


Ripresa neuromuscolare in ICU dopo infusione di miorilassanti in neonati sottoposti a chirurgia cardiaca;da

Reich e coll


Time to no fade in TOFR:min

30 180

Prolonged paralysis:patients

0 3


Infusion of muscle relaxants in critically ill children requiring mechanical ventilation in ICU,da Burmester


Time to recovery,min

(52 ,range 35-73) than with

123 ,range , 80-480).

Prolonged recovery of neuromuscular function (>24 h)

0 1


Effetti emodinamici


Wastila WB,Maehr RB The pharmacological profile of 51w89,the R cis-R’ cis isomer of atracurium in cats.Anesthesiology 1993;79,abstract A 946.

0

5

10

15

20

25

30

ID50 vagal/nmED95

cisatracatracvecu


Belmont et al.Comparative pharmacology of atracurium and one of its isomers 51w89 in rhesus monkeys.Anesthesiology 1993;79:Abstract A 947.

024

68

1012

1416

1820

% HR % MAP

cisatracatrac

Variazioni % rispetto al basale fino a 14 ED95

2 animali con

flushin

g


Lien CA,Belmont MR,Abalos A,Eppich L,Quesny S,Abou-Donia MM,Savarese J. The cardiovascular effects and histamine releasing properties of 51W 89 in patients receiving nitrous oxide-opioid/ barbiturate anesthesia.Anesthesiology 1995;82:1131-38.

� ASA 1 & 2� anest:midaz/fent/tps� iot senza miorilass� campionamento sangue venoso + monitoraggio

intraarterioso continuo per PA.� SIu8 Grass 0.15 Hz,ST,meccanomiografia� boli in 5 sec di cis: 2 ED5,4 Ed95,8 Ed95


Lien CA,Belmont MR,Abalos A,Eppich L,Quesny S,Abou-Donia MM,Savarese J. The cardiovascular effects and histamine releasing properties of 51W 89 in patients receiving nitrous oxide-opioid/ barbiturate anesthesia.Anesthesiology 1995;82:1131-38.


Reich DL, Mulier J, Viby-Mogensen J, Konstadt SN,van Aken HK,Jensen FS,De Perio M, Buckley S. Comparison of the cardiovascular effects of cisatracurium and vecuronium in patients with coronary artery disease .Can J Anaesth 1998 / 45 / 794-797

� cisatracurium, 0.20 mg×kg-1 (4 x ED95)� cisatracurium, 0.30 mg×k-1 (6 x ED95)� vecuronium, 0.30 mg×kg-1 (6 x ED95) � cisatracurium, 0.40 mg×kg-1(8 x ED95) � vecuronium. 0.30 mg×kg-1 (6 x ED95)� . The haemodynamic measurements were repeated at 2,

5, and 10 min after cisatracurium or vecuronium. � The haemodynamic changes from pre- to post-

injection in the cisatracurium patients were minimal and similar to patients receiving vecuronium.


No HR/BP changes

HR or BP changes requiring drug treatment

Haemodynamic stability after initial dose(Puhringer et al)

cisatracurium0.15 mg/kg

vecuronium0.1 mg/kg

4.1%0%

n = 137 n = 140


Liberazione di istamina


Lien et al. The cardiovascular effects and histamine releasing properties of 51W 89 in patients receiving nitrous oxide-opioid/barbiturate anesthesia. Anesthesiology 1995;82:1131-38


Schramm WM,Papousek A,Michalek-Sauberer A, Czech T,Illievich U. The Cerebral and Cardiovascular Effects of Cisatracurium and Atracurium in Neurosurgical Patients .

Anesth Analg 1998; 86:123–7

� Paz ICU sedati,intub e ventilati

� Cis 0.15 mg/kg vs atrac 0.75 mg/kg

� Effetti NCh scomparsi dopo rimoss dallo studio dei 5 paz con evidente flush cutaneo


Schramm WM,Papousek A,Michalek-Sauberer A, Czech T,Illievich U. The Cerebral and Cardiovascular Effects of Cisatracurium and Atracurium in Neurosurgical Patients . Anesth Analg 1998; 86:123–7

-20

-15

-10

-5

0

ICP CPP CBFV MAP HR

Cis

atra

c Atr

ac

Cisatrac

Atrac

²

Transcranial Doppler


Quoziente di sicurezza:ED95 istaminoliberatrice/ED95 blocco nm.

0

1

2

3

4

5

6

7

8

safety factor

Dtcmetocatracmivaccisatrac

??


Reazioni allergiche attribuite ai miorilassanti in %;da Laxenaire MCEpidemiology of anesthetic anaphylactoid reactions. Fourth multicenter survey (July 1994-

December 1996)]Ann Fr Anesth Reanim. 1999 Aug;18(7):796-809.

0,00

5,00

10,00

15,00

20,00

25,00

30,00

%

reaz allergiche

cisatracuriumatracuriummivacuriumpancuroniumvecuroniumrocuroniumsuccinilcolina

69.2% delle 477 reazioni allergiche durante anestesia

in Francia

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Strategie per attenuazione della liberazione di istamina

� Iniezione lenta (30 sec);� Pretrattamento con antiistaminici…..


Struttura chimica del besilato di cisatracurium(Nimbex)


Livelli plasmatici di laudanosina(Eastwood,NB,Boyd

AH,Parker cir,Hunter,JM.Pharmacokinetics of 1r-cis1’rcis atracurium besylate(51W89)and plasma laudanosine concentrations in health and chronic renal failure ,BJA 1995,75.431-5.

Fahey MR,Rupp SM,Canfell C,Mier RD,Sharma M,Castagnoli K,Hennis PJ.Effect of renal failure on laudanosine excretion in man.BJA 1995;57:1049-51)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

sani insuff ren

atrac

cis


Chapple DJ, Miller AA, Ward JB, Wheatley PL: Cardiovascular and neurological effects of laudanosine, BrJ Anaesth 1987; 59:218-25

� Topi:dosi di laudanosina > 15 mg/kg →convulsioni� ratti:dosi > 14 mg/kg → convulsioni in tutti:nel 66% a

10 mg/kg,prevenute da prettrattamento con diaz (34 mg/kg)(ED 50 2 mg/kg)

� cani coscienti:boli di 2 e 4 mg/kg→ » agitaz(liv plasm 0.88+-0.16 µg /kg;1 salivaz,1 si

lecca di labbra;Hr aum di 41 bpm» liv.plasm di 1-1.4 µg /ml:,no effetti comportamentali,ma

Hr aum.



� Inf cont di laudanosina in cani anestetizzati(haloth):a 10-17µg/ml di conc plasma ,attività epilettogena in tutti all’EEG:

� HR ↑ poi↓ e BP↓� in tutti i cani l’attività epilettogena EEG

cessa dopo diaz i.v



Aum.ampiezza e frequenza EEG

Ch onde appuntite(spiking) e rapide

Spikes,polispikes,bursts parossisticiè+ mioclonie

Convulsioni cloniche


CIsatracurium nell’anziano

Vantaggi a confronto del vecuronium


Spontaneous Complete Recovery Time

0

10

20

30

40

50

60

70

80

90

25%

T1 -

TO

F r

ati

o > 0

.8 (

min

)


18 - 64 years > 65 years

p < 0.001


5665 6365N =

Time Interval final 25%T1 to Tof Ratio >=0.8

Treatment

VecuroniumNimbex

min

ute

s

140

120

100

80

60

40

20

0

Age Category

<65

>=65

Variance in SCRT


Clinical Duration of Block

0

10

20

30

40

50

60

70

Tim

e t

o 2

5%

T 1 (m

in)

cisatracurium0.15 mg/kg

vecuronium0.1 mg/kg

18 - 64 years > 65 years

p < 0.001


Potenziamento :da parte dei vapori anestetici,terapia anticonvulsivante


Richard A, Girard F, Girard DC, Boudreault D, Chouinard P, Moumdjian R, Bouthilier A, Ruel M, Couture J, Varin F. Cisatracurium-induced neuromuscular blockade is affected by chronic phenytoin or carbamazepine treatment in neurosurgical patients.Anesth Analg. 2005 Feb;100(2):538-44.

» La terapia anticonvulsivante cronica con carbamazepina e fenitoina aumenta del 44% la necessità di cis per mantenere costante un blocco del 95%

» Aumenta la CL 7.12 vs 5.72 lt/kg » Aumenta la Cp(ss)95 :191 +/- 45 versus 159 +/- 36

ng/mL, P = 0.04)» Insomma, i paz in terapia anticonvulsivante cronica

necessitano di dosi maggiori a parità di profondità di blocco,ossia hanno una ripresa più rapida,ossia risultano più resistenti al cisatracurium

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Wulf,H,Kahl,M,Ledowski,T.Augmentation of the neuromuscular blocking effects of cisatracurium during desflurane,sevoflurane,isoflurane or total i.v.anesthesia.British Journal of Anesthesia 1998,80:308-312.

� 84 paz,18-65 anni,ASA 1 & 2� procedure elettive minori extraddominali ed

extratoraciche� anestesia a 1.5 MAC(DES 4.2%,SEVO 1.05%,ISO

0.75%)+N2O 70%. Vs TIVA Propofol/fentanil.� Monitoraggio neuromuscolare: Tof Guard con Tof

ogni 12 sec � dosi cumulative di cisatracurium 15 µg/kg fino a T1

5%.quando equilibrio fra Fi/Fe del vapore


Risultati dello studio di Wulf et al.

0%10%20%30%40%50%60%70%80%90%

100%

depressione % di T1

15 mu/kg 30 mu/kg 45 mu/kg

dosi di cisatracurium

DESISOSEVOTIVA

*

**


Durate cliniche del cisatracurium

0

5

10

15

20

25

30

35

40

45

min

T125% RI25-75% TOF0.70

DESISOSEVOTIVA

**

* *


Diagramma Log-probit delle curve dose-risposta del cisatracurium e depressione del T1/T0 % :confronto fra 1.5 Mac di DES,ISO,SEVO e tiva (Wulf ).

10

100

15 30 45

microgr/kg di cisatracurium

depressione

T1/T0%

DESISSEVOTIVA


: Turan G, Dincer E, Ozgultekm A, Akgun N.R Recovery from neuromuscular block following infusion of cisatracurium using either sevoflurane or propofol for anaesthesia.Eur J Anaesthesiol. 2004 Sep;21(9):751-753

0

10

20

30

40

50

60

70

min

T1 25 dose bolo T1 25 infus RI 25-75 Tof 70

Sevoflurane 1-2%

propofol 75-150microgr/kg/min

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Riprese nm dopo cisatracurium in infusione :confronto fra

TIVA e isoflurane :da Jellish WS, Brody M, Sawicki K, Slogoff S. Recovery from neuromuscular blockade after either bolus and prolonged infusions of cisatracurium or

rocuronium using either isoflurane or propofol-based anesthetics. Anesth Analg. 2000 Nov;91(5):1250-5.

05

101520253035404550

min

T1 25 T1 75 TOF 0.70 RI 25-75

ISOfluranepropofol

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Potenziamento del cisatracurium con gli anestetici alogenati vs propofol

� Turan :sevo 1-2% :Tof 70 +8%� Ortiz:desf >sevo>isof :RI e Tof 70 +� Melloni: sevo 1.5 e 2 Mac: + ED95� Hemmerling:IR di cis meno con

desf,sevo,isof� Jellish isof=sevo :TOF 70 +


Cisatracurium nell’obeso


Tempi di ripresa dopo cisatracurium 0.2 mg/kg Leykin Y, Pellis T, Lucca M, Lomangino G, Marzano B, Gullo A.The effects of cisatracurium on morbidly obese women. Anesth Analg. 2004 Oct;99(4):1090-4

0

20

40

60

80

100

120

140

160

180

200

onset sec dur 25%min dose mg

obesi RBW

obesi IBW

normali RBW

*

Cisatr 0.2 mg/kgRemifentanil propofol

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Messaggio da portare a casa per il cisatracurium

� Dose iniziale e supplementari basate sull’IBW


Mean infusion rates� Cisatracurium/atracurium:

» The infusion rates for a 95% ± 4% neuromuscular block were 1.5 ± 0.4 µg × kg-1 × min-1 for cisatracurium and 6.6 ± 1.7 µ g × kg-1 × min-1 for atracurium, 3.3 times those of cisatracurium when referenced to the active cations. After the infusion, the spontaneous recovery intervals 25%–75% of 18 ± 11 min and 18 ± 8 min for cisatracurium and atracurium (P = 0.896) were shortened to 5 ± 2 min and 4 ± 3 min (P = 0.921) after neostigmine.Mellinghoff,et al


Cisatracuriumµg/kg/min

� 3.1 ± 1:Jellish� 1.5 ± 0.4:Mellinghoff� 0.75/1 Cammu� 61.7 ± 25.3 µg/m2/min Hemmerling � 0.81 ± 0.02 -MIller


FINE


Jellish WS, Brody M, Sawicki K, Slogoff S. Recovery from neuromuscular blockade after either bolus and prolonged infusions of cisatracurium or rocuronium using either isoflurane or propofol-based anesthetics. Anesth Analg. 2000 Nov;91(5):1250-5.

Fin qui» Department of Anesthesiology, Loyola University Medical

Center, Maywood, Illinois 60153, USA. [email protected]» We examined the recovery characteristics of cisatracurium or

rocuronium after bolus or prolonged infusion under either isoflurane or propofol anesthesia. Sixty patients undergoing neurosurgical procedures of at least 5 h were randomized to receive either isoflurane with fentanyl (Groups 1 and 2) or propofol and fentanyl (Groups 3 and 4) as their anesthetic. Groups 1 and 3 received cisatracurium 0.2 mg/kg IV bolus, spontaneously recovered, after which time an infusion was begun. Groups 2 and 4 received rocuronium 0.6 mg/kg IV, spontaneously recovered, and an infusion was begun. Before the end of surgery, the infusion was stopped and recovery of first twitch (T(1)), recovery index, clinical duration, and train-of-four (TOF) recovery was recorded and compared among groups by using appropriate statistical methods. Clinical duration was shorter for rocuronium compared with cisatracurium using either anesthetic. Cisatracurium T(1) 75% recovery after the infusion was shorter with propofol compared with isoflurane. Cisatracurium TOF 75% recovery was similar after either bolus or infusion, but rocuronium TOF 75% recovery after the infusion was delayed. Infusion rates decreased for cisatracurium but remained relatively constant for rocuronium regardless of the anesthetic used. Isoflurane enhances the effect of both muscle relaxants but prolonged cisatracurium recovery more than rocuronium. Of the two muscle relaxants studied, rocuronium's recovery was most affected by length of the infusion. Cisatracurium may be a more desired muscle relaxant for prolonged procedures because recovery was least affected by prolonged infusion. Implications: This study describes the effect of different anesthetic techniques on the recovery of two different muscle relaxants, cisatracurium and rocuronium, when administered as either a single bolus or prolonged infusion during neurosurgery. This study demonstrates the feasibility of using these relaxants for these prolonged procedures.

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Table 3

Table 3. Mean Infusion Rates Compared Among Groups Over TimeAll rates are µg · kg-1 · min-1 and represented as mean ± sd.The first six 10-min periods were used for infusion adjustments and were not included in the data analysis. Average infusion rate was calculated by adding the hourly rate after 180 min and dividing by the remaining number of hours the infusion was maintained. ISO/CIS = patients receiving isoflurane and cisatracurium, PROP/CIS = patients receiving total IV anesthesia with propofol and cisatracurium, ISO/ROC = patients receiving isoflurane and rocuronium, PROP/ROC = patients receiving total IV anesthesia with propofol and rocuronium.


Table 2


Figure 1

Figure 1. T1 percent recovery times compared among the four groups after bolus and infusion dosing of muscle relaxant. Iso/Cis = patients receiving isoflurane and cisatracurium, Prop/Cis = patients receiving total IV anesthesia (TIVA) with propofol and cisatracurium, Iso/Roc = patients

receiving isoflurane and rocuronium, Prop/Roc = patients receiving TIVA with propofol and rocuronium. *P < 0.05 compared with Iso/Cis. From: Jellish: Anesth Analg, Volume 91(5).November 2000.1250-1255


Tran TV, Fiset P, Varin F. Pharmacokinetics and pharmacodynamics of cisatracurium after a short infusion in patients under propofol anesthesia. Anesth Analg 1998; 87:1158-63.

mean terminal half-life of cisatracurium was 23.9 ± 3.3 min total clearance averaged 3.7 ± 0.8 mL × min-1 × kg-1. Using this model, the volume of distribution at steady state was significantly increased

compared with that obtained when central elimination only was assumed (0.118 ± 0.027 vs 0.089 ± 0.017 L/kg).

The effect-plasma equilibration rate constant was 0.054 ± 0.013 min-1. The 50% effective concentration (153 ± 33 ng/mL) was 56% higher than that reported in

patients anesthetized with volatile anesthetics, which suggests that, compared with inhaled anesthetics, a cisatracurium neuromuscular block is less enhanced by propofol. Implications:

The drug concentration-effect relationship of the muscle relaxant cisatracurium has been characterized under balanced and isoflurane anesthesia. Because propofol is now widely used as an IV anesthetic, it is important to characterize the biological fate and the concentration-effect relationship of cisatracurium under propofol anesthesia as well.


Curve individuali delle concentrazioni plasmatiche dopo 0.1 mg/kg di cisatracurium in tiva e andamento del blocco nm.Tran TV, Fiset P, Varin F. Pharmacokinetics and pharmacodynamics of cisatracurium after a short infusion in patients under propofol anesthesia. Anesth Analg 1998; 87:1158-63.

Blocco nm

Curve di decadimento


Blocco nm/curve di concentrazione nel compart. effetto Tran TV, Fiset P, Varin F. Pharmacokinetics and pharmacodynamics of cisatracurium after a short infusion in patients under propofol anesthesia. Anesth Analg 1998; 87:1158-63.


EC50 cisatracurium

� TRAN 153 ± 33 ng/mL� SOROSHIAN 98+30


Atracurium:µg/kg/min

� 4.0 ± 0.7 / 5.0 ± 1.0� 6.6 ± 1.7

» Mellinghoff� 0.25–0.44 mg/ kg/ h=4.16 / 7.3

Ross, J. J.; Mason, D. G.; Linkens, D. A.; Edwards, N. D.Self-learning fuzzy logic control of neuromuscular block Br. J. Anaesth. 1997; 78:412-415


But several studies reported that the effect site concentration depressing twitch tension 50% (C50) varies as a function of dose.

� Bergeron L, Bevan DR, Berrill A, Kahwaji R, Varin F: Concentration–effect relationship of cisatracurium at three different dose levels in the anesthetized patient. Anesthesiology 95:314–23, 2001

� Bragg P, Fisher DM, Shi J, Donati F, Meistelman C, Lau M, Sheiner LB: Comparison of twitch depression of the adductor pollicis and the respiratory muscles. Anesthesiology 80:310–9, 1994

� Fisher DM, Szenohradszky J, Wright PMC, Lau M, Brown R, Sharma M: Pharmacodynamic modeling of vecuronium-induced twitch depression. Anesthesiology 86:558–66, 1997

� Sorooshian SS, Stafford MA, Eastwood NB, Boyd AH, Hull CJ, Wright PMC: Pharmacokinetics and pharmacodynamics of cisatracurium in young and elderly adult patients. Anesthesiology 84:1083–91, 1996


Cisatracurium

� Based on the pharmacokinetic–pharmacodynamic data of Bergeron et al. for the 75-µg/kg dose, we estimated that the doses producing 20% (ED20), 50% (ED50), 80% (ED80), and 99% (ED99) effect were approximately 30, 37.5, 45, and 75 µg/kg, respectively.


Time of C peak and Keo variano al variare della dose!!


La determinazione dei parametri farmacocinetici dipende dalla descrizione più accurata possibile dell’andamento iniziale della Cp

� “estimation of pharmacodynamic parameters depends on an accurate description of the early time course of Cp.”

– Ducharme J, Varin F, Bevan DR, Donati F: Importance of early blood sampling on vecuronium pharmacokinetic and pharmacodynamic parameters. Clin Pharmacokinet 24:507–18, 1993

» For example, to demonstrate that vecuronium’s C50 varied with dose (as was suggested by Bragg et al., who modeled pharmacodynamics without plasma concentration data), Fisher et al. sampled arterial plasma at 0.5 min (in addition to a sampling regimen similar to that of Bergeron et al.


L’andamento iniziale della Cp dipende dal sito di campionamento….� Our simulations indicate the importance of early samples when effect peaks early. If

early samples cannot be obtained, pharmacodynamic modeling may be flawed. Another design issue that could lead to incorrect modeling of the early plasma concentration-versus-time course is the use of venous samples. For example, Donati et al. demonstrated that atracurium’s arterial Cp is markedly larger than venous Cp

during the initial 2 min. In that arterial Cp accurately describes the input to the neuromuscular junction, use of venous samples may lead to inaccurate estimates of pharmacodynamic parameters. The inaccuracy of pharmacodynamic parameters is likely to be largest for those drugs with the largest difference between arterial and venous Cp values. If arterial blood cannot be sampled (e.g., for ethical reasons), then the dosing regimen should be designed so as to minimize the difference between arterial and venous Cp during times critical for the pharmacodynamic analysis. This can presumably be accomplished by administering the muscle relaxant as a brief infusion, as was suggested originally by Sheiner et al.


Piccoli errori nel timing di somministrazione producono …….


Quindi

� Problemi pratici di applicazione degli studi PK/Pd


� Anesth Analg. 2006 Mar;102(3):738-43. Links

» Pharmacokinetics and pharmacodynamics of a 0.1 mg/kg dose of cisatracurium besylate in children during N2O/O2/propofol anesthesia.

– Imbeault K, – Withington DE, – Varin F.

» Faculte de Pharmacie, Universite de Montreal, Department of Anesthesia, Montreal Children's Hospital/McGill University, Montreal, Quebec, Canada.

» We studied the pharmacokinetics and pharmacodynamics of cisatracurium in 9 children (mean weight, 17.1 kg) aged 1-6 yr (mean, 3.75 yr) during propofol-nitrous oxide anesthesia. Neuromuscular monitoring was performed. Venous samples were taken before injection of a 0.1 mg/kg dose of cisatracurium and then at 2, 5, 10, 30, 60, 90, and 120 min. Cisatracurium plasma concentrations were determined by high performance liquid chromatography. Onset time was 2.5 +/- 0.8 min, recovery to 25% of baseline twitch height was 37.6 +/- 10.2 min, and the 25%-75% recovery index was 10.9 +/- 3.7 min. Distribution and elimination half-lives were 3.5 +/- 0.9 min and 22.9 +/- 4.5 min, respectively. Steady-state volume of distribution (0.207 +/- 0.031 L/kg) and total body clearance (6.8 +/- 0.7 mL/min/kg) were significantly larger than those published for adults. Pharmacodynamic results were comparable to those obtained in pediatric studies during halothane or opioid anesthesia with the exception of a longer recovery to 25% baseline. Although the plasma-effect compartment equilibration rate constant was twofold faster (0.115 +/- 0.025 min(-1)) than that published for cisatracurium in adults, the effect compartment concentration corresponding to 50% block was similar (129 +/- 27 ng/mL






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Variabilità di durata clinica nell’ anziano Arain SR,Kern S, Ficke DJ, Ebert TJ. Variability of duration of action of neuromuscular-blocking drugs in

elderly patients. Acta Anaesthesiol Scand. 2005 Mar;49(3):312-5. � : Steroid-based, non-depolarizing neuromuscular-blocking (NMB) drugs

(e.g. rocuronium, vecuronium) are characterized by organ-dependent elimination and significantly longer durations of action in elderly compared to young patients. Cisatracurium is a benzylisoquinolinium NMB drug with a duration of action not altered by ageing. The objective of the study was to determine if elderly patients had less variability in duration of action with 2 x ED95 of cisatracurium compared to equipotent doses of rocuronium or vecuronium. METHODS: Informed consent was obtained from 66 elderly patients with normal renal and liver function. Preoperative midazolam (1 mg) was given IV. The anaesthestic induction was with 5 mg kg(-1) thiopental and 2 microg kg(-1) fentanyl. The patients received 0.6 mg kg(-1) rocuronium, 0.1 mg kg(-1) vecuronium or 0.1 mg kg(-1) cisatracurium. Anaesthetic maintenance was with sevoflurane in oxygen/nitrous oxide. Neuromuscular-blocking duration of action was defined as the return of T1 twitch height to 25% of control. Variability was determined by subtracting the actual duration of action from the mean duration of action for each drug. RESULTS: The durations of action (range, min) were: cisatracurium, 37-81; vecuronium, 35-137; and rocuronium, 33-119. The median of the variability of duration was significantly less with cisatracurium (7 min) compared to vecuronium (18 min) and rocuronium (18 min) (P < 0.05). CONCLUSION: When used with sevoflurane/N(2)O, there was a two-fold greater variability of duration of neuromuscular blockade in elderly patients receiving rocuronium or vecuronium compared with cisatracurium

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Kopman AF,Zank LM,Ng J,Neuman GG. Antagonism of Cisatracurium and Rocuronium Block at a Tactile Train-of-Four Count of 2: Should Quantitative Assessment of Neuromuscular Function Be Mandatory? Anesth Analg 2004; 98:102-6.

�

� ABSTRACT: With a train-of-four (TOF) ratio > 0.70 as the standard of acceptable recovery, postoperative residual paralysis is a frequent occurrence in postanesthesia care units (PACUs). However, detailed information regarding prior anesthetic management is rarely provided. We examined the incidence of postoperative weakness after the administration of cisatracurium and rocuronium when using a rigid protocol for muscle relaxant and subsequent neostigmine administration. Under desflurane, N2O, and opioid anesthesia, tracheal intubation was accomplished after either cisatracurium 0.15 mg/kg or rocuronium 0.60 mg/kg. The response of the thumb to ulnar nerve stimulation was estimated by palpation. Additional increments of muscle relaxant were given as needed to maintain the TOF count at 1 or 2. At the conclusion of surgery, at a TOF count of 2, neostigmine 0.05 mg/kg plus glycopyrrolate 10 µg/kg was administered. The mechanical TOF response was then measured with a force transducer starting 5 min postreversal. Patients were observed until a TOF ratio of 0.90 was achieved. There were no significant differences in the recovery profiles of cisatracurium versus rocuronium. TOF ratios at 10 min postreversal were 0.72 ± 0.10 and 0.76 ± 0.11, respectively. At 15 min postreversal, only one subject in each group had a TOF ratio of < 0.70. No patient in either group arrived in the PACU with a TOF ratio < 0.70. Our results suggest that if cisatracurium or rocuronium is administered by using the TOF count as a guide, critical episodes of postoperative weakness in the PACU should be an infrequent occurrence.

�


Kopman AF,Zank LM,Ng J,Neuman GG. Antagonism of Cisatracurium and Rocuronium Block at a Tactile Train-of-Four Count of 2: Should

Quantitative Assessment of Neuromuscular Function Be Mandatory? Anesth Analg 2004; 98:102-6


Sorooshian, Shahpoor S., F.R.C.A.*; Stafford, Michael A.,

M.Sc., F.R.C.A.†; Eastwood, Nigel B., B.Sc., F.R.C.A.‡; Boyd, Alastair H., F.R.C.A.‡; Hull, Christopher J., F.R.C.A.§; Wright, Peter M.C.,

M.D., F.F.A.R.C.S.I., †

� Background: The effects of a muscle relaxant may differ in elderly compared with young adult patients for a variety of reasons. The authors compared the effects of a new muscle relaxant (cisatracurium) in young and elderly adults and used pharmacokinetic/pharmacodynamic modeling to identify factors explaining differences in time course of effect.

� Methods: Thirty-one young (18—50 yr) and 33 elderly (>65 yr) patients anesthetized with nitrous oxide, isoflurane, and fentanyl were studied. Cisatracurium (0.1 mg/kg) was given after induction of anesthesia and later additional boluses of 0.025 mg/kg or an infusion of cisatracurium was given. Neuromuscular transmission was measured using the first twitch of the train-of-four response at the adductor pollicis after supramaximal stimulation of the ulnar nerve at 2 Hz every 15 s. Five venous blood samples were obtained for plasma drug concentration at intervals ranging from 2 to 120 min from every patient. Three additional samples were obtained from those who received an infusion. A population pharmacokinetic/pharmacodynamic model was fitted to the plasma concentration and effect data. The parameters of the model were permitted to vary with age to identify where differences existed between young and elderly adults.

� Results: Onset of block was delayed in the elderly; values being mean 3.0 (95% confidence interval 1.75—11.4) min and 4.0 (2.4—6.5) min in the young and elderly, respectively (P < 0.01). Duration of action was similar in the two groups. Plasma clearance was 319 (293—345) ml/min in the study population and did not differ between young and elderly patients. Apparent volume of distribution was 13.28 (9.9—16.7) l and 9.6 (7.6—11.7) l in the elderly and young adults, respectively (P < 0.05). There also were differences in pharmacodynamic parameters between the young and elderly; the predominant change being a slower rate of biophase equilibration (ke0) in the elderly (0.060 [0.052—0.068])/min compared with the young (0.071 [0.065—0.077]/min; P < 0.05).

� Conclusions: The pharmacokinetics of cisatracurium differ only marginally between young and elderly adults. Onset is delayed in the elderly because of slower biophase equilibration.


Imbeault K, Withington DE, Varin F. Pharmacokinetics and pharmacodynamics of a 0.1 mg/kg dose of cisatracurium besylate in children duringN2O/O2/propofol anesthesia.Anesth Analg. 2006 Mar;102(3):738-43� Cisatracurium has a unique organ-independent elimination called Hofmann elimination

that depends solely on pH and temperature and accounts for 77% of the Cltot (21). As expected with this type of elimination, the PKs of cisatracurium are linear up to 0.3 mg/kg (22). Only in adults have PK studies of cisatracurium been performed during propofol anesthesia (10). Our PK data indicate that both half-lives for the distribution and elimination rate constants are similar to those reported in adults. This is consistent with previous observations made for atracurium in which the elimination half-life was shown to be similar in infants, children, and adults (23).

� To calculate the apparent volume of distribution (an exit-site dependent parameter), the elimination rate from the peripheral compartment was assumed to be equal to the mean in vitro degradation rate in plasma published by Welch et al. (17). In a previous study (9), this value proved to be equal to or higher than the corresponding elimination rate from the central compartment in 4 of 48 patients, resulting in a null or negative organ clearance (model mis-specification). This limitation was not observed in our study. In our opinion, the difference in pH between plasma and tissue interstitial fluid is not large enough to significantly alter cisatracurium elimination.

� In our patients, an almost twofold increase in the volume of distribution and Cltot of cisatracurium was observed when compared with adults (10). Parallel changes (approximately 20%) in the apparent Vss and Cltot of atracurium have also been reported with increasing age (23); the progressive decrease in the extracellular fluid results in a proportional diminution of organ-independent elimination. These findings were corroborated in another PK study with atracurium in children and infants (24). Nonetheless, it remains that the increase in Cltot we observed in children versus adults is larger than that observed for atracurium. Many factors may explain this discrepancy. In contrast to its cis isomer, atracurium is eliminated by a dual mechanism: Hofmann degradation and metabolism by nonspecific esterases. In our study, venous concentrations were used, whereas other PK studies sampled arterial blood (10). Sampling site is often a confounding factor in PK studies. For example, the clearance of atracurium and mivacurium based on venous blood proved to be 25% and 50% larger, respectively, than that based on arterial levels (25,26). Arterial sampling was not clinically justified in our children.

� Compared with adults (9,10), our PK/PD analysis revealed an almost twofold faster keo in children. Part of this difference is also attributable to the sampling site. For atracurium, a 47% increase in keo was observed when venous instead of arterial samples were used for modeling (26). However, physiological factors (increased heart rate, blood flow, and tissue permeability) certainly contribute to the large increase in keo observed in children. This observation is compatible with the shorter onset observed in children when compared with adults. The slope values were quite similar to those reported in adults (9,10). With regards to sensitivity, the EC50 observed in our children is quite similar (20% lower) to that observed in adults during propofol anesthesia (10). This is in agreement with previous findings for atracurium in which the steady-state plasma concentration resulting in 50% of neuromuscular blockade appeared independent of age-related changes (23).





� Pharmacological studies have been performed in children with cisatracurium during inhaled (3,5–7,18) and opioid (3–5) anesthesia but not during propofol anesthesia. Using a similar dose, the effect data for our patients showed a comparable onset time (2.5 min) to that obtained during nitrous oxide/opioid anesthesia (2.3 min) (3) and halothane anesthesia (2.2 min or 2.5 min) (3,6), but the clinical duration (recovery time to 25% of baseline twitch height) was 38 ± 10 min in our patients, longer than that observed for the opioid group in Meretoja et al.’s (3) study (27 min; range, 24–33 min). In fact, it was comparable to that observed in Taivainen et al.’s study (19) (36 ± 5 min), in which a larger dose (0.15 mg/kg) was administered during N2O/opioid anesthesia. Thus, in the light of our effect data alone, one would suggest that propofol has an enhancing effect on neuromuscular blockade, comparable to that seen in adults receiving inhaled anesthetics. However, in Meretoja et al. s’ study, the clinical duration of cisatracurium in children during inhaled anesthesia (34 min; range, 22–40 min) was within the range observed for the opioid group (3). Because no comparative study was conducted, it is difficult to exclude the possibility that the longer clinical duration observed in our children is not merely the result of a different anesthetic setting.

� In our patients, the recovery index from 25% to 75% of baseline twitch height (11 ± 4 min) was virtually identical to that reported in the abovementioned studies (3,6,19). This observation suggests that although the biological half-life of cisatracurium was not measured in other studies, it may not differ significantly among treatment groups. Moreover, spontaneous recovery rate seems independent of initial dosage and duration of infusion or the number of maintenance doses of cisatracurium administered. In one case report, a 7-kg infant received an overdose of 0.86 mg/kg and nevertheless obtained a recovery index between 10 and 15 min (20). This is also consistent with the previously demonstrated noncumulative effect of cisatracurium. Nonetheless, the overall recovery period to 75% of baseline twitch height in our patients remains clinically longer than that reported in previous pediatric studies.


Tof count unreliable in the reversal of deep rocu or cisatrac

block

� J Clin Anesth. 2005 Feb;17(1):30-5. Links

» Antagonism of profound cisatracurium and rocuronium block: the role of objective assessment of neuromuscular function.– Kopman AF, – Kopman DJ, – Ng J, – Zank LM.

» Department of Anesthesiology, New York Medical College, Valhalla, NY, USA. [email protected]

» STUDY OBJECTIVE: The purpose of this study is to determine the incidence of significant (train-of-four [TOF] ratio <0.70), but clinically undetectable (TOF ratio >0.40), residual neuromuscular block after neostigmine antagonism of profound cisatracurium (CIS) or rocuronium (ROC) block. DESIGN: Prospective, randomized, open-label study. SETTING: University hospital. PATIENTS: Forty ASA physical status I and II undergoing elective surgical procedures. INTERVENTIONS: Anesthesia was induced with propofol 1.5 to 2.5 mg/kg IV plus fentanyl 2 to 4 mug/kg and maintained with N(2)O/desflurane plus narcotic supplementation. The electromyographic response of the adductor pollicis was recorded. Train-of-four stimulation was given every 20 seconds. Twitch height (T1) and TOF fade ratio were continuously recorded. In group 1 (n = 20), neuromuscular block was induced with CIS 0.10 mg/kg, and T1 was maintained at 5% of control by a constant infusion of CIS until the end of surgery. One minute after the termination of the infusion, neostigmine 0.05 mg/kg was administered. T1 and TOF values were monitored continuously for the next 20 minutes. Group 2 (n = 20) is identical to group 1 except that the initial drug was ROC 0.60 mg/kg, and paralysis was maintained with an infusion of ROC. MEASUREMENTS AND MAIN RESULTS: There were no significant differences in the recovery patterns of CIS vs ROC. The duration (bolus to end of infusion) in both groups averaged 2.7 hours, and the mean cumulative dose of relaxant approximated 4 x the ED(95). T1 at the time of reversal was 6% (4%-10%) of control. Mean TOF ratios at 10, 15, and 20 minutes were 0.55, 0.71, and 0.0.81, respectively. Return to a TOF ratio >0.40 was always achieved in 15 minutes or less. However, at 20 minutes postreversal, 5 of 40 subjects had TOF ratios <0.70 and only 11 individuals had recovered to a TOF ratio of 0.90 or greater. CONCLUSIONS: Most clinicians cannot detect tactile fade once the TOF ratio exceeds 0.40. When reversing profound block, an objective monitor of neuromuscular function is required if the extent of residual block is to be assessed with any confidence.


» .The effect of chronic anticonvulsant therapy (CAT) on the maintenance and recovery profiles of cisatracurium-induced neuromuscular blockade has not been adequately studied. In this study, we compared the pharmacokinetics and pharmacodynamics of cisatracurium after a prolonged infusion in patients with or without CAT. Thirty patients undergoing intracranial surgery were enrolled in the study: 15 patients under CAT (carbamazepine and phenytoin, Group A) and 15 controls receiving no anticonvulsant therapy (Group C). Anesthesia was standardized and both groups received a bolus of cisatracurium followed by an infusion to maintain a 95% twitch depression. A steady-state was obtained and the infusion was kept constant for 2 additional hours. Neuromuscular blockade was then allowed to spontaneously recover. Blood samples were taken for measurement of cisatracurium plasma concentration during the steady-state period (Cp(ss)95) and at various times during recovery. Demographic and intraoperative data were similar. CAT resulted in faster 25% and 75% recovery of the first twitch. The rate of infusion of cisatracurium needed to maintain a 95% twitch depression at steady-state was 44% faster in Group A (P < 0.001). The clearance of cisatracurium was significantly faster in Group A when compared with Group C (7.12 +/- 1.87 versus 5.72 +/- 0.70 L . kg(-1) . min(-1), P = 0.01). The Cp(ss)95 was also significantly larger in Group A (191 +/- 45 versus 159 +/- 36 ng/mL, P = 0.04). In addition, patients receiving CAT had a 20% increase in the clearance of cisatracurium that, in turn, resulted in a faster recovery of neuromuscular blockade after an infusion of the drug. Also, patients under CAT had a 20% increase in their Cp(ss)95, indicating an increased resistance to the effect of cisatracurium.


Generalità sui miorilassanti


Elementi di sicurezza deimiorilassanti

Elementi di sicurezza deimiorilassanti

safetysafety

fastonsetfast

onset

fast offsetfast offset

no residualcurarizationno residualcurarization

non cumulativenon cumulative

no activemetabolitesno active

metabolites

no histamine releaseno histamine release

lack ofcardiovascular

effects

lack ofcardiovascular

effects

organindependent

organindependent

goodshelf life

goodshelf life


metabolismo

� “plasmatico”:atracurium,cisatracurium� pseudocolinesterasico:mivacurium,SCC� esterasico:atracurium,(cisatracurium)� epatico:vecuronium,rocuronium,panc


BreveBreve

Scc,MivaScc,Miva

IntermediaIntermedia

Atrac,Cisatrac,Vecu,RocuAtrac,Cisatrac,Vecu,Rocu

LungaLunga

Panc,Doxa,Pipec.Panc,Doxa,Pipec.


BenzilisochinolineBenzilisochinoline

liberazistaminaliberazistamina

intsabilitàchimicaintsabilitàchimica

Effettiemodinamici

Effettiemodinamici


AminosteroideiAminosteroidei

menoliberazistamina

menoliberazistamina

StabilitàchimicaStabilitàchimica

maggiorestabilità

cardiovasc.

maggiorestabilità

cardiovasc.


struttura chimica

� benzilisochinoline:atrac,cisatrac,miva

� liberazione istaminica� maggiore instabilità chimica

� aminosteroidei:panc,vecu,rocu,org 9487

� stabilità frequenza cardiaca� maggiore stabilità chimica


criteri di scelta:� rapidità iot

:succi,rocuroniumsucci,rocuronium� brevità di azione:succinilcolina,mivacuriumsuccinilcolina,mivacurium� non

cumulatività:atracurium,cisatracurium,mivacuriumatracurium,cisatracurium,mivacurium� insufficienza epatica e/o

renale:atracurium,cisatracuriumatracurium,cisatracurium� stabilità cardiovascolare:vecuronium,cisatracuriumvecuronium,cisatracurium� costi:pancuroniumpancuronium


scelta dipendente anche da:

� durata intervento� stato clinico del paziente:asmatici,......� interazioni farmacologiche� disponibilità strumentazione:pompe per infusione,monitoraggio.....

� costi


Costi� Diretti:

� acquisto� conservazione

� indiretti:� trattamento ;

� lib istamina� mialgie� bocca secca� PONV…..

� prolungamento degenza,:sala op,RR,Pacu...� Ospedalizzazione non prevista � aumento del discomfort,ansietà,stress…


Dosi di laudanosina(µg/ml):subepilettogene….

0

0,2

0,4

0,6

0,8

1

1,2

atrac 2 ED95 atrac cis 4 ED95

Fahey 1984Chapple 1987Lien 1996


Concentrazioni di laudanosina dalla letteratura

0

1

2

3

4

5

6

microgr/ml

normali insuff renale

Fahey 1984Ward 1985Ward 1986Yate(1985)

0,7-1.9 mg/kg/hr per 40-139 hr,ICU

↓

↓


Problemi della laudanosina

� Metabolismo:» 70% biliare» 30% renale

� metabolizzazione epatica?:tetraidropapaverina?

� Rapporto CSF/plasma:0.3-0.6(Fahey 1985)

� Hennis( 1985):segni di risveglio dopo bolo di 2 mg/kg(cani in anestesia alotanica):

� Miller (1985): Mac dell’alotano aumentato del 30% nei conigli a conc tra 0.4-0.8 µg/ml


� Tran, Tuong-Vi, BPharm*; Fiset, Pierre, MD†; Varin, France, PhD*� � *Faculté de Pharmacie, Université de Montréal; and †Department of Anaesthesia, Royal Victoria Hospital, McGill

University, Montreal, Canada � This study was funded in part by Glaxo Wellcome Canada. � Presented in part at the annual meeting of the American Society of Anesthesiologists, New Orleans, LA, October 19–23,

1996. � Accepted for publication July 8, 1998. � Address correspondence and reprint requests to France Varin, PhD, Faculté de Pharmacie, Université de Montréal, C.P.

6128, succursale Centre-ville, Montréal, Québec, Canada H3C 3J7.� � ABSTRACT: Fourteen patients, ASA physical status I or II, were recruited to assess the pharmacokinetic-

pharmacodynamic relationship of cisatracurium under nitrous oxide/sufentanil/propofol anesthesia. The electromyographic response of the abductor digiti minimi muscle was recorded on train-of-four stimulation of the ulnar nerve. A 0.1-mg/kg dose of cisatracurium was given as an infusion over 5 min. Arterial plasma concentrations of cisatracurium and its major metabolites were measured by using high-performance liquid chromatography. A nontraditional two-compartment pharmacokinetic model with elimination from central and peripheral compartments was used. The elimination rate constant from the peripheral compartment was fixed to the in vitro rate of degradation of cisatracurium in human plasma (0.0237 min-1). The mean terminal half-life of cisatracurium was 23.9 ± 3.3 min, and its total clearance averaged 3.7 ± 0.8 mL × min-1 × kg-1. Using this model, the volume of distribution at steady state was significantly increased compared with that obtained when central elimination only was assumed (0.118 ± 0.027 vs 0.089 ± 0.017 L/kg). The effect-plasma equilibration rate constant was 0.054 ± 0.013 min-1. The 50% effective concentration (153 ± 33 ng/mL) was 56% higher than that reported in patients anesthetized with volatile anesthetics, which suggests that, compared with inhaled anesthetics, a cisatracurium neuromuscular block is less enhanced by propofol. Implications: The drug concentration-effect relationship of the muscle relaxant cisatracurium has been characterized under balanced and isoflurane anesthesia. Because propofol is now widely used as an IV anesthetic, it is important to characterize the biological fate and the concentration-effect relationship of cisatracurium under propofol anesthesia as well.


De Wolf AM.,Freeman JA, Scott VL,Tullock W,Smith DA,Kisor DF, Kerls S,Cook,DR. Pharmacokinetics and

pharmacodynamics of cisatracurium in patients with end-stage liver disease undergoing liver transplantation.

Br. J. Anaesth. 1996; 76:624-628� : We determined the pharmacokinetics and pharmacodynamics of cisatracurium, one of the 10 isomers of atracurium, in 14 patients with end-stage liver disease undergoing liver transplantation and in 11 control patients with normal hepatic and renal function undergoing elective surgery. Blood samples were collected for 8 h after i.v. bolus administration of cisatracurium 0.1 mg kg-1 (2´ED95). Plasma concentrations of cisatracurium and its metabolites were determined using an HPLC method with fluorescence detection. Pharmacokinetic variables were determined using non-compartmental methods. Neuromuscular block was assessed by measuring the electromyographic evoked response of the adductor pollicis muscle to train-of-four stimulation of the ulnar nerve using a Puritan-Bennett Datex (Helsinki, Finland) monitor. Pharmacodynamic modelling was completed using semi-parametric effect-compartment analysis. Volume of distribution at steady state was 195 (SD 38) ml kg-1 in liver transplant patients and 161 (23) ml kg-1 in control patients (P < 0.05), plasma clearance was 6.6 (1.1) ml kg-1 min-1 in liver transplant patients and 5.7 (0.8) ml kg-1 min-1 in control patients (P < 0.05), but elimination half-lives were similar: 24.4 (2.9) min in liver transplant patients vs 23.5 (3.5) min in control patients (ns). The time to maximum block was 2.4 (0.8) min in liver transplant patients compared with 3.3 (1.0) min in control patients (P < 0.05), but the clinical effective duration of action (time to 25% recovery) was similar: 53.5 (11.9) min in liver transplant patients compared with 46.9 (6.9) min in control patients (ns). The recovery index (25-75% recovery) was also similar in both groups: 15.4 (4.2) min in liver transplant patients and 12.8 (1.9) min in control patients (ns). After cisatracurium, peak laudanosine concentrations were 16 (5) and 21 (5) ng ml-1 in liver transplant and control patients, respectively. In summary, minor differences in the pharmacokinetics and pharmacodynamics of cis-atracurium in liver transplant and control patients were not associated with any clinically significant differences in recovery profiles after a single dose of cisatracurium.


Prielipp RC, Coursin DB, Scuderi PE, Bowton DL, Ford SR, ardenas VJ Jr, Vender J, Howard D, Casale EJ, Murray MJ. Comparison of the infusion requirements and recovery profiles of vecuronium and cisatracurium 51W89 in intensive care unit patients. Anesth Analg. 1995 Jul;81(1):3-12.

» prospective, randomized, double-blind, multicenter study in critically ill adults. » 58 mechanically ventilated ICU patients from five medical centers were

randomized to receive either cisatracurium or VEC. » Fifty-four of the 58 patients received NMB drugs before entering this study but

demonstrated at least partial recovery (> or = one twitch) in the train-of-four (TOF) response before initiation of the NMB study drug.

» NMB drug infusion was titrated by peripheral nerve stimulation to maintain at least one twitch in the TOF response.

» NMB drugs were infused for 1-5 days. After discontinuation of NMB drug infusion, recovery of neuromuscular transmission was monitored with an accelerometer.

» NMB drug infusion for 28 cisatracurium patients averaged 2.6 +/- 0.2 (mean +/- SEM) micrograms.kg-1.min-1 with a mean duration of 80 +/- 7 h.

» After discontinuing cisatracurium administration, recovery to 70% TOF ratio averaged 68 +/- 13 min. The mean infusion rate for 30 VEC patients was 0.9 +/- 0.1 micrograms.kg-1.min-1 with a mean duration of 66 +/- 12 h.

» Neuromuscular recovery after VEC averaged 387 +/- 163 min, which was significantly longer (P = 0.02) than that after cisatracurium. Prolonged recovery of neuromuscular function after discontinuation of NMB drug infusion (identified by the primary investigator at each medical center) was reported in two cisatracurium patients and 13 VEC patients (P = 0.002), and occurred despite the routine use of neuromuscular twitch monitoring. Seven VEC and one cisatracurium patients died during the infusion of study drug or within 48 h after discontinuation of the NMB drug infusion. In summary, we found recovery of neuromuscular function after discontinuation of NMB drug infusion in ICU patients is significantly faster with cisatracurium than with VEC. In addition, routine neuromuscular monitoring was not sufficient to eliminate prolonged recovery and myopathy in ICU patients.


Reich DL, Hollinger I, Harrington DJ, Seiden HS, Chakravorti S, Cook DR. Comparison of cisatracurium and vecuronium by infusion in neonates and small infants after congenital heart surgery. Anesthesiology. 2004 101(5):1122-7.

» BACKGROUND: Neonates and infants often require extended periods of mechanical ventilation facilitated by sedation and neuromuscular blockade. METHODS:

» Twenty-three patients aged younger than 2 yr were randomly assigned to receive either cisatracurium or vecuronium infusions postoperatively in a double-blinded fashion after undergoing congenital heart surgery.

» The infusion was titrated to maintain one twitch of a train-of-four. The times to full spontaneous recovery of train-of-four without fade, extubation, intensive care unit discharge, and hospital discharge were documented after drug discontinuation. Sparse sampling after termination of the infusion and a one-compartment model were used for pharmacokinetic analysis. The Mann-Whitney U test and Student t test were used to compare data between groups. RESULTS: There were no significant differences between groups with respect to demographic data or duration of postoperative neuromuscular blockade infusion. The median recovery time for train-of-four for cisatracurium (30 min) was less than that for vecuronium (180 min) (P < 0.05). Three patients in the vecuronium group had prolonged train-of-four recovery: Two had long elimination half-lives for vecuronium, and one had a high concentration of 3-OH vecuronium. There were no differences in extubation times, intensive care unit stays, or hospital stays between groups. CONCLUSIONS: Our results parallel data from adults demonstrating a markedly shorter recovery of neuromuscular transmission after cisatracurium compared with vecuronium. Decreased clearance of vecuronium and the accumulation of 3-OH vecuronium may contribute to prolonged spontaneous recovery times. Cisatracurium is associated with faster spontaneous recovery of neuromuscular function compared with vecuronium but not with any differences in intermediate outcome measures in neonates and infants.


Burmester M, Mok Q. Randomised controlled trial comparing cisatracurium and vecuronium infusions in a paediatric intensive care unit.Intensive Care Med. 2005 May;31(5):686-92..

» OBJECTIVE: To evaluate and compare the efficacy, infusion rate and recovery profile of vecuronium and cisatracurium continuous infusion in critically ill children requiring mechanical ventilation. DESIGN AND SETTING: Prospective, randomised, double-blind, single-centre study in critically ill children in a paediatric intensive care unit in a tertiary children's hospital. METHODS: Thirty-seven children from 3 months to 16 years old (median 4.1 year) were randomised to receive either drug; those already receiving more than 6 h of neuromuscular blocking drugs were excluded. The Train-of-Four (TOF) Watch maintained neuromuscular blockade to at least one twitch in the TOF response. Recovery time was measured from cessation of infusion until spontaneous TOF ratio recovery of 70%. RESULTS: The cisatracurium infusion rate in nineteen children averaged 3.9+/-1.3 microg kg(-1) min(-1) with a median duration of 63 h (IQR 23-88). The vecuronium infusion rate in 18 children averaged mean 2.6+/-1.3 microg kg(-1) min(-1) with a median duration of 40 h (IQR 27-72). Median time to recovery was significantly shorter with cisatracurium (52 min, 35-73) than with vecuronium (123 min, 80-480). Prolonged recovery of neuromuscular function (>24 h) occurred in one child (6%) on vecuronium. CONCLUSIONS: Recovery of neuromuscular function after discontinuation of neuromuscular blocking drug infusion in children is significantly faster with cisatracurium than vecuronium. Neuromuscular monitoring was not sufficient to eliminate prolonged recovery in children on vecuronium infusions.


Reich DL, Mulier J, Viby-Mogensen J, Konstadt SN,van Aken HK,Jensen FS,De Perio M, Buckley S. Comparison of the cardiovascular effects of cisatracurium and vecuronium in patients with coronary artery disease Can J Anaesth 1998 / 45 / 794-797

� One hundred patients undergoing myocarcial revascularization participated in a pilot study (seven patients) and a double-binded, randomized, controlled trial comparing the haemodynamic effects of cisatracurium with vecuronium at three centres. The patients were anaesthetized using oxygen 100%, with etomidate, fentanyl and a benzodiazepine, and tracheal intubation was facilitated using succinylcholine. After baseline haemodynamic measurements, the study drug was administered over 5–10 sec according to group assignment: Group A (pilot) cisatracurium, 0.20 mg×kg-1 (4 x ED95), (n = 7); Group B cisatracurium, 0.30 mg×k-1 (6 x ED95), (n = 31); Group C-vecuronium, 0.30 mg×kg-1 (6 x ED95), (n = 31); Group D cisatracurium, 0.40 mg×kg-1(8 x ED95), (n = 21); Group E-vecuronium. 0.30 mg×kg-1 (6 x ED95), (n = 10). The haemodynamic measurements were repeated at 2, 5, and 10 min after cisatracurium or vecuronium.

� Results: Two patients in Group D had >20% decreases in MAP but only one required therapy for hypotension. The haemodynamic changes from pre- to post-injection in the cisatracurium patients were minimal and similar to patients receiving vecuronium.

� Conclusions: In patients with coronary artery disease, rapid cisatracurium (4–8xED95) boluses and vecuronium 6xED95) result in minor, clinically insignificant haemodynamic side effects.


Bluestein LS,Stinson L W, Lennon R L ,Quessy S N.,Wilson RM. Evaluation of cisatracurium, a new neuromuscular blocking agent, for tracheal intubation. CAN J ANAESTH 1996 / 43: 9 / pp925-31

Purpose: The primary objective of this study was a blinded, randomized comparison of the recommended intubating dose of atracurium (0.5 mg × kg-1) with an approximately equipotent dose of cisatracurium (0.1 mg × kg-1) during N2O/O2/propofol/fentanyl anaesthesia.

� Methods: Eighty ASA physical status 1 or 2 patients, 18–70 yr of age, within 30% of ideal body weight, scheduled for elective low to moderate risk surgical procedures were studied. Adductor pollicis evoked twitch responses were measured with a Grass FT 10 force displacement transducer (Grass Instruments, Quincy, MA) and continuously recorded on a Gould multichannel polygraph (Gould Instrument Systems, Cleveland, OH) after induction of anaesthesia.

� Results: Increasing the initial dose of cisatracurium (from 0.1 to 0.15 and 0.2 mg × k-1, decreased mean time of onset (from 4.6 to 3.4 and 2.8 min, respectively), and increased mean time of clinically effective duration (45 to 55 and 61 min, respectively). Recovery to a T4:T1 ratio of 0.7 occurred approximately seven minutes following administration of the reversal agent neostigmine for all treatment groups. Intubation conditions were good or excellent in over 90% of patients in all treatment groups (two minutes after approximately 2 x ED95 doses of cisatracurium or atracurium and 1.5 minutes after 3 x and 4 x ED95 doses of cisatracurium).

� Conclusion: The intubation results reported in this study together with the combination of predictable recovery from neuromuscular block and apparent haemodynamic stability make cisatracurium a potentially useful muscle relaxant in clinical practice.

� Objectif: Comparer aléatoirement et en aveugle la dose d'atracurium recommandée pour l'intubation (0,5 mg × kg-1) avec une dose approximative équipotente de cisatracurium (0,1 mg × kg-1) pendant une anesthésie associant N2O/O2/propofol/fentanyl.

� Méthodes: L'étude portait sur 84 patients ASA 1 et 2, âgés de 18 à 70 ans, dont le poids ne déviait pas de plus de 30% du poids idéal, programmés pour une chirurgie non urgente comportant un risque faible ou modéré. Le twitch évoqué à l'adducteur du pouce était mesuré après l'induction de l'anesthésie à l'aide d'un transducteur Grass FT 10 (Grass Instrument, Quincy, MA) et enregistré en continu sur un polygraphe Gould (Gould Instrument System, Cleveland, OH).

� Résultats: L'augmentation de la dose initiale de cisatracurium (de 0,1 à 0,15 et à 0,2 mg × kg-1) diminuait l'installation du bloc (respectivement de 4,6 à 2,8 min) et augmentait la durée moyenne d'efficacité clinique (respectivement de 45 à 55 et à 61 min). La récupération à 0,7 du rapport T4/T1 survenait environ sept minutes après l'administration de l'antagoniste néostigmine dans tous les groupes. Les conditions pour l'intubation étaient de bonnes à excellentes chez plus de 90% des patients de tous les groupes (deux minutes après des doses d'environ 2 x ED50 de cisatracurium ou d'atracurium et 1,5 min après 3 x et 4 x ED50 de cisatracurium).

� Conclusion: Les résultats rapportés dans cette étude concernant l'intubation associés avec un récupération prévisible du bloc au cisatracurium et sa stabilité hémodynamique apparente montrent que le cisatracurium pourrait être un relaxant musculaire utile en clinique.

�

Cisatracurium 2006

Health & Medicine

Transcript of Cisatracurium 2006