Corso sul cisatracurium per glaxo 2007 ottobre

Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)
Perché il cisatracurium:Nimbex
Claudio Melloni
l.p.
Già Direttore UO Anestesia e Rianimazione Ospedale di
Faenza
Consulente di anestesia per l’Azienda Ausl di Ravenna e
l’Ospedale privato accreditato Villa Torri,Bologna

Un po’ di leggenda.....
L’asterisco * nei grafici ;in genere sopra o a
fianco delle colonne degli
istogrammi,identifica la significatività
statistica.
Abbreviazioni:
» SCRT;spontaneous recovery time
» IBW :ideal body weight.
» RBW;real body weight

Problemi di sicurezza dei miorilassanti
Fast onset
Fast offset
No blocco residuo
Evita antagonismo
No metaboliti attivi
Mancanza effetti collaterali
Profilo
di
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
T
1
T
4
TOFR 0.25

RI,ossia recovery index...:min
0
10
20
30
40
50
60
70
80
90
100
%
T1/TC
5
T1/tc
25
T1/tc
75
T1/TC
95
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/kg
0.1 mg/kg
0.1 mg/kg bambini
0.2 mg/kg
0.4 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%
succinilcolina
rocuronium
vecuronium
atracurium
mivacurium
cisatracurium

Farmacodinamica del
cisatracurium(Sorooshian,Anesthesiology 1996)
0
20
40
60
80
100
120
onset T1 25% T1 75% RI 25-75%
2 mg:giov
2 mg anzi
4 mg giov
4 mg anzia
6 mg giov
6 mg anzia
8 mg giov
8 mg anzia
10 mg giov
10 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 dopo
reversal
0.1 mg/kg
0.15 mg/kg
0.2 mg/kg
N2O,propofol,fentanyl

Ripresa spontanea del T1 dopo
una bolo di cisatrac o atrac

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
0
5
10
15
20
25
30
35
40
45
50
min
onset T1 25% T1 75% RI 25-75%

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 mg
induction 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

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/min
V1
Vss ml/kg
T 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
anziani
giovani
*
*

Farmacocinetica del cisatracurium
nell’anziano(Sorooshian et al,Anesthesiology,1996)
319319
47.647
13.39.7
36.328.4
0
50
100
150
200
250
300
350
Clp ml/min V1 lt Vss lt T 1/2 beta
min
anziani
giovani

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 adulto
Sorooshian
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
low
max
min
mediana

to TOFR 0.80
0
5
10
15
20
25
30
35
low
max
min
mediana

to TOFR 0.90
0
10
20
30
40
50
60
70
80
low
max
min
mediana

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%
low
max
min
mediana

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???

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

In definitiva,con un rigido protocollo di
mantenimento del blocco ad 1 max 2
risposte evocate,dopo prostigmina
nessun paziente esibisce blocco residuo
dopo cisatracurium o rocuronium.

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 rip
inf 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

Il cisatracurium non modifica la sua
dinamica nelle insuffiicienze
d’organo,mentre i competitori
vengono influenzati
parecchio..............

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
0
20
40
60
80
100
120
140
160
180
200
Vd ml/kg Clp ml/kg/min T 1/2 min T1 25 RI 25-75 Peak
laudanosine
conc
ng/ml
liver transpl
normal

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%
sani
cirrotici
min
*

Repeated doses of rocuronium in cirrhotic and control
patients receiving isoflurane(Servin et
al.,Anesthesiology,1996,84,)1092
0
5
10
15
20
25
30
35
40
45
50
T1 25%
a 75
microgr
T1 25%
150
micrg
T1 25%
225
micrg
T1 90% TOF
70%
RI 25-
75%
cirrotici
normali
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
norm
cirrotici

Rocuronium nella insuff renale ed
epatica
0
10
20
30
40
50
60
70
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
aumento%
T 1 25 T1 90 RI 25-75
rocu ins epat
rocu cirrosi
vecu
atrac
cisatrac
mivac

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
cisatrac
atrac
vecu

Belmont et al.Comparative pharmacology of atracurium and
one of its isomers 51w89 in rhesus monkeys.Anesthesiology
1993;79:Abstract A 947.
0
2
4
6
8
10
12
14
16
18
20
% HR % MAP
cisatrac
atrac
Variazioni % rispetto al basale fino a 14
ED95
2animaliconflushing

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)
cisatracurium
0.15 mg/kg
vecuronium
0.1 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 NeuroChirurgici 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
Cisatrac
Atrac
Cisatra
Atrac
²
Transcranial
Doppler

Quoziente di sicurezza:
ED95 istaminoliberatrice/ED95 blocco nm.
0
1
2
3
4
5
6
7
8
safety factor
Dtc
metoc
atrac
mivac
cisatrac
??

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
cisatracurium
atracurium
mivacurium
pancuronium
vecuronium
rocuronium
succinilcolina
69.2% delle 477
reazioni allergiche
durante anestesia
in Francia

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
Chondeappuntite(spiking)erapide
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-TOFratio>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
minutes
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
Timeto25%T1(min)
cisatracurium
0.15 mg/kg
vecuronium
0.1 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 a 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

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
DES
ISO
SEVO
TIVA
*
*
*

Durate cliniche del
cisatracurium
0
5
10
15
20
25
30
35
40
45
min
T125% RI25-75% TOF0.70
DES
ISO
SEVO
TIVA
*
*
* *

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
d
e
p
r
e
s
s
i
o
n
e
T
1
/
T
0
%
DES
IS
SEVO
TIVA

: 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 75-150
microgr/kg/min

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.
0
5
10
15
20
25
30
35
40
45
50
min
T1 25 T1 75 TOF 0.70 RI 25-75
ISOflurane
propofol

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/kg
Remifentanil propofol

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

Infusione di
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

Cisatracurium
µg/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

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. wjellis@luc.edu
» 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

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

Table 2

of muscle relaxant. Iso/Cis = patients receiving isoflurane and cisatracurium, Prop/Ci
um. *P < 0.05 compared with Iso/Cis.

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

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

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)

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

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

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. akopman@svcmcny.org
» 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.

» .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%

Generalità sui miorilassanti

Elementi di sicurezza dei
miorilassanti
Elementi di sicurezza dei
miorilassanti
safetysafety
fast
onset
fast
onset
fast offsetfast offset
no residual
curarization
no residual
curarization
non cumulativenon cumulative
no active
metabolites
no active
metabolites
no histamine releaseno histamine release
lack of
cardiovascular
effects
lack of
cardiovascular
effects
organ
independent
organ
independent
good
shelf life
good
shelf 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
liberaz
istamina
liberaz
istamina
intsabilità
chimica
intsabilità
chimica
Effetti
emodinamici
Effetti
emodinamici

AminosteroideiAminosteroidei
meno
liberaz
istamina
meno
liberaz
istamina
Stabilità
chimica
Stabilità
chimica
maggiore
stabilità
cardiovasc.
maggiore
stabilità
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 1984
Chapple 1987
Lien 1996

Concentrazioni di laudanosina
dalla letteratura
0
1
2
3
4
5
6
microgr/ml
normali insuff renale
Fahey 1984
Ward 1985
Ward 1986
Yate(1985)
0,7-1.9 mg/kg/hr per 40-139 hr,ICU
↓
↓

Problemi della laudanosina
Metabolismo:
» 70% biliare
» 30% renale
metabolizzazione
epatica?:tetraidropa
paverina?
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

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

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.

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.

Corso sul cisatracurium per glaxo 2007 ottobre

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