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 .
-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

Residual curarization
Is the main problem?

Frequency of residual
curarization
0
5
10
15
20
25
30
35
40
45
% of patients
postop
Viby 1979
Beemer
Pedersen
Bevanpanc

Ballard et al.Residual curarization in the
recovery room after vecuronium.BJA
2000;84:394-
Incidence of residual block following
vecu evaluated in the RR in 565
patients:
nerve stimulator not used and block not
antagonized
RE:clinicallly significant residual block
found in 42% of patients;33% extubated
before the arrival in RR.

Is your practice
different?

POPC after pancuronium and atracurium(Pedersen AAS
1992;36;312-18)
0
2
4
6
8
10
12
%
POPC
panc
atrac
1559
1057

Viby Mogensen et al,AAS 1997
• 693 paz.randomizzati,cieco
• chir elettiva
• monitoraggio periop con Myotest e Tof
• confronto fra 1-5-2 ED95 di
atrac,vecu,panc.
• Antagonismo se necessario;
• estubaz a tof eguale, tattile e resp adeguata.

Paralisi residua e % di tof<0.40 in RR,subito dopo
trasferimento
0
5
10
15
20
25
30
35
40
45
Tof <0.70 tof<0.40
panc
atrac
vecu

Residual neuromuscular block
and POPC
TOFR Panc Atrac &
vecu
>0.7 4,8% 5,4%
<0.7 16,9%* 4,2%

Andamento temporale del tof
<0.80 nella RR
0
10
20
30
40
50
0 5 10 15 20 30 40 50
min
%tof<0.80
panc
atrac
vecu

Risk of POPC following
abdominal surgery
0
10
20
30
40
50
60
70
20 30 40 50 60 70 80
age
%
panc
vecu & atra

Postoperative pulmonary
complications
0
5
10
15
20
%
popc popc con
blocco
residuo
popc
senza
blocco
residuo
panc
vecu
atrac
panc
vecu
atrac

Popc secondo il tipo di
chirurgia
0
2
4
6
8
10
12
14
16
%
popc
addom
ortop
ginecol

Fattori di rischio per POPC nello studio
AAS 1997
Tipo di chirurgia;freq * 2-10(addominale)
età:ogni 10 anni * 1.68
durata di anestesia(> o < 200 min)*3.3
panc e tof<0.70:*5

How to avoid residual
nmblock
Do not use long acting nmb
Monitoring!!!
At a minimun,measure TOFR at the end
of the case without antagonizing or
before antagonizing
consider always the response to nerve
stimulation together with clinical signs
and symptoms…..

Clinical tests of postoperative
neuromuscular recovery
Unreliable
» sustained eye opening
» tongue protrusion
» arm lift to opposite
shoulder
» normal TV
» normal or near normal
VC
» max insp pressure < = 25
cmH2O
Reliable
» sustained head lift for 5
sec
» sustained arm lift for 5
sec
» sustained hand grip for 5
sec
» sustained tongue
depressor test
» max insp press > 50 cm
H2O

Time from neostigmine
administration to TOFR 0.70
0,00
5,00
10,00
15,00
20,00
25,00
low
max
min
mediana

to TOFR 0.80
0
10
20
30
40
50
60
70
80
low
max
min
mediana

17 O'Hara DA, Fragen RJ, Shanks CA.
Comparison of visual and measured
train of four recovery after‑ ‑
vecuronium induced neuromuscular blockade‑
using two anaesthetic techniques. Br J
Anaesth 1986; 58:1300 1302.‑
18 Kopman AF. Tactile evaluation of
train of four count as an indicator of reliability‑ ‑
of antagonism of vecuronium or‑
atracurium induced neuromuscular blockade.‑
Anesthesiology 1991; 75:588 593.‑
19 Lien CA, Belmont MR, Abalos A, at al. The

31 Eikermann M, Groeben H, Peters J.
Prediction of the effects of partial
neuromuscular blockade on pulmonary
function by accelerography and
mechanomyography of adductor pollicis
muscle [Abstract]. Anesthesiology 2001;
95:A1021.

Valutazione del blocco residuo
Valutazione della ripresa neuromuscolare:
» prima del risveglio:
– valutazione della forza contrattile in risposta alla
stimolazione:MMG,EMG.accelerometria,qualitative e
quantitative:TOF,DBS,tetano 50,100 HZ…….;
– TV,RR,forza insp ed esp
» dopo il risveglio,volontarietà:
– sollevamento testa> 5 sec
– sollevamento braccio
– stretta di mano
– protrusione lingua
– apertura ampia occhi

Kopman et al.Relationship of the train of four fade ratio to
clinical signes and symptoms of residual paralysis in awake
volunteers.Anesthesioloogy,1997;86:765-71.
Volontari sani
infusione di mivacurium
monitoraggio Datex 221 NMT
valutazione;stretta di mano
sollev,testa & gamba per 5 sec.
Ritenzione di abbassalingua

Clinical signs of residual weakness vs tof
at the AP(Kopman,Anesthesiology,1997;86:765-71)
0,00
0,10
0,20
0,30
0,40
0,50
0,60
0,70
0,80
0,90
lowest tof highest tof
at which test passed or failed
head lift
leg lift
retain tongue
depressor

Osservazioni cliniche sulla relazione fra tof e correlati di
forza:
disturbi visivi sempre con tof di
0.90(diplopia,diff.seguire oggetti in moto,ecc)
forza dei masseteri ridotta sempre
sollev.testa e gamba sempre possibile > 0.60
stretta di mano variabile,ma 83% del basale a
tof 0.90
per tof < 0.75 tutti disturbati

Conclusioni delle correlazioni fra segni clinici di forza
muscolare e tof
Capacità di ritenzione
dell’abbassalingua è un test più
sensibile del sollevamento del capo
tof <1 ancora residuano disturbi visivi e
senso generalizzato di fatica
tof = 1 (o altri monitoraggi) per
dimissione in chirurgia ambulatoriale??

Assiomi della ripresa nm.
TOF > 0.70 sicuro indice della ripresa
nm……….. Ali HH, Wilson RS, Savarese JJ, Kitz RJ:
The effect of tubocurarine on indirectly elicited train-
of-four muscle response and respiratory
measurements in humans. Br J Anaesth 47:570-4,
1975
Brand JB, Cullen DJ, Wilson NE, Ali HH:
Spontaneous recovery from nondepolarizing
neuromuscular blockade: Correlation between clinical
and evoked responses. Anesth Analg 56:55-8, 1977

Mutazioni occorse
Esplosione della chirurgia ambulatoriale
pressione per la diminuzione della
spesa sanitaria
aumento delle persone anziane e
debilitate anche in chir amb.
Disponibilità di nuovi farmaci

Rivalutazione della pratica
clinica
Età e stato di salute differiscono fra volontari sani e
pazienti!
La prassi clinica e l’utilizzo dei miorilassanti variano fra i
diversi centri ambulatoriali
il monitoraggio degli effetti nm non è praticato in
ospedale,figurarsi nei centri ambulatoriali!
I metodi di monitoraggio usati da Kopman et al si applico
ad una ampia gamma di situazioni cliniche.
Esistono pesanti pressioni economiche per la
diminuzione della spesa sanitaria.

Implicazioni del lavoro di
Kopman:1
I paz chirurgici sono in genere più anziani e ammalati dei
volontari sani dello studio di Kopman/( ASA 1, entro il 15%
del peso ideale,tra 23—33 anni….)
gli effetti residui dei miorilassanti è probabile possano essere
+ significativi nella pratica ambulatoriale con pazienti +
anziani e debilitati.
Si potrebbe arguire che i paz.con sedazione residua siano
meno attenti a disturbi visivi e
debolezza dei muscoli facciali;ma è anche vero che dal punto
di vista della sicurezza i paz postop siano esposti a rischio
maggiore di aumento della morbilità,poichè la debolezza
residua nm può essere aggravata da residui dell’anestesia.

Implicazioni del lavoro di
Kopman:2
mivacurium non è rappresentativo dei
miorilassanti usati in chir amb;il mercato è
dominato dai miorilassanti ad azione
intermedia quali vecuronium, atracurium,
rocuronium, cisatracurium
se una paralisi residua permane per un’ora
dopo interruzione del mivac,caratterizzato da
un RI di pochi min,che succede dopo la
somministrazione dei mioril a durata
intermedia(RI 20-30 min )?

Correlazione soggettiva-
oggettiva(palpazione-
meccanomiografia)
1 Twitch= T110%
3 twitches=T1 25%

Maybauer D,Geldner G,Blobn,er M et al.Incidence and
duration of residual paralysis at the end of surgery after
multiple administrations of cisatracurium and
rocuronium.Anaesthesia 2007;62:12-17.
Incidence of residual paralysis after cisatracurium and
rocuronium
0
20
40
60
80
100
incid of
residual
paralysis
Time
between
skin closure
and
extubation
T4 T1 0.9 Variab of
duration
%ormin
cisatracurium
rocuronium

In summary, our data show that after repeated administration,
the duration of action and its variability are greater with
rocuronium than with cisatracurium. These pharmacodynamic
differences do not necessarily translate into a higher incidence of
residual paralysis, because clinicians who monitor
neuromuscular transmission can balance some effects of the
greater duration of action and variability of rocuronium by
terminating repeated NBD administration earlier. Cisatracurium
may, however, have some clinically relevant advantages when
NB is required for long term (major) surgery, particularly when‑
anaesthetists do not monitor neuromuscular function.

Chemrorecet perif
Chemrecett.centr SNC
Ipossia
ipercapnia iperventilazione

Corpi carotidei
Sito nicotinico
Sito
muscari
nico
nmb
atropina
ipossia

Conclusioni
Esiste evidenza sperimentale e
clinica che i nmb nondepolarizzanti
inteferiscano con il controllo della
ventilazione in condizioni di
ipossia,verosimilmente attraverso
una depressione reversibile della
attività chemorecettoriale dei corpi
carotidei implicazioneclinica

Problems of tactile or visual assesmentProblems of tactile or visual assesment
usingusing
STST
basalbasal
frequence..frequence..
TOFTOF
fade assessment needs
experience
fade assessment needs
experience
sensibility when IV reappears:which
is the IV/I ratio > 25-30%?
sensibility when IV reappears:which
is the IV/I ratio > 25-30%?
tetanictetanic
fade assessment
needs experience
fade assessment
needs experience
do not repeat < 5
min..
do not repeat < 5
min..

tactile assessmenttactile assessment
TetanusTetanus
DBSDBS
TOFTOF

Meccanomiographic vs tactile
evaluation
Meccanomiographic vs tactile
evaluation
Drenck et al.Anesthesiology 79;578:1989.Drenck et al.Anesthesiology 79;578:1989.
qualitative tof
evaluation
qualitative tof
evaluation
48% chances of
evaluating a real fade
48% chances of
evaluating a real fade
qualitative DBS
evaluation
qualitative DBS
evaluation
9% chances of non
discerning a real fade
9% chances of non
discerning a real fade

Different muscle groups resistanceDifferent muscle groups resistance
Shows sequential relationshipsShows sequential relationships
DiaphragmDiaphragm mm.larinxmm.larinx
adductor
pollicis
adductor
pollicis

Clinical signsClinical signs
correlation with residual forcecorrelation with residual force
patient cooperation!patient cooperation!
tongue
depressor
clenching
tongue
depressor
clenching
head lift
> 5 sec
head lift
> 5 sec
arm or leg
lift> 5 sec
arm or leg
lift> 5 sec
sustained
hand grip
strenght
sustained
hand grip
strenght

clinical signsclinical signs
reliable vs not reliablereliable vs not reliable
TV normalTV normal unreliableunreliable
Neg Press < 25 mmHgNeg Press < 25 mmHg
unreliableunreliable
Neg press < 50 mmHgNeg press < 50 mmHg reliablereliable
coughcough unreliableunreliable
eye openingeye opening
unreliableunreliable
tongue protrusiontongue protrusion unreliableunreliable
before patient cooperationri....before patient cooperationri....

Special neuromuscular
moniring
Mantiene quello che
promette?

Drenck NE, Ueda N, Olsen NV, et al. Manual evaluation of
residual curarization using double burst stimulation: A
comparison with train-of-four. Anesthesiology 1989; 70:578-81
- Double burst stimulation (DBS) is a new mode of stimulation
developed to reveal residual neuromuscular blockade under clinical
conditions. The stimulus consists of two short bursts of 50 Hz tetanic
stimulation, separated by 750 ms, and the response to the stimulation is
two short muscle contractions. Fade in the response results from
neuromuscular blockade as with train-of-four stimulation (TOF). The
authors compared the sensitivity of DBS and TOF in the detection of
residual neuromuscular blockade during clinical anaesthesia. Fifty-two
healthy patients undergoing surgery were studied. For both stimulation
patterns the frequencies of manually detectable fade in the response to
stimulation were determined and compared at various
electromechanically measured TOF ratios. A total of 369 fade
evaluations for DBS and TOF were performed. Fade frequencies were
statistically significantly higher with DBS than with TOF, regardless of the TOF ratio
level. Absence of fade with TOF implied a 48% chance of considerable residual
:
AB

different clinical fade evaluations are given (Drenck NE, Ueda N,
Olsen NV, et al. Manual evaluation of residual curarization using double burst
stimulation: A comparison with train-of-four. Anesthesiology 1989; 70:578-81)
0
10
20
30
40
50
60
%
no tof fade no tof,no dbs
fade
fade in dbs,not
tof
tof<0.4
tof 0.41-0.50
tof 051-0.60
tof 0.61-0.70
tof >0.70

Dbs 3-3
Drenck NE, Ueda N, Olsen NV, et al. Manual evaluation of residual curarization using
double burst stimulation: A comparison with train-of-four. Anesthesiology 1989; 70:578-
81)
Absence of fade with tof implies a 52%
probability than tof>0.60
absence of fade with dbs implies a tof
>0.60 in 91% of cases
only tOFR<0.40 can be assessedd manually
therefore,evaluation of DBS is relevant only
when there is no fade to tof

Conclusions:
Drenck NE, Ueda N, Olsen NV, et al. Manual evaluation of residual curarization using
double burst stimulation: A comparison with train-of-four. Anesthesiology 1989; 70:578-
81)
absence of fade to DBS normally
excludes severe residual nm
blockade(tofr<0.60) BUT
DOESNOT NECESSARIKLY
INDICATE ADEQUATE CLINICAL
RECOVERY.

Comparison of double-burst and train-of-four stimulation to
assess neuromuscular blockade in children. Anesthesiology
1990; 73:401-3
Double-burst stimulation (DBS), a new technique to evaluate neuromuscular function,
consists of two 50-Hz trains of 60-ms duration and 750 ms apart. DBS was compared
with train-of-four (TOF) stimulation in 21 children aged 3-10 yr, during halothane
anesthesia. On one arm the ulnar nerve was stimulated supramaximally with TOF
stimulation every 12 s and the force of the evoked contraction of the adductor pollicis
measured with an FTO3 force transducer and recorded on paper. Atracurium (0.4-0.5
mg.kg-1) was administered. During recovery from neuromuscular blockade, TOF
stimulation was interrupted periodically and DBS substituted. The same stimulation
patterns were applied to the ulnar nerve of the other arm simultaneously, and the
clinical anesthesiologist was asked to estimate the degree of fade with both. There
was good correlation between the measured TOF ratio (ratio of fourth to first
response) and DBS ratio (ratio of second to first response). The TOF and DBS ratios
above which fade could no longer be appreciated manually were (mean +/- SEM) 0.44
+/- 0.03 and 0.67 +/- 0.04 (P = 0.0002). Corresponding ranges were 0.3-0.8 for TOF
and 0.4-0.9 for DBS, but DBS fade was always apparent if TOF fade could be
detected. Therefore, in children, DBS is more sensitive than is TOF stimulation for the
clinical assessment of recovery from neuromuscular blockade.

Saddler et al Comparison of double-burst and train-of-four
stimulation to assess neuromuscular blockade in children.
Anesthesiology 1990; 73:401-3
Children 3-10 years
TPS/N2O/haloth
atracurium 0.4-0.5 mg/kg
MMG
TOF vs DBS,MMG vs tactile.visual

Saddler et al Comparison of double-burst and train-of-four
stimulation to assess neuromuscular blockade in children.
TOF & DBS linearly related close to 1
anesthesioogist tended to overestimate
recovery with tof and DBS
fade could no longer be detected at a
value of TOF 0.44+/-0.03
with DBS fade detected until tof 0,67+/-
0.04

Skovgaard LT, Chæmmer-Jørgensen B. Tactile and visual
evaluation of response to train-of-four nerve stimulation.
Anesthesiology 1985; 63:440-3.
Diaz/tps/N2O 66%/haloth 0.75-1.5%
IOT with SC C ,then panc
simult MMG in one arm & visual/tactile
evaluation in the opposite.
Experienced and inexperienced
anesthesiologists
6 vdifferent TOFR forn every patient

Viby-Mogensen et al Tactile and visual evaluation of
response to train-of-four nerve stimulation. Anesthesiology
1985; 63:440-3.
0
10
20
30
40
50
60
70
80
90
100
fade
observed
%
inexp.observers exp.observers
true tofr <0.30
true tof 0.31-0.40
true tof 0.41-0.50
true tof 0.51-0.60
true tof 0.61-0.70
true tof>0.70

Viby-Mogensen et al. Tactile and visual evaluation of
response to train-of-four nerve stimulation. Anesthesiology
1985; 63:440-3.
0
5
10
15
20
25
30
35
40
45
50
onset offset
Est
Ovest
Nord

Patients Using One Hundred-Hertz, Five-Second Tetanic
Stimulation at the Adductor Pollicis Muscle
We were looking for a clinical test to indicate a
train-of-four (TOF) ratio of approximately 0.9.
We compared the adductor pollicis muscle
(AP) visually evaluated response to ulnar
nerve 100-Hz, 5-s tetanus (RF100 Hz) with
the measured AP TOF ratio in 30 ASA
physical status I or II adult anesthetized
(propofol, sufentanil, N2O/O2) patients. After
the induction of anesthesia, the left ulnar
nerve was stimulated at the wrist (single twitch
and TOF) and the resultant isometric force
was measured. When TOF was assessed, the

Tactile evaluation of fade of the train-of-four and double-
burst stimulation using the anaesthetist's non-dominant hand
Br. J. Anaesth. 1999; 83:275-278
We have studied detection of fade in
response to train-of-four (TOF), double-burst
stimulation3,3 (DBS3,3) or DBS3,2, assessed
tactilely by the anaesthetist using the index
finger of the non-dominant hand and the
thumb of the patient, compared with that
assessed when the index finger of the
dominant hand was used. The probability of
detection of any fade in response to TOF or
DBS3,3 using the non-dominant hand was
significantly less than when the dominant
hand was used (P<0.05). The probability of
identification of fade in response to DBS3,2

Finger Anesth Analg 1997;
84:1354
We examined the percentage of tactile
detection of fade in response to train-of-four
(TOF), double burst stimulation3,3 (DBS3,3),
or DBS3,2 at the index finger compared with
that at the thumb during continuous infusion of
vecuronium. One hundred five adult patients
were studied. At TOF ratios (T4/T1) of 0.41–
0.70, fades in response to TOF were more
frequently identified by tactile means at the
index finger than at the thumb (58% vs 26%,
P < 0.05). Similarly, at TOF ratios of 0.61–
0.90, fades in response to DBS3,3 were more

burst stimulation decreases, but not eliminates, the
problem of postoperative residual paralysis. Acta
Anaesthesiol Scand 1998; 42:1168-74
BACKGROUND: Routine perioperative monitoring with accelero-
myography might prevent residual block, whereas routine tactile
evaluation of the response to train-of-four (TOF) nerve
stimulation does not. The purpose of this prospective,
randomised and blinded study was to evaluate the effect of
manual evaluation of the response to double burst stimulation
(DBS3.3) upon the incidence of residual block. METHODS: Sixty
adult patients scheduled for elective abdominal surgery were
included in the study. Pancuronium 0.08 to 0.1 mg kg-1 was
given for relaxation and tracheal intubation. For maintenance of
neuromuscular block, pancuronium 1-2 mg was administered.
The patients were randomly allocated into two groups. In group
DBS (double burst stimulation) the degree of block during
anaesthesia was assessed by manual evaluation of the
response to TOF nerve stimulation. During reversal, when no
fade was detectable in the TOF response, the stimulation pattern
was changed to DBS3.3. The trachea was extubated when the

train-of-four monitoring and residual
curarization. Can J Anaesth 1995; 42:711-
15.<ldn>!
It has been suggested that perioperative train-of-four (TOF)
monitoring does not reduce the incidence of postoperative
residual curarization (PORC). The purpose of this study was to
examine whether the use of tactile assessment of the response
of the adductor pollicis to supramaximal TOF stimulation of the
ulnar nerve at the wrist during anaesthesia affected the
incidence of PORC. Thirty-nine ASA I or II surgical patients were
studied during thiopentone/fentanyl N2O/enflurane anaesthesia.
Pancuronium (70-100 micrograms.kg-1) was used to facilitate
tracheal intubation and additional pancuronium increments used
to maintain surgical relaxation. The requirement for incremental
doses of pancuronium and adequacy of recovery following
reversal were assessed according to random allocation, either
with (Group A; n = 20) or without (Group B; n = 19) access to
TOF monitoring. Patients in the two groups received neostigmine
in similar doses (Group A: 53 micrograms.kg-1 (5.9); Group B:
55 micrograms.kg-1 (5.4)). On arrival of the patient to the

influence the frequency of postoperative
residual neuromuscular blockade?
The authors conducted a randomized controlled clinical trial to
evaluate the usefulness of perioperative manual evaluation of
the response to train-of-four (TOF) nerve stimulation. A total of
80 patients were divided into four groups of 20 each. For two
groups (one given vecuronium and one pancuronium), the
anesthetists assessed the degree of neuromuscular blockade
during operation and during recovery from neuromuscular
blockade by manual evaluation of the response to TOF nerve
stimulation. In the other two groups, one of which received
vecuronium and the other pancuronium, the anesthetists
evaluated the degree of neuromuscular blockade solely by
clinical criteria. The use of a nerve stimulator was found to have
no effect on the dose of relaxant given during anesthesia, on the
need for supplementary doses of anticholinesterase in the
recovery room, on the time from end of surgery to end of
anesthesia, or on the incidence of postoperative residual
neuromuscular blockade evaluated clinically. The median (and

Recovery from neuromuscular blockade: residual curarisation
following atracurium or vecuronium by bolus dosing or
infusions. Acta Anaesthesiol Scand 1995; 39:288-93.
AB - We conducted a survey of the incidence of Postoperative
Residual Curarisation (PORC) in two groups of patients following
the use of atracurium or vecuronium. In the first group (B) the
neuromuscular blocking drugs were administered by bolus
dosing, and in the second group (I) by continuous fusion. On
arrival in the recovery room, neuromuscular function was
assessed both by compound evoked electromyogram (EMG) in
a train of four pattern and also clinically, by the ability to sustain
a headlift for > 5 seconds, and to cough. Results were obtained
from 150 patients (100 in group B and 50 in group I). The
incidence of PORC, as defined by a train of four ratio of < 0.7, on
arrival in the recovery room was 12% in group B, and 24% in
group I. Clinical criteria of adequate neuromuscular reversal
revealed different results, with the majority of patients being
unable to perform either clinical test on arrival in recovery. Those
patients in whom a peripheral nerve stimulator was used intra-
operatively did not have a reduced incidence of PORC. We have

Baillard C, Gehan G, Reboul-Marty J,
Larmignat P, Samama CM, Cupa M. Residual
curarization in the recovery room after
vecuronium. Br J Anaesth 394-5; 2000:84.
2: Viby-Mogensen J, Jørgensen BC, Ørding
M. Residual curarization in the recovery room.
Anesthesiology 1979; 50:539-41.
3: Bevan DR, Smith CE, Donati F.
Postoperative neuromuscular blockade: a
comparison between atracurium, vecuronium,
and pancuronium. Anesthesiology 1988;
69:272-6.

Reboul-Marty, J.2; Larmignat, P.1; Samama, C.
M.1; Cupa, M.1
Br. J. Anaesth. 2000; 84
residual block after
anaesthesia(propof/fent/isof)
only vecuronium but no anticholinesterase
568 consecutive patients
on admission to the recovery room. The ulnar
nerve was stimulated submaximally using
TOF stimulation (30 mA). Postoperative
residual curarization was defined as a TOF
ratio <0.7

Reboul-Marty, J.2; Larmignat,
P.1; Samama, C. M.1; Cupa, M
. Of the 568 patients, 239 (42%) had a TOF
<0.7 in the recovery room. These patients had
received a larger cumulative dose of
vecuronium than patients who had full
recovery (mean 7.7 (SD 3.6) mg vs 6.2 (2.7)
mg; P<0.05) and a shorter time had elapsed
since the last vecuronium dose (117 (70) min
vs 131 (80) min; P<0.05). Of 435 patients
whose trachea was extubated, 145 (33%)
exhibited inadequate recovery from
neuromuscular block. Six of these had one or
no response to TOF stimulation and were

Reboul-Marty, J.2; Larmignat,
P.1; Samama, C. M.1; Cupa, M

Inadequate recovery from nm
block:lieteraure data
author year Nm
blocker
Adm
mode
Assessm
ent:intrao
p/RR
% of
inadeq
reversal
Baillard 200 BJA Vecu intermitte
nt
Clinical/ac
cel
42%

Residual block after mivacurium with or
without edrophonium reversal in adults and
children. Anesthesiology 1996; 84:362-7.
AB - BACKGROUND: The rapid recovery
from mivacurium- induced neuromuscular
block has encouraged omission of its reversal.
The purpose of this study was to determine, in
children and in adults, whether failure to
reverse mivacurium neuromuscular block was
associated with residual neuromuscular block
on arrival in the postanesthesia care unit.
METHODS: In 50 children, aged 2-12 yr, and
50 adults, aged 20-60 yr, anesthesia was
induced and maintained with propofol and
fentanyl, and neuromuscular block was

Serge M., MD; Joucken, Kurt L., MD
Anesth Analg 2000; 90:232
We would like to present a hand and forearm
protection device that optimizes the
monitoring of neuromuscular function by
accelero-myography in a maximum of
surgical procedures while reducing spatial
obstructions and offering maximal protection
to the patient. In our opinion, this constitutes
an evolution compared with the setting
systems currently used for this purpose.
The structure is tubular () and made out of
rigid composite materials. Its limited length

AUTHOR(S): Dubois, Philippe E., MD; Broka,
Serge M., MD; Joucken, Kurt L., MD
Anesth Analg 2000; 90:232

Biblio da cercare
Fawcett WJ, Dash A, Francis GA, Liban JB, Cashman JN. Recovery from neuromuscular
blockade: residual curarisation following atracurium or vecuronium by bolus dosing or infusions.
Acta Anaesthesiol Scand 1995; 39:288-93.
Fruergaard K, Viby-Mogensen J, Berg H, El-Mahdy AM. Tactile evaluation of the response to
double burst stimulation decreases, but not eliminates, the problem of postoperative residual
paralysis. Acta Anaesthesiol Scand 1998; 42:1168-74
Beemer GH, Reeves JH, Bjorksten AR. Accurate monitoring of neuromuscuiar blockade using a
peripheral nerve stimulator: a review. Anaesth Intensive Care 1990; 18A90 496.‑
Hayes AH, Mirakhur RK, Breslin DS, at al. Postoperative residual block after intermediate acting‑
neuromuscular blocking drugs. Anaesthesia 2001; 56:312 318.‑

Biblio sulla residual curarization
1 Williams MT, Rice 1, Ewen SP, et al. A comparison ofthe effect
oftwo anaesthetic techniques on surgical conditions during
gynaecological laparoscopy. Anaesthesia 2003; 58: 574 8.‑
2 Ptwra AI, Rorarius MG, Manninen P, et al. The costs of intense neuromuscular block for anesthesia during endolaryngeal procedures due to waiting time. Anesthesia and Analgesia 1999; 88: 1335 9.‑
3 Sundman E, Witt H, 01sson R, et al. The incidence and mechanisms ofpharyngeal and upper esophageal dysfunction in partially paralyzed humans: pharyngeal videoradiography and simultaneous
manometry after atracurium. Anesthesiology 2000; 92: 977 84.‑
4 Eikermarm M, Vogt FM, Herbstreit F, Vahid Dastgerdi M,‑
Zenge MO, Ochterbeck C, de Greiff A, Peters J. The
predisposition to inspiratory upper airway collapse during partial neuromuscular blockade. Amj Respir Grit Med 2006: Oct 5; [Epub ahead ofprint].
5 Eikermann M, Groeben H, FlusingJ, et al. Accelerometry of adductor pollicis muscle predicts recovery of respiratory function from neuromuscular blockade. Anesthesiology 2003; 98: 1333 7.‑
6 Berg H, PLoed J, Viby Mogensen J, et al.‑ Residual neuromuscular block is a risk factor for postoperative pulmonary complications. A prospective, randon iised, and blinded study ofpostoperative‑
pulmonary complications after atracu
rium, vecuronium and pancuronium. Acta Anaesthesiologica Scandinavica 1997; 41: 1095 103.‑
@ 2007 The Authors Journal compilation @ 2007 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia, 2007, 62, pages 12 17‑
12
D. M. Maybauer et aL Residual paralysis after cisatracurium and rocuronium‑
7 Hayes AH, M~rakhur RK, Breslin DS, et al. Postoperative residual block after intermediate acting neuromuscular blocking drugs. Anaesthesia 2001; 56: 312 8.‑ ‑
8 Cammu G, De Witte J, De Veyider J, et al. Postoperative residual paralysis in outpatients versus inpatients. Anesthesia and Analgesia 2006; 102: 426 9.‑
9 Fuchs Buder T, Hofinnockel R, Geldner G, et al. The use of neurornuscular monitoring in Germany. Anaesthesist 2003; 52: 522 6~‑ ‑
10 Fuchs Buder T, Eikermann M. Residual neuromuscular blockades Clinical consequences, frequency and avoidance strategies. Anaesthesist 2006; 55: 7 16.‑ ‑
11 Arain SR, Kern S, Ficke DJ, et al. Variability of duration of
action of neuromuscular blocking drugs in elderly patients.‑
Acta Anaesthesiologica Scandinavica 2005; 49: 312 5.‑
Sparr Hj, Beaufort TM, Fuchs Buder T. Newer neuro-‑
muscular blocking agents: how do they compare with
established agents? Drugs 2001; 61: 919 42.‑
13 Cammu G, de Baerdemaeker L, den Blautwen N, et al. Postoperative residual curarization with cisatracurium and rocuronium infusions. European Journal of Anaesthesiology 2002; 19: 129 34.‑
14 Naguib M, Samarkandi AH, Ammar A, et al. Comparative clinical pharmacology of rocuronium, cisatracurium, and their combination. Anesthesiology 1998; 89: 1116 24.‑
@ 2007 The Authors
Journal compilation C 2007 The Association of Anaesthetists of Great Britain and Ireland
15 Puhringer FK, Heier T, Dodgson M, et al. Double blind comparison of the variability in spontaneous recovery of cisatracurium and vecuronium induced neuromuscular block in adult and elderly patients.‑ ‑ ‑
Acta Anaesthesiologica Scandinavica 2002; 46: 364 71.‑
16 Schmith VD, Fiedler~Kelly J, Phillips L et al. Dose proportionality of cisatracurium. Journal of Clinical Pharmacology 1997; 37: 625 9.‑
17 van Miert MM, Eastwood NB, Boyd AH, et al. The pharmacokinetics and pharmacodynarnics of rocuronium in patients with hepatic cirrhosis. Britishjournal of Clinical Pharmacology 1997, 44: 139 44.‑
18 Leshe K, Sessler 131, Bjorksten AR, et al. Mild hypothermia alters propofol pharmacokinetics and increases the duration of action of atracurium. Anesthesia and Analgesia 1995; 80: 1007 14.‑
19 Schleppers ABM, Berry M, Bender Hj, Geldner G, Martinj. Costs analysis of anaesthesia in German hospitals in the reference year 2002. Anaesthesiologie und Intensivmedizin 2005; 46: 23 8.‑
20 Foster JG, Kish SK, Keenan CH. National practice with
assessment and monitoring of neuromuscular blockade.
Critical Care Nursing Quality 2002; 25: 27 40.‑
Baillard C, ClecI C, Catineau J, et al. Postoperative
residual neuromuscular block: a survey of management.
British Journal of Anaesthesia 2005; 95: 622 6.‑

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

Corso sul cisatracurium per glaxo 2007 ottobre

Corso sul cisatracurium per glaxo 2007 ottobre

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