Corso sul cisatracurium per glaxo 2007 ottobre

Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)

Perché il cisatracurium:Nimbex

Claudio Mellonil.p.

Già Direttore UO Anestesia e Rianimazione Ospedale di Faenza

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 residuoEvita antagonismo

No metaboliti attivi

Mancanza effetti collaterali

Profilodi

sicurezza

Facile conservabilità e

Valutazione rischio/beneficio

No blocco residuo

No metaboliti attivi

No liberazione di istamina;no effetti emodinamici

Evita antagonismo

Facile conservabilità/utilizzo

Indipendenza da organi sicurezza


Dinamica


T1 5% T1 25%

T1 75%

Tempo dalla iniezione

T1

T4

TOFR 0.25


RI,ossia recovery index...:min

0102030405060708090

100

%

T1/TC5

T1/tc25

T1/tc75

T1/TC95

RI 5-25

RI 25-75

RI 5-95


2*ED95 dei principali miorilassanti

farmaco Dose(mg/kg)Succinilcolina 1,0

Rocuronium 0,6

Vecuronium 0,1

Atracurium 0,5

Mivacurium 0,2

Cisatracurium 0,1


onset del cisatracurium

0.00

1.12

2.24

3.36

4.48

6.00

7.12

onset

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


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

0.0

50.0

100.0

150.0

200.0

250.0

300.0

350.0

onset dur T1 25% R 25-75%

succinilcolina

rocuroniumvecuronium

atracuriummivacurium

cisatracurium


Farmacodinamica del cisatracurium(Sorooshian,Anesthesiology 1996)

0

20

40

60

80

100

120

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

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

min


Farmacodinamica del cisatracurium

0

20

40

60

80

100

120

140

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

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

0.1 mg/kg

0.2 mg/kg

0.4 mg/kg

inf cont

min


Dati da Bluestein Bluestein LS,Stinson L W, Lennon R L ,Quessy

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

0

10

20

30

40

50

60

70

min

t125% RI25-75% onset Tof 0.70 doporeversal

0.1 mg/kg

0.15 mg/kg

0.2 mg/kg

N2O,propofol,fentanyl


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

05

101520253035404550

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 mginduction 5 mg kg(-1) TPS

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

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


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

anzianigiovani

*

*


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

319319

47.6 4713.39.7

36.328.4

0

50

100

150

200

250

300

350

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

anzianigiovani


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

0,0

20,0

40,0

60,0

80,0

100,0

120,0

140,0

160,0

bambino adulto Tan adultoSorooshian

Clml/kg/min

V1 ml/kg

Vssml/kg

EC 50 micr/ml

t 1/2

*

*

*


Antagonizzazione


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

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

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


Time from neostigmine administration to TOFR 0.70

0.00

5.00

10.00

15.00

20.00

25.00

I twitch II twitch III twitch IV twitch

low

max

min

mediana



0

5

10

15

20

25

30

35


low

max

min

mediana



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 g/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 ripinf cont

min

microgr/kg/min


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


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


Cisatracurium e insufficienze d ’organo


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

020406080

100120140160180200

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

conc

ng/ml

liver transplnormal


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

0

20

40

60

80

100

120

140

T110% T125% T175% RI25-75%

Tof70

rocu 0.6 mg/kg,isoflurane 0.6%

sanicirrotici

min

*


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

05

101520253035404550

T1 25%a 75

microgr

T1 25%150

micrg

T1 25%225

micrg

T1 90% TOF70%

RI 25-75%

cirroticinormali

min


Mivacurium e insufficienza epatica

0

10

20

30

40

50

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

dati da Devlin et al.,BJA,1993

normcirrotici


Rocuronium nella insuff renale ed epatica

010

2030

4050

6070

80

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

dati da Magorian,Khalil e Szenohradsky

normali

insuff ren

insuff epati

min


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

0

10

20

30

40

50

60

aum

ento

%

T 1 25 T1 90 RI 25-75

rocu ins epatrocu cirrosivecuatraccisatracmivac


Cisatracurium in ICU


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

cisatracurium vecuronium

Recovery time after discontinuation:min to tof 0.70

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

Prolonged paralysis:patients

2 13


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

cardiaca;da Reich e coll


Time to no fade in TOFR:min

30 180

Prolonged paralysis:patients

0 3


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


Time to recovery,min

(52 ,range 35-73) than with

123 ,range , 80-480).

Prolonged recovery of neuromuscular function (>24 h)

0 1


Effetti emodinamici


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

0

5

10

15

20

25

30

ID50 vagal/nmED95

cisatracatracvecu


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

024

68

1012

1416

1820

% HR % MAP

cisatracatrac

Variazioni % rispetto al basale fino a 14 ED95

2 animali con

flu

shing


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

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

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


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


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

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

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

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


No HR/BP changes

HR or BP changes requiring drug treatment

Haemodynamic stability after initial dose(Puhringer et al)

cisatracurium0.15 mg/kg

vecuronium0.1 mg/kg

4.1%0%

n = 137 n = 140


Liberazione di istamina


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


Schramm WM,Papousek A,Michalek-Sauberer A, Czech T,Illievich U. The Cerebral and

Cardiovascular Effects of Cisatracurium and Atracurium in Neurosurgical Patients . Anesth

Analg 1998; 86:123–7

Paz ICU sedati,intub e ventilatiCis 0.15 mg/kg vs atrac 0.75 mg/kgEffetti 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

Cis

atra

c Atr

ac

Cisatrac

Atrac

²

Transcranial Doppler


Quoziente di sicurezza:ED95 istaminoliberatrice/ED95 blocco nm.

0

1

2

3

4

5

6

7

8

safety factor

Dtcmetocatracmivaccisatrac

??


Reazioni allergiche attribuite ai miorilassanti in %;da Laxenaire MCEpidemiology of anesthetic

anaphylactoid reactions. Fourth multicenter survey (July 1994-December 1996)]Ann Fr Anesth Reanim. 1999 Aug;18(7):796-809.

0,00

5,00

10,00

15,00

20,00

25,00

30,00

%

reaz allergiche

cisatracuriumatracuriummivacuriumpancuroniumvecuroniumrocuroniumsuccinilcolina

69.2% delle 477 reazioni

allergiche durante

anestesia in Francia


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 g /kg;1 salivaz,1 si lecca

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

aum.



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

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

cessa dopo diaz i.v



Aum.ampiezza e frequenza EEG

Ch onde appuntite(spiking) e rapide

Spikes,polispikes,bursts parossisticiè+ mioclonie

Convulsioni cloniche


Cisatracurium nell’anziano

Vantaggi a confronto del vecuronium


Spontaneous Complete Recovery Time

0

10

20

30

40

50

60

70

80

90

25%

T1 -

TO

F r

ati

o > 0

.8 (

min

)


18 - 64 years > 65 years

p < 0.001


5665 6365N =

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

Treatment

VecuroniumNimbex

min

ute

s

140

120

100

80

60

40

20

0

Age Category

<65

>=65

Variance in SCRT


Clinical Duration of Block

0

10

20

30

40

50

60

70

Tim

e t

o 2

5%

T 1 (m

in)

cisatracurium0.15 mg/kg

vecuronium0.1 mg/kg

18 - 64 years > 65 years

p < 0.001


Potenziamento :da parte dei vapori anestetici,terapia

anticonvulsivante


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

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

» Aumenta la CL 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 g/kg fino a T1

5%.quando equilibrio fra Fi/Fe del vapore


Risultati dello studio di Wulf et al.

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

100%

depressione % di T1

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

dosi di cisatracurium

DESISOSEVOTIVA

*

**


Durate cliniche del cisatracurium

0

5

10

15

20

25

30

35

40

45

min

T125% RI25-75% TOF0.70

DESISOSEVOTIVA

**

* *


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

10

100

15 30 45microgr/kg di cisatracurium

depressione

T1/T0%

DESISSEVOTIVA


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

0

10

20

30

40

50

60

70

min

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

Sevoflurane 1-2%

propofol 75-150microgr/kg/min


Riprese nm dopo cisatracurium in

infusione :confronto fra TIVA e isoflurane :da J

ellish WS, Brody M, Sawicki K, Slogoff S. Recovery from neuromuscular blockade after either bolus and prolonged infusions of cisatracurium

or rocuronium using either isoflurane or propofol-based anesthetics. Anesth Analg. 2000

Nov;91(5):1250-5.

05

101520253035404550

min

T1 25 T1 75 TOF 0.70 RI 25-75

ISOfluranepropofol


Potenziamento del cisatracurium con gli anestetici alogenati vs propofol

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

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


Cisatracurium nell’obeso


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

0

20

40

60

80

100

120

140

160

180

200

onset sec dur 25%min dose mg

obesi RBW

obesi IBW

normali RBW

*

Cisatr 0.2 mg/kgRemifentanil propofol


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:g/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


Cisatracuriumg/kg/min

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


FINE


Residual curarization

Is the main problem?


Frequency of residual curarization

05

1015202530354045

% of patients postop

Viby 1979BeemerPedersenBevanpanc


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 diatrac,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

% t

of<

0.8

0

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 conbloccoresiduo

popcsenzabloccoresiduo

pancvecu

atracpanc

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


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


low

max

min

mediana



0

10

20

30

40

50

60

70

80


low

max

min

mediana


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

tactile TOF responses.

0

10

20

30

40

50

60

70

80


T1

%

lowmaxminmediana


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.


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 nature of spontaneous recovery from mivacurium‑induced neuromuscular block. Anesth AnaIg 1999; 88:648653,

20 Eriksson U, Sundman E, Olsson R, at al. Functional assessment of the pharynx at rest and during swallowing in partially paralyzed humans, Simultaneous videomanometry and mechanomyography of awake human volunteers. Anesthesiology 1997; 87:1035‑1043.

21 Eriksson LI, Sato M, Severinghaus JW. Effect of a vecuronium‑induced partial neuromuscular block on hypoxic ventilatory response. Anesthesiology 1993; 78:693‑699.

22 Viby‑Mogensen J, Jorgensen BC, Ording H. Residual curarization in the recovery room. Anesthesiology 1979; 50:539‑541,


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)

0,000,100,200,300,400,500,600,700,800,90

lowest tof highest tof

at which test passed or failed

head lift

leg lift

retain tonguedepressor


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

020406080

100

incid ofresidualparalysis

Timebetween

skin closureand

extubation

T4 T1 0.9 Variab ofduration

% o

r m

in

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 muscarinico

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 assesmentusingusing

STST

basalbasal

frequence..frequence..

TOFTOF

fade assessment needsexperiencefade assessment needsexperience

sensibility when IV reappears:whichis the IV/I ratio > 25-30%?sensibility when IV reappears:whichis the IV/I ratio > 25-30%?

tetanictetanic

fade assessmentneeds experiencefade assessmentneeds experience

do not repeat < 5min..do not repeat < 5min..


tactile assessmenttactile assessment

TetanusTetanus

DBSDBS

TOFTOF


Meccanomiographic vs tactileevaluation

Meccanomiographic vs tactileevaluation

Drenck et al.Anesthesiology 79;578:1989.Drenck et al.Anesthesiology 79;578:1989.

qualitative tofevaluation

qualitative tofevaluation

48% chances ofevaluating a real fade48% chances ofevaluating a real fade

qualitative DBSevaluation

qualitative DBSevaluation

9% chances of nondiscerning a real fade9% chances of nondiscerning a real fade


Different muscle groups resistanceDifferent muscle groups resistanceShows sequential relationshipsShows sequential relationships

DiaphragmDiaphragmmm.larinxmm.larinxadductorpollicis

adductorpollicis


Clinical signsClinical signscorrelation with residual forcecorrelation with residual force

patient cooperation!patient cooperation!

tonguedepressorclenching

tonguedepressorclenching

head lift> 5 sechead lift> 5 sec

arm or leglift> 5 secarm or leglift> 5 sec

sustainedhand gripstrenght

sustainedhand gripstrenght


clinical signsclinical signsreliable vs not reliablereliable vs not reliable

TV normalTV normal unreliableunreliable

Neg Press < 25 mmHgNeg Press < 25 mmHgunreliableunreliable

Neg press < 50 mmHgNeg press < 50 mmHgreliablereliable

coughcough unreliableunreliable

eye openingeye openingunreliableunreliable

tongue protrusiontongue protrusionunreliableunreliable

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 relaxation as compared with 9% when fade was absent with DBS. The results demonstrate that DBS is more sensitive than TOF in the manual detection of residual neuromuscular blockade.

:

AB


Probability of being within defined TOFR intervals when 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 dbsfade

fade in dbs,nottof

tof<0.4tof 0.41-0.50tof 051-0.60tof 0.61-0.70tof >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.


Saddler JM, Bevan JC, Donati F, Bevan DR, Pinto MB. 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. Anesthesiology 1990; 73:401-3

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


Viby-Mogensen J, Jensen NH, Engbæk J, Ørding H, 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.

0102030405060708090

100

fade observed

%

inexp.observers exp.observers

true tofr <0.30true tof 0.31-0.40true tof 0.41-0.50true tof 0.51-0.60true tof 0.61-0.70true tof>0.70


Viby-Mogensen et al. Tactile and visual evaluation of response to train-of-four nerve stimulation. Anesthesiology 1985; 63:440-3.

05

101520253035404550

onset offset

Est

Ovest

Nord


Baurain, Michel J., MD, PhD*; Hennart, Daniele A., MD*; Godschalx, Alexandre, MD*; Huybrechts,

Isabelle, MD*; Nasrallah, Georges, MD*; d'Hollander, Alain A., MD, PhD*; Cantraine,

Francis, MS, PhD†Visual Evaluation of Residual Curarization in

Anesthetized Patients Using One Hundred-Hertz, Five-Second Tetanic Stimulation at the Adductor

Pollicis Muscle Anesth Analg 1998; 87:185–9

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 independent investigators, unaware of the left AP-measured TOF ratios, visually evaluated the presence or absence of AP fading elicited by right ulnar nerve 100-Hz, 5-s tetanus. The 30 patients were randomly allocated to receive either 0.5 mg/kg atracurium (n = 15) or 0.1 mg/kg vecuronium (n = 15). The neuromuscular blockade was allowed to resolve spontaneously. A multiple logistic regression analysis was performed by computing the 771 visual observations. The probabilities of success of 100-Hz, 5-s tetanus to detect TOF ratios of 0.8, 0.85, and 0.9 were 99%, 96%, and 67%, respectively. The sensitivity and specificity of 100-Hz, 5-s tetanus as an indicator of TOF ratios of 0.85 and 0.9 are 100% and 75%, 54% and 67%, respectively. We conclude that RF100 Hz visual assessment seems to be highly sensitive in evaluating residual paralysis, as the absence of RF100 Hz visual fading at the AP is compatible with a TOF ratio >0.85. Implications: After the administration of muscle relaxants, the absence of visual fading at the adductor pollicis, elicited in anesthetized patients by 100-Hz, 5-s tetanus, is compatible with a train-of four ratio >0.85. Therefore, clinical observation of fading after 100-Hz, 5-s tetanus seems to be a highly sensitive test in evaluating residual paralysis.


Saitoh, Y.1*; Narumi, Y.1; Fujii, Y.2; Ueki, M.3

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 assessed using the non-dominant hand was comparable with that evaluated using the dominant hand when TOF ratios were 0–0.9, but when TOF ratios reached 0.91–1.00, detection using the non-dominant hand was significantly less common than with the dominant hand (12% vs 33%; P<0.05). Using the non-dominant hand, the probability of detection of fade in response to ulnar nerve stimulation was less than that with the dominant hand and only the absence of DBS3,2 fade ensured sufficient recovery of neuromuscular block.


Saitoh, Yuhji, MD*; Nakazawa, Koichi, MD*;

Makita, Koshi, MD*; Tanaka, Hiroyoshi, MD†;

Amaha, Keisuke, MD*Evaluation of Residual Neuromuscular Block

Using Train-of-Four and Double Burst Stimulation

at the Index 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 frequently detected at the index finger than at the thumb (55% vs 15%, P < 0.05), and at TOF ratios of 0.81–1.00, the percentage of detection of fade in response to DBS3,2 was higher at the index finger than at the thumb (72% vs 40%, P < 0.05). In addition, baseline displacement of the index finger or thumb during tactile assessment of fade in response to neurostimulation was measured videographically. The baseline displacement of the index finger was significantly less than that of the thumb (P < 0.05). In summary, the percentage of tactile detection of fade in response to neurostimulation at the index finger is higher than at the thumb, and the absence of fade in response to DBS3,3 at the index finger is a good indicator of adequate recovery from neuromuscular block. This is probably because of the smaller baseline displacement of the index finger.


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

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 anaesthetist judged the neuromuscular function to have recovered adequately and no fade in the DBS3.3 response could be felt. In group CC (clinical criteria) patients were managed without the use of a nerve stimulator, and the level of neuromuscular block and reversal were evaluated solely on the basis of clinical criteria. In both groups, the TOF ratio was measured by mechanomyography immediately after tracheal extubation. Also, the ability to sustain head lift for 5 s, to protrude the tongue, to open the eyes, and to lift one arm to the opposite shoulder were tested. RESULTS: The TOF ratio, as measured immediately after tracheal extubation, was significantly lower in group CC than in group DBS (means: 0.68 and 0.78, respectively), and the incidence of residual neuromuscular block defined as a TOF ratio < 0.7 was significantly higher in group CC than in group DBS (57 and 24%, respectively). The time from the first TOF measurement until the TOF ratio reached 0.8 was significantly longer in group CC than in group DBs (means: 11.5 and 6.2 min, respectively). No significant differences between the two groups of patients were found in duration of anaesthesia, in times from end of surgery to injection of neostigmine, tracheal extubation or TOF ratio 0.8, in dose of pancuronium, or in any other postoperative variable. CONCLUSION: Routine perioperative manual evaluation of the responses to TOF and DBS3.3 decreased the incidence and the degree of residual block following the use of pancuronium. It did not, however, exclude clinically significant residual paralysis, nor did it influence the amount of pancuronium used during the operation, the duration of anaesthesia or the time from end of surgery to tracheal extubation or to sufficient recovery of neuromuscular function (TOF = 0.8).


Shorten GD, Merk H, Sieber T. Perioperative 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 recovery area, neuromuscular function was assessed electromyographically (using the Datex NMT 221 to measure TOF ratio) and clinically. The incidence of PORC (TOF ratio < 70%) was greater in Group B (47%) than in Group A (15%) (P = 0.029). We conclude that the use of perioperative TOF monitoring decreases the incidence of pancuronium-induced PORC.


Pedersen T, Viby-Mogensen J, Bang U, Olsen NV, Jensen E, Engbæk J. Does

perioperative tactile evaluation of the train-of-four response influence the frequency of postoperative residual

neuromuscular blockade? Anesthesiology 1990; 73:835-9

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 range of) TOF ratios recorded in the recovery room were 0.75 (0.33-0.96) and 0.79 (0.10-0.97) in the vecuronium groups monitored with and without a nerve stimulator, respectively. These ratios were significantly higher than those found in the pancuronium groups, which wre 0.66 (0.06-0.90) and 0.63 (0.29-0.95), respectively. However, no difference was found between the vecuronium and pancuronium groups in the number of patients showing clinical signs of residual neuromuscular blockade, as evaluated by the 5-s head-lift test.(ABSTRACT TRUNCATED AT 250 WORDS).


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.

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 demonstrated that PORC is still a common occurrence even with intermediate duration of action neuromuscular blocking drugs.


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.


Residual curarization in the recovery room after vecuronium†

Short Communication

AUTHOR(S): Baillard, C.1*; Gehan, G.1; 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


Baillard, C.1*; Gehan, G.1; 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 reintubated. In the remaining 139 patients, neuromuscular block was successfully antagonized. Only 20 patients (3.5%) remembered TOF stimulation when questioned 2 h later in the recovery room, and discomfort associated with it was assessed using a visual analogue scale before discharge. We conclude that it is necessary to antagonize residual block produced by vecuronium.


Baillard, C.1*; Gehan, G.1; Reboul-Marty, J.2;

Larmignat, P.1; Samama, C. M.1; Cupa, M


Inadequate recovery from nm block:lieteraure data

author year Nmblocker

Admmode

Assessment:intraop/RR

% ofinadeqreversal

Baillard 200 BJA Vecu intermittent

Clinical/accel

42%


Bevan DR, Kahwaji R, Ansermino LM, et al. 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 achieved by an infusion of mivacurium, to maintain one or two visible responses to train-of-four (TOF) stimulation of the ulnar nerve. At the end of surgery, mivacurium infusion was stopped, and 10 min later, reversal was attempted with saline or 0.5 mg x kg(-1) edrophonium by random allocation. On arrival in the postanesthesia care unit, a blinded observer assessed patients clinically and by stimulation of the ulnar nerve with a Datex electromyogram in the uncalibrated TOF mode. RESULTS: Children arrived in the postanesthesia care unit 8.2 +/- 3-4 min after reversal of neuromuscular block and showed no sign of weakness, either clinically or by TOF stimulation. Although TOF ratio was greater in children who had received edrophonium (1.00 +/- 0.05 vs. 0.93 +/- 0.01, P<0.01), TOF was >0.7 in all children. Adults arrived in the postanesthesia care unit 12.9 +/- 5.3 min after reversal of neuromuscular block(P<0.01 vs. children). Six in the saline group demonstrated weakness (two required immediate reversal of neuromuscular block, and TOF was <0.7 in four others), compared with TOF <0.7 in only one of the edrophonium group (P<0.05). CONCLUSIONS: This study demonstrated that, in adults, failure to reverse mivacurium neuromuscular block was associated with an increased incidence of residual block. Such weakness was not observed in children receiving similar anesthetic and neuromuscular blocking regimens.


TOF-Tube LETTER TO THE EDITOR

AUTHOR(S): Dubois, Philippe E., MD; Broka, 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 (35 cm) prevents any compression lesion around the elbow. Its large diameter ovoid section (13 cm ´ 11 cm) allows the inserting of hands of any size and insures total thumb mobility. Two of the extremities on this apparatus are cut off in order to permit the fingers and the fore-arm to be set, whereas an internal fixation insures the stability of the wrist. A groove located on the upper part of the tube allows for the adaptation of an elastic preload of the thumb, thereby improving the reproduction of the measures (). The symmetrical structure allows bilateral use. The tubular form prevents any thermal variation.

The whole set exhibits minimal encumbrances and is compatible with most surgical installations.

Philippe E. Dubois, MD Serge M. Broka, MD Kurt L. Joucken, MD


TOF-Tube LETTER TO THE EDITOR

AUTHOR(S): Dubois, Philippe E., MD; Broka, Serge M., MD; Joucken, Kurt

L., MDAnesth 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.


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

Fin qui» Department of Anesthesiology, Loyola University Medical Center, Maywood, Illinois 60153,

USA. [email protected]» We examined the recovery characteristics of cisatracurium or rocuronium after bolus or

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


Table 3

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


Table 2


Figure 1

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

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


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

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

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

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

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

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


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

Blocco nm

Curve di decadimento


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


EC50 cisatracurium

TRAN 153 ± 33 ng/mL SOROSHIAN 98+30


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-g/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 g/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


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

2005 Mar;49(3):312-5. : Steroid-based, non-depolarizing neuromuscular-blocking (NMB) drugs (e.g.

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


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

A., M.Sc., F.R.C.A.†; Eastwood, Nigel B., B.Sc.,

F.R.C.A.‡; Boyd, Alastair H., F.R.C.A.‡; Hull, Christopher J., F.R.C.A.§; Wright, Peter M.C.,

M.D., F.F.A.R.C.S.I., †

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

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

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

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


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

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

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

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

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


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

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


Tof count unreliable in the reversal of deep rocu or

cisatrac block

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

» Antagonism of profound cisatracurium and rocuronium block: the role of objective assessment of neuromuscular function.

– Kopman AF, – Kopman DJ, – Ng J, – Zank LM.

» Department of Anesthesiology, New York Medical College, Valhalla, NY, USA. [email protected]» STUDY OBJECTIVE: The purpose of this study is to determine the incidence of significant (train-of-four [TOF] ratio

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


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


Generalità sui miorilassanti


Elementi di sicurezza deimiorilassanti

Elementi di sicurezza deimiorilassanti

safetysafety

fastonset

fastonset

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

organindependent

organindependent

goodshelf life

goodshelf life


metabolismo

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


BreveBreve

Scc,MivaScc,Miva

IntermediaIntermedia

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

LungaLunga

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


BenzilisochinolineBenzilisochinoline

liberazistaminaliberaz

istamina

intsabilitàchimica

intsabilitàchimica

Effettiemodinamici

Effettiemodinamici


AminosteroideiAminosteroidei

menoliberaz

istamina

menoliberaz

istamina

StabilitàchimicaStabilitàchimica

maggiorestabilità

cardiovasc.

maggiorestabilità

cardiovasc.


struttura chimica

benzilisochinoline:atrac,cisatrac,miva

liberazione istaminica maggiore instabilità chimica aminosteroidei:

panc,vecu,rocu,org 9487 stabilità frequenza cardiaca maggiore stabilità chimica


criteri di scelta:

rapidità iot:succi,rocuroniumsucci,rocuronium

brevità di azione:succinilcolina,mivacuriumsuccinilcolina,mivacurium non

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

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


scelta dipendente anche da:

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

infusione,monitoraggio..... costi


Costi Diretti:

acquistoconservazione

indiretti: trattamento ;

lib istaminamialgiebocca seccaPONV…..

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


Dosi di laudanosina(g/ml):subepilettogen

e….

0

0,2

0,4

0,6

0,8

1

1,2

atrac 2 ED95 atrac cis 4 ED95

Fahey 1984Chapple 1987Lien 1996


Concentrazioni di laudanosina dalla

letteratura

0

1

2

3

4

5

6

microgr/ml

normali insuff renale

Fahey 1984Ward 1985Ward 1986Yate(1985)

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


Problemi della laudanosina

Metabolismo:» 70% biliare» 30% renale

metabolizzazione epatica?:tetraidropapaverina?

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

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

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


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

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

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

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

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


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

Pharmacokinetics and pharmacodynamics of cisatracurium in patients with end-stage liver

disease undergoing liver transplantation. Br. J. Anaesth. 1996; 76:624-628 : We determined the pharmacokinetics and pharmacodynamics of cisatracurium, one of the 10

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


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

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

cisatracurium or VEC. » Fifty-four of the 58 patients received NMB drugs before entering this study but demonstrated at least partial

recovery (> or = one twitch) in the train-of-four (TOF) response before initiation of the NMB study drug. » NMB drug infusion was titrated by peripheral nerve stimulation to maintain at least one twitch in the TOF

response. » NMB drugs were infused for 1-5 days. After discontinuation of NMB drug infusion, recovery of neuromuscular

transmission was monitored with an accelerometer. » NMB drug infusion for 28 cisatracurium patients averaged 2.6 +/- 0.2 (mean +/- SEM) micrograms.kg-1.min-1

with a mean duration of 80 +/- 7 h. » After discontinuing cisatracurium administration, recovery to 70% TOF ratio averaged 68 +/- 13 min. The mean

infusion rate for 30 VEC patients was 0.9 +/- 0.1 micrograms.kg-1.min-1 with a mean duration of 66 +/- 12 h. » Neuromuscular recovery after VEC averaged 387 +/- 163 min, which was significantly longer (P = 0.02) than

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


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

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

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

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


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

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


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

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

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

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


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

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

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

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

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

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

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

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

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

Corso sul cisatracurium per glaxo 2007 ottobre

Health & Medicine

Transcript of Corso sul cisatracurium per glaxo 2007 ottobre