S ugammadex messina

Le gammaciclodestrine:
Sugammadex
C.Melloni
Libero professionista
Messina,4 ottobre 2012),I-SIVA

Referenze biblio
 Ci sono 220 articoli in PubMed sul
Sugammadex……………..(8 settembre
2012)
Messina ,4 ottobre 2012),I-SIVA
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Organizzazione della lettura
 SAR
 La paralisi residua?
 Antagonismo del blocco;TIVa;inalatoria
 Antagonismo confronto AchE
 Rescue per CV CI
 Antagonismo anafilassi
 Considerazioni sul monitoraggio;a good
drug……….
Messina,4 ottobre 2012,I-SIVA

Utilizzi delle ciclodestrine(CD)Rajeswari
Challa, Alka Ahuja, Javed Ali, R.K. Khar.Cyclodextrins in Drug Delivery.AAPS
PharmSciTech 2005; 6 (2)
 Formano complessi di inclusione con importanti modificazioni nelle
proprietà dei farmaci,quali aumento di solublità,aumento della
stabilità chimica e fisica
» Nuovi modi di somministrare farmaci:liposomi, microsfere, microcapsule,
nanoparticelle
» Solubilità,
» dissoluzioine,
» biodisponibilità,
» sicurezza ,
» stabilità,
» eccipienti .
 ,ecc,ecc…………..

RELAZIONE STRUTTURA-
ATTIVITÀ

New reversal agents:i nuovi antagonisti
 Concetto della chelazione chimica
 Le ciclodestrine sono un gruppo di oligosaccaridi
capaci di incapsulare molecole lipofiliche,tra cui
anche gli steroidi.

Referenze in Pubmed.(sept 2003)
 Bom A, Bradley M, Cameron K, Clark JK, Van Egmond J, Feilden H, MacLean EJ, Muir AW, Palin R,
Rees DC, Zhang MQ.
A novel concept of reversing neuromuscular block: chemical
encapsulation of rocuronium bromide by a cyclodextrin-based synthetic
host.
Angew Chem Int Ed Engl. 2002 Jan 18;41(2):266-70.
 Sparr HJ.
Cyclodextrin. A new concept for antagonizing muscle relaxants]
Anaesthesist. 2002 Nov;51(11):929-30.

Prof.Bom

Referenze in Pubmed.(sept 2003):nascita chimico-fisica
 Epemolu O, Mayer I, Hope F, Scullion P, Desmond P.
Liquid chromatography/mass spectrometric bioanalysis of a modified gamma-
cyclodextrin (Org 25969) and Rocuronium bromide (Org 9426) in guinea pig plasma
and urine: its application to determine the plasma pharmacokinetics of Org 25969.
Rapid Commun Mass Spectrom. 2002;16(20):1946-52.
 Adam JM, Bennett DJ, Bom A, Clark JK, Feilden H, Hutchinson EJ, Palin R, Prosser
A, Rees DC, Rosair GM, Stevenson D, Tarver GJ, Zhang MQ.
Cyclodextrin-derived host molecules as reversal agents for the neuromuscular blocker
rocuronium bromide: synthesis and structure-activity relationships.
J Med Chem. 2002 Apr 25;45(9):1806-16.
 Tarver GJ, Grove SJ, Buchanan K, Bom A, Cooke A, Rutherford SJ, Zhang MQ.
2-O-substituted cyclodextrins as reversal agents for the neuromuscular blocker
rocuronium bromide.
Bioorg Med Chem. 2002 Jun;10(6):1819-27.

• The structure of gamma cyclodextrin is called a
TORROID
• It contains a hydrophilic exterior and a lipophilic
interior
• The hydrophilic exterior makes it water soluble , while
the interior acts as a host for guest molecules to get
encapsulate

• UNMODIFIED GAMMA CYCLODEXTRIN HAS A LARGE
LIPOPHILIC CAVITY
• BUT IT IS STILL NOT ROOMY TO ACCOMMODATE
ROCURONIUM

• Eight sugar side chains are added to make the gamma cyclodextrin
bigger to accommodate the rocuronium molecule
• Ethyl carboxyl groups are added to these side chains to provide
negative charges to hold the rocuronium electrostatically
• SU = sugar GAMMADEX = gammacyclodextrin

Rocuronium incapsulato nella gammaciclodestrinaCrystal
spectroscopy image of sugammadex encapsulating a rocuronium molecule.
Reprinted with permission from Zhang M-Q. 2003. Drug-specifi c cyclodextrins:
The future of rapid neuromuscular block reversal? Drugs Future, 28: 347–54. Copyright©
2003 Prous Scientifi c and Organon USA, a part of Schering-Plough Corporation

BRITISH JOURNAL OF ANAESTHESIA
Volume 97, Number 2, August 2006
British Journal of Anaesthesia 97 (2): 123–
6 (2006)
Editorial
The doughnut and the hole: a new
pharmacological concept for anaesthetists

X-ray crystal structures of Org 25969 (green) and
rocuronium (blue) with filled van der Waals surface

Complesso solubile sugammadex rocuronium

Encapsulation process: Sugammadex carboxyl groups interact with steroidal
rings A, B, C, and D, drawing the aminosteroidal NMBA molecule into the cavity
where additional non-covalent attractions hold the molecule securely in place.

Sugammadex encapsulates aminosteroidal NMBA molecules in the
plasma causing a concentration gradient that favors the extraction of
additional rocuronium molecules from the nicotinic junction into the
plasma

young
elderly
Old
Efficacy, Safety,
and
Pharmacokinetics
of Sugammadex
for the Reversal of
Rocuronium-
induced
Neuromuscular
Blockade in
Elderly
Patients.David L.
McDonagh,,
Patrick E.
Benedict,
Anthony L.
Kovac, ,David R.
Drover,, Neil W.
Brister, Jovino B.
Morte, Terri G.
Monk.Anesthesiol
ogy 2011:114;218

Benefici attesi con
Sugammadex
 Aumentata sicurezza per I pazienti
 Aumentata sicurezza in anestesia e
chirurgia
 Ridotta incidenza(eliminazione) del blocco
nm residuo
 Aumentata effficienza
» Benefici economici per accelerazione della
ripresa,turnover + rapido?

Effficacia clinica
 Antagonismo di blocco nm moderato
 Antagonismo di blocco nm profondo
 Antagonismo immediato del blocco nm
 Antagonismo con farmaci comparatori
 Confronto con gli effetti avversi degli altri
antidoti dei NMBA

Summary of time (minutes) from start of administration of sugammadex
or placebo to recovery of TOF ratio to 0.7, 0.8 and 0.9 in placebo-
controlled trials of sugammadex for reversal of
moderate nmmb.
0
10
20
30
40
50
60
70
80
90
100
tof0,7
tof 0,8
tof 0,9
Sorgenfrei Soy
Puhringer
Min

Spontaneous vs sugammadex reversal following rocuronium
0.6 mg/kg

Summary of time (minutes) from start of administration of sugammadex or
neostigmine to recovery of TOF ratio to 0.7, 0.8 or 0.9 in active-control studies
of sugammadex for reversal of moderate nmb
min

SUGAMMADEX IN BLOCCHI
PROFONDI

Results from studies of sugammadex for reversal of profound
NMB
0
20
40
60
80
100
120
140
rocu0,6+sugamma rocu 0,6 spont rocu1+sugamma rocu1 spont rocu1,2+sugamma rocu 1,2 spont
tof 0,7
tof 0,8
tof 0,9
Reversal at 15 min
Sparr Puhringer

Results from studies of sugammadex for reversal of profound NMB at
PTC 1-2
Tof 0.9

Time to recovery of TOF ratio to 0.9 (min) in the studies comparing different doses of
sugammadex for reversal of vecuronium or pancuronium-induced neuromuscular
blockade
0
10
20
30
40
50
60
70
0.5 1 2 4 6 8
Decoopman 2007
Duvaldestin 2007
Puhringer 2007
Sugammadex mg/kg
panc
vecu
min

VEDIAMO UN LAVORO IN
DETTAGLIO…………

Tempo di ricomparsa del tofr dopo antagonismo a vari dosaggi di
sugammadex(mg/kg) di rocuronium 0.6 mg/kg e vecuronium 0.10
mg/kg Koen Suy, Karl Morias,,Guy Cammu, , Pol Hans, Wilbert G. F. van Duijnhoven, Marten Heeringa, Ignace Demeyer.
Effective Reversal of Moderate Rocuronium- or Vecuronium-induced Neuromuscular Block with Sugammadex, a Selective Relaxant
Binding Agent.Anesthesiology 2007;106:283-8
min

Estimated dose–response relation of sugammadex dose
and time to recovery of the T4/T1 ratio to 0.9 in the rocuronium 0.60 mg/kg group (per-protocol
population; adapted weighted regression). T4/T1 ratio is the amplitude of the fourth response
[T4] over the first response [T1] to train-of-four stimulation. CI confidence interval.

Estimated dose–response relation of sugammadex dose and time to recovery of the T4/T1
ratio to 0.9 in the vecuronium 0.10 mg/kg group (per-protocol population). T4/T1 ratio is the
amplitude of the fourth response [T4] over the first response [T1]
to train-of-four stimulation. CI confidence interval. One data
point of 88:21 min is not shown

Rocuronium deep block > 2 h;reversal with different
dosages of Sugammadex (Shields ,BJA 2006,96,36.)
0
1
2
3
4
5
6
sugammadex
0,5 mg/kg
1,0 mg/kg 2,0 mg/kg 4,0 mg/kg 6 mg/kg
tofr 0.9
tofr 0.9
min

SUGAMMADEX SUBITO DOPO
ROCURONIUM

Summary of time to recovery in placebo-controlled trials of sugammadex for rapid
reversal of rocuronium-induced NMB
0
20
40
60
80
100
120
140
rocu1 +sugamma
16
rocu 1 spont rocu 1.2+sugamma
16
rocu 1.2 spont rocu1,2+sugamma rocu 1,2 spont
tof 0,7
#REF!
tof 0,9
Puhringer De Boer
3 min dopo rocu
5 min dopo rocu
3 min dopo
rocu

ROCU + SUGAMMADEX VS
SUCCI

Summary of time to recovery after rocuronium + sugammadex 16
mg/kg after 3 min and Succinylcholine 1 mg/kg spont recovery
0
2
4
6
8
10
12
T 1 10% T 1 90% tof 0,9
rocu + sugammadex
Succi 1 mg/kg
min

Rapid sequence induction and intubation with rocuronium-
sugammadex compared with succinylcholineBr J Anaesth. 2012 ;108:682-
9.Rapid sequence induction and intubation with rocuronium-sugammadex compared with succinylcholine:
a randomized trial.Sørensen MK, Bretlau C, Gätke MR, Sørensen AM, Rasmussen LS
 randomized ,patient- and observer-blinded
 GA ,elective surgical patients, RSI alfentanil (10
µg /kg, propofol (2 mg/kg
 Scc 1 mg/kg vs rocuronium 1 mg/kg
 After tracheal intubation, Sugammadex (16 mg/kg
vs spont.until a respiratory rate > 8/min and TV >3
ml/kgfor 30 s.

Br J Anaesth. 2012 ;108:682-9.Rapid sequence induction and intubation
with rocuronium-sugammadex compared with succinylcholine: a
randomized trial.Sørensen MK, Bretlau C, Gätke MR, Sørensen AM,
Rasmussen LS
0
100
200
300
400
500
600
Spont resp T1 90%
rocu+sugamm
Succi
sec Median times

Rocu 0,6 mg followed at 3 min by placebo or sugammadex 8 mg/kg
The blue line represents the
height of the twitch, and the
dashed red
line is the value of the train-
of-four ratio.
No recurarization was
observed
in the 90 min during which
the
neuromuscular block was
monitored.

Rocuronium reversal with sugammadex during
propofol or sevoflurane anesthesia

Sugammadex reversal following vecu or rocu

Sugammadex per il rovesciamento immediato di un blocco nm con
dose elevata di rocuronium
0
0.5
1
1.5
2
2.5
3
3.5
8 12 16
tof 0.9
min
mg/kg

Sugammadex 2 mg/kg vs 8 mg/kg reversal 3
min after rocuronium

Recovery parameters following neostigmine
administration
(Reid J, Breslin DS,Mirakhur R, Hayes A.Neostigmine antagonism of rocuronium block during anesthesia with sevoflurane,isoflurane or
propofol.Can.Anesth.J. 2001:48 :351-55)
0
2
4
6
8
10
12
14
16
18
20
min
prop
cont
prop
stop
sevo
cont
sevo
stop
iso
cont
iso
stop
onset
Tof 0.80
RI
pts at 0.8 tof at 15 min
6 groups ,20 each
Rocuronium,
Force,
neo at tof 25%!
*
*
**

TOF vs time after neostigmine 40 gr/kg (from T1
25%);control(fent/N2O),isoflurane stopped,isoflurane continued
(1.25%)Baurain MJ, d'Hollander AA,Melot C, Dernovoi BS,Barvais L.Effects of residual concentrations
of isoflurane on the reversal of vecuronium induced neuromuscular blockade.Anesthesiology 1991:71:474-
)

Valori del tetanic fade (stimolazione a 50 Hz sn,100 Hz
dx)dopo 15 min dalla somministrazione di
neostigmina 40 microgr/kg Baurain MJ, d'Hollander AA,Melot C, Dernovoi
BS,Barvais L.Effects of residual concentrations of isoflurane on the reversal of vecuronium induced
neuromuscular blockade.Anesthesiology 1991:71:474- )

• Insomma,continuare la soministraz del vapore
ritarda la ripresa nm anche dopo
rovesciamento……

Neo vs edrofonio e profondità del
blocco nm.

Mean first twitch height vs time after administration of various
doses of neostigmine and edrophonium starting from T 1 10%
following atracurium and vecuronium Smith, CE, Donati F., Bevan DR.Dose-Response
Relationships for Edrophonium and Neostigmine as Antagonists of Atracurium and Vecuronium neuromuscular
Blockade.Anesthesiology 1989;71: 37-43.
Inspired enflurane concentration maintained at 0.5-1%

Dose response relationship of first twitch and TOF assisted recovery
5 and 10 min. following administration of the antagonist as a
function of the dose of neostigmine and edrophonium following
atracurium and vecuronium. Smith, CE, Donati F., Bevan DR.Dose-Response Relationships
for Edrophonium and Neostigmine as Antagonists of Atracurium and Vecuronium Neuromuscular
????

Effect on Tof of 2 doses of neostigmine and edrophonium
following atracurium and vecuronium Smith, CE, Donati F., Bevan DR.Dose-Res
Relationships for Edrophonium and Neostigmine as Antagonists of Atracurium and Vecuronium Neuromuscular
0
10
20
30
40
50
60
70
80
neo 0.02
mg/kg
neo 0.04
mg/kg
edroph
0.5 mg/kg
edroph 1
mg/kg
atrac at 5'
atrac at 10'
vecu at 5'
vecu at 10'
Tof si ferma a 0.7!!!

Conclusione 1
• La dose giusta di neostigmina è…………
• Meditate gente meditate………………

Insomma,l’antagonismo dipende da:
• Profondità di blocco al momento della
somministrazione dell’antagonista
• Presenza o meno di potenzianti nmb.
• Tipo di antagonista somministrato
• Tipo di miorilassante somministrato
• Dose dell’antagonista somministrato
• end point scelto;T1/Tc,Tof,ecc.

Conclusione 2
• E’ meglio somministrare gli antidoti quando la ripresa
nm è iniziata
• È meglio cessare la somministrazione degli alogenati (
e monitorizzare la % et)…….

Effetti collaterali degli anti AchE

Effetti fisiologici della presenza di
Ach
• Bradicardia
• Salivazione
• Iperperistalsi
• Secrezioni bronchiali

Pericoli degli AntiAchE: arresto cardiaco
• Bjerke, Richard J., MD; Mangione, Michael P.Asystole after intravenous
neostigmine in a heart transplant recipinet.Can.Anaesth.J. 2001;48:305-
07.
• Purpose: To describe a heart transplant recipient who developed asystole after
administration of neostigmine which suggests that surgical dennervation of the heart
may not permanently prevent significant responses to anticholinesterases.
• Clinical features: A 67-yr-old man, 11 yr post heart transplant underwent left upper
lung lobectomy. He developed asystole after intravenous administration of 4 mg
neostigmine with 0.8 mg glycopyrrolate for reversal of the muscle relaxant. He had no
history of rate or rhythm abnormalities either prior to or subsequent to the event.
• Conclusion: When administering anticholinesterase medications to heart transplant
patients, despite surgical dennervation, one must be prepared for a possible profound
cardiac response.

Pericoli degli ACHE:FA con rapida
risposta ventricolare…..
• Kadoya, TSA, Aoyama K, Takenaka I.Development of rapid atrial fibrillation with
wide QRS complex after neostigmine in a patient with intermittent WPW
stndrome.BJA 1999;83:815-818
•
• 1Department of Anaesthesia, Nippon Steel Yawata Memorial Hospital, 1-1-1 Harunomachi, Yahatahigashi-ku,
• ABSTRACT: We report the case of a 67-yr-old man with intermittent Wolff-Parkinson-White (WPW) syndrome
in whom neostigmine produced life-threatening tachyarrhythmias. The patient was scheduled for microsurgery
for a laryngeal tumour. When he arrived in the operating room, the electrocardiogram showed normal sinus
rhythm with a rate of 82 beat min-1 and a narrow QRS complex which remained normal throughout the
operative period. On emergence from anaesthesia, the sinus rhythm (87 beat min-1) changed to atrial
fibrillation with a rate of 80–120 beat min-1 and a normal QRS complex. We did not treat the atrial fibrillation
because the patient was haemodynamically stable. Neostigmine 1 mg without atropine was then administered
to antagonize residual neuromuscular block produced by vecuronium. Two minutes later, the narrow QRS
complexes changed to a wide QRS complex tachycardia with a rate of 110–180 beat min-1, which was
diagnosed as rapid atrial fibrillation. As the patient was hypotensive, two synchronized DC cardioversions of
100 J and 200 J were given, which restored sinus rhythm. No electrophysiological studies of anticholinesterase
drugs have been performed in patients with WPW syndrome. We discuss the use of these drugs in this
condition.

Pericoli degli antiAchE:broncocostrizione
• Shibata O,Tsuda A,Makita T, Iwanaga S,Hara T,Shibata S,Sumikawa K.
Contractile and phosphadytilinositol responses of rat trachea to
anticholinesterase drugs.Can.Anaesth.J.1998;45:1190-95
Purpose: Some anticholinesterases (anti-ChE) such as neostigmine and pyridostigmine but not edrophonium, stimulate phosphaticlylinositol (PI) response.
Although a direct relationship was suggested between the increase in PI response and airway smooth muscle contraction,
there are no data regarding the effects of anti-ChE drugs on airway smooth muscle. Thus, we examined the contractile
properties and PI responses produced by anti-ChE drugs.
• Methods: Contractile response. Rat tracheal ring was suspended between two stainless hooks in Krebs-Henseleit (K-H)
solution. (1) Carbachol (CCh), anti-ChE drugs (neostigmine, pyridostigmine, edrophonium) or DMPP (a selective ganglionic
nicotinic agonist) were added to induce active contraction. (2) The effects of 4-diphenylacetoxy-N-methyl-piperidine
methobromide (4-DAMP), an M3 muscarinic receptor antagonist, on neostigmine- or pyridostigmine-induced contraction of
rat tracheal ring were examined. (3) Tetrodotoxin (TTX) was tested on the anti-ChE drugs-induced responses. PI response.
The tracheal slices were incubated in K-H solution containing LiCl and 3[H]myo-inositol in the presence of neostigmine or
pyridostigmine with or without 4-DAMP, an M3 muscarinic receptor antagonist. 3[H]inositol monophosphate (IP1) formed
was counted with a liquid scintillation counter.
• Results: Carbachol (0.1 mM), neostigmine. (1 mM), pyridostigmine (10 mM) but not edrophonium or DMPP, caused tracheal
ring contraction. 4-DAMP, but not tetrodotoxin, inhibited neostigmine and pyridostigmine-induced contraction. Neostigmine-
or pyridostigmine-induced IP1 accumulation was inhibited by 4-DAMP.
• Conclusions: The data suggest that anti-ChE drugs activate the M3 receptors at the tracheal effector site.

Schema delle afferenze
parasimpatiche a livello tracheale

Effetti contrattili di antiACHE,carbacolo e dimetilfenilpiperazinio
sugli anelli tracheali di ratto.
Shibata O,Tsuda A,Makita T, Iwanaga S,Hara T,Shibata S,Sumikawa K. Contractile and
phosphadytilinositol responses of rat trachea to anticholinesterase
drugs.Can.Anaesth.J.1998;45:1190-95

Tramèr, M. R. Fuchs-Buder, T..Omitting antagonism of nm
block:effect on PONV and risk of residual paralysis.A
systematic review.BJA 1999;82:379-386
• A systematic search (MEDLINE, EMBASE, Biological Abstracts, Cochrane library,
reference lists and hand searching; no language restriction, up to March 1998) was
performed for relevant randomized controlled trials. In eight studies (1134 patients),
antagonism with neostigmine or edrophonium was compared with spontaneous
recovery after general anaesthesia with pancuronium, vecuronium, mivacurium or
tubocurarine. On combining neostigmine data, there was no evidence of an antiemetic
effect when it was omitted. However, the highest incidence of emesis with neostigmine
1.5 mg was lower than the lowest incidence of emesis with 2.5 mg. These data
suggested a clinically relevant emetogenic effect with the higher
dose of neostigmine in the immediate postoperative period but not
thereafter.
• Numbers-needed-to-treat to prevent emesis by omitting neostigmine compared with
using it were consistently negative with 1.5 mg, and consistently positive (3–6) with 2.5
mg. There was a lack of evidence for edrophonium. In two studies, three patients with
spontaneous recovery after mivacurium or vecuronium needed rescue
anticholinesterase drugs because of clinically relevant muscle weakness (number-
needed-to-harm, 30). Omitting neostigmine may have a clinically
relevant antiemetic effect when high doses are used. Omitting
antagonism, however, introduces a non-negligent risk of residual
paralysis even with short-acting neuromuscular blocking agents.

Risk of omitting neostigmine….
• Residual paralysis!!!

Comportamento suggerito per l’antagonismo dei miorilassanti a
lunga e media durata di azione secondo le risposte al Tof
TOF esaurimento farmaco dose
Twitch visibili
nessuno Posponi antagonismo finchè almeno 1 o 2 contrazioni
visibili!!
1-2 ++++ neostigmina 0.07 mg/kg
3-4 +++ neostigmina 0.04 mg/kg
4 ++ edrofonio 0.5 mg/kg
4 +/- edrofonio 0.25

PORC % nella metanalisi di Naguib
Br J Anaesth. 2007 Mar;98(3):302-16.Neuromuscular monitoring and postoperative residual
curarisation: a meta-analysis.Naguib M, Kopman AF, Ensor JE.
Dtc
Galla
panc
vari
Atrac 0
panc
Atrac 0
galla
Panc
vecu Panc
vecu
panc
panc
panc
tof70
Tof 90

PORC % nella metanalisi di Naguib ;parte II
0
10
20
30
40
50
60
70
80
90
100
tof <0.70
tof < 0.90

incidence of PORC was more frequent after the use of traditional long-acting
neuromuscular blocking drugs(da Naguib)

Ma la PORC perchè è importante?

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

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

Andamento temporale del tof <0.80
nella RR
0
5
10
15
20
25
30
35
40
45
50
0 5 10 15 20 30 40 50
min
%
tof<0.80
panc
atrac
vecu

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

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

Fattori di rischio per POPC nello
studio AAS1997
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

Eur J Anaesthesiol. 201128(12):842-8.
The influence of residual neuromuscular block on the incidence of critical
respiratory events. A randomised, prospective, placebo-controlled trial.
Sauer M, Stahn A, Soltesz S, Noeldge-Schomburg G, Mencke T.
• Department of Anaesthesiology and Intensive Care Medicine, University of Rostock, Rostock, Germany.
• incidence of critical respiratory events, such as hypoxaemia, in patients with minimal
residual neuromuscular blockade and compared these data with those from patients with full
recovery of blockade.
• Randomised, prospective, placebo-controlled trial.
• 132 adult patients, 18-80ASA I-III ,orthopaedic surgery ,GA with rocuronium
• randomised to one of two groups: neostigmine group (neostigmine 20 μg kg-1) or placebo
group (saline).
• In the patients in the neostigmine group, the tracheal tube was removed at a train-of-
four (TOF) ratio of 1.0; in the patients in the placebo group, the trachea was extubated
at a TOF ratio less than 1.0, but without fade in TOF and double-burst stimulation
(DBS).
• Neuromuscular monitoring was assessed simultaneously with qualitative TOF/DBS
monitoring, and with quantitative calibrated acceleromyography.
• Critical respiratory events, such as hypoxaemia, were assessed in the post-anaesthesia care
unit.

The influence of residual neuromuscular block on the incidence of critical
respiratory events. A randomised, prospective, placebo-controlled trial
• 45 pts (39.5%) became hypoxaemic (SaO2 < 93%);
• there was a significant difference between the groups (29 patients in
the placebo group versus 16 in the neostigmine group; P = 0.021).
• In the neostigmine group, all patients were extubated at a TOF ratio of 1.0. In the
placebo group, the median TOF ratio was 0.7 (range: 0.46-0.9; P < 0.001). The median
time for spontaneous recovery in the placebo group was 16 min (range 3-49 min).
Neostigmine 20 μg kg was effective in antagonising rocuronium-induced blockade
without fade in TOF and DBS.
• In this randomised, prospective, placebo-controlled trial, minimal
residual block was associated with hypoxaemia in the post-anaesthesia
care unit. Neostigmine 20 μg kg was effective in antagonising
rocuronium-induced (minimal) blockade

MA CHE CI IMPORTA DEL TOFR
0.90?

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

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 )?

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

Chemrorecet perif
Chemrecett.centr SNC
Ipossia
ipercapnia iperventilazione

Corpi carotidei
Sito nicotinico
Sito
muscari
nico
nmb
atropina
ipossia

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

SUGAMMADEX IN SPECIAL
POPULATIONS

Sugammadex is not influenced by renal insufficiency
Staals LM, Snoeck MM, Driessen JJ, Flockton EA, Heeringa M, Hunter JM. Multicentre, parallel-group, comparative
trial evaluating the efficacy and safety of sugammadex in patients with end-stage renal failure or normal renal function.
Br J Anaesth 2008;101:492-7.

Bom AH,Hope H. Rapid reversal of rocuronium induced
neuromuscular block by ORG 25969 in the guinea pig is not
modified by occlusion of the blood supply to one kidney.Eur
J,Anesth.20003;20:suppl A 486
0
2
4
6
8
10
12
min
spont org 25969 69
mmol/kg
org 25969 230
mmol/kg
org 25969 460
mmol/kg
2 kidneys
1 kidney

Minerva Anestesiol. 2012 Jan;78(1):112-3.
Prolonged neuromuscular block associated to non-alcoholic steatohepatitis in morbidly obese
patient: neostigmine versus sugammadex.Carron M, Parotto E, Ori C.
 Paz MO dopo sleeve gastrectomy; a 150 min dal
rocu la neostigmina non supera Tof
0.20;sugammadex 2 mg/kg normalizza in 2 min.!

Obese patients
 Somministrare la dose sul peso reale ,non
IBW!
» Anesthesiology. 2012 Jul;117(1):93-8.Sugammadex ideal body weight dose adjusted
by level of neuromuscular blockade in laparoscopic bariatric surgery.Llauradó
S, Sabaté A, Ferreres E, Camprubí I, Cabrera A.

Per saperne di +:review
 Anaesthesia. 2009 Mar;64 Suppl 1:55-65.Neuromuscular
blocking drugs and their antagonists in patients with
organ disease.Craig RG, Hunter JM.

Efficacy, Safety, and Pharmacokinetics of Sugammadex for the Reversal of Rocuronium-
induced NeuromuscularBlockade in Elderly Patients.David L. McDonagh,, Patrick E.
Benedict, Anthony L. Kovac, ,David R. Drover,, Neil W. Brister, Jovino B. Morte, Terri G.
Monk.Anesthesiology 2011:114;218
 adult (aged 18–64 yr) versus elderly adult (aged 65 yr or older)
patients.
 phase 3a, multicenter, parallel-group, comparative,open-label study
 162 patients ASA 1–3,
 rocuronium, 0.6 mg/kg + maintenance doses of 0.15 mg/kg as
required.
 At the end of surgery, patients received sugammadex, 2.0 mg/kg, at
reappearance of the second twitch of TOF
 primary efficacy variable was time from sugammadex administration to
recovery of the
 TOF ratio to 0.9 or greater.
 Pharmacokinetics and safety were also evaluated.

Efficacy, Safety, and Pharmacokinetics of Sugammadex for the Reversal of
Rocuronium-induced NeuromuscularBlockade in Elderly Patients.David L.
McDonagh,, Patrick E. Benedict, Anthony L. Kovac, ,David R. Drover,, Neil W. Brister,
Jovino B. Morte, Terri G. Monk.Anesthesiology 2011:114;218
 Results: Overall, 150 patients were treated and had at least one
postbaseline efficacy assessment; 48 were aged 18–64 yr
 (adult), 62 were aged 65–74 yr (elderly), and 40 were aged 75 yr or
older (old-elderly).
 The geometric mean time (95% confidence interval) from
sugammadex administration to recovery of the TOF ratio to 0.9
increased with age, from 2.3 (2.0 –2.6) min (adults) to 2.9 (2.7–3.2)
min (elderly/oldelderly groups combined).
 Recovery of the TOF ratio to 0.9 was estimated to be 0.7 min faster in
adults compared with patients aged 65 yr or older (P 0.022).
Sugammadex was well tolerated by all patients.

Individual patient recovery times to a TOF ratio of 0.9
Efficacy, Safety, and Pharmacokinetics of Sugammadex for the Reversal of Rocuronium-induced
NeuromuscularBlockade in Elderly Patients.David L. McDonagh,, Patrick E. Benedict, Anthony L. Kovac,
,David R. Drover,, Neil W. Brister, Jovino B. Morte, Terri G. Monk.Anesthesiology 2011:114;218
geometric mean time sugammadex administration to TOFr
0.9 increased with age, from 2.3
(2.0 –2.6) min (adults) to 2.9 (2.7–3.2) min (elderly/oldelderly
groups combined). 0.7 min faster in adults compared with
patients aged 65 yr or older

SAFETY

J Smooth Muscle Res. 2012;48(2-3):59-64.Effect of sugammadex on bronchial smooth muscle
function in rats.
Yoshioka N, Hanazaki M, Fujita Y, Nakatsuka H, Katayama H, Chiba Y
 .
 Sugammadex can encapsulate the steroid-based neuromuscular blocker molecule and
results in rapid reversal of neuromuscular blockade induced by rocuronium and vecuronium.
However, several cases of bronchospasm after the administration of sugammadex have
been reported. The current study was carried out to determine whether sugammadex
directly affects smooth muscle function of the airways. The ring strips of left main bronchi
were isolated from male Wistar rats and isometric forces were measured. In the isolated
bronchial smooth muscle tissues, sugammadex (10<sup>-8</sup> - 10 <sup>-3</sup> M)
had no effect on baseline tension or the acetylcholine (ACh; 30 µM)-induced sustained
contraction. Moreover, sugammadex did not affect bronchial smooth muscle responsiveness
to ACh. These findings indicate that sugammadex itself does not
affect contractile function in bronchial smooth muscle
of the rat

Effect of sugammadex or saline on Rhesus monkey

 Gamma ciclodestrina non ha attività
biologica!
 Pochissimi effetti collaterali durante la
sperimentazione;
» KO anestetiche e 1 caso di possibile
reazione allergica (= ai comparatori)

Urinary N-acetyl-glucosaminidase (NAG) as a measure
of proximal tubule damage
 Valori anormali :
» Sorgenfrei et al.:5/22 pts
» Sparr et al.: 2/88 pts + microalbuminuria in
» 4 + 3 con anormali concentrazioni di b2-
microglobulin concentration
» Flockton et al. : 7/34
»Significato????

Affinità per altre molecole
 Per cortisone,idrocortisone,aldosterone
<120 volte del rocu
 Per atropina.verapamil,ketamina da 400
a 700 volte < rocuro
 Contraccettivi orali?
» Dobbiamo informare le pazienti?????????

Interazioni significative
 Tamoxifene 17%
 Noretindrone 14%
 Betametasone 7%
 Estradiolo 7%
 Flucloxacina ?
 Acido fusidico?
 Toremifene?
Clin Drug Investig. 2011;31(2):101-11.
Assessment of the potential for displacement
interactions with sugammadex: a
pharmacokinetic-pharmacodynamic modelling
approach..Zwiers A, van den Heuvel M, Smeets J,
Rutherford

 Eikermann M, Zaremba S, Malhotra A,
et al. Neostigmine but not sugammadex
impairs upper airway dilator muscle
activity and breathing. Br J.Anaesth
2008; 101:344–349.

Int J Clin Pharmacol Ther. 2012 ;50:595-604.Sugammadex is not
associated with QT/QTc prolongation: methodology aspects
of an intravenous moxifloxacin-controlled thorough QT study.de Kam PJ,
van Kuijk J, Smeets J, Thomsen T, Peeters P.
 Clinical Pharmacology, Merck Sharp & Dohme Corp., Whitehouse Station,
NJ 07065-0900, USA. pieterjan.de.kam@merck.com
 Sugammadex is a novel γ-cyclodextrin and the first selective relaxant
binding agent to be developed for the reversal of rocuronium and
vecuroniuminduced neuromuscular blockade. According to International
Conference on Harmonization (ICH) E14, a thorough QT/QTc study is
required for most new compounds to assess the potential to cause QT
prolongation, because a delay in cardiac repolarization may create an
electrophysiological environment that favors the development of cardiac
arrhythmias, most notably Torsade de Pointes. Therefore a thorough QTc
study was conducted to evaluate the effect of sugammadex on the
individually corrected QTc interval (QTcI).
 METHODS:
 Following two baseline electrocardiogram (ECG) days (Day -2 and Day -1),
in this randomized, double-blind, cross-over study, healthy volunteers

Uso clinico del sugammadex
 Antagonismo alla fine dell’intervento:
» Tof 1-2; 2mg/kg
» Ptc 1-2:4 mg/kg
 Se dopo sugammadex è urgente ricurarizzare il
poaziente(sanguinamento);atrac,cisatrac!
 Intubazione difficile imprevista dopo bolo di rocu;
sugammadex 16 mg/kg
 È costoso:Uso selettivo?Malattie neuro
muscolari,insuff epatica,insuff renale,chir amb,C/S
….. Messina,4 ottobre 2012,I-SIVA

E se bisogna ricurarizzare urgentemente il paziente dopo
rovesciamento con Sugammadex?
Utilizza un miorilassante non
steroideo;cisatracurium,atracurium…
Oppure………

Altri vantaggi del sugammadex
 Riduzione del tempo di ripresa:aumento
dell’efficienza di sala op;diminuzione del
soggiorno in TIPO………….
 Riduzione della severità della reazione allergica
da rocu e vecu:
» -Can sugammadex encapsulation eliminate the antigenic activity of aminosteroidal
neuromuscular blocking agent?Kawano T, Yokoyama M..
» J Anesth. 2011 Dec;25(6):953-4. Epub 2011 Sep 9. No abstract available.
» -Drug-specific cyclodextrins with emphasis on sugammadex, the neuromuscular blocker
rocuronium and perioperative anaphylaxis: implications for drug allergy.Baldo BA, McDonnell
NJ, Pham NH..
» Clin Exp Allergy. 2011 Dec;41(12):1663-78. doi: 10.1111/j.1365-2222.2011.03805.x. Epub
2011 Jul 7. Review.

Sugammadex and rocuronium allergy/anaphylaxis
 The role of sugammadex in the development and modification of an allergic
response to rocuronium: evidence from a cutaneous model.Clarke RC, Sadleir
PH, Platt PR.Anaesthesia. 2012 Mar;67(3):266-73.
 [Fast recovery of haemodynamic and ventilatory functions after
sugammadex bolus following rocuronium-induced anaphylactic shock
refractory to conventional treatment].Raft J, Leclercq M, Longrois D,
Meistelman C.Ann Fr Anesth Reanim. 2012 Feb;31(2):158-61. 3.
 Successful management of rocuronium-
induced anaphylactic reactions with

ASSESSMENT OF
COST-EFFECTIVENESS
EVIDENCE
Health Technology Assessment 2010; Vol. 14: No. 39
Health Technology. Sugammadex for the reversal
of muscle relaxation in general
anaesthesia: a systematic review and
economic assessment
D Chambers, M Paulden, F Paton,
M Heirs, S Duffy, D Craig, J Hunter,
J Wilson, M Sculpher and N Woolacott

associated with sugammadex and value of each minute of recovery time saved at which
sugammadex is (is not) cost-effective under the base-case assumptions for each
scenario. Separate graphs are plotted for rocuronium- and vecuronium-induced blockade and for
moderate and profound blockade.The horizontal dashed (dotted) line represents an estimate of the
value of each minute saved were all the time savings to occur in the
operating room (recovery room), while the dotted and dashed vertical line represents an estimate of
the reduction in recovery time associated with sugammadex (see Routine reversal of
neuromuscular block, Methods).

Bridion® Organon N.v
 ev 10 fl 100 mg/ml 2 ml - € 819,95* - € 667,85**;
» 2 mg/kg in paz di 70 kg:200 mg,1 fiala,82-67 euro
» 4 mg/kg in paz di 70 kg ;280 mg ,1 fiala e mezzo,122-
102 euro
 ev 10 fl 100 mg/ml 5 ml - € 2.049,85* - €
1669,62**
» 16 mg/kg in paz di 70 kg 1120 mg,2 fiale da 500 e 1
da 100=410+82=500 euro…

E’ POSSIBILE UN REBOUND DI
MIORILASSANTE SE LA DOSE DI
SUGAMMADEX È INSUFFICIENTE?

Douglas J. Eleveld,,Karel Kuizenga,,Johannes H. Proost, J. Mark K. H. Wierda, .Temporary
Decrease in Twitch Response During Reversal of Rocuronium-Induced Muscle Relaxation
with a Small Dose of Sugammadex. (Anesth Analg 2007;104:582–4)
Temporary
decrease TOF ratio
and
T1 during reversal
of rocuronium-
induced muscle
relaxation
(0.9 mg/kg) with
sugammadex (0.5
mg/kg
administered 42
min after
rocuronium). At
the time of
sugammadex
administration
the posttetanic-
count (PTC) value
was 1.

Rebound…
 REBOUND might occur because redistribution of unbound muscle relaxant
molecules from peripheral compartments back into central and effect compartments.
After sugammadex administration,the concentration of unbound rocuronium
molecules in the central compartment decreases rapidly,leading to a rapid decrease
in muscle relaxation intensity.
 The decreased unbound rocuronium concentration in the central compartment leads
to a redistribution of unbound rocuronium from peripheral compartments back into the
central compartment. If insufficient sugammadex is present for additional complex
formation, then this redistribution process will lead to a temporary increase in
unbound rocuronium concentration in the central compartment and in the effect
compartment.
 Thereafter, the unbound rocuronium concentration decreases because of clearance of
the drug.
 that muscle relaxation rebound can occur for doses of sugammadex in a limited critical range. These
observations support our hypothesis that rebound may occur because of redistribution of unbound muscle
relaxant molecules from peripheral compartments back into central and effect compartments.
 Muscle relaxation rebound can therefore occur without dissociation of the sugammadex/ rocuronium
complex. This implies that for a reliable reversal of neuromuscular blockade without muscle
 relaxation rebound, a sufficiently large dose of sugammadex is necessary. Presumably, the recommended
doses of sugammadex under these conditions (PTC 1) will be larger than 0.5 mg/kg, and will thus prevent

Simulazione con dosi crescenti di sugammadex
secondo un modello Pk Pd
Observed train-of-four (TOF)
data () and the
results of simulations (solid
lines) of various sugammadex
dosing amounts. Muscle
relaxation rebound only occurs
for sugammadex doses in a
limited range. The simulations
indicate that for this patient,
doses larger than about 1
mg/kg are sufficient to achieve
rapid muscle relaxation
reversal and avoid muscle
relaxation rebound.

Che cosa ci manca ancora?
 Un sostituto non depolarizzante ad
azione rapida più della succinilcolina( o
per lo meno simile….)
 Che il sugammadex sia impiegato in
milioni di casi in modo che si possa
vedere qualche effetto collaterale…

PICO Question:
 P- In patients requiring neuromuscular blockade
reversal
 I- is the selective relaxant binding agent (SRBA)
sugammadex an improvement on
 C- cholinesterase inhibitors
 O- for more effective reversal, less side effects
and greater safety profile?

FINEEEEEE

Posterior predictive check of the pharmacokinetic–pharmacodynamic model for
sugammadex-mediated reversal times [time to train-of-four ratio of 0.9
(TOF90)] of rocuronium-induced neuromuscular block, observed (OBS) and predicted
(PRED) reversal times. Crosses represent individual values, bars
represent range and horizontal lines represent the median.Relative difference between
reversal times [(OBS–PRED)/OBS ¥ 100] is presented above the bars

Posterior predictive check of the pharmacokinetic–pharmacodynamic model for sugammadex-
mediated reversal times [time to train-of-four ratio of 0.9
(TOF90)] of rocuronium-induced neuromuscular block, observed (OBS) and predicted (PRED)
reversal times. Crosses represent individual values, bars
represent range and horizontal lines represent the median.Relative difference between reversal
times [(OBS–PRED)/OBS ¥ 100] is presented above the bars

Residual curarization
Is the main problem?

Summary of studies without reversal

Summary of studies with reversal

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

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:

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

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-

 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.

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

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,

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

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

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

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.

Anesth Analg. 2007 Mar;104(3):585-6.
Emergency use of sugammadex after failure of standard reversal drugs.Lenz A, Hill
G, White PF
 .Administration of sugammadex, 350 mg IV (4
mg/kg), in the postanesthesia care unit immediately
(<60 s) relieved acute respiratory distress due to
residual neuromuscular blockade in a 42-yr-old
patient with chronic renal failure who had received
vecuronium, 10 mg IV, for tracheal intubation, after
inadequate reversal of neuromuscular blockade in
the operating room with neostigmine, 5 mg IV, and
glycopyrrolate, 1 mg IV

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

Paralisi residua
Che cosa implica e come evitarla...
C.Melloni
Servizio Anestesia e Rianimazione
Ospedale di Faenza(RA)

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.

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

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

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

Is your practice
different?

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

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

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

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

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

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

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

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

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

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

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

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

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

Time from neostigmine administration
to TOFR 0.90
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
%
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.

 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

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

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

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

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

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

Chemrorecet perif
Chemrecett.centr SNC
Ipossia
ipercapnia iperventilazione

Corpi carotidei
Sito nicotinico
Sito
muscari
nico
nmb
atropina
ipossia

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

Sugammadex efficace anche in blocco profondo
alla ricomparsa di T2
• sugammadex given as a reversal agent at the
reappearance of T2 was effective in reversing
neuromuscular block induced by either rocuronium (0.60
mg/kg) or vecuronium (0.10 mg/kg) in patients with an
American Society of Anesthesiologists physical status of I or II.
Cholinesterase inhibitors are only effective in reversing
neuromuscular block if given when partial spontaneous
recovery has already occurred.17
• The present study showed that sugammadex was effective as a
reversal agent for both rocuronium- and vecuronium- induced
block when given at such a depth of block i.e., the
reappearance of T2.18

• Expert Opin Pharmacother. 2008 May;9(8):1375-86. Links
• Sugammadex: a cyclodextrin to reverse neuromuscular blockade in anaesthesia.
• Donati F.
• University of Montréal, Hôpital Maisonneuve-Rosemont, Department of Anesthesiology, 5415, boul
l'Assomption, Montréal, Québec, H1T 2M4, Canada. francois.donati@umontreal.ca
• BACKGROUND: Neuromuscular blocking agents are used to provide relaxation and immobility during surgery. To
avoid residual paralysis after anaesthesia, reversal of blockade is commonly accomplished with
anticholinesterase agents but these drugs have cardiovascular side effects and incomplete effectiveness.
Sugammadex is a cyclodextrin that binds rocuronium and chemically similar neuromuscular blocking drugs.
OBJECTIVE: Published data on the effectiveness of sugammadex as a reversal agent were examined. METHODS:
Peer-reviewed articles on residual postoperative paralysis and sugammadex (ORG 25969) were analysed.
RESULTS: Rocuronium-sugammadex complexes are formed and excreted via the kidney. The dissociation constant
of the reaction is estimated at 0.1 microM. Sugammadex produces more rapid reversal of rocuronium- and
vecuronium-induced blockade than current reversal agents. The dose required depends directly on intensity of
blockade. To date, there appear to be few side effects. Inadequate dosage may lead to reparalysis. CONCLUSION:
More data are needed, especially in patients with renal failure and those who require neuromuscular blockade
again soon after receiving sugammadex.

• Br J Anaesth. 2008 May;100(5):622-30. Epub 2008 Apr 2. Links
• Reversal of rocuronium-induced neuromuscular block with sugammadex is faster than reversal of
cisatracurium-induced block with neostigmine.
• Flockton EA, Mastronardi P, Hunter JM, Gomar C, Mirakhur RK, Aguilera L, Giunta FG, Meistelman C, Prins ME.
• University Department of Anaesthesia, School of Clinical Sciences, Duncan Building, Daulby Street, Liverpool L69
3GA, UK. lizzy@lizzyflockton.fsnet.co.uk
• BACKGROUND: Reversal of the residual effect of rocuronium or cisatracurium by neostigmine may be slow and
associated with side-effects. This randomized, safety-assessor-blinded study compared the efficacy of
sugammadex, a selective relaxant binding agent for reversal of rocuronium-induced neuromuscular block, with
that of neostigmine for reversal of cisatracurium-induced neuromuscular block. The safety of sugammadex and
neostigmine was also evaluated. METHODS: Adult surgical patients (ASA class I-III) were randomized to
sugammadex 2.0 mg kg(-1) for reversal of block induced by rocuronium 0.6 mg kg(-1), or neostigmine 50 microg
kg(-1) for reversal of block induced by cisatracurium 0.15 mg kg(-1). Anaesthesia was induced and maintained
using i.v. propofol and remifentanil, fentanyl, or sufentanil. Neuromuscular function was monitored using
acceleromyography (TOF-Watch SX). Sugammadex or neostigmine was administered at reappearance of T(2). The
primary efficacy variable was time for recovery of the train-of-four (TOF) ratio to 0.9. RESULTS: Eighty-four
patients were randomized, 73 of whom received sugammadex (n=34) or neostigmine (n=39). Time from start of
administration of reversal agent to recovery of the TOF ratio to 0.9 was 4.7 times faster with sugammadex than
with neostigmine (geometric mean=1.9 vs 9.0 min, P<0.0001). Reversal of block was sustained in all patients.
There were no serious adverse effects from either reversal agent and no significant changes in any measure of
safety, except for similar elevations in urinary N-acetyl glucosaminidase in both groups. CONCLUSIONS:
Sugammadex 2.0 mg kg(-1) administered at reappearance of T(2) was significantly faster in reversing
rocuronium-induced blockade than neostigmine was in reversing cisatracurium-induced block.

neuromuscular block with sugammadex is faster than reversal of
cisatracurium-induced block with neostigmine. Br J Anaesth. 2008 ;100:622-
30.
• Tiva propofol /remifentanil o sufentanil
• Alla ricomparsa del T2
• Rocuronium 0.6 mg/kg antagonizzato con
sugammadex 2 mg/kg
• Cisatracurium 0.15 mg/kg antagonizzato con
neostigmnma 50 microgr/kg
• Tempo di ritorno del Tofr 0.9:1.9 min dopo
sugammadex,9 min dopo neostigmina

• : Can J Anaesth. 2008 Feb;55(2):124-5; author reply
125-6. Links
• Comment on: Can J Anaesth. 2007 Sep;54(9):689-95.
Non-steroidal neuromuscular blocking agents to re-
establish paralysis after reversal of rocuronium-
induced neuromuscular block with sugammadex.
• de Boer HD, Driessen JJ, van Egmond J, Booij LH.

• 1: J Pharmacokinet Pharmacodyn. 2007 Dec;34(6):771-88. Epub 2007 Sep 21. Links
• Simulation of the reversal of neuromuscular block by sequestration of the free molecules of the muscle
relaxant.
• Nigrovic V, Bhatt SB, Amann A.
• Department of Anesthesiology, College of Medicine, University of Toledo, 3000 Arlington Avenue, Toledo, OH
43614-2598, USA. vladimir.nigrovic@utoledo.edu
• The study examined in simulations the interaction between a muscle relaxant and an antagonist that binds the
free molecules of the relaxant, as experimentally demonstrated for rocuronium and sugammadex. The
hypothetical muscle relaxant D and the hypothetical antagonist X were assigned pharmacokinetic properties to
define the time course of their concentrations in plasma, and pharmacodynamic properties to define binding of
D to either X or the receptors at the motor end plates. D, X, and their complex DX were postulated to diffuse
between plasma and the effect compartment. The first and the fourth twitch elicited in sequential trains of four
stimuli were evaluated in a model of neuromuscular transmission. The rates of reactions were formulated as
differential equations and the equations solved numerically. If the affinity of D for X is comparable to that of D
for the postsynaptic receptors, doses of X two to four times larger than the dose of D produce a fast and a
complete recovery of the twitches. Smaller doses of X or lower affinities of D for X accomplish a slower and only
partial recovery. Additionally, the complete restoration of twitch strength within 2 min after the injection of X
requires that X and DX diffuse into the effect compartment. The simulations reveal the physicochemical,
pharmacokinetic, and pharmacodynamic properties of an antagonist that restores twitch strength by
sequestering the free molecules of the muscle relaxant.

• : Anesthesiology. 2007 Aug;107(2):239-44. Links
• Reversal of rocuronium-induced (1.2 mg/kg) profound neuromuscular block by sugammadex: a multicenter, dose-finding and
safety study.
• de Boer HD, Driessen JJ, Marcus MA, Kerkkamp H, Heeringa M, Klimek M.
• Department of Anesthesiology, Radboud University Medical Center Nijmegen, The Netherlands. pm.mertes@chu-nancy.fr
• BACKGROUND: Reversal of rocuronium-induced neuromuscular blockade can be accomplished by chemical encapsulation of
rocuronium by sugammadex, a modified gamma-cyclodextrin derivative. This study investigated the efficacy and safety of
sugammadex in reversing rocuronium-induced profound neuromuscular blockade at 5 min in American Society of
Anesthesiologists physical status I and II patients. METHODS: Forty-five American Society of Anesthesiologists physical status I and
II patients (aged 18-64 yr) scheduled to undergo surgical procedures (anticipated anesthesia duration >/= 90 min) were randomly
assigned to a phase II, multicenter, assessor-blinded, placebo-controlled, parallel, dose-finding study. Anesthesia was induced and
maintained with propofol and an opioid. Profound neuromuscular blockade was induced with 1.2 mg/kg rocuronium bromide.
Sugammadex (2.0, 4.0, 8.0, 12.0, or 16.0 mg/kg) or placebo (0.9% saline) was then administered 5 min after the administration of
rocuronium. Neuromuscular function was monitored by acceleromyography, using train-of-four nerve stimulation. Recovery time
was the time from the start of administration of sugammadex or placebo, to recovery of the train-of-four ratio to 0.9. Safety
assessments were performed on the day of the operation and during the postoperative and follow-up period. RESULTS: A total of
43 patients received either sugammadex or placebo. Increasing doses of sugammadex reduced the mean recovery time from 122
min (spontaneous recovery) to less than 2 min in a dose-dependent manner. Signs of recurrence of blockade were not observed.
No serious adverse events related to sugammadex were reported. Two adverse events possibly related to sugammadex were
reported in two patients (diarrhea and light anesthesia); however, both patients recovered without sequelae. CONCLUSIONS:
Sugammadex rapidly and effectively reversed profound rocuronium-induced neuromuscular blockade in humans and was well
tolerated.

Antagonismo immediato di un blocco profondode Boer HD, Driessen JJ, Marcus MA, Kerkkamp
H, Heeringa M, Klimek M. Reversal of rocuronium-induced (1.2 mg/kg) profound neuromuscular block by sugammadex: a
multicenter, dose-finding and safety study. Anesthesiology. 2007 ;107:239-44.
• Rocuronium 1.2 mg/kg
• Dopo 5 min
• placebo o sugammadex 2.0, 4.0, 8.0, 12.0,16.0
mg/kg
• TOFR 0.9 <2 min dopo sugammadex,122 min dopo
placebo

• Berg H, Roed J, Viby-Mogensen J, Mortensen CR, Engbaek J,
Skovgaard LT,Krintel JJ: Residual neuromuscular block is a
risk factor for postoperative pulmonary complications: A
prospective, randomised, and blinded study of
postoperative pulmonary complications after atracurium,
vecuronium and pancuronium. Acta Anaesthesiol Scand
1997; 41:1095–103
• 2. Arbous MS, Meursing AE, van Kleef JW, de Lange JJ,
Spoormans HH, Touw
• P, Werner FM, Grobbee DE: Impact of anesthesia
management characteristics on

• 1: Pharmacotherapy. 2007 Aug;27(8):1181-8. Links
• Sugammadex: a novel agent for the reversal of neuromuscular blockade.
• Nicholson WT, Sprung J, Jankowski CJ.
• Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
nicholson.wayne@mayo.edu
• To achieve spontaneous ventilation after completion of surgery, the nondepolarizing effects on skeletal muscle
relaxation are often reversed by administration of an acetylcholinesterase inhibitor. However, these agents
increase acetylcholine at both the neuromuscular junction and the muscarinic receptors. Therefore,
coadministration of an anticholinergic agent is required to prevent parasympathetic adverse effects. In addition,
a relative pharmacologic ceiling effect is seen with inhibition of acetylcholinesterase, necessitating some
recovery of neuromuscular function before an acetylcholinesterase inhibitor is administered. Sugammadex is a
new modified gamma-cyclodextrin compound under clinical investigation in the United States. It does not
interact with cholinergic mechanisms to elicit reversal. Instead, it is a selective relaxant binding agent and acts by
forming a 1:1 complex with steroidal nondepolarizing neuromuscular blockers in the plasma, lowering the
effective concentration available at the receptor. Due to its selectivity, sugammadex does not inhibit the effects
of nondepolarizing agents of the benzylisoquinolinium class. In contrast to acetylcholinesterase inhibition,
sugammadex is effective even when administered during profound blockade, and it does not require
coadministration of an anticholinergic agent. It provides a novel mechanism of action for reversal of the
neuromuscular block induced by nondepolarizing aminosteroidal agents.

• 1: Anesthesiology. 2007 May;106(5):935-43. Links
• Early reversal of profound rocuronium-induced neuromuscular blockade by sugammadex in a randomized multicenter study:
efficacy, safety, and pharmacokinetics.
• Sparr HJ, Vermeyen KM, Beaufort AM, Rietbergen H, Proost JH, Saldien V, Velik-Salchner C, Wierda JM.
• Department of Anesthesiology and Critical Care Medicine, Medical University Innsbruck, Innsbruck, Austria.
harald.sparr@dornbirn.at
• BACKGROUND: Sugammadex reverses the neuromuscular blocking effects of rocuronium by chemical encapsulation. The efficacy,
safety, and pharmacokinetics of sugammadex for reversal of profound rocuronium-induced neuromuscular blockade were
evaluated. METHODS: Ninety-eight male adult patients were randomly assigned to receive sugammadex (1, 2, 4, 6, or 8 mg/kg) or
placebo at 3, 5, or 15 min after 0.6 mg/kg rocuronium. Patients were anesthetized with propofol and fentanyl. The primary
endpoint of the study was the time to achieve a recovery of train-of-four ratio to 0.9. Neuromuscular blockade was measured
using acceleromyography. Concentrations of rocuronium and sugammadex were determined in venous blood and urine samples.
A population pharmacokinetic model using NONMEM (GloboMax LLC, Hanover, MD) was applied. RESULTS: The mean time to
recovery of the train-of-four ratio to 0.9 after dosing at 3, 5, and 15 min decreased from 52.1, 51.7, and 35.6 min, respectively,
after administration of placebo to 1.8, 1.5, and 1.4 min, respectively, after 8 mg/kg sugammadex. Sugammadex was safe and well
tolerated. However, 20.4% of patients showed signs of inadequate anesthesia after its administration. The median cumulative
excretion of rocuronium in the urine over 24 h was 26% in the placebo group and increased to 58-74% after 4-8 mg/kg
sugammadex. The mean plasma clearances of sugammadex and rocuronium were 0.084 and 0.26 l/min, respectively.
CONCLUSIONS: In male subjects, sugammadex safely reversed profound neuromuscular blockade induced by 0.6 mg/kg
rocuronium in a dose-dependent manner. Sugammadex enhanced the renal excretion of rocuronium, and its clearance is
approximately one third that of rocuronium.
• PMID: 17457124 [PubMed - indexed for MEDLINE]

Sparr HJ, Vermeyen KM, Beaufort AM, Rietbergen H, Proost JH, Saldien V, Velik-Salchner C,
Wierda JM. Early reversal of profound rocuronium-induced neuromuscular blockade by
sugammadex in a randomized multicenter study: efficacy, safety, and pharmacokinetics
Anesthesiology. 2007 ;106:935-43
• Propofol/fentanyl anestesia
• Rocuronium 0.6 mg/kg
• Sugammadex 1,2,4,6,8 mg/kg o placebo dopo 3,5,o
15 min

Sparr HJ, Vermeyen KM, Beaufort AM, Rietbergen H, Proost JH, Saldien V, Velik-Salchner C,
Wierda JM. Early reversal of profound rocuronium-induced neuromuscular blockade by
sugammadex in a randomized multicenter study: efficacy, safety, and pharmacokinetics
Anesthesiology. 2007 ;106:935-43.

• Br J Anaesth. 2007 May;98(5):624-7. Epub 2007 Mar 8. Links
• Reversal of rocuronium-induced (1.2 mg kg-1) profound neuromuscular
block by accidental high dose of sugammadex (40 mg kg-1).
• Molina AL, de Boer HD, Klimek M, Heeringa M, Klein J.
• Department of Anaesthesiology, Erasmus University Medical Centre,
Rotterdam, and Martini Hospital Groningen, The Netherlands.
• Sugammadex is the first selective relaxant binding agent and reverses
rocuronium-induced neuromuscular block. A case is reported in which a
patient accidentally received a high dose of sugammadex (40 mg kg-1) to
reverse a rocuronium-induced (1.2 mg kg-1) profound neuromuscular block.
A fast and efficient recovery from profound neuromuscular block was
achieved and no adverse events or other safety concerns were reported.

• 1: Anesth Analg. 2007 Mar;104(3):585-6. Links
• Comment in: Anesth Analg. 2007 Sep;105(3):876-7; author reply 878. Anesth
Analg. 2007 Sep;105(3):876; author reply 876, 878. Anesth Analg. 2007
Sep;105(3):877-8; author reply 878. Anesth Analg. 2007 Sep;105(3):877;
author reply 878. Emergency use of sugammadex after failure of standard
reversal drugs.
• Lenz A, Hill G, White PF.
• Department of Anesthesiology and Pain Management; University of Texas
Southwestern Medical Center, Dallas, Texas 75390-9068, USA.
• Administration of sugammadex, 350 mg IV (4 mg/kg), in the postanesthesia
care unit immediately (<60 s) relieved acute respiratory distress due to
residual neuromuscular blockade in a 42-yr-old patient with chronic renal
failure who had received vecuronium, 10 mg IV, for tracheal intubation, after
inadequate reversal of neuromuscular blockade in the operating room with
neostigmine, 5 mg IV, and glycopyrrolate, 1 mg IV.

• : Anesth Analg. 2007 Mar;104(3):582-4. Links
• A temporary decrease in twitch response during reversal of rocuronium-induced muscle relaxation with a
small dose of sugammadex.
• Eleveld DJ, Kuizenga K, Proost JH, Wierda JM.
• Research Group for Experimental Anesthesiology and Clinical Pharmacology, University Medical Center,
University of Groningen, Groningen, The Netherlands. d.j.eleveld@anest.umcg.nl
• BACKGROUND: We present a case in which a temporary decrease in train-of-four (TOF) response was observed
after reversal of muscle relaxation with a small dose (0.5 mg/kg) of sugammadex administered 42 min after 0.9
mg/kg of rocuronium. At the end of the operation, the TOF ratio was >0.9, and the patient woke normally,
without signs of muscle weakness. We describe this temporary decrease in muscle response during muscle
relaxation reversal as muscle relaxation rebound and hypothesize that it occurs when the dose of
sugammadex is sufficient for complex formation with rocuronium in the central
compartment, but insufficient for redistribution of rocuronium from peripheral to
central compartments. METHODS: To investigate our hypothesis, we developed and fit a simple
pharmacokinetic- pharmacodynamic model of rocuronium, sugammadex, and their interaction to the patient
TOF response data. RESULTS: Simulations using the fitted model indicate that muscle relaxation rebound can
occur for doses of sugammadex in a limited critical range. CONCLUSIONS: Sufficiently large doses of sugammadex
eliminate the possibility for muscle relaxation rebound, which does not require dissociation of the sugammadex/
rocuronium complex.

Sacan O, White PF, Tufanogullari B, Klein KSugammadex reversal of
rocuronium-induced neuromuscular blockade: a comparison with
neostigmine-glycopyrrolate and edrophonium-atropine. Anesth Analg. 2007
;104:569-74.
• .
• Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas
75390-9068, USA.
• BACKGROUND: Sugammadex is a modified [gamma] cyclodextrin compound, which encapsulates rocuronium to provide for a
rapid reversal of residual neuromuscular blockade. We tested the hypothesis that sugammadex would provide for a more rapid
reversal of a moderately profound residual rocuronium-induced blockade than the commonly used cholinesterase inhibitors,
edrophonium and neostigmine. METHODS: Sixty patients undergoing elective surgery procedures with a standardized desflurane-
remifentanil-rocuronium anesthetic technique received either sugammadex, 4 mg/kg IV (n = 20), edrophonium, 1 mg/kg IV and
atropine, 10 microg/kg IV (n = 20), or neostigmine, 70 microg/kg IV and glycopyrrolate, 14 microg/kg IV (n = 20) for reversal of
neuromuscular blockade at 15 min or longer after the last dose of rocuronium using acceleromyography to record the train-of-
four (TOF) responses. Mean arterial blood pressure and heart rate values were recorded immediately before and for 30 min after
reversal drug administration. Side effects were noted at discharge from the postanesthesia care unit. RESULTS: The three groups
were similar with respect to their demographic characteristics and total dosages of rocuronium prior to administering the study
medication. Although the initial twitch heights (T1) at the time of reversal were similar in all three groups, the time to achieve
TOF ratios of 0.7 and 0.9 were significantly shorter with sugammadex (71 +/- 25 and 107 +/- 61 s) than edrophonium (202 +/- 171
and 331 +/- 27 s) or neostigmine (625 +/- 341 and 1044 +/- 590 s). All patients in the sugammadex group achieved a TOF ratio of
0.9 < or =5 min after reversal administration compared with none and 5% in the edrophonium and neostigmine groups,
respectively. Heart rate values at 2 and 5 min after reversal were significantly higher in the neostigmine-glycopyrrolate group
compared with that in sugammadex. Finally, the incidence of dry mouth was significantly reduced in the sugammadex group (5%
vs 85% and 95% in the neostigmine and edrophonium groups, respectively). CONCLUSION: Sugammadex, 4 mg/kg IV, more
rapidly and effectively reversed residual neuromuscular blockade when compared with neostigmine (70 microg/kg IV) and
edrophonium (1 mg/kg IV). Use of sugammadex was associated with less frequent dry mouth than that with the currently used
reversal drug combinations.

Sugammadex reversal of rocuronium-induced neuromuscular blockade:
a comparison with neostigmine-glycopyrrolate and edrophonium-
atropine
sugammadex, 4
mg/kg
edrophonium, 1
mg/kg IV and
atropine, 10
microg/kg
Neostimine 70
microgr/Kg, and
glycopirrolate 14
microg/kg
Tofr 0.7 71 +/- 25 202 +/- 171 s 625 +/- 341 s
Tofr 0.9 107 +/- 61 s 331 +/- 27 1044 +/- 590 s)
Tofr 0.9 <5 min all none 5%

Vanacker BF, Vermeyen KM, Struys MM, Rietbergen H, Vandermeersch E, Saldien V, Kalmar
AF, Prins ME. Reversal of rocuronium-induced neuromuscular block with the novel drug
sugammadex is equally effective under maintenance anesthesia with propofol or
sevoflurane. Anesth Analg. 2007 ;104:563-8.
• Department of Anesthesiology, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
bernard.vanacker@uz.kuleuven.ac.be
• In this study we investigated whether the novel reversal drug, sugammadex, is equally
effective at reversing rocuronium-induced neuromuscular block (NMB) in patients under
propofol or sevoflurane maintenance anesthesia. After receiving propofol for induction,
patients were randomized to propofol (n = 21) or sevoflurane (n = 21). Rocuronium 0.6 mg/kg
was administered for tracheal intubation. NMB was monitored using acceleromyography. At
reappearance of the second twitch of the train-of-four ratio, sugammadex 2.0 mg/kg was
administered by IV bolus. The primary end-point was time from start of sugammadex
administration to recovery of train-of-four ratio to 0.9. Mean recovery time was 1.8 min after
both propofol and sevoflurane anesthesia. The 95% confidence interval for the difference in
recovery time between the 2 groups (-0.5 to +0.4 min) was well within the predefined
equivalence interval (-1 to +1 min), indicating that recovery from NMB was unaffected by
maintenance anesthesia. Thirteen patients (propofol n = 4; sevoflurane n = 9) experienced
adverse events; these were treatment-related in 4 patients (propofol n = 3; sevoflurane n = 1).
There were no treatment-related serious adverse events and no discontinuations or deaths.
No residual paralysis occurred. The safety profile of sugammadex was somewhat more
favorable under propofol than under sevoflurane anesthesia.

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