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27.11.2009
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MD Hanna IllmanTurku University Hospital
Finland
Current state of reversalLimitations of current methods of reversal Limitations of current methods of reversal Recognized potential risks associated with residual blockade
A new approach to reversalReversal with Bridion® (sugammadex)
Mechanism of actionPharmacokinetics and pharmacodynamicsEfficacySafety
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Relatively slow in reversing neuromuscular blockadeblockadeLimited ability to reverse deep blockadeEfficacy influenced by maintenance anesthetics Well-known side effect profileRequire concomitant administration of Require concomitant administration of anticholinergics
Bartkowski RR. Anesth Analg. 1987;66:594-598.Kim KS et al. Anesth Analg. 2004;99:1080-1085.Kopman AF et al. J Clin Anesth. 2005;17:30-35.
T1 = 100%Hatched area =
Vecuronium Protocol
NEO administered
10 min 20 min 30 min
T1 = 50%Solid area = height of T4
height of T1
Rocuronium Protocol
5 min 10 min 15 min 20 minROC 0.6 mg/kg
n = 20
TOF ratio 0.33 ±0.13
0.57 ±0.11
0.70 ±0.12
0.79 ± 0.12
TOF < 0.9 100% (20) 100% (20) 95% (19) 85% (17)
NEO, neostigmine; ROC, rocuronium; TOF, train-of-four. Kopman AF et al. J Clin Anesth. 2005;17:30-35.
Rocuronium Protocol
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1.0
0 8
Administration at 95% Twitch Depression
0.8TO
F Ra
tio
0.6
0.4
0.2
0.0
Neostigmine
Pyridostigmine
Edrophonium
The ability of ChE inhibitors to reverse to adequate TOF ratios is limited due to a ceiling effect that exists at deeper levels of neuromuscular blockade
ChE, cholinesterase; TOF, train-of-four. Bartkowski RR. Anesth Analg. 1987;66:594-598.
Concentration (µm)0.001 0.01 0.1 1 10 100
50 PROP (n = 20)
8 6
28,622,6
20
30
40
an T
ime
(min
) to
OF
Rat
io =
0.9
SEVO (n = 20)
**
8,6 7,5
0
10
Med
i TO
Kim KS et al. Anesth Analg. 2004;99:1080-1085.
*P <.0001PROP, propofol; SEVO, sevoflurane; TOF, train-of-four.
T1 T2
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ChE inhibitors in the reversal of neuromuscular block can cause BradycardiaHypersalivationBronchospasmIncreased bronchial secretionsUrinary frequencyNausea and vomiting
Coadministration of antimuscarinic agents aids in preventing cholinergic effects but may result in*
TachycardiaDryness of mouth and noseMydriasisUrinary retention
Neostigmine Methylsulfate Injection [package insert]; 2002. Atropine Sulfate Injection, USP [package insert]; 2003.
Glycopyrrolate Injection, USP [package insert]; 2006.ChE, cholinesterase. *Atropine use causes dose-dependent adverse effects.
St d
NMBA administere
dReversa
l
Definition of residual block,
(TOF ti )
Incidence of residual block,
(%)Study d l (TOF ratio) n (%)Bevan et al Pancuronium
Atracurium Vecuronium
+/- <0.7 17/47 (36)2/46 (4)5/57 (9)
Hayes et al Atracurium VecuroniumRocuronium
+/- <0.8 32/50 (64)26/50 (52)19/48 (39)
Baillard et al Vecuronium +/- <0.7 239/568 (42)
Debaene et al
Intermediate-acting agents
+/- <0.7<0.9
85/526 (16)237/526 (45)
Kim et al VecuroniumRocuronium
- <0.7 70/274 (25)35/203 (15)
Murphy et al Pancuronium Rocuronium
+ <0.7 14/35 (40)2/34 (5.9)
Murphy GS. Minerva Anestesiol. 2006;72:97-109.NMBA, neuromuscular blocking agent; TOF, train-of-four.+, used in patients; +/- used in some patients; -, not used in patients
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All patients (n = 526)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0 1
TOF
Rati
o
All patients (n = 526)
Debaene B et al. Anesthesiology. 2003;98:1042-1048.
0.1
0.0
0 50 100 150 200 250 300 350 400
Time (min)
*Significantly different from TOF <0.9 (P<0.01)TOF, train-of-four.
y s, %
60Abdominal Surgery
Pred
icti
ve P
roba
bilit
yof
Pos
tope
rati
velm
onar
y Co
mpl
icat
ions
0
20
40Abdominal Surgery
Berg H et al. Acta Anaesthesiol Scand. 1997;41:1095-1103.
Pancuronium, TOF <0.7 Pancuronium, Atracurium, and Vecuronium, TOF ≥0.7
P
Pul 0
20 30 40 50 60 70 80Age
TOF, train-of-four.
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The molecule
Cyclodextrins are cyclic oligosaccharides
Cyclodextrins are defined by α-CD β-CD
y ythe number of glucopyranoside units they contain
6 units - α7 units - β8 units - γ
Cyclodextrins have the following properties:
Lipophilic cavityHydrophilic exterior
These characteristics enable CDs to form water-soluble inclusion complexesγ-CD
Davis ME et al. Nat Rev Drug Discov. 2004;12:1023-1035.CD, cyclodextrin.
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Pharmaceutical applications Prostaglandin E1 (Caverject®)Prostaglandin E1 (Caverject )Ziprasidone maleate (Geodon®)Diclofenac ophthalmic (Voltaren®) Itraconazole (Sporanox®)
Dietary applicationsCarrier and stabilizer of flavors and colorsFat-soluble vitamins and polyunsaturated fatty acidsp y yFrozen dairy dessertsMany more
Estimated daily intake of γ-CD from dietary means*1 day intake = 4.1 g/person
*Intake based on an individual consuming at least1 food containing γ-CD on 1 occasion.CD, cyclodextrin.
Davis ME et al. Nat Rev Drug Discov. 2004;12:1023-1035.Munro IC et al. Regul Toxicol Pharmacol. 2004;39:S3-S13.
Mechanism of Action
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Cameron KS et al. Org Lett. 2002;4:3403-3406. Gijsenbergh F et al. Anesthesiology. 2005;103:695-703.
NMBA
NMB
Choline
AChEConventional NMB Reversal
Choline
AChE
+acetate ACh
nAChR
+acetate ACh
NMBA
nAChRChE inhibitors
(eg, neostigmine)
Reversal With Bridion
Choline
AChE
NMBA
Adam JM et al. J Med Chem. 2002;45:1806-1816.
Choline+
acetateACh
NMBA
nAChR Hostmolecule
ACh, acetylcholine; AChE, acetylcholinesterase.ChE, cholinesterase; nAChR, nicotinic acetylcholine receptor;NMBA, neuromuscular blocking agent; NMB, neuromuscular blockade.
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Vss 11 to 14 LT elimination 1 8 hours T½ elimination 1.8 hours Cl estimated to be ~88 mL/minMajor route of elimination: renal
96% of the dose excreted in urine, of which at least 95% could be attributed to unchanged Bridiong
Cl, clearance; T½, half-life; Vss, volume of distribution at steady state.
Data on file.Bridion® [summary of product characteristics]. Organon, Europe; 2008.
Recovery of TOF Ratio to 0.9
20)
17,6
68
101214161820
me
to R
ecov
ery
(min
)
1,4
0246
Med
ian
Ti
CI, confidence interval; TOF, train-of-four, NEO, neostigmine. Data from Aurora trial.
n = 48 n = 48Bridion 2 mg/kg NEO 50 µg/kg
95% CI (1.2–1.5 min) 95% CI (12.7–26.4 min)
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100
Reversal From T2 Following rocuronium 0.6 mg/kg
40
60
80
ents
retu
rnin
g to
TO
F 0.
9
Bridion 2 mg/kg (n = 48)
NEO 50 µg/kg (n = 48)
0
20
0 30 60 90 120 150Time (min)
% o
f pat
i
NEO, neostigmine. Data from Auroral trial.
Recovery of TOF Ratio to 0.918 920) 18,9
68
101214161820
ime
to R
ecov
ery
(min
)
2,13
0246
Med
ian
Ti
CI, confidence interval; NEO, neostigmine; TOF, train-of-four. Data from Aurora trial.
n = 45NEO 50 µg/kg
95% CI (12.2–25.5 min)
Bridion 2 mg/kg
95% CI (1.9–3.0 min)n = 48
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Recovery of TOF Ratio to 0.960
n)
49
20
30
40
50
Tim
e to
Rec
over
y (m
in
2,70
10
Med
ian
T
CI, confidence interval, NEO, neostigmine. Data from Signal trial.
n = 37NEO 70 µg/kg
95% CI (35.7–59.5 min)
Bridion 4 mg/kg
95% CI (2.3–3.3 min)n = 37
14
Rocuronium 1.2 mg/kg Bridion 16 mg/kg Succinylcholine 1 mg/kg
4
6
8
10
12
n (2
*SEM
) Tim
e (m
in)
*
*3.2
7.1
10.9
0
2
4
Mea
n
*P < 0.0001 versus succinylcholine treatment group; results based on intent-to-treat population.SEM, standard error of mean. Data from Spectrum trial.
3 minBridionadministered
T1 to 10% T1 to 90%
1.4
n = 56 n = 54 n = 56 n = 54
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20
n n
5
10
15
Min
utes
n = 56
n = 54
T1=10% T1=90% T1=10% T1=90%Rocuronium 1.2 mg/kg +
Bridion 16 mg/kgSuccinylcholine 1.0 mg/kg
0
Data from Spectrum trial.
Sugammadex available since September 2008>300 patients have received sugammadex>300 patients have received sugammadexChildren, adults, elderlyASA physical status I‐IV
Elective surgeryORL, neurosurgeryg yGeneral surgery
’On‐call procedures’Appendicectomy, laparotomy etc.
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>200 patients since September 2008
All kinds of ORL‐surgery requiring general anaesthesia and neuromuscular blockadeEsophagoscopyPanendoscopyBronchoscopyLaser surgery of tracheal/endobronchial tumorsTonsillectomy
Endoscopies performed with a rigid scope :Bronchoscopy esophagoscopy (foreign objects)Bronchoscopy, esophagoscopy (foreign objects)
Inadequate level of neuromuscular blockademay lead to severe and irreversible trauma
Such procedures are typically of short durationSuch procedures are typically of short duration
6‐7 procedures are performed in the same roomSmooth exchange of patients necessary.... succinyl choline was usually chosen over rocuronium
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Laser surgery of tumor tissue in the airways:V l h d h i b hiVocal chords, trachea, main bronchi
Jet ventilation (through a catheter or a rigid bronchoscope) is typically usedProper neuromuscular block is of vital importance as severe damage to the airway is possible
Procedure is typically finished quite abruptlyEndotracheal intubation should be avoided
Tonsillectomy (adult patients):
Experienced oto‐rhino‐laryngologists perform the procedure in 5‐15 minutes
Sugammadex allows much faster extubation
Small children receive no NMBA:s for intubation
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80
100
120
80
100
120
0
20
40
60
11:0
3:39
11:0
4:09
11:0
4:39
11:0
5:09
11:0
5:39
11:0
6:09
11:0
6:39
11:0
7:09
11:0
7:39
11:2
3:09
11:2
3:39
11:2
4:09
11:2
4:39
11:2
5:09
11:2
5:39
11:2
6:09
11:2
6:39
11:2
7:09
11:2
7:39
11:2
8:09
T1%TOF%
83‐year female. Coronary artery disease. Previously carcinoma of thyroid gland, currently metastasized to neck and mediastinum. Tracheostomized due to recurrens paresis Difficulty swallowing food ASA status 4
0
20
40
60
80
11:0
3:39
11:0
4:09
11:0
4:39
11:0
5:09
11:0
5:39
11:0
6:09
11:0
6:39
11:0
7:09
11:0
7:39
11:2
3:09
11:2
3:39
11:2
4:09
11:2
4:39
11:2
5:09
11:2
5:39
11:2
6:09
11:2
6:39
11:2
7:09
11:2
7:39
11:2
8:09
T1%TOF%
recurrens paresis. Difficulty swallowing food. ASA‐status 4.Scheduled for esophagoscopy and dilation of esophageal stricture.
Induction: propofol, fentanyl. Rocuronium 36 mg (54 kg) at 11.04 am.Maintenance of anesthesia with desflurane. Some efedrin boluses.
At 11.24 am: Procedure finished. No TOF‐responses detected at this point. Sugammadex 200 mg (4 mg/kg) is administered. End‐tidal desflurane 4.2%.
At 11.27 am: full reversal of the block (TOF‐ratio > 0.9).
CraniotomiesEl i i ( )Elective craniotomy (tumor surgery etc.)
Spinal surgery
Endovascular coiling of aneurysms
Assessment of patient’s neurological state
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Craniotomy patients:
Coughing at any time may be detrimental ▪ neuromuscular blockade should be kept at an adequate level until the wound has been covered ‐without any delay
Elective craniotomy patients are usually extubated in the OR before transfer to the ICU▪ reversal of the block should be fast and complete since retention of carbon dioxide must be avoided
Lumbar spinal surgery: Laminectomy disk surgery spondylodesis etc Laminectomy, disk surgery, spondylodesis etc.
Tension of dorsal muscles makes surgery and even closing of the wound difficult▪ an adequate level of neuromuscular blockade during suturation should be maintained without delaysuturation should be maintained ‐without delay
Coughing or choking the endotracheal tube in the prone position must be avoided
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Endovascular coiling of aneurysms:
Coughing or movement during the coiling procedure must be strictly avoided
intracerebral bleeding may lead to paralysis or death
The procedure is performed outside the OR and the The procedure is performed outside the OR and the patient is extubated before transfer to PACU
hypercapnia must be avoided
Assessment of neurological state:
Patients with a suspected brain injury are typically intubated outside the hospital in the field
Neuromuscular blockade must be reversed at arrival in the hospital in order for the neurologist to be able in the hospital in order for the neurologist to be able to assess the neurological state properly
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Approx. 80 obesity operations annually (2/week)R Y (b ) %Roux‐en‐Y (bypass) 50%’Sleeve’ (reduction of the ventricle) 50%
Possible difficult mask ventilation/intubationLaparoscopic technique: proper neuromuscular p p q p pblockade necessary until end of procedureThe severely overweight cannot tolerate even a slight degree of residual blockade ▪ COPD, sleep apnea, reduced response to hypoxemia..
53‐year‐old female, 159 cm, 75 kg
Otosclerosis, hypacusis conductive l.a., ASA I
Scheduled for tympanotomy
P di iPremedicationDiazepam 10 mg, paracetamol 2 g
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Anaesthesia regimen
TIVA propofol/remifentanil by TCI▪ Propofol: induction 6 ug/mL, maintenance 4 µg/mL▪ Remifentanil: 2 ng/mL throughout procedure
Rocuronium 50 mg at induction (9:02 AM) ▪ 10 + 10 + 10 mg additional boluses
Monitoring
3‐lead ECG, oxygen saturation, NIBP every 5 minEtCO2, Datex Electrosensor/TOF‐stimulation Datex E‐Enthropy
Reversal of rocuronium block by sugammadex 200 mg
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Recovery of T1% and TOF% Full recovery(TOF count 4)
40
60
80
100
120
T1%
Reversal of rocuronium block by sugammadex
200 mg
Percen
tage (%
)
0
20 TOF%
Time
6000
NMT RecoveryReversal of
rocuronium block by sugammadex
200 mg
0
1000
2000
3000
4000
5000
6000
NMT(R1)
NMT(R2)
Full recovery(TOF count 4)
0 NMT(R3)
NMT(R4)
Time
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58‐year‐old male, 173 cm, 90 kg
Hypertension, carcinoma prostatae (operated 2005), exostosis meati acustici ext l.a., ASA II
Scheduled for meatoplasty
PremedicationDiazepam 10 mg, paracetamol 2 g bisoprolol 5 mg (prescription drug)
Anaesthesia regimen
Induction: ▪ fentanyl 0.2 mg, propofol 200 mg ▪ rocuronium 50 mg at induction, 10 + 10 mg additional boluses
M i t Maintenance: ▪ desflurane (end‐tidal conc. 4.5%–8.2%) ▪ one additional 0.05‐mg fentanyl bolus ▪ ephedrine 5 mg + 5 mg boluses for hypotension
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Monitoring
3‐lead ECG, oxygen saturation, NIBP every 5 minEtCO2, Datex Electrosensor/TOF‐stimulationDatex E‐Enthropy
R l f i bl k b Reversal of rocuronium block by sugammadex 200 mg
NMT RecoveryReversal of rocuronium block by sugammadex
200 mg
1000
1500
2000
2500
NMT(R1)
0
500NMT(R2)
NMT(R3)
NMT(R4)
Time
Full recovery(TOF count 4)
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Recovery of T1% and TOF% Full recovery(TOF count 4)
40
60
80
100
120
T1%
Percen
tage (%
)
Reversal of rocuronium block by sugammadex
200 mg
0
20
14:00:44 14:01:14 14:01:44 14:02:14 14:02:44 14:03:14 14:03:44 14:04:14
TOF%
Time
P
>300 patients have received Bridion® in TurkuN d h b dNo adverse events have been reported
2‐4 mg/kg (usually 200 mg) doses administered Objective monitoring most often used
All collegues satisfied with efficacy of the drug
High cost is a general concern among collegues Cost issue currently limits use of sugammadex
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Neostigmine is still the routine reversal agentC i h d i i fCost is the determining factor
Awareness of the limitations of neostigmine has increased among anesthesists?Hopefully this will lead to increased monitoring and to a change in the use of NMBA:S
Use of succinyl choline has decreased dramatically since September 2008