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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10

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