1. The place of Sugammadex (Bridion®) in laparoscopic bariatric surgery
The place of Sugammadex (Bridion®) in laparoscopic bariatric surgery
Jan Paul Mulier, MD PhD
Sint Jan Brugge-Oostende
Logo SP
J P Mulier 1

2. Overview Current state of reversal Reversal with bridion® (Sugammadex)
Limitations / Potential risks with residual blockade
Techniques to reduce need for reversal
Reversal with bridion® (Sugammadex)
Mechanism of action / Pharmacokinetics, pharmacodynamics
Efficacy / Safety - Practical dosage
Indications for bridion ® (Sugammadex)
“Can not intubate / can not ventilate”
Rapid sequence induction for short procedures
Continuous deep blockade till end of surgery
Sudden / not predicted / need for awakening
Need for an amfetamine like arousal effect
Practical use in bariatric laparoscopy
Anaesthesia induction
Anaesthesia maintenance
Anaesthesia awakening ERAS technique of Bruges
J P Mulier 2

3. Limitations of Cholinesterase Inhibitors
Relatively slow in reversing neuromuscular blockade
Insufficient or impossible to reverse deep blockade
Require concomitant administration of anticholinergics
Well-known side effect profile
Key point:
Cholinesterase inhibitors have limitations
There are many drawbacks to the use of cholinesterase inhibitors in the reversal of neuromuscular blockade. When compared with Bridion, the most prominent characteristic of cholinesterase inhibitors is that they are relatively slow at reversing neuromuscular blockade. Another important limitation of cholinesterase inhibitors is the fact that these drugs are incapable of reversing deep blockade, as documented by Kopman et al and Bartkowski.1,2 Their efficacy is also influenced by the maintenance anesthetic used during the procedure, making their effects even more variable.3
Aside from efficacy, cholinesterase inhibitors are renowned for their side effects if they are not properly managed. These effects are mostly cardiovascular (ie, heart rate, blood pressure) but also include smooth muscle contractions and postoperative nausea and vomiting at higher doses.4,5
These side effects are due to an abundance of acetylcholine. To mitigate these effects, the use of cholinesterase inhibitors should be accompanied by the administration of anticholinergics.
References
1. Kopman AF, Kopman DJ, Ng J, Zank LM. Antagonism of profound cisatracurium and rocuronium block: the role of objective assessment of neuromuscular function. J Clin Anesth. 2005;17:30-35.
2. Bartkowski RR. Incomplete reversal of pancuronium neuromuscular blockade by neostigmine, pyridostigmine, and edrophonium. Anesth Analg. 1987;66:
3. Kim KS, Cheong MA, Lee HJ, Lee JM. Tactile assessment for the reversibility of rocuronium-induced neuromuscular blockade during propofol or sevoflurane anaesthesiology. Anesth Analg. 2004;99:
4. Tramer MR, Fuchs-Buder T. Omitting antagonism of neuromuscular block: effect on postoperative nausea and vomiting and risk of residual paralysis. A systematic review. Br J Anaesth. 1999;82:
5. Caldwell JE. Reversal of residual neuromuscular block with neostigmine at one to four hours after a single intubating dose of vecuronium. Anesth Analg. 1995;80:
Bartkowski RR. Anesth Analg. 1987;66:
Kim KS et al. Anesth Analg. 2004;99:
Kopman AF et al. J Clin Anesth. 2005;17:30-35.
J P Mulier 3

4. Neostigmine (50 µg/kg) Inadequately Reverses 95% Twitch Depression
Vecuronium Protocol
T1 = 100%
Hatched area = height of T1
T1 = 50%
Solid area = height of T4
NEO administered
10 min
20 min
30 min
Rocuronium Protocol
Key point:
Neostigmine inadequately reverses deep neuromuscular blockade
Twenty patients with American Society of Anesthesiologists classes 1 and 2 status who were to undergo surgical procedures were given anaesthesiology induced with propofol 1.5 to 2.5 mg/kg IV plus fentanyl 2 to 4 µg/kg and maintained on nitrous oxide/desflurane plus narcotic supplementation. Train-of-four (TOF) was monitored via electromyographic response at the adductor pollicis. Neuromuscular blockade was induced with rocuronium 0.6 mg/kg, infused for ≥90 min at 95% twitch depression; reversal was attempted using neostigmine 50 µg/kg administered 2 min after stopping the rocuronium infusion.1
It was demonstrated that the neostigmine could not satisfactorily antagonize deep neuromuscular blockade. For example, 2 of the 20 patents failed to reach a TOF ratio of 0.7 within 20 minutes of attempted reversal, and only 3 (15%) subjects recovered to a TOF ratio of 0.9 or greater in the same time period. The conclusion was that if the level of block at the neuromuscular junction is great enough, the extent of recovery becomes finite.1
This tracing is from a pilot study (identical protocol) using vecuronium as the test drug. The infusion lasted 2 hours and 48 minutes. Two minutes after the infusion was stopped at a twitch height equal to 3% of control, neostigmine 50 µg/kg was administered. The TOF ratio did not exceed 0.7 until 27 minutes postreversal. The time interval from a TOF ratio of 0.4 to a value of 0.7 was approximately 17 minutes.
Note: This tracing is the printout from the Datex EMG monitor. Solid blue area represents the height of the fourth twitch. The hatched area represents the height of T1.1
Reference
1. Kopman AF, Kopman DJ, Ng J, Zank LM. Antagonism of profound cisatracurium and rocuronium block: the role of objective assessment of neuromuscular function. J Clin Anesth. 2005;17:30-35.
5 min
10 min
15 min
20 min
ROC 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)
95% (19)
85% (17)
NEO, neostigmine; ROC, rocuronium; TOF, train-of-four.
Kopman AF et al. J Clin Anesth. 2005;17:30-35.
J P Mulier 4

5. Side Effects Associated With Current Reversal Agents
ChE inhibitors in the reversal can cause
Bradycardia / Hypersalivation
Bronchospasm / Increased bronchial secretions
Urinary frequency / Nausea and vomiting
Coadministration of antimuscarinic agents
Tachycardia
Dryness of mouth and nose
Mydriasis / Urinary retention
Key point:
Current reversal agents are associated with several side effects
Recovery from neuromuscular blockade is often hastened by the administration of cholinesterase inhibitors such as neostigmine, pyridostigmine, or edrophonium. While effective, cholinesterase inhibitors have limitations. Not only do they increase the amount of acetylcholine at the neuromuscular junction, cholinesterase inhibition increases the availability of acetylcholine at the muscarinic receptors, which may result in bradycardia, hypersalivation, bronchospasm, increased bronchial secretions, urinary frequency, and nausea and vomiting.1 Furthermore, the use of these agents may not completely avoid the occurrence of residual neuromuscular blockade even after large doses. This was found even after use of intermediate-acting neuromuscular blockers, which are sometimes not monitored because of their decreased incidence of residual neuromuscular blockade.2 Spontaneous recovery will depend on the inherent pharmacokinetics of the neuromuscular blocking agent administered for the surgical procedure.
References
1. Neostigmine Methylsulfate [package insert]. Shirley, NY: American Regent Laboratories, Inc; 2002.
2. Kim KS, Lew SH, Cho HY, Cheong MA. Residual paralysis induced by either vecuronium or rocuronium after reversal with pyridostigmine. Anesth Analg. 2002;95:
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.
J P Mulier 5

6. Increased Risk Associated With Residual Blockade
Increased risk of postoperative pulmonary complications
coughing, expectoration, pain when breathing, increased risk of aspiration; Hypoxemia, hypercapnia, the need for reintubation, non invasive ventilation
delay in meeting PACU discharge criteria and achieving actual discharge
Key point:
Many potential risks associated with residual neuromuscular blockade
The above side effects are often due to impaired neuromuscular function in the early postoperative period following general anaesthesiology.1 As a result, postoperative pulmonary complications may exist, causing a number of dangerous side effects.2-5
The potential for residual neuromuscular blockade is exacerbated by the fact that it is difficult to clinically recognize, and even minimal neuromuscular blockade may result in upper airway obstruction.2,6
In the Berg trial, a total of 691 adult patients scheduled to undergo abdominal, gynecologic, or orthopedic surgery under general anaesthesiology were randomized to receive pancuronium, atracurium, or vecuronium. The doses that were used for tracheal intubation in the study included 0.08 to 0.1 mg/kg for pancuronium or vecuronium and 0.4 to 0.5 mg/kg of atracurium. Maintenance doses were 1 to 2 mg for pancuronium or vecuronium and 5 to 10 mg for atracurium. Postoperatively, the response to TOF nerve stimulation was measured via mechanomyography, and through a 6-day follow-up the patients were examined for pulmonary complications. A postoperative pulmonary complication was considered present when pneumonic infiltrates or atelectasis were diagnosed by the radiologist. This study found that 46 (6.7%) patients displayed pneumonic infiltrates and/or atelectasis following pancuronium, vecuronium, or atracurium administration.3
References
1. Murphy GS. Residual neuromuscular blockade: incidence, assessment, and relevance in the postoperative period. Minerva Anestesiol. 2006;72:
2. Eikermann M, Blobner M, Groeben H et al. Postoperative upper airway obstruction after recovery of the train of four ratio of the adductor pollicis muscle from neuromuscular blockade. Anesth Analg. 2006;102:
3. Berg H, Roed J, Viby-Mogensen J et al. 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 ;41:
4. Bissinger U, Schimek F, Lenz G. Postoperative residual paralysis and respiratory status: a comparative study of pancuronium and vecuronium. Physiol Res. 2000;49:
5. Sundman E, Witt H, Olsson R, Ekberg O, Kuylenstierna R, Eriksson LI. The incidence and mechanisms of pharyngeal and upper esophageal dysfunction in partially paralyzed humans: pharyngeal videoradiography and simultaneous manometry after atracurium. Anesthesiology. 2000;92:
6. Gatke MR, Viby-Mogensen J, Rosenstock C, Jensen FS, Skovgaard LT. Postoperative muscle paralysis after rocuronium: less residual block when acceleromyography is used. Acta Anaesthesiol Scand. 2002;46:
Berg H et al. Acta Anaesthesiol Scand. 1997;41:
Bissinger U et al. Physiol Res. 2000;49:
Eikermann M et al. Anesth Analg. 2006;102:
Murphy GS. Minerva Anestesiol. 2006;72:
PACU, post anaesthesiology care unit
J P Mulier 6

7. What was our answer before Bridion?
Waiting for reversal before awakening, extubation and transfer to PACU
Turnover time increased or ventilation in PACU
Incomplete reversal at extubation
If patient can breath it is oke?
If patient can lift head it is oke?
Ad midazolam so patients are not aware?
Earlier decurarisation (spont or neostigmine)
Is every surgeon happy?
Extra dose neostigmine
has only little effect but could even worsen decurarisation.
Inject water instead of NMB
To make your surgeon happy?
Be a transdisciplinary team
do you really know what surgeons think?
Wat we als assistant geleerd hebben te doen
1 jaar GSO chirurg eist oudere jaars supervisor is veel beter
Wat we effectief deden midazolam at induction
Niet doorvertellen Happy chirurg en happy patient
Eenmaal vast benoemd, hoge rug
Chirurg niet tevreden
Lijm om anest te kleven
Zeer Lang, zeer sterk werkend spierverslapper, en dan plots afgezet
Je moet bij de chirurgen reklame maken, groter buget in operatie, direct akkoord, spijt dat maar in bij begin en dat op het einde
J P Mulier

8. Measure Abdominal Compliance
My technique (before Bridion) to reduce the need for reversal in laparoscopy
Measure Abdominal Compliance
Measure abdominal compliance and give less relaxants if Compliance is large.
Or use 2 MAC deep inhalation anaesthesia at end surgery.
Use pressure support ventilation to prevent patient from breathing against ventilator.
J P Mulier

9. Are NMB needed ? Gynecologic laparoscopy without curare is possible.
Chassard D. Ann Fr Anesth Reanim. 1996;15(7):1013-7
Only when compliance is very high?
Or when surgeons do not complain?
J P Mulier

10. APVR description Measure pressure volume relation
Angle is compliance or elastance E
Section with Y axis is PV0: pressure at zero vol
P = 3,30 V + 8,40 mmHg
Squared R = 0,96
E : 3,3 mmHg/L
PV0 : 8,4 mmHg
J P Mulier

11. E en PV0 determined by ? Mulier Dillemans ESA 2007 factors PV0 PVO sig
E sig
Age
Neg
0.828
Pos
0.003*
Length
0.356
0.245
Body weigth
0.012*
0.294
Bmi
neg
0.054
0.272
Sex
0.596
0.536
Gravidity
0.305
0.049*
Prev abd operation
0.191
0.009*
Muscle relaxation
0.001*
0.376
* Sig p<0.05
J P Mulier

12. Patient with no effect of NMB
No muscles in abd wall, diaphragm ?
Fully relaxed by other factors ?
TOF > 90%
TOF = ¼
TOF 0/4 and PTC < 5
J P Mulier

13. Why NMB sometimes have no effect on APVR?
Muscle total relaxed before giving NMB.
Deep anesthesia?
Volatile anesthetics?
Muscle very thin or non existent
Muscle fascia parallel
J P Mulier

14. Pig: High dose desfl sevo
Zelfde spier relaxatie effect sevo en desfl
data JPMulier 2009
J P Mulier

15. Effect of valsalva: breathing against ventilator
Valsalva is an active muscle contraction different from breathing to increase the abdominal pressure
Happens when patient reacts on Controlled Ventilation
J P Mulier

16. BMI effect on abdominal P/V relation
J Mulier ISPUB 2009
Pressure volume relation is linear
PV0 and E define each patient
J Mulier IFSO 2007
J P Mulier

17. Android versus Gynoid fat distribution has a different Elastance
J P Mulier

18. Waist to Hip ratio (WHR)
Man normal WHR: 0,9
Woman normal WHR: 0,7
Android fat distribution
WHR > 0,8
Gynoid fat distribution
WHR < 0,8
J P Mulier

19. Remember:Patient type with a high mortality risk
Elderly male diabetes patient with hypertension and being super obese, no weigth loss.
Buchwald 2007
Central abdominal fat, not stopped smoking, alcoholic
General risk
Asthma and coronary artery disease
Cardio pulmonary risks
J P Mulier

20. Two types of android obesity
Subcutaneus Fat Visceral fat
Intra visceral adiposity Extra visceral adiposity
Subcutaneus fat is scant and Subcutaneus fat is thick and
intra abdominal fat is thick and intra abdominal fat is scant.
J P Mulier

21. The obese patient is a challenge for anaesthesia if android shape with intra visceral fat.
J P Mulier

22. NMB effect on E - PV0 E or Compliance unchanged
E determined by fascia, size and shape
PV0 drops =extra volume at same pressure
J P Mulier

23. How to change PV0? Mulier Dillemans 2008 NMB
Inhalation anesthesia > 2 MAC
Table inclination: trendelenburg
Smaller tidal volume ventilation
Lower peep
J P Mulier

24. How to change E : hip flexion
Mulier JP, Dillemans B Obes Surg 2009
J P Mulier

25. Begin – End of first laparoscopy
Abdominal compliance changes during pneumoperitoneum
Inflation volume rises more than 1 liter!
No NMB needed at end of operation ?
One Hour Laparoscopy at 15 mmHg Elongates the Abdominal Wall
Mulier IFSO 2009
J P Mulier

26. Laparoscopy without muscle relaxants ?
Laparoscopy is possible without muscle relaxants or at reduced dose if
adominal compliance > 0,5 L/mmHg
IAV > 4 L at 15 mmHg at start laparoscopy
Gravidity > 3
Previous multiple laparoscopies/laparotomies
> 10 kg weight reduction
No man with android fat distribution
and
Sufficient deep sleep
As patient should not breath against ventilator.
Pressure support ventilation
Easier to prevent breathing against ventilator
J P Mulier

27. Are NMB needed in laparoscopy?
No if abdominal compliance is large
Yes as inflation pressure can be lower
Yes to prevent breathing agains ventilator
After one hour laparoscopy compliance is rosen
J P Mulier

28. PSV PSV is not a valsalva effect: IAV is not changing.
PSV is possible during deep muscle relaxation.
PROFOUND MUSCLE RELAXATION DOES NOT DISTURB
PRESSURE SUPPORT VENTILATION.
Mulier J, Blacoe D PGA 2009
J P Mulier

29. Is deep relaxation needed and possible?
Time between end pneumoperitoneum and end operation is very short: in 5 min from TOF 0/4 -¼ till 90% is not possible with neostigmine.
Sugammadex
TOF 0/4 till end pneumoperitoneum
Very deep NMB PTC < 5 is possible till the end
J P Mulier

30. Effect deep muscle relaxation on IAP with constant IAV
Gradual pressure drop until flat line
Max effect at TOF 0/4
At PTC 0 no extra pressure drop
TOF 4/ TOF ¼ PTC 10 PTC 5 PTC 0
J P Mulier

31. Effect of deep muscle relaxation on abdominal PV loop
TOF 0/4 and PTC < 5
J P Mulier

32. Conclusion: NMB needed
Yes
Larger surgical workvolume for lower pressures
At low pressures less structural damage and less post op pain?
Sometimes no sufficient workspace and angry surgeons: try to do everything. No
Abd Compliance sometimes large enough
Work at higher intra abd pressure?
2 MAC inhalation has same effect?
Effect of position and of time?
Meten is weten (Measuring is knowing!)
J P Mulier

33. If Yes -> decurarisation needed
Only Brideon is able to do so ?
J P Mulier

34. Bridion’s Mechanism of Action Is Unlike Traditional Reversal Agents
NMB
Choline + acetate
AChE
ACh
nAChR
Conventional NMB Reversal
Choline + acetate
AChE
ACh
NMBA
nAChR
ChE inhibitors (eg, neostigmine)
NMBA
Reversal With Bridion
Choline + acetate
AChE
ACh
NMBA
nAChR
Host molecule
Neuromuscular Blockade: Signal transmission via the neuromuscular junction through the transfer of acetylcholine to the nicotinic acetylcholine receptor is blocked by the competitive inhibition of neuromuscular blockers.1
Conventional Neuromuscular Blockade Reversal: Conventionally, reversal is achieved by inhibiting acetylcholinesterase. This prevents acetylcholine from being metabolized, causing an increase in acetylcholine at the neuromuscular junction giving a competitive advantage to acetylcholine over the neuromuscular blocker. This results in the displacement of the neuromuscular blocker and allows for signal transmission to return. A side effect of this technique is an abundance of acetylcholine that can result in cardiovascular side effects.1
Reversal With Bridion: The manner in which Bridion functions is by acting as a surrogate receptor for the neuromuscular blocking agent. Because Bridion has such high affinity for rocuronium and vecuronium, these neuromuscular blockers readily dissociate from the nicotinic acetylcholine receptor. This results in a concentration gradient away from the neuromuscular junction, culminating in rapid reversal. Because this has no effect on acetylcholine homeostasis, there are no cardiovascular side effects.1
Reference
1. Adam JM, Bennett DJ, Bom A et al. Cyclodextrin-derived host molecules as reversal agents for the neuromuscular blocker rocuronium bromide: synthesis and structure-activity relationships. J Med Chem. 2002;45:
ACh, acetylcholine; AChE, acetylcholinesterase. ChE, cholinesterase; nAChR, nicotinic acetylcholine receptor; NMBA, neuromuscular blocking agent; NMB, neuromuscular blockade.
Adam JM et al. J Med Chem. 2002;45:
J P Mulier 34

35. Encapsulation of Rocuronium By Bridion
X-ray crystal structures of Bridion (green) and rocuronium (blue) with filled van der Waals surface, showing that the two structures have many close contacts and are highly compatible with each other.
Reference
1. Gijsenbergh F et al. First human exposure of Org 25969, a novel agent to reverse the action of rocuronium bromide. Anesthesiology. 2005;103:
Cameron KS et al. Org Lett. 2002;4:
Gijsenbergh F et al. Anesthesiology. 2005;103:
J P Mulier 35

36. What happens when Bridion is injected?
= Esmeron
J P Mulier

37. What happens when Bridion is injected?
J P Mulier

38. What happens when Bridion is injected?
= Bridion - Esmeron complex
J P Mulier

39. What happens when Bridion is injected?
= Bridion - Esmeron complex
J P Mulier

40. What happens when Bridion is injected?
= Bridion - Esmeron complex
J P Mulier

41. Bridion Pharmacokinetics
Vss 11 to 14 L
T½ elimination 1.8 hours
Cl estimated to be ~88 mL/min
Major route of elimination: renal
96% of the dose excreted in urine, of which at least 95% could be attributed to unchanged Bridion
References
1. Data on file.
2. Bridion® (sugammadex) [Summary of Product Characteristics]. N.V. Organon, Kloosterstraat 6, 5349 AB Oss, The Netherlands; August 2008.
Cl, clearance; T½, half-life; Vss, volume of distribution at steady state.
Data on file. Bridion® [summary of product characteristics]Organon, Europe; 2008.
J P Mulier 41

42. Various Depths of Blockade
Posttetanic count
Twitch response
Twitch percentage
Level of block
Intense block
Deep block
Moderate block
Superficial block
Response to TOF
TOF count 0
TOF count 0
TOF count 1-3
TOF count 4
T1/T4 %
Response to PTC
PTC 0
PTC ≥1
Intense block: no response to either TOF or PTC stimulation
Deep block: response to PTC but not to TOF stimulation
Moderate block: reappearance of response to TOF stimulation
Superficial block: reappearance of T4 T4/T1 ratio > 1%
No block: T4/T1 ratio > 90 %
This slide provides an explanation of the various depths of neuromuscular blockade.
Reference
1. Fuchs-Buder T, Claudius C, Skovgaard LT et al. Good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents II: the Stockholm revision. Acta Anaesthesiol Scand. 2007;51:
PTC, posttetanic count; TOF, train-of-four.
Fuchs-Buder T et al. Acta Anaesthesiol Scand. 2007;51:
J P Mulier 42

43. Increased Flexibility in the Time of Reversal
Immediate Reversal*
Within 3 min following administration of rocuronium, 16 mg/kg
Routine Reversal
4 mg/kg if recovery has reached 1–2 PTC (deep blockade)
2 mg/kg if spontaneous recovery has reached the reappearance of T2 (moderate blockade)
Bridion allows full relaxation until the end of surgical procedures
References
1. Data on file, Schering-Plough Corporation
2. Bridion® (sugammadex) [Summary of Product Characteristics]. N.V. Organon, Kloosterstraat 6, 5349 AB Oss, The Netherlands; August 2008.
*Only recommended with rocuronium-induced blockade. PTC, posttetanic count.
Data on file. Bridion® [summary of product characteristics]. Organon, Europe; 2008.
J P Mulier 43

44. Recommended dosage Maximum safety: Less? TBW or IBW ?
16 mg/kg intense block
4 mg/kg deep block
2 mg/kg all other blocks
Maximum safety:
overloading t1/2 longer than roc
Fastest reversal
Never recurarisation
Individual variation covered
Less?
No studies yet
Re-occurrence of relaxation
TBW or IBW ?
No studies yet but as rocuronium is dosed according to IBW and has the same water solubility ???
Combination with neostigmine is possible but you get the side effects back.
J P Mulier

45. Is the patient, willing to pay for it?
Practical bridion use
Vial 2 ml, 100 mg/ml mg per vial
2 mg/kg in a 70 kg person:
140 mg one vial
2 mg/kg in a 200 kg person:
400 mg or two vials or IBW 140 mg?
Is the patient, willing to pay for it?
Yes if
previous history of rest curarisation
you explain that procedure
is otherwise not safe
might take longer
Is not possible
You prevent post op complications?
J P Mulier

46. Measure Depth of Blockade
Posttetanic count
Twitch response
Twitch percentage
Level of block
Intense block
Deep block
Moderate block
Superficial block
Response to TOF
TOF count 0
TOF count 0
TOF count 1-3
TOF count 4
T1/T4 %
Response to PTC
PTC 0
PTC ≥1
Intense block: 16 mg/kg
Deep block: 4 mg/kg
Moderate block: 2 mg/kg + Neostigmine?
Superficial block: 1 mg/kg + Neostigmine?
No block: 0 mg/kg
This slide provides an explanation of the various depths of neuromuscular blockade.
Reference
1. Fuchs-Buder T, Claudius C, Skovgaard LT et al. Good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents II: the Stockholm revision. Acta Anaesthesiol Scand. 2007;51:
PTC, posttetanic count; TOF, train-of-four.
Fuchs-Buder T et al. Acta Anaesthesiol Scand. 2007;51:
J P Mulier 46

47. More Rapid Recovery With Bridion From T2 Following Rocuronium
Rocuronium 0.6 mg/kg
Bridion 2 mg/kg
(%)
100 50
10:21:06
10:32:38
10:44:08
10:55:38
11:07:08
11:18:53
11:30:38
11:42:08
11:53:53
12:04:39
12:13:56
Rocuronium 0.6 mg/kg
Neostigmine 50 µg/kg
(%)
100 50
7:49:34
7:59:34
8:09:34
8:19:34
8:29:49
8:39:49
8:50:03
9:00:19
9:10:19
9:20:34
9:30:49
9:41:04
Key point:
Dramatically faster reversal
This slide represents a TOF tracing from 2 patients treated with rocuronium 0.6 mg/kg followed by Bridion 2 mg/kg or neostigmine 50 µg/kg combined with glycopyrrolate 10 µg/kg. The solid orange and blue lines represent the height of the muscle twitches, and the grey circles are the value of the TOF ratio.
Reference
1. CSR
TOF ratio Twitch height
TOF, train-of-four.
Data from Aurora trial.
J P Mulier 47

48. Faster Reversal from Rocuronium at reappearance of 2 Counts
Clinical study was a randomized, parallel-group, comparative, active controlled, safety-assessor–blinded, phase IIIa, pivotal trial that compared neostigmine with Bridion in the reversal of rocuronium at 1–2 PTCs. Seventy-five subjects were studied: 37 in the Bridion group and 38 in the neostigmine group. One subject in the neostigmine group was treated but did not participate in the ITT analysis. Subjects had to be ASA class 1–4 and the ages ranged from 19 up to and including 85 years. Subjects must have been scheduled for a surgical procedure with general anaesthesiology requiring the use of rocuronium (0.6 mg/kg), which was monitored using TOF via acceleromyography. The subjects were then reversed after the reappearance of 1–2 PTCs with either 4 mg/kg Bridion or 70 µg/kg neostigmine combined with 14 µg/kg glycopyrrolate, based on randomization.
Times from the start of administration of Bridion to recovery of the T4/T1 ratio to 0.9 ranged from 1 minute 13 seconds to 16 minutes 5 seconds in the Bridion-treated group, and from 13 minutes 16 seconds to 145 minutes 40 seconds in the neostigmine-treated group. Median recovery times were 2 minutes 42 seconds and 49 minutes in subjects treated with Bridion and neostigmine, respectively.
Reference
1. CSR
Bridion 4 mg/kg
NEO 70 µg/kg
n = 37
n = 37
95% CI (2.3–3.3 min)
95% CI (35.7–59.5 min)
CI, confidence interval, NEO, neostigmine.
Data from Signal trial.
J P Mulier 48

49. Time From T1 10% to 90% Within Subject20
n = 56
n = 54 15
Minutes 10 5
This graphically represents each patient who received the investigative protocol with respect to T1 to 10% or T1 to 90% for both treatment groups.1 The important thing to take away from this slide is the limited variability seen in the rocuronium and Bridion group compared with the succinylcholine group and the time in which this reversal takes place. This reduced variability adds to the dependability of Bridion to produce consistent results that are superior to succinylcholine in terms of reversal time.
References
CSR
T1=10%
T1=90%
T1=10%
T1=90%
Rocuronium 1.2 mg/kg + Bridion 16 mg/kg
Succinylcholine 1.0 mg/kg
Data from Spectrum trial.
J P Mulier 49

50. Immediate Reversal of Intense Blockade
10.9 *
7.1
3.2 *
1.4
Clinical study was a randomized, parallel-group, comparative, active controlled, safety-assessor–blinded, phase IIIa, trial that compared rocuronium followed by Bridion at 3 minutes with single-dose succinylcholine. One hundred ten subjects were studied: 56 in the rocuronium with Bridion group and 54 in the succinylcholine group. Subjects had to be ASA class 1 or 2 and ages ranged from 18 up to and including 65 years with a body mass index <30 kg/m2. These subjects must have been scheduled for a surgical procedure in the supine position with general anaesthesiology requiring short-duration neuromuscular relaxation, which was monitored using TOF via acceleromyography.
As seen in the graph, subjects who were randomized to the succinylcholine group received a single intubating dose of 1 mg/kg, whereas the other subjects were administered rocuronium 1.2 mg/kg and then 3 minutes later Bridion 16 mg/kg. The data are represented here as mean time (min), with regard to either T1 to 10% or T1 to 90%. Rocuronium followed 3 minutes later by Bridion was found to be superior in both measurements (P <0.0001).
Reference
1. CSR
3 min
Bridion
administered
n = 56
n = 54
n = 56
n = 54
T1 to 10%
T1 to 90%
*P < versus succinylcholine treatment group; results based on intent-to-treat population. SEM, standard error of mean.
Data from Spectrum trial.
J P Mulier 50

51. Rapid Dose-Dependent Reversal From T2 in Children and Adolescents Following Rocuronium 0.6 mg/kg
Clinical study was a multicenter, randomized, parallel dose-finding, safety-assessor–blinded trial to explore the efficacy, safety, and pharmacokinetics of 4 doses of Bridion (0.5 mg/kg, 1 mg/kg, 2 mg/kg, and 4 mg/kg) and placebo in pediatric and adult subjects. Ninety-one subjects were studied: 8 infants (28 days to 23 months), 24 children (2 to 11 years), 31 adolescents (12 to 17 years), and 28 adults (18 to 65 years). Subjects had to be ASA class 1 or 2 and must have been scheduled for a surgical procedure with general anaesthesiology lasting at least 60 minutes. The neuromuscular block was only to require a single dose of rocuronium (0.6 mg/kg), which was monitored using TOF via acceleromyography.
This graphically represents the dose response in children and adolescents at TOF 0.9. There is a dramatic difference between placebo and all doses of Bridion, most notably 2 and 4 mg/kg Bridion.
Children
Times from start of Bridion administration to recovery of T4/T1 ratio to 0.9
• Placebo, n=4: range, 8 min 25 sec to 31 min 47 sec; median, 19 min 2 sec
• Bridion 2 mg/kg, n=5: range, 51 sec to 1 min 37 sec; median, 1 min 9 sec
• Bridion 4 mg/kg, n=4: range, 36 sec to 4 min 25 sec; median, 38 sec
Adolescents
• Placebo, n=6: range, 6 min 50 sec to 41 min 40 sec; median, 23 min 22 sec
• Bridion 2 mg/kg, n=6: range, 42 sec to 5 min 14 sec; median, 1 min 8 sec
• Bridion 4 mg/kg, n=8: range, 44 sec to 1 min 26 sec; median, 1 min 5 sec
Adults
• Placebo, n=6: range, 19 min 37 sec to 43 min 57 sec; median, 28 min 22 sec
• Bridion 2 mg/kg, n=5: range, 54 sec to 1 min 34 sec; median, 1 min 13 sec
• Bridion 4 mg/kg, n=5: range, 57 sec to 1 min 57 sec; median, 1 min 24 sec
Reference
1. CSR
TOF, train-of-four. *Approved dose in children and adolescents.
Data from Libra trial.
J P Mulier 51

52. No Dose Adjustment Required With Increasing Age
Clinical study was a multicenter, parallel-group, comparative, phase IIIa, trial that compared elderly patients with adult patients in terms of efficacy, safety, and pharmacokinetics. One hundred and fifty subjects were studied: 48 in the adult group, 62 in the 65–74 year group, and 40 in the ≥75 year group. Subjects had to be ASA class 1–3 and ≥18 years of age, scheduled for a surgical procedure in the supine position with general anaesthesiology requiring neuromuscular relaxation with the use of rocuronium, which was monitored using TOF via acceleromyography. Subjects received a single bolus dose of rocuronium 0.6 mg/kg. If further neuromuscular block was required after endotracheal intubation, maintenance dose(s) of rocuronium 0.15 mg/kg may have been administered. Subjects were reversed at reappearance of T2 with a single bolus dose of Bridion 2 mg/kg.
The median times of recovery to T4/T1 ratio to 0.9 for the adult group, age year group, and the ≥75 year group were 2.2, 2.6, and 3.6 minutes, respectively. Even though recovery times tend to be slower in the elderly no dose adjustment is necessary.
References
1. CSR
2. Bridion® (sugammadex) [Summary of Product Characteristics]. N.V. Organon, Kloosterstraat 6, 5349 AB Oss, The Netherlands; August 2008.
n = 48
n = 62
n = 40
Age, yr
Data from Diamond trial. Bridion® [summary of product characteristics]. Organon, Europe; 2008.
TOF, train-of-four. *Reversal from T2 following rocuronium 0.6 mg/kg
J P Mulier 52

53. Bridion Has a Demonstrated Safety Profile
Bridion has been studied in >2000 clinical trial subjects
Safety has been demonstrated in patients with cardiac and pulmonary disease
Bridion is not recommended in patients with severe renal failure (CrCl <30 ml/min)
Great caution should be taken in patients with severe hepatic disease
Dedicated studies in this population have not taken place
The safety of Bridion has been described from 2369 exposures in 2054 patients or volunteers who were mostly between 18 and 64 years of age, ASA class 1–2, and predominantly white and not Hispanic or Latino. In these exposures the incidence of AEs was low; however, dysgeusia (metallic, bitter taste) and anesthetic complications (restoration of neuromuscular function) showed a dose response, occurred with a frequency of ≤2%, and was observed twice as often as placebo.1
Trial studied patients who were diagnosed with or had a history of cardiac disease (ie, patients with ischemic heart disease, chronic heart failure, or arrhythmia) of New York Heart Association class II to III. The study investigated time to recovery from neuromuscular blockade induced by rocuronium 0.6 mg/kg following administration of 2 or 4 mg/kg Bridion given at the first signs of recovery (reappearance of T2). The trial showed that the median time to recovery of the T4/T1 ratio to 0.9 was 1.7 and 1.3 minutes, respectively, in the 2 and 4 mg/kg Bridion dose groups. It was also found that Bridion can be used safely in cardiac patients.2
Trial involved patients who were diagnosed with or had a history of pulmonary complications. The study investigated the time to recovery from neuromuscular blockade induced by rocuronium (0.6 mg/kg) following administration of 2 or 4 mg/kg Bridion given at the first signs of recovery (reappearance of T2). Two patients in the 4 mg/kg group experienced a bronchospasm. The trial showed that for these patients the median time to recovery of the T4/T1 ratio to 0.9 was 2.1 and 1.9 minutes for the 2 mg/kg and 4 mg/kg Bridion dose groups, respectively. It was also found that Bridion can be used safely in patients diagnosed with or having a past history of pulmonary disease.3
Caution should be taken in patients with severe renal failure (creatinine clearance <30 mL/min) because of the delayed excretion of the Bridion-rocuronium complex. The use of Bridion in this patient population is strongly discouraged.4
Because Bridion is not metabolized or excreted hepatically, dedicated trials in patients with hepatic dysfunction have not been performed. Therefore, Bridion should be administered very cautiously to this patient population.4
References
1. Integrated Summary of Safety
2. CSR
3. CSR
4. Bridion® (sugammadex) [Summary of Product Characteristics]. N.V. Organon, Kloosterstraat 6, 5349 AB Oss, The Netherlands; August 2008.
Data on file. Bridion® [summary of product characteristics]. Organon, Europe; 2008.
CrCl, creatinine clearance.
J P Mulier 53

54. Drug-Drug Interactions Affecting the Efficacy of Bridion
No clinically relevant drug interactions have been reported with Bridion
Pharmacokinetic-pharmacodynamic simulations show that the following displacement interactions are possible:
Toremifene
The recovery to T4/T1 ratio of 0.9 could be delayed in patients who have received toremifene on the same day of surgery
Intravenous administration of high-dose flucloxacillin* and fusidic acid
The recovery to T4/T1 ratio of 0.9 could be delayed in patients who receive these products in the preoperative phase
Administration of these products in the postoperative phase (6 hours) is to be avoided
Throughout the clinical trials, consisting of >2000 patients, no clinically relevant interactions were reported during the clinical development of Bridion. However, through the use of pharmacokinetic and pharmacodynamic simulation models, interactions with toremifene, hormonal contraceptives, high-dose flucloxacillin, and fusidic acid were discovered.1,2
The toremifene interaction involves a possible displacement of rocuronium or vecuronium due to the high affinity constant and relatively high plasma concentration associated with toremifene. As a result, the recovery to T4/T1 ratio of 0.9 could be delayed in patients who have received toremifene on the same day of surgery.1,2
The high dose-flucloxacillin (infusion of 500 mg or more) and fusidic acid interactions involve a possible displacement of rocuronium or vecuronium. As a result, the recovery to T4/T1 ratio to 0.9 could be delayed in patients who have received these products in the preoperative phase. The use of these products in the postoperative phase (6 hours) is to be avoided.1,2
References
1. Integrated Summary of Safety
2. Bridion® (sugammadex) [Summary of Product Characteristics]. N.V. Organon, Kloosterstraat 6, 5349 AB Oss, The Netherlands; August 2008.
Data on file. Bridion® [summary of product characteristics]. Organon, Europe; 2008.
*Infusion of 500 mg or more.
J P Mulier 54

55. Drug-Drug Interactions Affecting the Efficacy of Other Drugs
Pharmacokinetic-pharmacodynamic simulations show that the following capturing interaction is possible:
Hormonal contraceptives
An interaction between 4 mg/kg Bridion and a progestogen could lead to a decrease in progestogen exposure, 34% of AUC, which is similar to that of a missed dose of oral contraceptive
The interaction discovered with hormonal contraceptives found a potential interaction between 4 mg/kg Bridion and a progestogen that could lead to a decrease in exposure (34% of area under the curve). This is similar to the decrease seen when a daily dose of oral contraceptive was missed. For this reason, the administration of a bolus dose of Bridion is considered to be equivalent to 1 missed daily dose of oral contraceptive.1,2
References
1. Data on file.
2. Bridion® (sugammadex) [Summary of Product Characteristics]. N.V. Organon, Kloosterstraat 6, 5349 AB Oss, The Netherlands; August 2008.
Data on file. Bridion® [summary of product characteristics]. Organon, Europe; 2008.
AUC, area under the curve.
J P Mulier 55

56. “Can not intubate / can not ventilate”
How frequently ?
Did you ever awakened your patient immediately within the first 30 minutes?
Conclusion:
It feels safe to have a drug available to bring patient immediately back to spontaneous breathing and to cancel the surgery.
Always have it never use it?
J P Mulier

57. Rapid sequence / Crush induction
Who is at Risk for aspiration?
Food or drank recently
Obstruction
Pregnant
Super obese
Previous bariatric surgery
Long procedure: high dose of NMB
No need for bridion or succinylcholine
Short procedure: high dose Rocuronium and bridion
Esmeron 1,2 mg/kg IBW measure TOF: bridion
J P Mulier

58. Very short and superficial blockade
Superficial blockade is sufficient for ECT
Succinylcholine: 0,5 mg/kg (normal: 2 mg/kg) is sufficient
Relative rapid onset, within 2 minutes
Spontaneous recovery within 5 minutes possible
Rocuronium 0,15 mg/kg (normal: 0,6 mg/kg) slower onset, longer duration
Dose of bridion dependent on TOF
Neostigmine possible but side effects
J P Mulier

59. Tof monitoring TOF measurement is needed To justify use of bridion
To lower dose of bridion
J P Mulier

60. Immediate effects in morbid obese patients
Deep breaths possible
Less collaps
Aurosal effect
Like Amfetamine awakening
Sudden muscle fiber stimulation gives aurosal
Patient transfers him/her self in bed
50 % of cases instead of only10%
Spontaneous movements easier
Deep venous trombosis prevention
J P Mulier

61. Our Results in lap RNY
J P Mulier

62. Adjustable Gastric band Biliary pancreatic div DuodenalSwitch
Jejuno ileal bypass
Vertical banded gastroplasty Roux & Y Gastric bypass Sleeve Gastrectomy
J P Mulier

63. Andere vragen in de anesthesie bij morbide obesitas
Pre operatieve voorbereiding
Inductie en intubatie
Patient positionering
Medicatie dosering
Extubatie en postoperatief beleid
Post op pijn behandeling
Enkele items nu belichten
J P Mulier

64. Waarom onvoldoende spierrelaxatie geven?
Restcurarisatie is zeer beangstigend, slecht ademen post op, lage saturatie, hoge CO2
Liever geen neostigmine gebruiken omdat
Bradycardie tot totaal AV block
Bronchospasme bij asthma patienten
Braken en onwel gevoel post op
Relaxatie moet voldoende uitgewerkt zijn om te decurariseren met neostigmine
TOF minimum één antwoord
J P Mulier

65. Continuous deep blockade till end of surgery.
3. Laparoscopy
Rapid awakening
Keep your surgeon in the OR
Quality surgery =
short surgical time
High volumes
Quality anaesthesia =
short turn over
J P Mulier

66. Our Results in lap RNY gastric bypass
J P Mulier

67. ERAS 1 (early recovery after surgery)
Halfway surgery (last 30 min)
Large abdomen stop esmeron infusion,
Small abd keep esmeron infusion till end of operation.
Last stapler
Reduce/stop remifentanyl infusion
Start pressure support ventilation
Hypercapnic PSV increases CO and BP
Keep inhalation conc high if small abd till end of pneumoperitoneum.
J P Mulier

68. PSV voorkomt tegenademen bij onvoldoende relaxatie
PSV is not a valsalva effect: IAV is not changing.
PSV is possible during deep muscle relaxation.
PROFOUND MUSCLE RELAXATION DOES NOT DISTURB
PRESSURE SUPPORT VENTILATION.
Mulier J, Blacoe D PGA 2009
J P Mulier

69. Hypercapnia / Pressure support
Table
normocapny
hypercapny
Minute vol *
L/min
11,6 +/- 1,7
7,1 +/- 1,1
Airw pres *
cmH20
32 +/- 5
26 +/- 3
Et PCO2 *
mmHg
38 +/- 6
56 +/- 8
O2 sat %
96 +/- 3
97 +/- 2
Ephedrine * mg
30 +/- 15
5 +/- 8
Breathing *
min
4 +/- 4
2 +/- 4
Extubation *
8 +/- 4
4 +/- 5
Table
PCV
PSV
Number of TOF *
0,6
1,4
Cisatracurium mg *
32 +/- 4
23 +/-2
etPCO2
mmHg
44 +/- 6
54 +/- 10
Extubation
min
5 +/- 6
3 +/- 2
J P Mulier, B Dillemans, Use of pressure support ventilation during laparoscopic bariatric surgery is possible and facilitates weaning and extubation. In:Obes Surg 2008; 18:444
J P Mulier, B Dillemans, Hypercapnic lung ventilation reduces airway pressure during laparoscopic surgery. In:Eur J Anesth 2008; 25, S44:78
J P Mulier

70. ERAS 2 Leaktest Last surgical stich High volume load SAP > 140 mmHg
Et CO2 to 60; PSV give extra suf if tachypnoe
Ephedrine/phenylephrine bolus
dose sufenta till RR < 16
Last surgical stich
Lower PSV further, keep peep
Stop inhalation
TOF 4/4 <50% neostigmine
TOF < 2/4 bridion dose according to TOF and IBW
give bridion after patient is secured on the table
J P Mulier

71. PSV pain therapy optimalisation
Before after extra suf bolus
J P Mulier

72. Hypercapnic pressure support: easier SAP rise
Table
Normocapnic
Hypercapnic
SAP mmHg
143 +/- 25
148 +/- 13
Et P CO2 mmHg
39 +/- 7
53 * +/-6
CO L/min
6,2 +/- 1,8
14,3 * +/- 2,9
Min Vol L:min
9 +/- 1,3
7,6 *+/- 1,2
Ephedrine mg
11 +/- 7
3 * +/- 3
J P Mulier (2008) Hypercapnic support ventilation during laparoscopic gastric bypass increases the cardiac output. Anesthesiology 2008 A174
J P Mulier

73. Can anesthesiology help to prevent post op bleeding? yes
110/ /78
J.P.Mulier, B Dillemans, G Vandrogenbroek, F Akin
The effect of systolic arterial pressure on bleeding of the gastric stapling during laparoscopic gastric bypass surgery.
Obes Surg 2007; 17: 1051
J P Mulier

74. Hypercapnic pressure support ventilation
Increases cardiac output
Less wound infections
Lowers airway pressures
Resp freq: morfine if too low stop PSV
TV: curarisation corrected by support level
Improves saturation per op if low
Rapid awakening and spontaneous breathing
Non surgical time between OP < 20 min
Less pain when awakening
Extra doses given during end of surgery
Better post op breathing
less post ventilation
J P Mulier

75. ERAS 3 Reversed induction technique ?
50 à 100 mg propofol in bolus
Gastric tube suction, oral cavity clean?
PSV to Spontaneous, TV > 200 ml
Extubation beach chair if possible
Diep ademen, benen bewegen
Nooit sedativa, benzodiazepines,…
Voldoende pijn medicatie perop starten
Test: patient moet zich zelf verbedden 3 minuten na extubatie!
Turnover time between end surgery - incision next patient < 20 minuten.
J P Mulier

76. Conclusion Always have Bridion available.
Decide when long and deep relaxation is needed till end.
Measure TOF ctu or at end
Never believe without control clinical relaxation
According to TOF at end operation.
(Nothing)
(Neostigmine)
Bridion
J P Mulier

77. Second ESPCOP Scientific meeting Multidisciplinarity Pordenone, Italy 18 sept 2010
J P Mulier

78. More info www.publicationslist.com/jan.mulier www.espcop.org
J P Mulier