Reversal of Neuromuscular Block

Merle F de la Cruz-Odi, MD, MBA

Professor of Anesthesiology
College of Medicine
University of the Philippines, Manila

Slides revised from the file of Dr. Merle F. dela Cruz-Odi

 Outline:
• What is residual block?
• What is the new surrogate benchmark for adequare
recovery from neuromuscular block?
• What is the implication of residual paralysis on
postoperative outcome?
• What is the mechanism of action, efficacy, and safety of
anticholinesterases
• What is the mechanism of action, efficacy, safety of
sugammadex?
• Summary
– Reverse all neuromuscular blocks?
Has anyone of you ever observed a patient
exhibiting clinically significant residual
neuromuscular paralysis after the
administration of a muscle relaxant in the
recovery room or the PACU?
Question: Has respondent
ever observed a patient
exhibiting clinically
significant residual NM
paralysis after the
administration of a muscle
relaxant in the RR/PACU
Naguib M, Kopman AF, Lien CA, et al. Anesth Analg 2010;111:110119
Internet based survey
APSF and ESA through email
2,636 completed surveys
64.1% (US) and 52.2% Eu estimated
incidence of residual block 1%
Routine reversal less in US than EU
Less quanti monitoring in US than EU
More Eu never use NM monitors
Eu & US report no need for monitoring
What constitutes reversal of NMB?
NMBA TOFC 4 TOFR 0.9

1 SPONTANEOUS RECOVERY (70 mins)

NMBA NEOS TOFR 0.9 2 SPONTANEOUS
RECOVERY TO TOFC 4
PLUS DIRECT
NEOSTIGMINE
ANTAGONISM

NMBA NEOS TOFR 0.9 3 EARLY DIRECT

NEOSTIGMINE
ANTOGONISM PLUS
SPONTANEOUS
RECOVERY
What constitutes reversal of NMB?
NMBA TOFC 4 TOFR 0.9

1 spontaneous recovery (70 mins)

NMBA SUGA TOFR 0.9
2 spontaneous
recovery to TOFC 4 plus
direct encapsulation by
sugammadex
SUGA

NMBA TOFR 0.9 3 early direct

encapsulation by
sugammadex plus
spontaneous recovery
Two processes determine neuro-muscular
recovery from relaxants

• Direct antagonism by
anticholinesterase/sugammadex

• Spontaneous recovery from the

neuromuscular blocker

Kopman AF. Anesthesiology 1997;87:1029-31

More than 40 years ago, Kalow suggested that if
the endplate receptors are occupied by an
overdose of a NM blocking agent (that) reversal
will only be achieved after enough time has
elapsed to allow for lowering its concentration
by redistribution and elimination.

Kalow W.
Anesthesiology 1959;20:505-518

This principle remains valid today

 Two processes determine neuro-
muscular recovery from relaxants
• Profound neuromuscular block was induced by
atracurium or vecuronium in 59 healthy patients
• Spontaneous recovery from both NMBAs: 65-70 mins
• Neostigmine given 5 mins after loss of twitch response
decreased recovery time for both NMBAs to 45 mins;
• Edrophonium had no effect on duration of vecuronium
relaxation, but decreased recovery wIth atracurium by
15 mins.
• Neither anticholinesterase antagonized profound block
after the two NMBAs
Caldwel JE et al. Brit J Anaesth 1986; 58:1285-89
 Classification

Muscle relaxant Reversal

Agents

Steroidal Muscle Relaxant-

Antagonists
Encapsulators

Neostigmine Sugammadex
Pyridostigmine
Fuchs-Buder T et al. Anaesthesist 2007
 What is residual block?
What is the new surrogate benchmark for adequate recovery from
neuromucular block?
For many years, an adductor pollicis train-of-
four (TOF) ratio of 0.70 has been regarded to
be associated with adequately recovered
muscle function, to allow safe extubation and
spontaneous ventilation in the postoperative
period.

Ali HH et al. Anesthesiology 1975;:570-4

Just when I learned all the
answers,
 Great Variability in Reversal After a Single
Intubating Dose of Neuromuscular Blocking Agent

All patients (n = 526)

1.0 70
0.9
TOF <0.7
0.8
60
TOF <0.9

Patients (%)
0.7 50
TOF Ratio

0.6 40
0.5
0.4
30
* *
0.3 20
*
0.2
10 *
0.1
0.0 0

0 50 100 150 200 250 300 350 400

<60 [60-90] [90-120] >120 min
n = 23 n = 101 n = 164 n = 238
Time (min)

Incidents of residual paralysis were seen as long as 2

hours after administration
*Significantly different from TOF <0.9 (P <0.01).
TOF, train-of-four. Debaene B et al. Anesthesiology. 2003;98:1042-1048.
Respiratory Function and
Neuromuscular Blockade

Eikermann M et al. Anesthesiology 2003;98:1333-1337

Dino J, dela Cruz-Odi M. Incidence of Residual Neuromuscular
Blockade with the Use of Intermediate Acting Non-depolarizing
Neuromuscular Blockers in the Post Anesthesia Care Unit at The
Medical City

Residual Frequency (Percent)

Neuromuscular Block
TOF Ratio 144
0.9 or > (61.80)

TOF < 0.9 89 (38.20%)

n = 233
Cabrera FG and Dela Cruz-Odi M. The Prevalence of Residual
Neuromuscular Blockade in Makati Medical Center Post Anesthesia
Care Unit at the Makati Medical Center

Residual Neuromuscular Frequency (Percent)

Block
TOF Ratio 76
0.9 or > (64.96)

TOF < 0.9 41

(35.04)
n =117
Geronimo RA and Dela Cruz-Odi M. Incidence of Residual
Neuromuscular Blockade with the Use of Intermediate Acting Non-
depolarizing Neuromuscular Blockers in the Post Anesthesia Care
Unit at the Makati Medical Center.2013

Residual Neuromuscular Frequency (Percent)

Block
TOF Ratio 176 (69.8%)
0.9 or >

TOF < 0.9 76 (30.2%)

n = 252
Upper Esophageal Dysfunction after
Atracurium

Sundman E et al. Anesthesiology 2000;92:988-984

 What then is residual NM block?
What is adequte recovery

 Residual neuromuscular block is defined as the presence of muscle

weakness postop after intraop use of NMBD
 Residual NMB is present whenTOF ratio is less than 0.9
 Patients with adequate neuromuscular recovery should have the
ability to breathe normally, maintain a patent upper airway,
preserve protective airway reflexes, swallow, cough, smile, and talk.
 These physiologic end points are achieved in most patients (and
volunteers) at a TOF ratio of 0.9.
 This surrogate endpoint (TOF ratio 0.9) should be matched with
clinical assessment

Murphy GS, Brull SJ. Anesth Analg 2010;111:120–8

What is it’s the implication of residual paralysis on
postoperative outcome?
Landmark Study of the Deaths
Associated with Anesthesia & Surgery

Methods
• Data collected by 10 teams at 10 hospitals over a 5-year period in
the United States
• All cases of deaths on the surgical services were examined
• Causes of death were determined by the team at each hospital

Results
• Data collected on 599,548 anesthetics
• Mortality rates when NMBAs were used (1:370) were 6x higher than
when NMBAs were avoided (1:2100)
• 63% of the deaths involving NMBAs were caused by respiratory
failure

Beecher HK, Todd DP. Ann Surg. 1954;104:2-35

Residual Block – Hypoxic Ventilatory Control

Eriksson L. Acta Anaesthesiol Scand1996;40:5

Relationship of the TOF fade ratio to clinical signs
and symptoms of residual paralysis
METHODS:
• Infusion of mivacurium in 10
healthy volunteers to achieve
TOF ratio of 0.65 to 0.75.
Recovery to TOF ratio to 0.85-
0.90
• Patients carefully examined for
signs and symptoms of muscle
weakness
Kopman et al. Anesthesiology 1997;86:765-71
RESULTS
TOF 0.70-0.75
• Diplopia, visual disturbances
• Decreased grip strength
• Inability to maintain incisor teeth
apposition
• Inability to sit up without assistance
• Severe facial weakness; flat affect
• Inability to drink from a straw
TOF 0.85-0.90
• Visual problems, generalized fatigue
TOF ratio of 0.90-1.00
• Visual problems
Residual Neuromuscular Blockade is a risk factor for
Postoperative Pulmonary Complications

To determine incidence of POPC

691 patients randomly assigned
NM management standardized
All patients reversed
TOF measured in PACU by MMG
Patients examined on POD 1-6 for
radiographic POPC

Berg et al found that 46 (6.7%) patients displayed pneumonic

infiltrations and/or atelectasis following pancuronium, vecuronium,
or atracurium administration
Berg H, Roed J, Viby-Mogensen J et al. Acta Anaesth Scand. 1997;41:1095-1103
 PORC

• 7459 pat., 61 CREs, 42 matched with similar CTRL

• 53% serious hypoxemia, 36% airway obstruction

CASES CTRL

mean TOF 0.62±0.2 0.98±0.07

TOF < 0.7 73.8% 0%

TOF < 0.9 90.5% 9.5%

Murphy GS et al., Anesth Analg 2008
What is the mechanism of action, efficacy, and safety of
anticholinesterases
Administration of acetylcholinesterase inhibitors
(anticholinesterase) has been used for many years in the
reversal of muscle paralysis with MRs/NMBs.

Anticholinesterase inhibits the enzyme acetylcholinesterase,

thereby increasing the acetylcholine (Ach) survival time in the
synaptic cleft.

Increase of Ach results in undesirable stimulation of other

muscarinic and nicotinic receptors in other tissues

Anticholinesterase has a ceiling effect

 Early reversal of neuromuscular block

• Neostigmine was administered among adults

and children 5 min after vecuronium or
rocuronium, or at T1 recovery of 1%, 10%, or
25%. Times from relaxant administration to
TOF of 0.70 were similar and independent of
the timing of neostigmine administration,

Bevan JC et al. Anesth Analg

1999;89:333-9
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 10 min 20 min 30 min

administered
Rocuronium Protocol

5 min 10 min 15 min 20 min

ROC TOF ratio 0.33 ± 0.13 0.57 ± 0.11 0.70 ± 0.12 0.79 ± 0.12
0.6 mg/kg
n = 20 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.
Great Variability in Reversal Is Seen Depending
on the Administered Anesthetic*

T1 T2
*Rocuronium 0.1 mg/kg followed by neostigmine 70 μg/kg.
†
P <0.0001.
PROP, propofol; SEVO, sevoflurane; TOF, train-of-four. Kim KS et al. Anesth Analg. 2004;99:1080-1085.
Scene 1

Acetylcholine

Cholinesterase
Scene 2

Acetylcholine

Cholinesterase

Rocuronium
 Scene 3

Acetylcholine

Cholinesterase

Rocuronium

Cholinesterase
Inhibitor
Scene 4

Acetylcholine

Cholinesterase

Rocuronium

Bridion
What is the mechanism of action,
efficacy, safety of sugammadex?
Structure of Cyclodextrins
Upper / Bottom view Side view
hydrophilic lipophilic
-Cyclodextrin
6 Glucose Units

-Cyclodextrin

7 Glucose Units

g-Cyclodextrin
8 Glucose Units

M.W. Hollmann, Academic Medical Center, University of Amsterdam

Sugammadex (ORG 25969)

6A,6B,6C,6D,6E,6F,6G,6H-octakis-S-(2-carboxyethyl)-
6A,6B,6C,6D,6E,6F,6G, 6H-octathio-γ-cyclodextrin
Encapsulation of Rocuronium
Binding Forces:
• Van der Waals-Forces Sugammadex
• Electrostatic Interactions

O
+ Rocuronium
N
O
H N
H H
O

Sugammadex-
Adam J et al., J Med Chem 2002 Rocuronium
Complex
 Molecular Structure

Rocuronium Sugammadex
Rocuronium-Sugammadex Complex
In vitro Selectivity Sugammadex

Hemidiaphragma Mouse-Model
NMBs max. Recovery [%]
rocuronium 95.5

vecuronium 91.0
pancuronium 60.4
rapacuronium 64.2
mivacurium None
atracurium None
suxamethonium 24.5* * Artefact
Mode of action Sugammadex

= Rocuronium (Roc)
Mode of action Sugammadex

= Sugammadex
Mode of action Sugammadex

= Roc-Sugammadex Complex
Mode of action Sugammadex

= Roc-Sugammadex Complex
Mode of action Sugammadex

= Roc-Sugammadex Complex
Mode of action Sugammadex

= Roc-Sugammadex Complex
 Pharmacology of Sugammadex
• Elimination t1/2 ≈ 100 min
• Clearance 120 ml/min (≈ GFR)
• VD ≈ 18 L
• ≈ 70-100% renal excretion within 24 h
• ↓ VD of Roc: from ≈ 50 L → ≈ 15 L
• ↑ Elimination of Roc: from ≈ 15% → ≈ 40-70%
• No Interaction w/ nicotinic/muscarinic
receptors
M.W. Hollmann, Academic Medical Center, University of Amsterdam
Rocuronium – Sugammadex Complex

M.W. Hollmann, Academic Medical Centre, University of Amsterdam

 Human Studies with Sugammadex
1. Question:
Does it also work in humans ???
• for “moderate” block (Re-appearance of T2)
• for deep block (1-2 posttetanic counts)
• in emergency (cannot intubate-cannot
ventilate)

M.W. Hollmann, Academic Medical Center, University of Amsterdam

 Effectivity
Sugammadex at Re-appearance of T2 after 0.6 mg/kg Roc
summarized data of all studies
Placebo 0,5 1,0 2,0 3,0 4,0 6,0
mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg

N 25 35 38 38 8 39 4

Mean 60.0 7.2 2.9 1.6 1.6 1.4 2.6

(SD) (38.8) (10.8) (2.9) (0.7) (1.0) (0.7) (1.3)

Median 47.3 4.2 2.2 1.5 1.3 1.2 2.7

Min-Max 15-153 1.3- 1.2- 0.7-4.8 0.7-3.2 0.7-4.8 1.1-3.9

55.5 19.3

M.W. Hollmann, Academic Medical Centre, University of Amsterdam

 Effectivity
Conclusion:

Sugammadex 2 mg/kg is effective for

reversal of moderate NMB
(Re-appearance of T2)
 Effectivity
Sugammadex at 1-2 PTC after 0.6 mg/kg Roc
summarized data of all studies
placebo 0,5 1,0 2,0 6,0 8,0
mg/kg mg/kg mg/kg mg/kg mg/kg

N 3 18 27 34 31 6 34

Mean 35.6 66.3 14.7 3.6 1.8 2.1 1.3

(SD) (9.0) (35.2) (26.9) (2.6) (1.0) (2.0) (0.4)

Median 30.6 65.5 5.5 3.0 1.6 1.1 1.2

Min-Max 30.1-46 15.5- 1.6- 1.1-15.2 0.8-4.5 1.0-5.9 0.6-2.4

131.7 117.1
 Effectivity
Conclusion:

Sugammadex 4 mg/kg is effective for reversal

of deep NMB
(1-2 PTC)
 Effectivity

Time to TOF 0.9 after 16 mg/kg Sugammadex

3 min. after 1.2 mg/kg Rocuronium
Rocuronium + Rocuronium +
sugammadex Placebo

N 65 5
Mean (SD) 1.7 134.4
95% CI 1.4-1.9 92.6-195.6
Median 1.5 129.7
Min-Max 0.5-14.3 87.3-209.1
Cannot intubate- cannot ventilate

M.W. Hollmann, Academic Medical Centre, University of Amsterdam

 Effectivity
Conclusion:

Sugammadex 16 mg/kg is effective for

instantaneous reversal of NMB
(Cannot intubate – cannot ventilate)
 Summary Dose-finding Studies
Dose-dependent Recovery
when adequately dosed
 complete Recovery within max. 2 min
• Circulation Time is limiting Factor

Dose Recommendations:
• 2 mg/kg at T2 (moderate block)
• 4 mg/kg at 1-2 PTC / 15 min (deep block)
• 16 mg/kg (immediate reversal - after 1.2 mg/kg Rocuronium)
Influence of Anesthesia technique ???

Vanacker B F et al., Anesth Analg 2007

 Human Studies with Sugammadex
2. Question:
Effectivity compared with Standard ???
 Faster than Neostigmine ???

Moderate Block (T2) n=98:

Sugammadex Neostigmine +
glycopyrrolate
1.4 min 17.6 min [3.7-106.9]
Blobner M & Scholz J et al. ESA 2007

Deep Block (1-2 PTC) n=74:

Sugammadex Neostigmine +
glycopyrrolate
2.9 min 50.4 min [13.1-145.7]
Sacan O et al., Anesth Analg 2007
 Faster than Neostigmine ???
Rocuronium + 2.0 cisatracurium + 50
mg/kg sugammadex mcg/kg neostigmine

N 399 39
Mean (SD) 2.0 8.8
95% CI 1.9-2.1 7.4-10.4
Median 1.9 7.2
Min-Max 0.7-12.0 4.2-28.2

Flockton EA et al., Br J Anaesth 2008

 Faster/Safer than Succinylcholine ?
• Preoxygenation Limit maximal 8.7 min

• Adequate spontaneous ventilation after

1 mg/kg Sux min. 50% reversal of T1
(single twich)  8.5 min

• Sux + cannot intubate - cannot ventilate

 Risk critical desaturation ↑↑↑

Benumof JL et al., Anesthesiology 1997

Faster/Safer than Succinylcholine ?

3 min.

T1 to 10% T1 to 90%
Lee C et al., ASA 2007
 Faster/Safer than Succinylcholine ?
20

15
Minutes

10
8.7
min.
5

0
T1=10% T1=90% T1=10% T1=90%

Rocuronium + Succinylcholine
Sugammadex
Sugammadex acts extremely fast !!!

M.W. Hollmann, Academic Medical Center, University of Amsterdam

 Human Studies with Sugammadex
3. Question:

Is it safe ???
 Safety of Sugammadex
• Safe & effective reversal of moderate Roc-induced
NMB in ped., adult, old & very old Patients
Plaud B et al. ESA 2007 & McDonagh D, ASA 2007

• Safe (2.0 & 4.0 mg/kg) for pat. with pulmonary disease
Amao R et al., ASA 2007

• Safe (2.0 & 4.0 mg/kg) for pat. with cardiac disease
Dahl V et al., ASA 2007

• NO QTc prolongation with 32 mg/kg (62 volunteers)

De Kam PJ et al., ASA 2007

• Safe (2.0 mg/kg) for pat. with moderately reduced Renal

Function (fast & complete reversal without Re-curarisation)
Staals LM et al., ESA 2007
 Adverse Events
Bridion* Placebo
(N = 640) (N = 140)

Total 68.3% 72.1%

Rocuronium 66.7% 69.8%

Vecuronium 75.4% 83.3%

Serious AEs 5.8% 4.3%

No Dose-dependence
 Adverse Events
Side effects:

– Bitter Taste 1.6% ( > 32

mg/kg)

– Coughing & Moving 3%

– Hypersensitivity < 0.1%

M.W. Hollmann, Academic Medical Centre, University of Amsterdam

 Adverse Events
Allergic Reactions:
– < 0.1%
– 1 volunteer, exanthem (positive skin test)
– No treatment necessary
– In vitro no histamine liberation

 US FDA APPROVED ITS USE IN THE US IN 2015

 Additional Informations
Interactions:
A. Binding:
– Hormonal Contraception
 Effect “Pil” unreliable
B. Displacement:
– Toremifene
– Fusidine acid
– Flucloxacilline
 Re-curarisation possible
 Sugammadex could be used:
… for children (> 2 years) with moderate Block

… Liver insufficiency (NM Monitoring)

… Pregnancy (Risk-Benefit Analysis)

… during Breast Feeding (enteral Uptake CDs ↓)

… Obese (Dose related to Real BW)

… repeat Roc/Vec earliest after 24 h

 Hallmarks of Sugammadex
• Therapeutically used Cyclodextrin
• Selective for steroidal NM Blocker
(Encapsulation completely different MoA than AchE
Inhibitors)
• No Interaction w/ nicotinic/muscarinic receptors
• Roc/Sugammadex close to “ideal” NMBA
- Non-depolarizing - Fast Onset
- Short Action - Fast Recovery
• Good safety profile (only mild side effects yet)
• No significant cardiovascular side effects
 Specific Indications
• Difficult Airway (Can’t intubate – can’t ventilate)
• Severely impaired lung function
• C-Section
• Intense NMB required: Bariatric & laparoscopic
Surgery
• Relaxation till end of surgery (Robot, Neuro, Prone)
• “Open – Close” Operations
• NM Diseases (Myasth. gravis), Facialis monitoring
• Small staff (overnight, PACU, ward-ready)
 Summary:
• Introduction
• What is residual block? What is the new surrogate benchmark
for adequate recovery from neuromuscular block?
• What is the implication of residual paralysis on postoperative
outcome?
• What is the mechanism of action, efficacy, and safety of
anticholinesterases
• What is the mechanism of action, efficacy, safety of
sugammadex?
• Summary
– Reverse all neuromuscular blocks?
 Published Expert Opinions...

“…Cyclodextrin-mediated reversal of neuromuscular

block is potentially the greatest advance in
neuromuscular pharmacology in the last 20 years.”
Jim Caldwell, ASA Newsletter, Sept 2003
 Be prepared
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