Neuromuscular Blockade in
Patients with Myasthenia Gravis
(MG)
Gardy Mak
PharmD 2011
Western University
August 5, 2010
Objectives
• Review my patient case
• Define myasthenia gravis
• Describe the pathophysiology, epidemiology, clinical
signs/symptoms, diagnostic tests, treatment options and prognosis
of myasthenia gravis
• Review the medications that can worsen symptoms of MG
• Discuss neuromuscular blockade use in clinical practice and the
importance of reversal
• Introduce Sugammadex
• Evaluate and review relevant literature
• Discuss status of Sugammadex
• Apply literature findings to my patient
Patient Presentation
•
SS is a 56 yo female admitted to
COH to start induction therapy for
her newly diagnosed AML
•
Gait becomes a waddle and
difficulty using a straw if she
misses a dose
•
PMH: Myasthenia gravis
diagnosed in 1997
•
Hx of ptosis and diplopia
•
She also experiences SOB, but
was never intubated
•
PET scan and X-ray of the thymus
were negative for thymoma
•
•
Remission after 5 years of tx w/
pyridostigmine and prednisone
In 2007 after her gastric by-pass
surgery  experienced relapse 
treated briefly w/ prednisone
now back on pyridostigmine
Patient Presentation
• PMH (other)
– Morbid obesity
– Gastric by-pass surgery (lost
120 lbs)
– Past HTN and sleep apnea
– Osteopenia
– Degenerative arthritis of lower
back and knee
• FH
– Father melanoma
– mother breast CA
– grandmother breast & uterine
CA
– 2 sisters and 3 brothers:
sister ovarian CA, brother
melanoma
• SH
– Past hx of methamphetamine
and marijuana use
– Cigarette smoke x 25 years,
quit 15-20 years ago
– No hx of alcohol abuse
• Allergies
– NKDA
Patient Presentation
• Current Medications:
-Boniva 150mg po qmonth
-Mestinon 60mg po tid
-Vicodin 2 tabs po q4h prn mod. Pain
-Acyclovir, protonix, antiemetics
-Decadron eye drops
-Allopurinol 300 mg qday
-Levaquin, micafungin
-Cytarabine 376 mg IV daily x 7
-Idarubicin 22.5 mg daily x 3
• Labs on Admission:
WBC 1.3 (L)
RBC 2.28 (L)
Hgb/Hct 8.3/23.1 (L)
Platelet 129 (L)
Neutrophil% 11
Lymphocyte% 84.0(H)
Na 140
K 3.7
CO2 25
BUN 16
SCr 0.76
Glucose 114 (H)
Ca 9.1
Mg N/A
P N/A
Uric acid 5.3
T. bili 0.6
LDH 538
Background of Myasthenia Gravis
•
Definitinon: Myasthenia gravis is an
autoimmune disorder of the
postsynaptic neuromuscular junction
resulting in skeletal muscle weakness
and fatigue.
•
Pathophysiology:
1)Acquired immunologic abnormality:
-Autoantibodies against the
nicotinic Ach receptors (AChR)
in the muscles (80-90%)
-MuSK (muscle specific
receptor tyrosine kinase)
antibodies
jama.ama-assn.org
2)Structural abnormality
3)Thymus
Robinson, J. et al. Bope: Conn’s Current Therapy 2010, 1st ed.
Myasthenia Gravis
• Epidemiology:
-Prevalence: 14 per 100,000
people in the US
-All ethnic groups, both
genders
-Any age: Women (onset 2030), Men (onset 70-80)
-About 10% of MG patients
have thymoma and 50-70%
have thymus hyperplasia
-Uncommon but increased
incidence of MG in 1st degree
relatives
Robinson, J. et al. Bope: Conn’s Current Therapy 2010, 1st ed.
• Clinical Signs/Symptoms:
-Initial presentation with ptosis
or diplopia in 60% of patients
-Fluctuating muscular
weakness and fatigue
-Bulbar symptoms ~10%
-leg weakness ~10-20%
-generalized weakness ~10%
-initial respiratory symptoms
~1%
Myasthenia Gravis
Diagnostic tests:
1) Edrophonium chloride (Tensilon) test: >90%
sensitivity, but low specificity
2) Antibody testing (most specific for MG)
3) CT scan of chest for the presence of thymoma
4) Electromyography w/ repetitive nerve stimulation
Treatment options:
1) Cholinesterase Inhibitors
2) Chronic immunosuppressive agents
3) Rapid immunotherapy agents
4) Thymectomy
Robinson, J. et al. Bope: Conn’s Current Therapy 2010, 1st ed.
Summary of Therapy
•
•
•
•
Ocular symptoms only or mild weakness  cholinesterase inhibitors
Moderate to severe weakness  cholinesterase inhibitors and thymectomy
for pts <60 yo
Uncontrolled symptoms w/ cholinesterase inhibitors  immunosuppression
-Prednisone if urgent or severe
-Azathioprine or mycophenolate mofetil
Myasthenia crisis or preoperative (ie before thymectomy)  plasma
exchange or IVIG
• Prognosis:
-Patients initially present with ocular symptoms followed by
generalized weakness
-Low mortality but decrease quality of life
-Spontaneous remission in about 10-15% of patients if no
immunosuppressive agents are used Robinson, J. et al. Bope: Conn’s Current Therapy 2010, 1st ed.
Exacerbation of MG
•Infection
Medications
•Stress ie surgery
•Medications
Antibiotics
FQ
Aminoglycosides**
Macrolides
Cardiovascular agents
CCB
BB
Anti-arrhythmic
Neuromuscular Blocking
Agents**
Others
Penicillamine
Eye medications
Anticholinergic agents
Corticosteroids (initially)
Chemotherapeutic agents
ie doxorubicin, etoposide,
cisplatin
A. Ahmed & Z. Simmons: Drugs Which May Exacerbate of Induce Myasthenia Gravis: A Clinician’s Guide. The Internet Journal of Neurology.
2009 Volume 10 Number 2.
http://www.ispub.com/journal/the_internet_journal_of_neurology/volume_10_number_2_6/article/drugs_which_may_exacerbate_or_induce_myasthenia_gravis_
a_clinician_s_guide.html
Robinson, J. et al. Bope: Conn’s Current Therapy 2010, 1st ed.
Do you recall which medications SS was
on that can potentially interact w/ her
disease state?
-Boniva 150mg po qmonth
-Mestinon 60mg po tid
-Vicodin 2 tabs po q4h prn mod. pain
-Acyclovir, protonix, antiemetics
-Decadron eye drops
-Allopurinol 300 mg qday
-Levaquin, micafungin
-Cytarabine 376 mg IV daily x 7
-Idarubicin 22.5 mg daily x 3
http://www.mdconsult.com.proxy.westernu.edu/das/article/body/21314727410/jorg=journal&source=&sp=21635437&sid=0/N/679929/s0733862708000990.pdf?issn=0733-8627
Neuromuscular Blocking Agents
(NMBA) in General Anesthesia
•
Indication: Endotracheal intubation and
surgeries where skeletal muscle relaxation is
desired
• 2 types:
1) Depolarizing NMBA
2) Non-depolarizing NMBA
Caro, D. UpToDate 2010
NMBA
Depolarizing
• Analogue of ACh that binds
directly to the postsynaptic ACh
receptors and causes continuous
stimulation of the ACh receptors
• Succinylcholine (Anectine)
-1.5 mg/kg IV
-onset 45-60 seconds
-duration 6-10 mins
-SEs: hyperkalemia, malignant
hyperthermia, bradycardia, rhabdomyolysis
-Advantages: fast onset and short duration
Non-depolarizing
• Indicated when succinylcholine is
contraindicated or when prolonged
NMB is desired
• Competitive inhibitors of the
postsynaptic ACh receptors of the
neuromuscular motor endplate
preventing membrane
depolarization
• 2 categories:
Benzylisoquinolinium &
aminosteroid agents
• Rocuronium (Zemuron),
vecuronium, pancuronium
-1.0 mg/kg IV
-onset 45-60 seconds
-duration 45 mins
-SEs: hypertension (≤2%) (Lexicomp)
Caro, D. UpToDate 2010
NMBA
Depolarizing
Non-depolarizing
Depolarizing agents depend on the availability of ACh receptors for
their neuromuscular blocking effect
Myasthenia pts have fewer available ACh receptors d/t inactivation by
autoantibodies
Therefore, pts with MG have varying responses to depolarizing and
non-depolarizing neuromuscular blocking agents
More sensitive to non-depolarizing agents  lower doses needed
Less sensitive to depolarizing agents  higher doses needed to
achieve NMB
NMB
• Pts w/o MG
• MG pts
Pharmacologic Reversal of
Neuromuscular Block
•
NMBAs can predispose MG pts to severe postoperative residual paralysis
and respiratory complications
-aspiration, airway obstruction, respiratory distress, reintubations
•
It is important to ensure reversal of NMB in MG patients who undergo NMB
ie w/ rocuronium to prevent complications associated w/ residual NMB after
surgery
Reversal of NMB with Cholinesterase inhibitors
• Neostigmine, Pyridostigmine
-0.06-0.08 mg/kg IV
-indirect mechanism of action
-potential reappearance of NMB
-time required for complete reversal of NMB
-Side effects associated w/ neostigmine
-codadministration w/ glycopyrrolate or atropine
 Ineffective in reversing profound NMB
Caro, D. UpToDate 2010
FDA Sugammadex Powerpoint
De Boer, HD., et al. Ana, 2010:653.
Reversal of NMB with
Sugammadex
• Indications:
-Routine and immediate (at 3 minutes after rocuronium
administration) reversal of neuromuscular blockade induced by
rocuronium and vecuronium
• Dosing
-Routine
-2.0 mg/kg (shallow blockade)
-4.0 mg/kg (profound blockade)
-Immediate
(at 3 mins after administration
of rocuronium)
-16.0 mg/kg
Rocuronium-Sugammadex Complex. FDA Sugammadex
Powerpoint.
Sugammadex
• MOA: a γ-cyclodextrin ring with lipophilic center cavity
-Binds and encapsulates steroidal rocuronium and vecuronium
-Not active against non-steroidal NMBA ie succinylcholine
-Water-soluble, not metabolized, and renally excreted
• What does it offer in current clinical practice?
-1st agent that can reverse a profound neuromuscular block
-Can provide immediate reversal when needed
-Avoid the use of acetylcholinesterase inhibitors, muscarinic
antagonists, and their associated side effects
FDA Sugammadex Powerpoint.
Sugammadex
Sugammadex Affinity
NMBA
Affinity
(Ka megaM-1)
Rocuronium
25.0
Vecuronium
10.0
Pancuronium
2.6
Cisatracurium
0.005
Succinylcholine 0.000
FDA Sugammadex Powerpoint.
Comparison NMBAs
http://www.bridion.com/HCP/NMB_Management/Neuromuscular_Blockad
e/Mechanism_of_Action_of_NMBAs/index.asp
• In patients with myasthenia gravis, is
Sugammadex more effective in reversing
neuromuscular blockade than
neostigmine?
Neuromuscular Monitoring
•
Train of Four (TOF): measures more shallow blockade. “Ratio” of T4 to T1
Miller, RD, et al. Miller’s Anesthesia, 7th ed
Neuromuscular Monitoring
•
Post-Tetanic Count (PTC): measures deeper blockade. PTC 1-2 ~
profound blockade
.
Miller, RD, et al. Miller’s Anesthesia, 7th ed
Reversal of Profound Rocuronium-induced Blockade
with Sugammadex: A Randomized Comparison with
Neostigmine
AKA SIGNAL Study
• Objective: To determine the efficacy and safety of
sugammadex vs. neostigmine for reversal of profound
rocuronium-induced neuromuscular blockade
• Design:
-Phase III, multicenter, randomized, parallel-group,
safety assessor-blinded study
-Eight sites in the US
-N=75
-Sugammadex group N=37
-Neostigmine group N=38
-Trial conducted b/w Nov 2005 and Nov 2006
Jones, RK., et al. Anesthesiology 2008;109:816-24
SIGNAL Study
Inclusion:
• Adults 18 yr or older
• American Society of
Anesthesiologist physical
status I-IV
• Scheduled surgery during
gneral anesthesia in the
supine position
• Rocuronium for tracheal
intubation & maintenance of
NMB
Jones, RK., et al. Anesthesiology 2008;109:816-24
Exclusion:
• Suspected to have difficult
airway or neuromuscular
disorders that might impair
NMB, significant renal
dysfunction, family hx of
malignant hyperthermia,
allergy or contraindication to
study medications, pts taking
meds that can interfere w/
NMBA, female pts who are
pregnant, breast-feeding or not
using birth control if of childbearing age, and pts who had
already participated in another
clinical trial
SIGNAL Study
•
Intervention
-Rocuronium 0.6 mg/kg w/
maintenance doses 0.15 mg/kg as
needed
-Control arm: Neostigmine 70
µg/kg + Glycopyrrolate 14 µg/kg
-Experimental arm: Sugammadex
4.0 mg/kg
•
Methods
-Induction of anesthesia
-Start neuromuscular monitoring
w/ acceleromyograph after
induction of anesthesia, & before
rocuronium adminstration (w/
calibration)
Jones, RK., et al. Anesthesiology 2008;109:816-24
-TOF stimulation every 15 secs at
ulnar nerve
-Rocuronium given right before
surgery
-After disappearance of T1
response, start PTC stimulation
-When 1-2 PTCs appear
(profound neuromuscular block),
give sugammadex or neostigmine
+ glycopyrrolate
-Ventilation support & anesthesia
were maintained until recovery of
TOF ratio of 0.9 or when tracheal
extubation is indicated
SIGNAL Study
Primary endpoints:
• Time from start of sugammadex or
neostigmine administration until
recovery of the TOF ratio to 0.9
Secondary endpoints:
• Time from sugammadex or
neostigmine administration to
recovery of the TOF ratio to 0.7
and 0.8, and clinical signs of
recovery
•
Statistical analysis:
• Primary efficacy analysis
-ITT
• Missing data
-Imputation w/ conservative
approach
•
Jones, RK., et al. Anesthesiology 2008;109:816-24
•
•
Treatment groups & centers
-Two-way analysis of
variance model
-Statistical sign if p < 0.05
Recovery times
-Skewed distribution
-Geometric means reported
95% power to detect a difference
of 5 mins or greater b/w tx groups
-32 pts were needed per grp
Interim analysis
-When 10 pts from each grp
had completed the study and
provided data
-Results assessed and
decisions made by the Data
& Safety Monitoring Board
SIGNAL Study
• Baseline characteristics: Gender, age, weight,
height, race, and ASA physical status are
comparable b/w groups
• Results:
-After interim analysis, the Data and Safety
Monitoring Board recommended to discontinue
the neostigmine group d/t significant differences
in efficacy b/w treatments
Jones, RK., et al. Anesthesiology 2008;109:816-24
SIGNAL Study
•
Results, cont.
Primary outcome:
Sugammadex
group, N = 37
Imputated:
Geometric mean time
from start of drug
administration to TOF
ratio of 0.9
Collected data:
Geometric mean
time from start of
drug administration
to TOF ratio of 0.9
Median time (range
[interquartile range])
to recovery of TOF
ratio 0.9
2.9 min
2.6 min, N = 30
2.7 min (1.2-16.1
[2.1-4.1])
56.0 min, N = 22
49.0 min (13.3-145.7
[35.7-65.6])
Neostigmine group, 50.4 min
N = 37
P < 0.0001
Jones, RK., et al. Anesthesiology 2008;109:816-24
SIGNAL Study
Safety outcomes:
-Comparable rates of AEs b/w sugammadex
& neostigmine group (97.3 vs 97.4)
Results, cont.
49
40.9
-Most frequent reported AEs include
procedural pain, nausea, incision-site
complications
32.1
-One pt from the neostigmine group dc’d
from the study because of gastric perforation
and procedural complications (SAE)
1.7
2.3
2.7
P <0.0001
**values are reported medians instead of geometric means
-Clinical signs of recovery
were also assessed 
similar b/w groups
Jones, RK., et al. Anesthesiology 2008;109:816-24
-97% of sugammadex pts recovered to a
TOF ratio of 0.9 within 5 mins after
administration
-73% of neostigmine pts recovered b/w 30
and 60 mins after administration, and 23%
needing more than 60 mins to return to TOF
ratio of 0.9.
SIGNAL Study
Strengths:
• Multicenter and sites in
the US
• Calibration of
acceleromyograph at
baseline
• Used standard
recommended doses of
neostigmine,
glycopyrrolate and
sugammadex
• Addressed missing data
conservatively with
imputations
Weaknesses:
• Small study N = 75
• Study sponsored by
Schering-Plough
company
• P values for baseline
characteristics and
adverse events were not
reported
Reversal of Profound Neuromuscular Block by
Sugammadex Administered Three Minutes after
Rocuronium: A Comparison with Spontaneous
Recovery from Succinylcholine
AKA SPECTRUM Study
• Compared time to sugammadex reversal of profound neuromuscular
block by rocuronium
• With the time to spontaneous recovery with succinylcholine
• Design: Randomized, multicenter, safety-assesor-blinded, parallel
group, active-controlled phase III trial
• N = 110 adult American Society of Anesthesiologists Class I-II pts
• 11 centers, 9 in the US, 2 in Canada
• Nueromuscular blockade using
-1.2 mg/kg rocuronium (N =55)
-1 mg/kg succinylcholine (N=55)
• Reversal: sugammadex 16 mg/kg IV 3 mins after rocuronium
administration
• Primary endpoint: time from start of relaxant admin. to recovery of
first TOF twitch (T1) to 10%
Lee, C., et al. Anesthesiology 2009;110:1020-5.
SPECTRUM Study
Results:
Mean time to recovery
of T1 to 10%
Mean time to recovery
of T1 to 90%
RocuroniumSugammadex
4.4 min
6.2 min
Succinylcholine
7.1 min
10.9 min
All P-value < 0.001
Conclusion:
-Succinylcholine is effective when fast & short duration NMB is optimal, ie during
Rapid sequence intubation (RSI)
-At 1 mg/kg, a complete block occurs in ~1 min and recovery in 6-9 mins
(T1 to 10%) or 10-13 mins (T1 to 90%)
-Rocuronium at 0.6-1.2 mg/kg on avg. provides a complete NMB in <2 mins
-Sugammadex offers faster recovery than succinylcholine
-Important when pts cannot be intubated or ventilated & spontaneous
respiration is crucial
Lee, C., et al. Anesthesiology 2009;110:1020-5.
Summary of the two articles
• SIGNAL: Sugammadex vs. Neostigmine reversal of
rocuronium-induced profound NMB
– Rapid reversal of NMB at any depth with Sugammadex
– Not possible w/ current neostigmine reversal
• SPECTRUM: Rocuronium-sugammadex vs.
Succinylcholine-spontaneous recovery of profound NMB
– Sugammadex has a much faster reversal than spontaneous
reversal of succinylcholine
– Rocuronium followed by sugammadex is useful if unexpected
need for immediate recovery is indicated
• Results from both studies were statistically significant
and supported Sugammadex use in different settings.
Sugammadex Status
• Sugammadex (Schering-Plough/Merck & Co)
NDA was granted a priority review by the FDA in
December 2007
• It had the potential to fullfill an unmet medical
need
• August 2008 FDA had announced disapproval of
Sugammadex due to hypersensitivity and
allergic reactions
• Sugammadex was approved for marketing in the
European Union (EU) as Bridion
FDA Rejects Schering-Plough’s Anaestetic Drug Sugammadex NDA. Medical News Today. Aug 5, 2008.
http://www.medicalnewstoday.com/articles/117156.php
Sugammadex Final Main Advisory Committee Presentation. March 2008. http://www.fda.gov/ohrms/dockets/ac/08/slides/2008-4346s1-01Schering-Plough-corebackup.pdf
Case Reports
Patient
Level of NMB
before admin.
of
Sugammadex
Treatment
Result
Comment
72 yo male w/
MG scheduled
for
prostatectomy
Recovery of T2
(ie shallow
blockade)
-Rocuronium
0.3 mg/kg
-Sugammadex
2 mg/kg
-TOF ratio >
90% w/in 210
sec
-50% of rec.
roc. dose used
Pt 1 w/ mild
generalized
muscle
weakness
Intense
blockade
-Roc 0.15
mg/kg
-Sugammadex
4 mg/kg
-Time to TOF
ratio >90% 162
sec
-25% of rec.
roc. dose used
Pt 2 w/ mild
generalized
muscle
weakness
Intense
blockade
-Roc 0.15
mg/kg
-Sugammadex
4 mg/kg
-Time to TOF
ratio > 90% 135
sec
-25% of rec..
roc. dose used
Unterbuchner, C., et al. Anaesthesia, 2010;65:302-305.
De Boer, HD., et al. Anaesthesia, 2010:653.
Conclusion
•
•
•
•
•
•
•
•
It is important for healthcare providers to recognize medications that can
exacerbate MG
There are varying responses to NMBAs in MG pts. To prevent
complications associated w/ residual NMB, we consider the use of reversal
agents
There were positive results from phase III studies and case reports
However, there are limited studies done on Sugammadex in pts w/ MG
Sugammadex was not approved by the FDA d/t hypersensitivity and allergic
rxns
Sugammadex is a likely beneficial NMB reversal agent for pts w/ MG, and
SS if she were to undergo surgery such as thymectomy or stem cell
transplant necessitating anesthesia
Issues to consider include the cost of sugammadex, FDA status, and limited
studies on pts w/ MG
Possible future studies can consider resolving FDA issues and addressing
the hypersensitivity reactions, ie premeds
References
•
•
•
Robinson, J. et al. Myasthenia Gravis and Related Disorders. Bope: Conn’s Current Therapy 2010, 1st 3d. 2009:
Saunders.
A. Ahmed & Z. Simmons. Drugs Which May Exacerbate of Induce Myasthenia Gravis: A Clinician’s Guide. The
Internet Journal of Neurology. 2009. Volume 10 Number 2.
http://www.ispub.com/journal/the_internet_journal_of_neurology/volume_10_number_2_6/article/drugs_which_ma
y_exacerbate_or_induce_myasthenia_gravis_a_clinician_s_guide.html
Caro, David. Neuromuscular blocking agents (NMBA) for rapid sequence intubation in adults. UpToDate 2010.
•
FDA Sugammadex Powerpoint. Sugammadex Final Main Advisory Committee Presentation. March 2008.
http://www.fda.gov/ohrms/dockets/ac/08/slides/2008-4346s1-01-Schering-Plough-corebackup.pdf
•
Miller, RD, et al. Chapter 47-Neuromuscular Monitoring Patterns of Stimulation. Miller’s Anesthesia, 7th ed.; 2009.
•
•
•
•
http://www.mdconsult.com.proxy.westernu.edu/das/book/body/212974319-3/1034164379/2053/50.html#4-u1.0B978-0-443-06959-8..00047-9--s0050_2822
Lee, C., et al. Reversal of Profound Neuromuscular Block by Sugammadex Administered Three Minutes after
Rocuronium: A Comparison with Spontaneous Recovery from Succinylcholine. Anesthesiology 2009;110:1020-5.
Jones, RK., et al. Reversal of Profound Rocuronium-induced Blockade with Sugammadex: A Randomized
Comparison with Neostigmine. Anesthesiology 2008;109:816-24.
Unterbuchner, C., et al. The use of sugammadex in a patient with myasthenia gravis. Anaesthesia;2010:302-305.
De Boer, HD., et al. Sugammadex in patients with myasthenia gravis. Anaesthesia;2101:653.
Thank you!