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Neuromuscular Blockade in Patients with Myasthenia Gravis (MG)

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Neuromuscular Blockade in Patients with Myasthenia Gravis (MG) Gardy Mak PharmD 2011 Western University August 5, 2010 Objectives Review my patient case Define ... – PowerPoint PPT presentation

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Title: Neuromuscular Blockade in Patients with Myasthenia Gravis (MG)


1
Neuromuscular Blockade in Patients with
Myasthenia Gravis (MG)
  • Gardy Mak
  • PharmD 2011
  • Western University
  • August 5, 2010

2
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

3
Patient Presentation
  • SS is a 56 yo female admitted to COH to start
    induction therapy for her newly diagnosed AML
  • PMH Myasthenia gravis diagnosed in 1997
  • 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
  • Gait becomes a waddle and difficulty using a
    straw if she misses a dose
  • 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

4
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

5
Patient Presentation
  • Current Medications
  • -Boniva 150mg po qmonth -Allopurinol 300 mg
    qday
  • -Mestinon 60mg po tid -Levaquin, micafungin
  • -Vicodin 2 tabs po q4h prn mod. Pain -Cytarabine
    376 mg IV daily x 7
  • -Acyclovir, protonix, antiemetics -Idarubicin
    22.5 mg daily x 3
  • -Decadron eye drops
  • Labs on Admission
  • WBC 1.3 (L) Na 140 Ca 9.1
  • RBC 2.28 (L) K 3.7 Mg N/A
  • Hgb/Hct 8.3/23.1 (L) CO2 25 P N/A
  • Platelet 129 (L) BUN 16 Uric acid 5.3
  • Neutrophil 11 SCr 0.76 T. bili 0.6
  • Lymphocyte 84.0(H) Glucose 114 (H) LDH 538

6
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
  • 2)Structural abnormality
  • 3)Thymus

jama.ama-assn.org
Robinson, J. et al. Bope Conns Current Therapy
2010, 1st ed.
7
Myasthenia Gravis
  • Epidemiology
  • -Prevalence 14 per 100,000 people in the US
  • -All ethnic groups, both genders
  • -Any age Women (onset 20-30), 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
  • 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

Robinson, J. et al. Bope Conns Current Therapy
2010, 1st ed.
8
Myasthenia Gravis
  • Diagnostic tests
  • Edrophonium chloride (Tensilon) test gt90
    sensitivity, but low specificity
  • Antibody testing (most specific for MG)
  • CT scan of chest for the presence of thymoma
  • Electromyography w/ repetitive nerve stimulation
  • Treatment options
  • Cholinesterase Inhibitors
  • Chronic immunosuppressive agents
  • Rapid immunotherapy agents
  • Thymectomy

Robinson, J. et al. Bope Conns Current Therapy
2010, 1st ed.
9
Summary of Therapy
  • Ocular symptoms only or mild weakness ?
    cholinesterase inhibitors
  • Moderate to severe weakness ? cholinesterase
    inhibitors and thymectomy for pts lt60 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 Conns Current Therapy
2010, 1st ed.
10
Exacerbation of MG
  • Infection
  • Stress ie surgery
  • Medications
  • A. Ahmed Z. Simmons Drugs Which May
    Exacerbate of Induce Myasthenia Gravis A
    Clinicians Guide. The Internet Journal of
    Neurology.
  • Volume 10 Number 2.
  • http//www.ispub.com/journal/the_internet_journal_
    of_neurology/volume_10_number_2_6/article/drugs_wh
    ich_may_exacerbate_or_induce_myasthenia_gravis_a_c
    linician_s_guide.html
  • Robinson, J. et al. Bope Conns Current Therapy
    2010, 1st ed.

11
  • Do you recall which medications SS was on that
    can potentially interact w/ her disease state?
  • -Boniva 150mg po qmonth -Allopurinol 300 mg
    qday
  • -Mestinon 60mg po tid -Levaquin, micafungin
  • -Vicodin 2 tabs po q4h prn mod. pain -Cytarabine
    376 mg IV daily x 7
  • -Acyclovir, protonix, antiemetics -Idarubicin
    22.5 mg daily x 3
  • -Decadron eye drops

12
http//www.mdconsult.com.proxy.westernu.edu/das/ar
ticle/body/213147274-10/jorgjournalsourcesp21
635437sid0/N/679929/s0733862708000990.pdf?issn0
733-8627
13
Neuromuscular Blocking Agents (NMBA) in General
Anesthesia
  • Indication Endotracheal intubation and
    surgeries where skeletal muscle relaxation is
    desired
  • 2 types
  • Depolarizing NMBA
  • Non-depolarizing NMBA

Caro, D. UpToDate 2010
14
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
15
NMBA
  • Depolarizing
  • Non-depolarizing

16
  • 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

17
NMB
  • Pts w/o MG
  • MG pts

18
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, 2010653.
esthesia
19
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.
20
Sugammadex
  • MOA a ?-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.
21
Sugammadex
  • Sugammadex Affinity
  • Comparison NMBAs

NMBA Affinity (Ka megaM-1)
Rocuronium 25.0
Vecuronium 10.0
Pancuronium 2.6
Cisatracurium 0.005
Succinylcholine 0.000
http//www.bridion.com/HCP/NMB_Management/Neuromus
cular_Blockade/Mechanism_of_Action_of_NMBAs/index.
asp
FDA Sugammadex Powerpoint.
22
  • In patients with myasthenia gravis, is Sugammadex
    more effective in reversing neuromuscular
    blockade than neostigmine?

23
Neuromuscular Monitoring
  • Train of Four (TOF) measures more shallow
    blockade. Ratio of T4 to T1

Miller, RD, et al. Millers Anesthesia, 7th ed
24
Neuromuscular Monitoring
  • Post-Tetanic Count (PTC) measures deeper
    blockade. PTC 1-2 profound blockade

Miller, RD, et al. Millers Anesthesia, 7th ed.
25
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
  • -N75
  • -Sugammadex group N37
  • -Neostigmine group N38
  • -Trial conducted b/w Nov 2005 and Nov 2006

Jones, RK., et al. Anesthesiology 2008109816-24
26
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
  • 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 child-bearing age, and pts who had
    already participated in another clinical trial

Jones, RK., et al. Anesthesiology 2008109816-24
27
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)
  • -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

Jones, RK., et al. Anesthesiology 2008109816-24
28
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
  • Treatment groups centers
  • -Two-way analysis of variance model
  • -Statistical sign if p lt 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

Jones, RK., et al. Anesthesiology 2008109816-24
29
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 2008109816-24
30
SIGNAL Study
  • Results, cont.

Primary outcome
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
Sugammadex group, N 37 2.9 min 2.6 min, N 30 2.7 min (1.2-16.1 2.1-4.1)
Neostigmine group, N 37 50.4 min 56.0 min, N 22 49.0 min (13.3-145.7 35.7-65.6)
P lt 0.0001
Jones, RK., et al. Anesthesiology 2008109816-24
31
SIGNAL Study
Safety outcomes -Comparable rates of AEs b/w
sugammadex neostigmine group (97.3 vs
97.4) -Most frequent reported AEs include
procedural pain, nausea, incision-site
complications -One pt from the neostigmine group
dcd from the study because of gastric
perforation and procedural complications
(SAE) -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.
  • Results, cont.

49
40.9
32.1
2.7
1.7
2.3
P lt0.0001 values are reported medians instead
of geometric means
-Clinical signs of recovery were also assessed ?
similar b/w groups
Jones, RK., et al. Anesthesiology 2008109816-24
32
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

33
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 (N55)
  • 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 20091101020-5.
34
SPECTRUM Study
  • Results

Mean time to recovery of T1 to 10 Mean time to recovery of T1 to 90
Rocuronium-Sugammadex 4.4 min 6.2 min
Succinylcholine 7.1 min 10.9 min
All P-value lt 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 lt2 mins -Sugammadex
offers faster recovery than succinylcholine -Impo
rtant when pts cannot be intubated or ventilated
spontaneous respiration is crucial
Lee, C., et al. Anesthesiology 20091101020-5.
35
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.

36
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-Ploughs Anaestetic Drug
Sugammadex NDA. Medical News Today. Aug 5,
2008. http//www.medicalnewstoday.com/articles/117
156.php Sugammadex Final Main Advisory Committee
Presentation. March 2008. http//www.fda.gov/ohrm
s/dockets/ac/08/slides/2008-4346s1-01-Schering-Plo
ugh-corebackup.pdf
37
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 gt 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 gt90 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 gt 90 135 sec -25 of rec.. roc. dose used
Unterbuchner, C., et al. Anaesthesia,
201065302-305. De Boer, HD., et al.
Anaesthesia, 2010653.
38
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

39
References
  • Robinson, J. et al. Myasthenia Gravis and
    Related Disorders. Bope Conns Current Therapy
    2010, 1st 3d. 2009 Saunders.
  • A. Ahmed Z. Simmons. Drugs Which May
    Exacerbate of Induce Myasthenia Gravis A
    Clinicians 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_w
    hich_may_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. Millers
    Anesthesia, 7th ed. 2009.
  • http//www.mdconsult.com.proxy.westernu.edu/das/b
    ook/body/212974319-3/1034164379/2053/50.html4-u1.
    0-B978-0-443-06959-8..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 20091101020-5.
  • Jones, RK., et al. Reversal of Profound
    Rocuronium-induced Blockade with Sugammadex A
    Randomized Comparison with Neostigmine.
    Anesthesiology 2008109816-24.
  • Unterbuchner, C., et al. The use of sugammadex
    in a patient with myasthenia gravis.
    Anaesthesia2010302-305.
  • De Boer, HD., et al. Sugammadex in patients with
    myasthenia gravis. Anaesthesia2101653.

40
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