Neuromuscular Blockade in Patients with Myasthenia Gravis (MG)

Neuromuscular Blockade in Patients with Myasthenia Gravis

(MG)

Gardy MakPharmD 2011

Western UniversityAugust 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

• 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

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 -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 9.1RBC 2.28 (L) K 3.7 Mg N/AHgb/Hct 8.3/23.1 (L) CO2 25 P N/APlatelet 129 (L) BUN 16 Uric acid 5.3Neutrophil% 11 SCr 0.76 T. bili 0.6Lymphocyte% 84.0(H) Glucose 114 (H) 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

2)Structural abnormality3)Thymus

jama.ama-assn.org

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 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%


Myasthenia Gravis

Diagnostic tests:1) Edrophonium chloride (Tensilon) test: >90%

sensitivity, but low specificity2) Antibody testing (most specific for MG)3) CT scan of chest for the presence of thymoma4) Electromyography w/ repetitive nerve stimulation

Treatment options:1) Cholinesterase Inhibitors2) Chronic immunosuppressive agents3) Rapid immunotherapy agents4) Thymectomy


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


Exacerbation of MG

Medications

AntibioticsFQAminoglycosides**Macrolides

Cardiovascular agentsCCBBBAnti-arrhythmic

Neuromuscular Blocking Agents**

OthersPenicillamineEye medicationsAnticholinergic agentsCorticosteroids (initially)Chemotherapeutic agentsie doxorubicin, etoposide, cisplatin

•Infection

•Stress ie surgery

•Medications

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.htmlRobinson, J. et al. Bope: Conn’s Current Therapy 2010, 1st ed.

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


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

http://www.mdconsult.com.proxy.westernu.edu/das/article/body/213147274-10/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

NMBADepolarizing• 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

• RocuroniumRocuronium (Zemuron), vecuronium, pancuronium-1.0 mg/kg IV-onset 45-60 seconds-duration 45 mins-SEs: hypertension (≤2%) (Lexicomp)


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


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.

SugammadexSugammadex 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/Neuromuscular_Blockade/Mechanism_of_Action_of_NMBAs/index.asp

FDA Sugammadex Powerpoint.

• 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

NeostigmineAKA 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

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


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


SIGNAL StudyPrimary 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 < 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


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 < 0.0001


SIGNAL Study

Results, cont.

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 dc’d 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.


-Clinical signs of recovery were also assessed similar b/w groups

P <0.0001

**values are reported medians instead of geometric means

1.7 2.32.7

32.1

40.9

49

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 SuccinylcholineAKA 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 StudyResults:

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 < 0.001

Lee, C., et al. Anesthesiology 2009;110:1020-5.

Conclusion:-Succinylcholine is effective when fast & short duration NMB is optimal, ie duringRapid 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

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/2008-4346s1-01-Schering-Plough-corebackup.pdf

http://www.medicalnewstoday.com/articles/117156.php

Case ReportsPatient 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.


• 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-u1.0-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 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.



http://www.fda.gov/ohrms/dockets/ac/08/slides/2008-4346s1-01-Schering-Plough-corebackup.pdf

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Neuromuscular Blockade in Patients with Myasthenia Gravis (MG)