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Neuromuscular Blockade in Patients with Myasthenia Gravis (MG)

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

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Neuromuscular Blockade in Patients with Myasthenia Gravis (MG)

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  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. 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

  4. 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

  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: Conn’s Current Therapy 2010, 1st ed.

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

  8. Myasthenia Gravis Diagnostic tests: • Edrophonium chloride (Tensilon) test: >90% 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: Conn’s 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 <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.

  10. Exacerbation of MG • 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. • 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.

  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/article/body/213147274-10/jorg=journal&source=&sp=21635437&sid=0/N/679929/s0733862708000990.pdf?issn=0733-8627http://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

  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. 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) NMBA Caro, D. UpToDate 2010

  15. Non-depolarizing NMBA 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. Pts w/o MG MG pts NMB

  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, 2010:653. 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 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.

  21. Sugammadex Affinity Comparison NMBAs Sugammadex http://www.bridion.com/HCP/NMB_Management/Neuromuscular_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. Miller’s Anesthesia, 7th ed

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

  25. 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

  26. 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 Jones, RK., et al. Anesthesiology 2008;109:816-24

  27. 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 Study Jones, RK., et al. Anesthesiology 2008;109:816-24

  28. 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 < 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 Jones, RK., et al. Anesthesiology 2008;109:816-24

  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 2008;109:816-24

  30. SIGNAL Study • Results, cont. Primary outcome: Jones, RK., et al. Anesthesiology 2008;109:816-24

  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 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. Results, cont. 49 40.9 32.1 2.7 1.7 2.3 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

  32. 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 SIGNAL Study

  33. 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.

  34. SPECTRUM Study Results: 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.

  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-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

  37. Case Reports Unterbuchner, C., et al. Anaesthesia, 2010;65:302-305. De Boer, HD., et al. Anaesthesia, 2010:653.

  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: 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_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. 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.

  40. Thank you!

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