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EPIDEMIOLOGIC CHALLENGES IN MALIGNANT HYPERTHERMIA (MH)

EPIDEMIOLOGIC CHALLENGES IN MALIGNANT HYPERTHERMIA (MH). Department of Anesthesiology Children’s Hospital of Pittsburgh/ University of Pittsburgh. Barbara Brandom, MD. Jesus Apuya, MD. ACKNOWLEDGEMENTS. Marilyn Larach Sheila Muldoon Henry Rosenberg Debra Merritt Bettina Dixon

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EPIDEMIOLOGIC CHALLENGES IN MALIGNANT HYPERTHERMIA (MH)

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  1. EPIDEMIOLOGIC CHALLENGES IN MALIGNANT HYPERTHERMIA (MH) Department of Anesthesiology Children’s Hospital of Pittsburgh/ University of Pittsburgh Barbara Brandom, MD Jesus Apuya, MD

  2. ACKNOWLEDGEMENTS • Marilyn Larach • Sheila Muldoon • Henry Rosenberg • Debra Merritt • Bettina Dixon • and the Board of Malignant Hyperthermia Association of US

  3. AT A GLANCE... • Mimics of MH • Diseases Associated with MH • Possibly MH-Related • Rhabdomyolysis but not MH • Muscle Biopsy & IVCT • MHAUS, NAMHR, NMSIS • & MH Hotline • Bibliography • Epidemiology of MH • Pathogenesis of MH • 4 Different Case Scenarios • The MH Clinical Grading Scale • MH-like Anesthetic Events

  4. “Epidemiologic barriers” in defining the true incidence of MH” • Difficulty in establishing diagnosis of MH • No noninvasive diagnostic screening test

  5. “Epidemiologic barriers” in defining the true incidence of MH” (cont.) • All cases are not reported to MH Registry • Triggering of MH in susceptible patients may not occur • Lack of uniform criteria for MH diagnosis

  6. Incidence of Different Forms of MH in Relation to Type of Anesthesia Fulminant MH Abortive MH Overall incidence (all subgroups of suspected MH included) Total number of anesthetics 1:251,063 1:17,435 1:16,303 General anesthesia 1:221,811 1:15,404 1:14,403 Anesthesia with potent inhalation agent 1:84,488 1:6,653 1:6,167 With succinylcholine 1:61,961 1:4,506 1:4,201 Without succinylcholine 1:174,597 1:20,541 1:18,379 Anesthesia with administration of succinylcholine 1:140,006 1:8,819 1:8,297

  7. Pathogenesis: Key Concepts • Heterogeneous disorder • Genetically transmitted with variable expression/penetrance • Can be triggered by volatile anesthetics and succinylcholine

  8. Hereditary - multiple genes Several chromosomes: • 19q11.2-13.2 Ryanodine (RyR1) • Release of Ca2+stores from sarcoplasmic reticulum • 17q11.2-q24 • Altered sodium channel functioning • 7q21.1 • Dihydropyridine (DHP), voltage sensor for RyR1 • 1q32 • CACNL1A3 gene encoding the alpha 1-subunit of the voltage-gated DHP receptor that interacts with RyR1

  9. Non-specific clinical presentation • hypercarbia • tachycardia • fever • hyperventilation • metabolic and respiratory acidoses • cardiovascular collapse • rhabdomyolysis

  10. Case One in PACU A large 13 year old boy underwent 2 hours of uncomplicated halothane anesthesia.

  11. Case Two in OR A 10 year-old male was given propofol & mivacurium to facilitate tracheal intubation. Anesthesia was continued with isoflurane/N2O.

  12. Case Three Masseter Rigidity? A 16 year-old male who refused spinal anesthesia for lower extremity surgery, was given propofol and succinyl-choline (no potent anesthetic gas).

  13. Case Four Outside A 12 year old male collapsed after rigorous exercise. Tobin JR, Jason DR, Nelson TE, Sambuughin. Malignant Hyperthermia and Apparent Heat Stroke N. JAMA 2001; 286(2):168-169 http://jama.ama-assn.org/issues/v286n2/ffull/jlt0711-4.html

  14. Click for larger picture Process Indicator Points 1. Rigidity Generalized muscular rigidity 15 Masseter spasm________________________________ 15 2. Muscle Breakdown Creatine Kinase >20,000 IU after succinylcholine 15 Creatine Kinase >10,000 IU with no succinylcholine 15 Cola colored urine in perioperative period 10 Myoglobin in urine > 60 mcg/L 5 Myoglobin in serum > 170 mcg/L 5 Blood/plasma/serum 6 mEq/L no renal ills _____ 3 3. Respiratory Acidosis PETCO2 > 55 mmHg with controlled ventilation 15 ArterialPaCO2 > 60 mmHg, controlled ventilation 15 PETCO2 > 60 mmHg with spontaneous ventilation 15 ArterialPaCO2 > 65 mmHg, spontaneous ventilation 15 Inappropriate hypercarbia, Anesthesiologist’s call 15 Inappropriate tachypnea__________________________ 10 4. Temperature Increase Inappropriately rapid increase 15 Inappropriately increased temperature > 38.8C_______ 10 5. Cardiac Involvement Inappropriate sinus tachycardia 3 Ventricular tachycardia or fibrillation_________________ 3 6. Family History Positive family history in first degree relative 15 Positive family history, more distant relative ____ 5 7. Others Arterial base excess more negative than –8 mEq/L 10 Arterial pH <7.25 10 Rapid reversal of MH signs after iv dantrolene 5 Positive MH family history with another indicator from the patient’s anesthetic experienceother than increased CK 10 Elevated CK and a family history of MH______________ 10 Larach MG, Et Al, MH Clinical Grading Scale,Anesthesiology 1994; 80:771-9

  15. 20-34 Somewhat greater than likely 35-49 Very likely >50 Almost certain CGS Sum and Probability of MH

  16. Case 1 Case 2 Case 3 Case 4 Rigidity 0 0 15 15 Muscle Injury 15 15 15 0 Respiratory 0 15 0 15 Temperature 10 0 0 15 Cardiac 3 0 0 15 Family History 0 0 0 0 Other 10 5 0 0 SUM 38 35 30 45 Clinical Grading Scores (CGS)

  17. MYOPATHY INCIDENCE AGE at Dx Duchenne 0.0020 5 (<16) yrs Becker 0.00036 12 (4-19) Myotonia Dystrophica 0.000135 < 14 years MH-Like Anesthetic Events

  18. MH Thyrotoxicosis Pheochromocytoma ETCO2 +++ ++ ++ HR +++ +++ +++ BP + ++ +++ Rigidity ++ +/- - Acidosis +++ - + Differential Diagnosis

  19. Adverse drug reactions Arthrogryposis Carnitine palmitoyl transferase deficiency CNS diseases Contrast media in CSF Elevated ETCO2 with laparoscopic cases Cystinosis Glycogen storage disease Lymphoma Mitochondrial disease Neuroleptic malignant syndrome Viral myopathy William’s syndrome Some Mimics of MH

  20. Diseases Associated with MHS • Central core disease • Isolated elevation of creatine kinase • King Denborough syndrome

  21. Possibly MH Related • Dystrophinopathy • Emery Dreifuss MD • FascioScapuloHumeral MD • Abnormal Muscle Enzymes • Ion Channel Mutations • Na, K, Cl

  22. Rhabdomyolysis, but NOT MH • Brody’s disease • Deficient calcium adenosine triphosphatase • McArdle’s disease • Myophosphorylase B deficiency

  23. Muscle Biopsy and IVCT • Nearly 100% sensitive • 85% specific

  24. Anesthesia for MH Susceptible Patients • If your patient has had a muscle biopsy for MH contracture testing or is registered through the North American Malignant Hyperthermia Registry (NAMHR): • Call # 888-274-7899 • Complete & return report of anesthetic

  25. Bibliography 1. Larach, MG for the North American Malignant Hyperthermia Group. Standardization of the caffeine-halothane muscle contracture test. Anesth Analg 1989; 69:511-515 2. Laboratory diagnosis of malignant hyperpyrexia susceptibility (MHS). European MH Group. Br J Anaesth. 1985; 57(10):1038. 3. European Malignant Hyperpyrexia Group. A protocol for the investigation of malignant hyperpyrexia (MH) susceptibility. Br J Anaesth, 1984; 56: 1267-1269. 4. Allen, G, et al. The sensitivity and specificity of the caffeine-halothane contracture test. Anesthesiology 1998; 88:579-88. 5. Ording, H., et al. In-vitro contracture test for diagnosis of malignant hyperthermia following the protocol of the European MH Group: results of testing patients surviving fulminant MH and unrelated low-risk subjects. The European Malignant Hyperthermia Group. Acta Anesthesiol. Scand.,1997; 41: 955-966.

  26. Bibliography, cont. 6. Urwyler A., et.al. Guidelines for molecular genetic dectection of susceptibility to malignant hyperthermia. And editorial III. Br J Anaesth. 2001; 86(2): 283-7. 7. Brandt, A., et al. Screening of the ryanodine receptor gene in 105 malignant hyperthermia families: novel mutations and concordance with the in-vitro contracture test. Hum. Mol. Genet. 1999; 8: 2055-2062. 8. Brown, R., et al. A novel ryanodine receptor and genotype-phenotype correlation in a large malignant hyperthermia New Zealand Maori pedigree. Hum. Mol. Genet. 2000; 9: 1515-1524. 10. Larach, MG, et al. MH Clinical Grading Scale. Anesthesiology 1994; 80:771-9. 11. Ording, H. Incidence of Malignant Hyperthermia in Denmark. Anesth Analg 1985; 64:700-4. 12. Benumof, Jonathan. Muscle Diseases. Anesthesia & Uncommon Diseases. (4/e), Philadelphia, 1998.

  27. Bibliography, cont. . 13. Monnier N, et al. Malignant Hyperthermia susceptibility is associated with a mutation of the alpha 1 subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium channel receptor in skeletal muscle. Am J Hum Genet 1997;60(6):1316-25. 14. Tobin JR, Jason DR, Nelson TE, Sambuughin N. Malignant Hyperthermia and Apparent Heat Stroke, JAMA 2001; 286(2):168-169. 16. Larach, MG, et al. MH Clinical Grading Scale. Anesthesiology 1994; 80:771-9. 17. Dierdorf, Stephen. Anesthesia for Patients with Rare and Coexisting Diseases. Clinical Anesthesia (3/e), Philadelphia, 1996. p 461. 18. McPherson EW, Taylor CA Jr. The King Syndrome: MH, myopathy, and multiple anomalies. Am J Med Genet 8:159, 1981. 19. Loke JC, MacLennan DH. Bayesian modeling of muscle biopsy contracture testing for malignant hyperthermia susceptibility. Anesthesiology 1998;88(3):589-600.

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