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Malignant Hyperthermia      Syndrome          Henry Rosenberg, M.D.     President, Malignant Hyperthermia Association of  ...
Malignant Hyperthermia (MH)- Essential               Characteristics• An inherited disorder of skeletal muscle triggered i...
Trigger Agents for MHMH Trigger Agents                    Not MH Triggers• Potent Volatile                    • Intravenou...
Summary of Clinical Signs      Malignant Hyperthermia Association of the United States copyright © 2010 All Rights Reserved
Epidemiology of MHIncidence & Prevalence• Reported frequency of MH is 1 in 5,000 to1 in 100,000 anesthetics• Reported from...
Epidemiology of MH (continued)Mortality from MH Per data from the North American MH Registry, of 291 events, 8  (2.7%) re...
Epidemiology of MH (continued)Mortality: Hospital vs. Ambulatory Settings During the period January 2006 through May 2008...
Clinical Signs of MH• Specific                         • Non-Specific   – Muscle Rigidity                 – Tachycardia   ...
Spectrum of Clinical Presentations• Fulminant MH: muscle rigidity, high fever, increased HR  shortly after induction of an...
Masseter Muscle Rigidity (MMR) and MH• Masseter muscle rigidity (MMR) may occur after  succinylcholine• More common in chi...
Muscle disorders and MH-                  Susceptibility• CCD (Central Core Disease) and MmD (Multiminicore Disease)– diso...
Muscle disorders and MH-susceptibilityPatients with occult or known myopathies such as CCD, MmD, DMD,or BMD may have a hig...
Treatment and Management of MHImmediate Therapy•   Discontinue inhalation agents, succinlycholine•   Hyperventilate with 1...
Malignant Hyperthermia Association of the United States copyright © 2010 All Rights Reserved
Treatment and Management of MHAfter Crisis is controlled•   Give dantrolene 1 mg/kg every 4-6 hours for 24 – 48 hours•   M...
Prevention of Malignant Hyperthermia Avoid MH trigger agents in MH susceptibles or those  suspected of being susceptible...
Diagnostic Tests for MH-                    Susceptibility1. Muscle Contracture Test: Caffeine Halothane Contracture   Tes...
Diagnostic Tests (Continued)2. Genetic Testing (Ryanodine Receptor [RYR1] gene   sequencing)•   Involves isolation of DNA ...
Diagnostic Tests (Continued)2. Genetic Testing (Ryanodine Receptor [RYR1] gene   sequencing)    •   At this point, not all...
Preparation for the MH-Susceptible Patient    Shut/disable vaporizers    Flow 02 @ 10L/min for 20 minutes    (through m...
Management of the MH-susceptible Patient MH-Susceptible individuals may undergo surgery – inpatient  or outpatient; dantr...
Evidence for Association between                  Heat Stroke and MH   12 yr old boy with history of anesthesia-induced M...
MH Resources Malignant Hyperthermia Association of the United States (MHAUS)Not-for-profit organizationOver 2,000 member...
MH Resources (Continued)The North American Malignant Hyperthermia Registry of MHAUS Database which records detailed event...
MHAUS Current Services and Products                                   Educational and Training                            ...
Suggested Resources/ReadingBrandom BW. Genetics of malignant hyperthermia. The Scientific World Journal 2006; 6:1722-1730....
Suggested Resources/Reading (Continued)MHAUS Guidelines. Testing for MH Susceptibility. Slide set available athttp://medic...
For a more in-depth, annotated slide presentation,including:Historical landmarks in the discovery of MHCommon case prese...
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Malignant Hyperthermia Syndrome

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Malignant Hyperthermia - Essential Charactistics:
>An inherited disorder of skeletal muscle triggered in susceptibles (human or animal) in most instances by inhalation agents and/or succinylcholine, resulting in hypermetabolism, skeletal muscle damage, hyperthermia, and death if untreated.
>Underlying physiologic mechanism – abnormal handling of intracellular calcium levels.

Published in: Health & Medicine

Malignant Hyperthermia Syndrome

  1. 1. Malignant Hyperthermia Syndrome Henry Rosenberg, M.D. President, Malignant Hyperthermia Association of the United States (MHAUS) Director, Department of Medical Education, Saint Barnabas Medical Center, Livingston, NJ Malignant Hyperthermia Association of the United States copyright © 2010 All Rights Reserved
  2. 2. Malignant Hyperthermia (MH)- Essential Characteristics• An inherited disorder of skeletal muscle triggered in susceptibles (human or animal) in most instances by inhalation agents and/or succinylcholine, resulting in hypermetabolism, skeletal muscle damage, hyperthermia, and death if untreated.• Underlying physiologic mechanism – abnormal handling of intracellular calcium levels Malignant Hyperthermia Association of the United States copyright © 2010 All Rights Reserved
  3. 3. Trigger Agents for MHMH Trigger Agents Not MH Triggers• Potent Volatile • Intravenous agents Anesthetics (eg. • Opioids halothane, • Non-depolarizing sevoflurane, agents desflurane) • Ketamine• Succinylcholine • Propofol • Anxiolytics Malignant Hyperthermia Association of the United States copyright © 2010 All Rights Reserved
  4. 4. Summary of Clinical Signs Malignant Hyperthermia Association of the United States copyright © 2010 All Rights Reserved
  5. 5. Epidemiology of MHIncidence & Prevalence• Reported frequency of MH is 1 in 5,000 to1 in 100,000 anesthetics• Reported from every country and ethnic group• Based on reports to MHAUS, there are about 600 cases of MH per year in the US.• MH “hotspots:” Wisconsin, Michigan, West Virginia Malignant Hyperthermia Association of the United States copyright © 2010 All Rights Reserved
  6. 6. Epidemiology of MH (continued)Mortality from MH Per data from the North American MH Registry, of 291 events, 8 (2.7%) resulted in cardiac arrests and 4 (1.4%) resulted in death. The median age in cases of cardiac arrest/death was 20 yr (range, 2-31 yr). Factors associated with higher risk of poor outcome were muscular build and disseminated intravascular coagulation (DIC). Increased risk of cardiac arrest/death was related to a longer time period between anesthetic induction and maximum end-tidal carbon dioxide. Larach et al., 2008; Anesthesiology 108(4): 603-611. Malignant Hyperthermia Association of the United States copyright © 2010 All Rights Reserved
  7. 7. Epidemiology of MH (continued)Mortality: Hospital vs. Ambulatory Settings During the period January 2006 through May 2008, the MHAUS MH Hotline received:  503 calls from hospitals, 28 determined to be MH, with 2 deaths from MH (7% mortality)  44 calls from ambulatory settings,13 determined to be MH, with 3 deaths (21% mortality) A fulminant MH episode occurring outside of the hospital setting is more likely to lead to a bad outcome as compared with an episode which originates in a hospital setting. Malignant Hyperthermia Association of the United States copyright © 2010 All Rights Reserved
  8. 8. Clinical Signs of MH• Specific • Non-Specific – Muscle Rigidity – Tachycardia – Increased CO2 – Tachypnea Production – Acidosis – Rhabdomyolysis (Respiratory/ – Marked Metabolic) Temperature – Hyperkalemia Elevation Malignant Hyperthermia Association of the United States copyright © 2010 All Rights Reserved
  9. 9. Spectrum of Clinical Presentations• Fulminant MH: muscle rigidity, high fever, increased HR shortly after induction of anesthesia• Masseter muscle rigidity (MMR): jaw muscle rigidity after succinylchoine may be an early sign of MH (see next slide)• Late onset MH: uncommon, may begin shortly after anesthesia finish time (usually within first hour) Malignant Hyperthermia Association of the United States copyright © 2010 All Rights Reserved
  10. 10. Masseter Muscle Rigidity (MMR) and MH• Masseter muscle rigidity (MMR) may occur after succinylcholine• More common in children• Presages MH in 20-30% cases• All patients with MMR demonstrate elevated CK and often gross myoglobinuria• With muscle breakdown and CK > 20,000IU, the likelihood of MH is very high. Generalized rigidity not always present; if it occurs, MH is almost certain. Malignant Hyperthermia Association of the United States copyright © 2010 All Rights Reserved
  11. 11. Muscle disorders and MH- Susceptibility• CCD (Central Core Disease) and MmD (Multiminicore Disease)– disorders of muscles used for movement. Often associated with mutations in the skeletal muscle ryanodine receptor gene (RYR1), the same gene associated with MH susceptibility.• Duchenne’s Muscular Dystrophy (DMD) –progressive, fatal muscle wasting disorder in males, due to absence of dystrophin protein. Cardiac problems are common.• Becker’s Muscular Dystrophy (BMD) – late onset muscular dystrophy in males, abnormal dystrophin protein, relatively normal life span.• Myotonias – defects in various skeletal muscle ion channels leading to impaired relaxation after voluntary muscle contraction. Malignant Hyperthermia Association of the United States copyright © 2010 All Rights Reserved
  12. 12. Muscle disorders and MH-susceptibilityPatients with occult or known myopathies such as CCD, MmD, DMD,or BMD may have a higher risk for an MH or MH-like episode uponexposure to a triggering anesthetic agent. Such patients should beevaluated by a neurologist prior to providing treatment and/ordiagnostic testing recommendations.  CCD, MmD associated with MH susceptibility.  Patients with Duchenne’s or Becker’s muscular dystrophies are at risk for hyperkalemic cardiac arrest with succinylcholine or other MH triggering agents (but this is NOT MH).  Individuals with any form of myotonia should not receive succinylcholine. Malignant Hyperthermia Association of the United States copyright © 2010 All Rights Reserved
  13. 13. Treatment and Management of MHImmediate Therapy• Discontinue inhalation agents, succinlycholine• Hyperventilate with 100% O2• Bicarbonate 1-2 mg/kg as needed• Get additional help• Dantrolene 2.5 mg/kg push, repeat PRN• Cool patient: gastic lavage, surface, wound• Treat arrhythmias – do not use calcium channel blockers• Arterial or venous blood gases• Electrolytes, coagulation studies Malignant Hyperthermia Association of the United States copyright © 2010 All Rights Reserved
  14. 14. Malignant Hyperthermia Association of the United States copyright © 2010 All Rights Reserved
  15. 15. Treatment and Management of MHAfter Crisis is controlled• Give dantrolene 1 mg/kg every 4-6 hours for 24 – 48 hours• Monitor for recrudescence – rate is 25%• Follow electrolytes, blood gases, CK, core temperature, urine output and color, coagulation studies• Biochemical markers – Blood gases – esp pCO2, pH – Myoglobin levels in serum and urine – PT, PTT, INR, fibrin split products – Liver enzymes, BUN• Monitor for signs of myoglobinuria and rhabdomyolysis and institute therapy to prevent renal failure Malignant Hyperthermia Association of the United States copyright © 2010 All Rights Reserved
  16. 16. Prevention of Malignant Hyperthermia Avoid MH trigger agents in MH susceptibles or those suspected of being susceptible Preoperative personal/family history of anesthetic problems, neuromuscular disorders to identify those who may be MH-susceptible. Temperature/endtidal CO2 monitoring during general anesthesia Recognition of masseter muscle rigidity Prompt investigation of unexplained tachycardia, hypercarbia, hyperthermia Availability of Dantrolene ORs should perform regular MH drills to be prepared. Malignant Hyperthermia Association of the United States copyright © 2010 All Rights Reserved
  17. 17. Diagnostic Tests for MH- Susceptibility1. Muscle Contracture Test: Caffeine Halothane Contracture Test (CHCT) • Gold Standard • Requires skeletal muscle biopsy from patient’s thigh to assess muscle contractile properties upon exposure to ryanodine receptor agonists (eg. caffeine, halothane). • Must be performed at the MH Muscle Biopsy Center. • Abnormally high levels of contractile force indicate MH susceptibility. • Sensitivity: close to 100% (false negatives are rare) • Specificity: ~80% (~20% false positives) Malignant Hyperthermia Association of the United States copyright © 2010 All Rights Reserved
  18. 18. Diagnostic Tests (Continued)2. Genetic Testing (Ryanodine Receptor [RYR1] gene sequencing)• Involves isolation of DNA from patient sample (white blood, or muscle cells; or other tissue sample)• Primary genetic locus associated with MH susceptibility is the ryanodine receptor (RYR1) gene; a DNA variant in the gene is characterized as: a. Unrelated polymorphism (no significant functional effect) b. Causative mutation* (via functional studies) c. Indeterminate (variant of unknown significance)• Presence of causative mutation* in RYR1 gene is diagnostic for MH susceptibility. *Currently 29 listed MH causative RYR1 mutations (see www.emhg.org). Additional ones expected to be added to panel in near future. Malignant Hyperthermia Association of the United States copyright © 2010 All Rights Reserved
  19. 19. Diagnostic Tests (Continued)2. Genetic Testing (Ryanodine Receptor [RYR1] gene sequencing) • At this point, not all proven MHS individuals have been found to harbor a causative mutation. The sensitivity of the genetic test depends upon several factors, including the population selected and the methodology of the testing utilized.• Once a causative mutation is found, family members can be tested for that specific causative mutation; if found, the individual is considered MHS and a muscle biopsy for contracture testing can be avoided. For more details about testing options for MH susceptibility, please refer to the MHAUS slide set available on our website at http://medical.mhaus.org/PubData/PDFs/dx_tes ting_options.pdf . Malignant Hyperthermia Association of the United States copyright © 2010 All Rights Reserved
  20. 20. Preparation for the MH-Susceptible Patient  Shut/disable vaporizers  Flow 02 @ 10L/min for 20 minutes  (through machine and ventilator)  OPTIONAL - Change carbon dioxide absorbent  Use non-trigger agents or local anesthesia  Monitor temperature and for early signs of MH  Have dantrolene available Note: A separate, vapor-free anesthesia machine is not necessary. Malignant Hyperthermia Association of the United States copyright © 2010 All Rights Reserved
  21. 21. Management of the MH-susceptible Patient MH-Susceptible individuals may undergo surgery – inpatient or outpatient; dantrolene is not necessary preoperatively Avoid MH triggers (succinylcholine and potent inhalation agents) Suggested regimen: Anxiolytic(e.g midazolam (ketamine permissible)  Propofol/opioid induction  Non-depolarizing relaxant Nitrous/narcotic/propofol  Reversal of muscle relaxant  Discharge after about 1.5 hours in the recovery room if all signs are stable Malignant Hyperthermia Association of the United States copyright © 2010 All Rights Reserved
  22. 22. Evidence for Association between Heat Stroke and MH 12 yr old boy with history of anesthesia-induced MH, develops fever, rigidity, rhabdomyolysis after soccer practice and dies. RYR-1 mutation detected in him and his relatives (Tobin et al., JAMA 2001; 286:169-70). Experiments in genetically engineered mice provide evidence for mechanism underlying heat sensitivity in some MH patients - involves leakage of Ca2+ through the ryanodine receptor, coupled with the production of reactive nitrogen species which bind to the ryanodine receptor, making it more porous to Ca2+ leak when the muscle is heated. Ca2+ leak may lead to typical changes of MH and at same time lead to increased Ca2+ release (Durham et al., Cell Apr 4 2008; 133 (1): 53-65). Malignant Hyperthermia Association of the United States copyright © 2010 All Rights Reserved
  23. 23. MH Resources Malignant Hyperthermia Association of the United States (MHAUS)Not-for-profit organizationOver 2,000 members including MH-susceptible patients and their family,medical professionals, corporations, and other interested individuals.Mission of MHAUS - to promote optimum care and scientific understanding ofMH and related disorders.Provides the best medical and scientific advice available to patients andhealth care providers alike.HOTLINE for Medical Professionals - 1-800-MH-HYPER - Available 24/7/365to assist health providers in dealing with MH emergencies!General Information: 1-800-986-4287/1-800-98-MHAUS or 607-674-7901Email: info@mhaus.org; Website: www.mhaus.org Malignant Hyperthermia Association of the United States copyright © 2010 All Rights Reserved
  24. 24. MH Resources (Continued)The North American Malignant Hyperthermia Registry of MHAUS Database which records detailed events surrounding MH episodes as well as correlation between clinical history, genetic, and biopsy test results Patients and physicians can provide Registry with clinical history, thus the Registry acts as a service for patients/families and their health care professionals to communicate and store important medical histories relating to the risk for MH Approved by the IRB of the University of Pittsburgh Medical Center The Registry holds a certificate of confidentiality, reflective of its commitment to protect subject confidentiality Director, Dr. Barbara Brandom Phone: 1-888-274-7899; website: https://www.mhreg.org/ . Malignant Hyperthermia Association of the United States copyright © 2010 All Rights Reserved
  25. 25. MHAUS Current Services and Products Educational and Training MaterialsServices Reference and Crisis •Website/FAQs•MH Hotline Management Materials •Brochures•MH Expert Consult •MH Protocol as poster or •Conferences•MH Registry pocket card •Slide shows, some with CME•Speaker’s Bureau •Transfer Guidelines for credits offeredPatient Safety Products ASCs COMING SOON! •Newsletter•Medical ID program and tag •Safe/unsafe anesthetics •Podcasts•MH Alert band and sticker kit pocket card •MH Mock Drill Kit NEW•Family health history toolkit •Crisis Management •In-service kit (video/DVD with•Template letters for family and Sheets test for CEU credit)insurance companies •Dantrolene Dosage Chart •MH procedural manual for•Safe/unsafe anesthetics •MH Hotline Stickers hospital, ASC, and Office-basedpocket card settings Malignant Hyperthermia Association of the United States copyright © 2010 All Rights Reserved
  26. 26. Suggested Resources/ReadingBrandom BW. Genetics of malignant hyperthermia. The Scientific World Journal 2006; 6:1722-1730.Brandom BS. Ambulatory surgery and malignant hyperthermia. Curr Opin Anesthes 2009; 22: 744-747.Capacchione JF, Muldoon SM. The relationship between exertional heat illness, exertional rhabdomyolysis, andmalignant hyperthermia. Anesth Analg 2009; 109:1065-1069.Larach MG, Gronert GA, Allen GC, Brandom BW, Lehman EB. Clinical presentation, treatment, andcomplications of malignant hyperthermia in North America from 1987 to 2006. Anesth Analg 2010; 110:498-507.Larach MG, Brandom BW, Allen GC, Gronert GA, Lehman EB. Cardiac arrests and deaths associated withmalignant hyperthermia in North America from 1987 to 2006: A report from the North American MalignantHyperthermia Registry of the Malignant Hyperthermia Association of the United States. Anesthesiology 2008;108: 603-611.Larach MG, Localio AR, Allen GC, Denborough MA, Ellis FR, Gronert GA, Kaplan RF, Muldoon SM, Nelson TE,Ording H, Rosenberg H, Waud BE, Wedel DJ. A clinical grading scale to predict malignant hyperthermiasusceptibility. Anesthesiology 1994; 80:771-779. Malignant Hyperthermia Association of the United States copyright © 2010 All Rights Reserved
  27. 27. Suggested Resources/Reading (Continued)MHAUS Guidelines. Testing for MH Susceptibility. Slide set available athttp://medical.mhaus.org/PubData/PDFs/dx_testing_options.pdfMuldoon S, Deuster P, Voelkel M, Capacchione J, Bunger R. Exertional heat illness, exertional rhabdomyolysis,and malignant hyperthermia: is there a link? Current Sports Medicine Reports; March/April 2008; 7(2): 74-80.Parness J, Lerman J, Stough RC. Malignant Hyperthermia. In: A Practice of Anesthesia for Infants and Children,2009, Elsevier, Chapter 41, Fourth Edition (edition’s authors: Cote C, Lerman, J, Todres ID), pp. 847-866.Rosenberg H, Davis M, James D, Pollock N, Stowell K. Malignant hyperthermia. Orphanet J Rare Dis 2007; 2:21Rosenberg H, Sambuughin K, Dirksen RT. Malignant hyperthermia susceptibility. January 2010 in GeneReviewsat GeneTests: Medical Genetics Information Resource [database online]. Copyright, University of Washington,Seattle, 1997-2010. Available at http://www.genetests.org <http://www.genetests.org/.Stowell K. Malignant hyperthermia: a pharmacogenetic disorder. Pharmacogenomics 2008; 9(11): 1657-1672. Malignant Hyperthermia Association of the United States copyright © 2010 All Rights Reserved
  28. 28. For a more in-depth, annotated slide presentation,including:Historical landmarks in the discovery of MHCommon case presentations and errors in diagnosisHelpful visual aidesRecent progress in MH research….please refer to the slide set which can be orderedthrough the MHAUS website. Malignant Hyperthermia Association of the United States copyright © 2010 All Rights Reserved

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