1	Malignant Hyperthermia Syndrome: 2006 Henry Rosenberg, M.D. President, Malignant Hyperthermia Association of the United States Director, Department of Medical Education Saint Barnabas Medical Center, Livingston, NJ
2	Goals and Objectives To review progress made in the diagnosis, management and understanding of malignant hyperthermia syndrome To understand the varied clinical presentations of malignant hyperthermia in and out of the OR environment To understand current laboratory diagnostic tests for MH Based on the pathophysiology of MH, to understand progress in development of new diagnostic tests To be able to treat malignant hyperthermia appropriately and know where to obtain additional information concerning care of the MH patient
3	Anaesthetic Deaths in a Family Denborough MA, Forster JFA, Lovell RRH, et al Royal Melbourne Hospital British J. Anaesth. 1962;34,395
4	Some Landmarks in the Evolution of Understanding MH 1960/61 - Denborough and Lovell describe “Anesthetic deaths in a family” 1960s - Gordon (?) Names the syndrome “Malignant Hyperthermia” Porcine Stress Syndrome related to MH 1971 - First International symposium on MH,Toronto Caffeine contracture test identified Halothane contracture test 1970s - Relation of masseter muscle rigidity to MH
5	Some Landmarks in the Evolution of Understanding MH 1975 - Second International Symposium of MH, Denver Clinical presentation of MH Dantrolene as treatment for MH 1979 - FDA approval of Dantrolene 1981 - Formation of MHA and MHAUS 1982 - MH hotline formed 1980s - End tidal CO₂ as an early sign
6	Some Landmarks in the Evolution of Understanding of MH 1980s: European and North American MH groups. Patient organizations North American MH Registry 1990s: Identification of ryanodine receptor gene as causal in pigs, some humans 1990s: MH without anesthetics? More than 30 mutations are causal in humans 2000- Introduction of molecular genetic testing New tests proposed
7	"Malignant hyperthermia is an inherited..." Malignant hyperthermia is 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.
8	Malignant Hyperthermia Sustained, significant hypermetabolism Inherited component Abnormal handling of intracellular calcium levels “Triggered” by pharmacologic agents , possibly by heat/exercise
9	Trigger Agents for MH MH Trigger Agents Potent Volatile Anesthetics (eg. halothane, sevoflurane, desflurane) Succinylcholine Not MH Triggers Intravenous agents Opioids Non-depolarizing agents Ketamine Propofol Anxiolytics
10	Spectrum of Presentations of Malignant Hyperthermia The classic case Masseter muscle rigidity Associated with muscle disorders MH without anesthesia
11	What are the Clinical Manifestations of MH? Original Concepts: All patients have muscle rigidity High fever, acidosis High death rate Current Concepts Muscle rigidity may or may not be present Temperature is a late sign End tidal CO₂ is an early sign MH may occur at any point during anesthesia - or an emergence Recrudescence despite treatment
12	Signs of Malignant Hyperthermia Specific Muscle Rigidity Increased CO₂ Production Rhabdomyolysis Marked Temperature Elevation Non Specific Tachycardia Tachypnea Acidosis (Resp/Metabolic) Hyperkalemia
13	Summary of Clinical Signs
14	Marked increase in End-Tidal Carbon Dioxide in an MH crisis
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16	Metabolic Changes During MH 0₂ Consumption 3-5X Normal Paco₂ 59 +/- 4 Pvc0₂ 107 +/- 10 Pa 0₂ 142 +/- 10 Pv 0₂ 36 +/- 4
17	Recent Death from MH 16 year old female 4 hour TM joint surgery Forane and vecuronium Precipitous rise in end tidal CO₂ Arrhythmias and cardiac arrest Temperature 42.2 C Dantrolene, 10mg/kg Died from DIC after two days
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19	MH Death During Office Surgery 28 year old for breast augmentation Sevoflurane and succinylcholine After several hours, tachycardia, tachypnea Rise in ET CO2 Rise in skin temp from 34.4^oC to 36.6^oC Dantrolene not immediately available Sent to ER, temp 43^oC Dantrolene begun Died in 24 hours from DIC
20	Changing Pattern of Mortality From MH and its Variants Nine deaths/cardiac arrests from MH in 3 years Ages 16-70 years Isoflurane (6), Sevoflurane (1), Desflurane (2) Succinylcholine-6 Onset of MH in PACU (6) or emergence (3) 6 deaths One confirmed Becker’s dystrophy Dantrolene in 6 cases
21	Muscle Rigidity and MH Jaw muscle rigidity may occur after succinylcholine More common in children Presages MH in 20-30% Generalized rigidity not always present When present, regularly associated with MH susceptibility With muscle breakdown and creatine kinase above 20,00IU, the likelihood of MH is very high.
22	Incidence of MMR Retrospective in Children Halothane/Succ. 0.33-1.03% All Anesthesia 0.12% Prospective in Children Halothane/Succ. 0.9% Halo/STP/Succ. 0.4% Retrospective - Adults and Children All Anesthetics 0.008%
23	Masseter Muscle Rigidity Stop Inhalation Agent No further succinylcholine Continue with nontrigger agents Awaken follow ET C0₂ patient Observe in ICU for 24 hours CK/electrolytes,Myoglobin Dantrolene as needed Recommend for biopsy
24	Sudden Cardiac Arrest in a Child Five year old male, apparently healthy 8:00-Induction with halothane 8:05-Succ 40mg Intubate with 5.0-Leak Reintubate with 5.5 8:06-HR 130bpm, then vent fib, then asystole CPR atropine, EPI, lidocaine, bretylium Shock 8:28-Ph 6.81, PCO₂ 74, PO₂ 22, BE-21 11:15-Dead, despite 2+hours of resuscitation Autopsy Necrotizing myopathy (gastroc) CK over 63,000 Myoglobin in kidney
25	Duchenne Muscular Dystrophy A progressive, fatal muscle wasting disorder related to a genetic defect on the x chromosome Affects males Incidence of 1/3500 live male births Pathologically, an absence of dystrophin protein Signs begin by age 2-6, inability to walk, progressive Muscle wasting and death by age 20 Cardiac abnormalities common
26	Hyperkalemic Cardiac Arrest During Anesthesia in Children With Occult Myopathy Number 25 (92%, male) Age 3-151 months (45 months avg) Mortality 40% Potassium >6 13/18
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28	Hyperkalemic Cardiac Arrest During Anesthesia in Children with Occult Myopathies Previous anesthesia 32% Myopathy 9/15 DMD diagnosed 88% CK 118,558 (2,784-174,376)
29	Post Op Presentation Four year old boy with “no medical history” Uneventful ASD repair with isoflurane,pancuronium In ICU, awakening, extubated. Temp 37.7⁰ C 20 min post op V. Tach, then V. Fib Immediate treatment with calcium, glucose, insulin, bicarbonate and intubation Potassium >9meq/L CK 17,000 rising to 613,200 at 48hrs Positive diagnosis of DMD In retrospect, family mentions child did not walk until age 2
30	Postop Cardiac Arrest 18 year old male with history of non-progressive muscular dystrophy Normal development Isoflurane, fentanyl, rocuronium for 6 hour orthognathic surgery In PACU, awake, responding, intubated sudden cardiac arrest Prolonged resuscitation CK 267,976 Potassium 6.9 AST 1934
31	Becker’s Muscle Dystrophy Onset in adolescence of muscle weakness Genetic defect on X chromosome Affects males Pathologically, an abnormal dystrophin protein Relatively normal life span
32	Quelicin® Succinylcholine Chloride Injection, USP A short-acting depolarizing skeletal muscle relaxant. Abboject® Syringe, Ampul, Fliptop Vial, Pintop Vial Warning Risk of Cardiac Arrest From Hyperkalemic Rhabdomyolysis There have been rare reports of acute rhabdomyolysis with hyperkalemia followed by ventricular dysrhythmias, cardiac arrest and death after the administration of succinylcholine to apparently healthy children who were subsequently found to have undiagnosed skeletal muscle myopathy, most frequently Duchenne’s muscular dystrophy. This syndrome often presents as peaked T-waves and sudden cardiac arrest within minutes after the administration of the drug in healthy appearing children (usually, but not exclusively, males, and most frequently 8 years of age or younger). There have also been reports in adolescents. Therefore, when a healthy appearing infant or child develops cardiac arrest soon after administration of succinylcholine, not felt to be due to inadequate ventilation, oxygenation or anesthetic overdose, immediate treatment for hyperkalemia should be instituted. This should include administration of intravenous calcium, bicarbonate, and glucose with insulin, with hyperventilation. Due to the abrupt onset of this syndrome, routine resuscitative measures are likely to be unsuccessful. However, extraordinary and prolonged resuscitative efforts have resulted in successful resuscitation.
33	Succinylcholine Warning Therefore, when a healthy appearing infant or child develops cardiac arrest soon after administration of succinylcholine, not felt to be due to inadequate ventilation, oxygenation or anesthetic overdose, immediate treatment for hyperkalemia should be instituted. This should include administration of intravenous calcium, bicarbonate, and glucose with insulin, with hyperventilation. Due to the abrupt onset of this syndrome, routine resuscitative measures are likely to be unsuccessful. However, extraordinary and prolonged resuscitative efforts have resulted in successful resuscitation. Succinylcholine is not to be used routinely in children and young adults
34	Evidence for Susceptibility to Malignant Hyperthermia in Patients with Exercise-induced Rhabdomyloysis Wappler F, Fiege M, Antz M et al Anesthesiology 2000;92:268-72 Of 12 patients with EIR 9 where MH positive by IVCT Three showed a mutation in RYR-1 causal for MH
35	Malignant Hyperthermia associated with exercise-induced rhabdomyolysis or congenital abnormalities and a novel RYR-1 mutation in New Zealand and Australian Pedigrees Davis M, Brown R, Dickson A, et al Br. J Anesthesia 88:508-15,2002
36	MH associated with EIR …New Zealand and Australian pedigrees In three unrelated families, MH susceptiblily confirmed by in vitro contracture testing . Two cases showed exercise –induced rhabdomyolysis DNA sequence analysis showed a common mutation in the MH/CCD region I of RYR-1 gene
37	Malignant Hyperthermia and Apparent Heat Stroke Tobin J, Jason DR. Challa V, Nelson TE, Sambuughin N JAMA,286:169-70,2001 _________________________________ 12 yo 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.
38	Disorders Associated with MH Susceptibility Central Core Disease Evans Myopathy Hypokalemic Periodic Paralysis ?sodium channel myotonias
39	Mimics of Malignant Hyperthermia Fever (without rigidity) Thyrotoxicosis Sepsis Pheochromocytoma Iatrogenic overheating Anticholinergic syndrome Faulty equipment Tourniquet (children) Fever and muscle symptoms NMS Hypoxic encephalopathy Ionic contrast agents in CSF Cocaine, amphetamine, ecstasy
40	Neurolept Malignant Syndrome NMS is a potentially fatal, idiopathic hypermetabolic response to a variety of neuroleptics and dopamine receptor blocking agents. Although peripheral manifestations include rhabdomyolysis and rigidity, the pathophysiologic changes occur in the CNS Treatment with dantrolene, benzodiazepines, dopamine agonists have been effective
41	Principle Features of NMS Hypermetabolic response to potent neuroleptics and to dopamine receptor blocking drugs Incidence 0.2% of those taking neuroleptics/antipsychotics Onset may be gradual or slow Not inherited No animal model Responsive to a variety of drug treatments
42	Drugs that May Precipitate NMS Antipsychotics ,e.g. phenothiazines,Resperidal, Olanzapine, Quietepine Neuroleptics e.g. haloperidol, droperidol Acute withdrawal of anti parkinson drugs Dopamine blocking agents e.g. metoclopramide, promethazine, trifluoroperazine
43	Diagnostic Procedures
44	What Tests Are Used To Diagnose MH? Current Concepts: Halothane, caffeine contracture test is the only gold standard Current Investigations: -Molecular genetics -Nuclear magnetic resonance for assessing ATP and creatine phosphate with/without exercise in vivo -Calcium flux measurement in cultured muscle cells -Local increase in pC0₂ following IM caffeine -EMG changes in MH patients
45	Muscle Preparation
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47	Caffeine Dose Response
48	Muscle Biopsy Centers USA Bethesda, MD Chicago, IL Los Angeles, CA Minneapolis, MN Philadelphia, PA Rochester, MN Sacramento, CA Winston Salem, NC Canada Ottowa Toronto Europe Over 20 Far East Japan Australia (2) New Zealand
49	Sensitivity and Specificity of Muscle Biopsy Test Sensitivity: 100% Specificity: 80%-93%
50	Problems with Contracture Test Fresh muscle needed:Invasive Difficult to standardize completely Difficult to develop knowns and unknowns How to interpret in face of myopathy Expensive! Few , widely scattered biopsy centers
51	Pathophysiology of MH and Molecular Genetics
52	Muscle Cell
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54	The Triad
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58	Ryanodine receptor gene is a candidate for predisposition to malignant hyperthermia David H. MacLennan, Catherine Duff^†, Francesco Zorzato, Junichi Fujii, Michael Phillips, Robert G. Korneluk^‡, Wanda Frodis^§, Beverley A. Britt^§ & Ronald G. Worton^†
59	Identification of the Mutation in Porcine Ryanodine Receptor Associated with Malignant Hyperthermia JUNICHI FUJII,* KINYA OTSU, FRANCESCO ZORZATO,^† STELLA DE LEON, VIJAY K. KHANNA, JANICE E. WEILER, PETER J. O’BRIEN, DAVID H. MACLENNAN^‡ Malignant hyperthermia (MH) causes neurological, liver, and kidney damage and death in humans and major economic losses in the swine industry. A single point mutation in the porcine gene for the skeletal muscle ryanodine receptor (ryr1) was found to be correlated with MH in five major breeds of lean, heavily muscled swine. Haplotyping suggests that the mutation in all five breeds has a common origin. Assuming that this is the causal mutation for MH, the development of a noninvasive diagnostic test will provide the basis for elimination of the MH gene or its controlled inclusion in swine breeding programs.
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63	Molecular Genetics of MH Pigs Linkage to RYR Gene Autosomal Recessive Dogs/Horses ? Linked to RYR Humans Linkage to RYR Gene in 50% of families Autosomal Dominant Heterogenetic Sodium Channel, DHPR Gene
64	RYR-1,MH,CCD and Contracture Test 297 MHS/CCD UK patients tested by IVCT Search for 15 RYR-1 mutations 29% with one RYR-1 mutation Discordance: 5 IVCT pos, mutation neg 4 IVCT neg, mutation pos Severity of contracture dependent on mutation 17.5% prevalence of G2434R Robinson et al, 2002
65	Screening of the Entire Ryanodine Receptor Type 1 Coding Region...... Sambuughin N, et al Anesthesiology 2005;102:515-21 In 30 MHS , defects in the RYR-1 gene cause MH/MHS in at least 70% of MH /MH susceptible Individuals
66	Utility of Genetic Testing 208 patients from 62 Swiss families were tested for MH either by IVCT or genetic testing or both All those with mutation were MHS on halothane-caffeine test 19/20patients without MH mutation were negative on the halothane-caffeine test. Negative predictive value of >95% When known mutation is found, open biopsy avoided! Girard T, Treves S, Voronkov E et al Anesthesiology 2004;100:1076
67	RYR-1,MH,CCD and Contracture Test 297 MHS/CCD UK patients tested by IVCT Search for 15 RYR-1 mutations 29% with one RYR-1 mutation Discordance: 5 IVCT pos, mutation neg 4 IVCT neg, mutation pos Severity of contracture dependent on mutation 17.5% prevalence of G2434R Robinson et al, 2002
68	Guidelines for Molecular Genetic Detection of Susceptibility to Malignant Hyperthermia Urwyler, A , Deufel T, McCarthy T et al Br.J Anaesth. 86: 283,2001
69	European MHG Guidelines
70	Genetic Sensitivity and Specificity-2005 SENSITIVITY: 50-70% in known MHS SPECIFICITY: 99.5%
71	Guidelines for Mol Genetic Testing in USA Determine MHS by a. contracture test b. Definite/almost definite by MH Score RYR search for mutation(s) If mutation present, test other family members for the mutation If mutation neg, cannot screen family for mutations or determine MH status
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73	Molecular Genetics for Diagnosis of MH-the Future is Now Clinical Molecular genetic testing is in use in Europe, Australia, New Zealand and the US) Molecular genetic testing is available in the US from Prevention Genetics (www.preventiongenetics.com) and from the DNA lab at the University of Pittsburgh Medical Center(800-454-8155) More mutations on RYR-1 to be identified Other genes that predispose to MH Binding sites for dantrolene
74	Other Tests Under Development -Nuclear magnetic resonance for assessing ATP and creatine phosphate with/without exercise in vivo -Calcium flux measurement in cultured muscle cells from needle biopsy with caffeine -Calcium flux in B lymphocytes with caffeine -Local increase in pC0₂ following IM caffeine
75	MH Grading Scale Process I: Muscle Rigidity Generalized Rigidity 15 Masseter Rigidity 15 Process II: Myonecrosis Elevated CK>20,000 (+Succ.) 15 Elevated CK>20,000 (No Succ.) 15 Cola Colored Urine 10 Myoglobin in urine >60 ug/L 5 Blood/plasma/serum K>6 mEg/L 3
76	MH Grading Scale-II Process III: Respiratory Acidosis PetCO₂>55 with CV 15 PaCO₂>60 with CV 15 PetCO₂>60 with SV 15 Inappropriate hypercarbia 15 Inappropriate tachypnea 10 Process IV: Temperature Increase Rapid increase in temperature 15 Inappropriate temperature >38.8 10 in perioperative period Process V: Cardiac Involvement Inappropriate tachycadria 3 V. tach or V. fib 3
77	What is the Incidence of MH? Original Concepts: Rare. One in 50,000 anesthetics Current Concepts: Clinically based information: One in 20,000 to 50,000 anesthetics depending on drugs, population Molecular Genetics based information: MH trait in 1 in 2,000-3,000 patients. Low penetrance
78	Treatment and Management
79	Immediate Therapy of Malignant Hyperthermia Have a plan! Discontinue inhalation agents, Succ Hyperventilate with 100% 0₂ Bicarbonate 1-2 mg/kg as needed Get additional help Dantrolene 2.5mg/kg Push. Repeat PRN Cool patient: gastric lavage, surface, wound Treat arrhythmias-do not use calcium channel blockers Arterial or venous blood gases Electrolytes, coagulation studies
80	Treatment of Malignant Hyperthermia - Acute Dantrolene-1 The only specific treatment for MH Administer as soon as diagnosis made 20mg/bottle-dissolve with 60ml sterile water Shake vigorously or warm bottles to dissolve Give 2.5mg/kg STAT Repeat as needed to control signs of MH
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82	Dantrolene for MH Crisis 20 mg/60 ml = 1 mg/3ml 70 kg patient: 2.5 mg/kg = 175 mg or 525 ml (9 vials) ~10 mg/kg = 700 mg or 2100 ml (35 vials)
83	Treatment of Malignant Hyperthermia Dantrolene-2 After crisis controlled, give dantrolene 1mg/kg every 4-6 hours for 24 hours Continue dantrolene for 36 hours Recrudescence rate is 25%
84	Management of Malignant Hyperthermia Biochemical Markers Blood gasses – esp pCO₂, pH, CK Myoglobinuria PT, PTT, INR, fibrin split products Liver enzymes, BUN
85	Morbidity and Mortality RHABDOMYOLYSIS RENAL FAILURE DIC if temp >41.5⁰ C Hyperkalemia Acidosis
86	Prevention of Malignant Hyperthermia Preop personal/family history of anesthetic problems, neuromuscular disorders Temperature/endtidal CO₂ monitoring during general anesthesia Recognition of masseter rigidity Investigation of unexplained tachycardia, hypercarbia, hyperthermia Availability of Dantrolene Avoiding MH triggers in MH susceptibles Using Succinylcholine in indication
87	Principles of Management of MH Susceptible Dantrolene not necessary preoperatively (dantrolene available) Avoid succinylcholine Avoid potent inhalation agents Discharge after about 2 hours in the recovery room if all signs are stable
88	Preparation for MH Susceptible Shut/disable vaporizers Flow 02 @ 10L/min for 20 minutes (through machine and ventilator) Change carbon dioxide absorbent Use non-trigger agents or local anesthesia Monitor temperature Have dantrolene available
89	Suggested Regimen for MH Patient Anxiolytic (ketamine permissible) Propofol/opioid induction Non-depolarizing relaxant Nitrous/narcotic/propofol Reversal of muscle relaxant Observe 4 hours
90	Drug Safety in MH MH Trigger Agents Potent Volatile Anesthetics (eg. halothane, sevoflurane, desflurane) Succinylcholine Not MH Triggers Intravenous agents Opioids Non-depolarizing agents Ketamine Propofol Anxiolytics
91	Death From MH - 1998 74 Year Old Male For AAA Family History of MH Positive Biopsy in Family Trigger Agents Used MH at End of Surgery Treatment with Dantrolene Death Two Days Post OP DIC, Bowel Ischemia, Renal Failure
92	Malignant Hyperthermia Association of the United States HOTLINE 1-800-MH-HYPER General Information 1-800-98-MHAUS
93	North American MH Registry Collects and collates data on patients and families 412-692-5464 Dr. Barbara Brandom, director Children’s Hospital of Pittsburgh
94	Summary MH is a metabolic myopathy affecting skeletal muscle All potent inhalation agents and Succinylcholine are the triggers for MH Inheritance of MH in humans is autosomal dominant The basic defect in MH is an increase in intracellular calcium of the skeletal muscle MH effects all ages and races MH appears to be more common in children than adults
95	Summary Masseter muscle rigidity after Succinylcholine is associated with MH in 20-50% of cases Endtidal CO₂ increase is the most sensitive and specific clinical sign of MH Although hyperthermia is a late sign of MH, it is an important confirmatory sign in some cases Metabolic, respiratory acidosis are common Myoglobinuria, elevation of CK are common during and after MH MH may appear at any time during anesthesia and in the early part of the recovery period
96	Summary Prompt treatment with dantrolene 2.5mg/kg or more effectively treats MH Dantrolene should be continued for 24-48 hours Sudden cardiac arrest in young males with inhalation agents +/- Succ often indicates hyperkalemia and occult myopathy Only accepted diagnostic test is the halothane-caffeine contracture test MH testing indicated in patients and clinical episodes and their family members Help and assistance are available from mhaus and the hotline
97	Future Developments Using molecular genetic diagnostic tests in questionable cases Clarification of the relation between “awake” and exercise related muscle signs and MH Clarification of relation between MH and other myopathies Understanding of the pathophysiology of MH Through study of MH , clarification of metabolic control mechanisms in muscle A better dantrolene Use molecular genetic screening routinely for MHS and other pharmacogenetic disorders
98	Future Developments Through study of MH , clarification of metabolic control mechanisms in muscle A better dantrolene Use molecular genetic screening routinely for MHS and other pharmacogenetic disorders
99	THANK YOU If this slide show has been of value, a contribution to MHAUS would be greatly appreciated.