Malignant Hyperthermia Christopher Heine, MD Assistant Professor Medical University of South Carolina Charleston, SC Date updated: 4/2018

Disclosures None

Learning Objectives Review a brief history of MH Background and Epidemiology Discuss the Pathophysiology/Mechanism of MH Describe the presentation of an MH reaction and its differential diagnosis Review the Perioperative Management of a suspected MH-susceptible patient Management of an MH event Postoperative Counseling options Description of how to have facility prepared

History First described in Lancet in 1960 by Denborough & Lovell (1) “Metabolic error of metabolism” identified as source of MH by Kalow & Britt in 1970 (2) Dantrolene as treatment first described by Harrison in 1975 (in swine model) (3) Ryanodine Receptor identified as source of pathology in 1988 by Mickelson et al (4) 1. Denborough, M., and Lovell, R., “Anesthetic Deaths in a Family”. The Lancet, 1960; 2: 45-46 2. Kalow, W., Britt, B., Terreau, M., Haist, C., “Metabolic Error of Muscle Metabolism After Recovery from Malignant Hyperthermia”. The Lancet, 1970; 296(7679): 895-898 3. Harrison, G., “Control of the Malignant Hyperpyrexic Syndrome in MHS Swine by Dantrolene Sodium”. British Journal of Anaesthesia, 1975; 47(1): 62-65 4. Mickelson, J., Gallant, E., Litterer, L., Johnson, K., Rempel, W., Louis, C., “Abnormal Sarcoplasmic Reticulum Ryanodine Receptor in Malignant Hyperthermia”. The Journal of Biological Chemistry, 1988; 263(19): 9310-9315

Background Genetic disorder of skeletal muscle that, when triggered, results in a hyper-metabolic process Most common triggers: Succinylcholine Volatile Anesthetics Nitrous Oxide is safe

Background Hypermetabolism is result of uncontrolled release of calcium from the Sarcoplasmic Reticulum of muscle cells, resulting in: Sustained muscle contraction/rigidity Mixed metabolic/respiratory acidosis Hypercarbia, Hyperthermia, Tachycardia Myoglobinuria Disseminated Intravascular Coagulopathy

Epidemiology Incidence varies from 1:40,000-1:250,000, but may be as high as 1:15,000 in children Prevalence of MH susceptibility may be as high as 1:3,000 (5) United States Mortality from MH episode: Prior to Dantrolene, as high as 70% 1987-2006 – 1.4% 2007-2012 – 9.5% (6) Increased incidence in children may be due to increased exposure to triggering agents due to inhalational inductions 5. Rosenberg H, Davis M, James D, Pollock N, Stowell K: “Malignant hyperthermia.” Orphanet J Rare Dis 2007;2:21-35. 6. Larach MG, Brandom BW, Allen GC, Gronert GA, Lehman EB: “Malignant hyperthermia deaths related to inadequate temperature monitoring, 2007-2012: a report from the NAMHR of the Malignant Hyperthermia Association of the US.” Anesth Analg 2014;119:1359-66. Increase in mortality rates from most recent review of North American Malignant Hyperthermia Registry proposed to be due to lack of consistent core temperature monitoring

Associated Disorders Historically, Muscular Dystrophy (MD) patients thought to be at higher risk for MH Evidence shows that MD patients are in fact at no higher risk than the general population… …BUT the same triggering agents can cause hyperkalemia and rhabdomyolysis in MD patients 3 Diseases with clearest association with MH King-Denborough Syndrome Central Core Disease Multiminicore Disease

Pathophysiology Normal Contraction Acetylcholine is released at the neuro-muscular junction and binds to nicotinic receptors resulting in depolarization Depolarization of the Transverse Tubules results in a change to the Dihydropyridine Receptors which opens the Ryanodine Receptors, resulting in Calcium release into the myoplasm Calcium binds to Troponin-C which allows the interaction of actin and myosin resulting in contraction Muscle relaxation is the result of Calcium-ATPase transporting Calcium back into the Sarcoplasmic Reticulum

Pathophysiology Malignant Hypertension Susceptible Most commonly the result of a mutation in the Ryanodine Receptor Mutation results in an increased influx of Calcium from the Sarcoplasmic Reticulum which causes the marked contracture, hyper-metabolism, and rhabdomyolysis Abnormal relaxation occurs as the Ryanodine Receptor does not close normally The precise mechanism behind the triggering agents and their interaction with Ryanodine Receptors is unclear

Pathophysiology Genetics Autosomal dominant with incomplete penetrance Ryanodine Receptor mutations are responsible for 50-70% of the MH susceptible patients Located on Chromosome 19 Dihydropyridine Receptor mutations on Chromosomes 1 and 7 have also been identified as possible sources Genetic complexity may be responsible for variation in severity and clinical presentation Also means that genetic testing’s role, although valuable, is not definitive for diagnosis Additional Sources listed below (7-10) Swine models, often used for research purposes, have an autosomal receptive pattern Other knowledge gaps: - History of uneventful prior exposure to triggering agents does not mean one is not susceptible - Individuals may be weak MH responders and not have an MH reaction when exposed to brief anesthetics - Link between physical stress and possible MH-like reactions and Malignant Hyperthermia susceptibility For a more in depth discussion of the genetics of MH: 7. Nelson, T., “Malignant Hyperthermia: A Pharmacogenetic Disease of Ca+2 Regulating Proteins”. Current Molecular Medicine, 2002; 2: 347-369 8. Dirksen, S., Larach, M., Rosenberg, H., et al., “Future Directions in Malignant Hyperthermia Research and Patient Care”. Anesthesia & Analgesia, 2011; 113(5): 1108-1119 9. Brandom, B., Bina, S., Wong, C., et al., “Ryanodine Receptor Type 1 Gene Variants in the Malignant Hyperthermia-Susceptible Population of the United States”. Anesthesia & Analgesia, 2013; 116 (5): 1078-1086 10. Schiemann, A., Paul, N., Parker, R., et al., “Functional Characterization of 2 Known Ryanodine Receptor Mutations Causing Malignant Hyperthermia”. Anesthesia & Analgesia, 2014; 118(2): 375-380

Presentation Hyper-metabolic syndrome following exposure to triggering agent* Usually signs occur shortly after exposure, but they can occur post-operatively First sign is usually an increase in End-Tidal CO2(ETCO2) that is not amenable to increasing minute ventilation Tachycardia, hypertension, tachypnea (if spontaneously ventilating) are non-specific but common Masseter spasm and muscle rigidity Hyperthermia can be an early or late finding Presenting respiratory acidosis eventually mixes with a metabolic acidosis Rhabdomyolysis, hyperkalemia, and cardiac arrhythmias/arrest can occur if left untreated *Preparation for MH Susceptible patients will be discussed later, but accidental injection of succinylcholine or very small amounts of volatile (>5ppm) can result in an MH reaction even if preparation is done, so don’t ignore signs of an MH reaction just because the room was “prepped” Recent review of pediatric cases identified tachycardia (73.1%), hypercarbia (68.6%), and rapid temperature increase (48.5%) as most common signs of an acute MH episode (11) 11. Nelson, P., Litman, R., “Malignant Hyperthermia in Children: An Analysis of the North American Malignant Hyperthermia Registry”. Anesthesiology, 2014; 118(2): 369-374

Differential Diagnosis Simple explanations like hyperthermia due to warm air mattresses, hypercarbia due to hypoventilation, tachycardia due to inadequate anesthesia Sepsis, Thyroid Storm, Pheochromocytoma, Drug Intoxication, Neuroleptic Malignant Syndrome, Serotonin Syndrome Regionally appropriate inclusions like Dengue Fever or Malaria Despite previous belief, there are no areas that are immune to MH susceptibility* *Previously thought that the genetic background of those from the Indian subcontinent resulted in immunity to MH, but this has been refuted with several case reports in the last 15 years of MH cases in India (12) 12. Punj J, Bhatnagar S, Saxena A. “Malignant hyperthermia in the Indian subcontinent: non-availability of dantrolene – a cause for concern?” Internet J Pharmacol 2001;1(1).

Preoperative Management If patient or family member has a known history of MH, they likely should receive a non-triggering anesthetic No benefit to prophylactic Dantrolene use Room preparation Succinylcholine placed somewhere it can’t be accidentally administered Rapid Sequence Intubation can be done with 1.2mg/kg Rocuronium if necessary Vaporizer Canisters removed or taped to prevent administration CO2 absorbent, circuit, and reservoir bag replaced

Preoperative Management Machine Preparation Clears the machine of any residual volatile anesthesia Traditionally, continuous fresh gas flow (FGF) of 10L/min for at least 20 minutes was considered adequate to flush the machine Specific guidelines dependent on machine type “Newer” machines may require at least 120 minutes Maintain FGF of 10L/min throughout case to avoid volatile anesthesia concentration rebound Alternatively, charcoal filters can be placed on the inspiratory and expiratory limbs following a 90 second flush With FGF of at least 3L/min, the filters have been shown to maintain volatile concentration at <5ppm for up to 12 hours (13) Although possibly not an option in some locations, a dedicated MH machine that has never been exposed to volatile anesthesia or the use of an ICU ventilator have been utilized Would recommend knowing the manufacturer’s guidelines for the specific machines you are working with, especially if they are not “older” machines 13. Birgenheier, N., Stoker, R., Westenskow, D., Orr, J., “Activated Charcoal Effectively Removes Inhaled Anesthetics from Modern Anesthesia Machines”. Anesthesia & Analgesia, 2011; 112: 1363-1370

Intraoperative Management Monitoring Standard monitors including pulse oximeter, ECG, Non-invasive Blood Pressure, and Wave Form Capnography Core temperature monitoring, ideally, if procedure >30 minutes Diagnosis Variable presentation, as mentioned earlier If suspicious, an ABG and VBG (if available) should be obtained ABG to determine severity of acidosis VBG to help determine if a hypermetabolic process is ongoing

Intraoperative Management Treatment The earlier an MH episode is recognized and treated, the better patients do Turn off volatile anesthetics and hyperventilate with 100% Oxygen Inform the surgeon and discuss aborting or finishing the procedure as quickly as possible Call for help and resuscitation drugs (MH Cart) Call the Malignant Hyperthermia Association of the United States (MHAUS) at their international phone number 1-(209)-417-3722 If available, charcoal filters can be placed on the circuit Treat the patient with Dantrolene

Intraoperative Management Dantrolene (Dantrium, Ryanodex) Hydantoin derivative that inhibits Calcium release Dantrium packaged as a lypholized powder with 20mg of Dantrolene and 3g of mannitol Each vial must be reconstituted with 60cc of sterile water and shaken until the solution is clear-orange in color – 22 minute reconstitution time for a single dose Administered preferably through a large vein Ryanodex, a newer formulation, has 250mg of Dantrolene and 150mg of mannitol Each vial needs to be reconstituted with 5cc of sterile water – 1 minute reconstitution time for a single dose Dosing Regardless of Dantrolene formulation, the dosing is the same Initial Bolus 2.5mg/kg Repeat bolus until signs of MH subside Occasionally requires doses as high as 20-30 mg/kg, but once more than 10mg/kg has been given, another diagnosis on your differential should be considered as well Administration may result in weakness, so appropriate airway management is recommended If Dantrolene is not available, symptomatic treatment is the best option Other Calcium Channel blockers do not treat an MH episode Dantrolene should, ideally, either be brought on mission trips along with anesthetics, or should be available in at least one hospital in every city where triggering drugs may be administered. A communication and transport system should be in place in the event Dantrolene needs to be moved from one location to another Although chronic administration of Dantrolene has resulted in hepatic injury, there are no cases of toxicity from MH treatment

Intraoperative Management Symptomatic Treatment Hyperthermia If doesn’t respond to Dantrolene, external or internal cooling Foley catheter to monitor urine output Diurese to urine output of 1cc/kg/hr Dantrium contains 3g of mannitol per vial, but Ryanodex only contains 150mg, so particularly with Ryanodex, further diuretic use may be necessary Arterial Line for blood pressure and labs (Creatine Kinase and Myoglobin) Metabolic Acidosis Sodium Bicarbonate Hyperkalemia Calcium, Bicarbonate, Insulin/Glucose, Beta Agonist, Hyperventilation Cardiac Arrhythmias Treat per ACLS and PALS guidelines With the exception that calcium channel blockers in presence of Dantrolene may worsen cardiovascular collapse Symptomatic Treatment drugs and doses Sodium Bicarbonate – 1-2 mEq/kg initially Calcium Chloride or Gluconate – 10-20 mg/kg or 30-60 mg/kg, respectively Insulin – 0.1U/kg initially 25% Dextrose – 1-2 g/kg with insulin administration Furosemide – 0.5-1 mg/kg

Postoperative Management As blood levels of Dantrolene drop, its possible to get another MH reaction after the initial episode has subsided (recrudescence) MHAUS recommends either administering 1mg/kg of Dantrolene every 6 hours, starting an infusion at 0.25mg/kg/min, or just monitoring closely for 24-48 hours Serial Serum Creatine Kinase for 24-48 hours Diuresis and Alkalization to prevent myoglobin accumulation If patient has a known history of MH and undergoes an uneventful, triggering-agent free anesthetic, they can be discharged same day

Counseling/Testing Clinical presentation can guide diagnosis to a certain extent (14) For more definitive diagnosis, requires further testing which involve muscle biopsies that must be done at testing center Caffeine-Halothane Contracture Test (CHCT) Done in 5 locations in North America In-Vitro Contracture Test (IVCT) Europe Depending on results of CHCT or IVCT, patients can be referred for genetic testing, which only requires that a sample be sent to a testing center 14. Larach MG, Localio AR, Allen GC, Denborough MA, Ellis FR, Gronert GA, Kaplan RF, et al: A clinical grading scale to predict malignant hyperthermia susceptibility. Anesthesiology, 1994;80:771-79. CHCT and IVCT are similar tests but involve slightly different methods and result interpretation. In both tests, a muscle sample is taken from the patient’s Vastus Lateralis, exposed to halothane and caffeine, and the contracture response is recorded. The CHCT carries a sensitivity and specificity of 97% and 78% (15), respectively and if negative, the patient is considered not susceptible to MH. If positive, the patient can be referred for genetic testing to determine whether or not they have an identifiable mutation for which other family members could be tested. If a family member’s screen is negative, they can not safely consider themselves “non-susceptible”, though, due to MH’s complex genetics and the test’s sensitivity. 15. Allen GC, Larach MG, Kunselman AR: The sensitivity and specificity of the caffeine-halothane contracture test: a report from the NAMHR. Anesthesiology 1998;88:579-88

MH Preparedness MHAUS website MHAUS hotline international phone number www.mhaus.org MHAUS hotline international phone number 1-(209)-417-3722 iPhone App Weight based drug dosing for Dantrolene and symptomatic treatment $1.99 Supposed to be used for educational purposes only MH Cart Drugs Dantrolene and drugs noted earlier for symptomatic treatment 60 cc syringes and sterile water Equipment for venous or central venous access, arterial access Ideally, equipment for labs like ABG, Creatine Kinase, Myoglobin, Coagulation Profiles, and Lactate

Summary MH is rare and potentially lethal if not recognized quickly and treated, ideally with Dantrolene Proper preparation and anesthetic management of patients susceptible to MH can safely be done anywhere If feasible, patients can be sent for further testing if there is concern for an MH reaction

Sources 1. Denborough, M., and Lovell, R., “Anesthetic Deaths in a Family”. The Lancet, 1960; 2: 45-46 2. Kalow, W., Britt, B., Terreau, M., Haist, C., “Metabolic Error of Muscle Metabolism After Recovery from Malignant Hyperthermia”. The Lancet, 1970; 296(7679): 895-898 3. Harrison, G., “Control of the Malignant Hyperpyrexic Syndrome in MHS Swine by Dantrolene Sodium”. British Journal of Anaesthesia, 1975; 47(1): 62-65 4. Mickelson, J., Gallant, E., Litterer, L., Johnson, K., Rempel, W., Louis, C., “Abnormal Sarcoplasmic Reticulum Ryanodine Receptor in Malignant Hyperthermia”. The Journal of Biological Chemistry, 1988; 263(19): 9310-9315 5. Rosenberg H, Davis M, James D, Pollock N, Stowell K: “Malignant hyperthermia.” Orphanet J Rare Dis, 2007;2:21-35. 6. Larach MG, Brandom BW, Allen GC, Gronert GA, Lehman EB: “Malignant hyperthermia deaths related to inadequate temperature monitoring, 2007-2012: a report from the NAMHR of the Malignant Hyperthermia Association of the US.” Anesthesia & Analgesia, 2014;119:1359-66 7. Nelson, T., “Malignant Hyperthermia: A Pharmacogenetic Disease of Ca+2 Regulating Proteins”. Current Molecular Medicine, 2002; 2: 347-369 8. Dirksen, S., Larach, M., Rosenberg, H., et al., “Future Directions in Malignant Hyperthermia Research and Patient Care”. Anesthesia & Analgesia, 2011; 113(5): 1108-1119 9. Brandom, B., Bina, S., Wong, C., et al., “Ryanodine Receptor Type 1 Gene Variants in the Malignant Hyperthermia- Susceptible Population of the United States”. Anesthesia & Analgesia, 2013; 116 (5): 1078-1086 10. Schiemann, A., Paul, N., Parker, R., et al., “Functional Characterization of 2 Known Ryanodine Receptor Mutations Causing Malignant Hyperthermia”. Anesthesia & Analgesia, 2014; 118(2): 375-380 11. Nelson, P., Litman, R., “Malignant Hyperthermia in Children: An Analysis of the North American Malignant Hyperthermia Registry”. Anesthesiology, 2014; 118(2): 369-374 12. Punj J, Bhatnagar S, Saxena A. “Malignant hyperthermia in the Indian subcontinent: non-availability of dantrolene – a cause for concern?” Internet J Pharmacol 2001;1(1). 13. Birgenheier, N., Stoker, R., Westenskow, D., Orr, J., “Activated Charcoal Effectively Removes Inhaled Anesthetics from Modern Anesthesia Machines”. Anesthesia & Analgesia, 2011; 112: 1363-1370 14. Larach MG, Localio AR, Allen GC, Denborough MA, Ellis FR, Gronert GA, Kaplan RF, et al: A clinical grading scale to predict malignant hyperthermia susceptibility. Anesthesiology, 1994;80:771-79. 15. Allen GC, Larach MG, Kunselman AR: The sensitivity and specificity of the caffeine-halothane contracture test: a report from the NAMHR. Anesthesiology, 1998;88:579-88