Malignant Hyperthermia Christopher Heine, MD - PowerPoint Presentation

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Malignant Hyperthermia

Christopher Heine, MD

Assistant ProfessorMedical University of South CarolinaCharleston, SC

Date updated: 4/2018

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DisclosuresNone

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Learning ObjectivesReview a brief history of MHBackground and EpidemiologyDiscuss the Pathophysiology/Mechanism of MHDescribe the presentation of an MH reaction and its differential diagnosis

Review the Perioperative Management of a suspected MH-susceptible patientManagement of an MH eventPostoperative Counseling options

Description of how to have facility prepared

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HistoryFirst 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)

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BackgroundGenetic disorder of skeletal muscle that, when triggered, results in a hyper-metabolic processMost common triggers:SuccinylcholineVolatile Anesthetics

Nitrous Oxide is safe

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BackgroundHypermetabolism is result of uncontrolled release of calcium from the Sarcoplasmic Reticulum of muscle cells, resulting in:Sustained muscle contraction/rigidityMixed metabolic/respiratory acidosis

Hypercarbia, Hyperthermia, TachycardiaMyoglobinuriaDisseminated Intravascular Coagulopathy

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EpidemiologyIncidence varies from 1:40,000-1:250,000, but may be as high as 1:15,000 in childrenPrevalence 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)

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Associated DisordersHistorically, Muscular Dystrophy (MD) patients thought to be at higher risk for MHEvidence 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 patients3 Diseases with clearest association with MHKing-

Denborough SyndromeCentral Core DiseaseMultiminicore Disease

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PathophysiologyNormal ContractionAcetylcholine 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 contractionMuscle relaxation is the result of Calcium-ATPase transporting Calcium back into the Sarcoplasmic Reticulum

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PathophysiologyMalignant Hypertension Susceptible Most commonly the result of a mutation in the Ryanodine ReceptorMutation 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

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PathophysiologyGeneticsAutosomal dominant with incomplete penetranceRyanodine Receptor mutations are responsible for 50-70% of the MH susceptible patients

Located on Chromosome 19Dihydropyridine Receptor mutations on Chromosomes 1 and 7 have also been identified as possible sourcesGenetic complexity may be responsible for variation in severity and clinical presentation

Also means that genetic testing’s role, although valuable, is not definitive for diagnosisAdditional Sources listed below (7-10)

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PresentationHyper-metabolic syndrome following exposure to triggering agent*Usually signs occur shortly after exposure, but they can occur post-operativelyFirst sign is usually an increase in End-Tidal CO

2(ETCO2) that is not amenable to increasing minute ventilationTachycardia, hypertension, tachypnea (if spontaneously ventilating) are non-specific but common

Masseter spasm and muscle rigidityHyperthermia can be an early or late findingPresenting respiratory acidosis eventually mixes with a metabolic acidosisRhabdomyolysis, hyperkalemia, and cardiac arrhythmias/arrest can occur if left untreated

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Differential DiagnosisSimple explanations like hyperthermia due to warm air mattresses, hypercarbia due to hypoventilation, tachycardia due to inadequate anesthesiaSepsis, Thyroid Storm, Pheochromocytoma, Drug Intoxication, Neuroleptic Malignant Syndrome, Serotonin Syndrome

Regionally appropriate inclusions like Dengue Fever or MalariaDespite previous belief, there are no areas that are immune to MH susceptibility*

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Preoperative ManagementIf patient or family member has a known history of MH, they likely should receive a non-triggering anesthetic No benefit to prophylactic Dantrolene useRoom preparation

Succinylcholine placed somewhere it can’t be accidentally administeredRapid Sequence Intubation can be done with 1.2mg/kg Rocuronium if necessary

Vaporizer Canisters removed or taped to prevent administrationCO2 absorbent, circuit, and reservoir bag replaced

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Preoperative ManagementMachine PreparationClears the machine of any residual volatile anesthesiaTraditionally, 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 minutesMaintain 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 flushWith 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

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Intraoperative ManagementMonitoringStandard monitors including pulse oximeter, ECG, Non-invasive Blood Pressure, and Wave Form CapnographyCore temperature monitoring, ideally, if procedure >30 minutes

DiagnosisVariable presentation, as mentioned earlierIf suspicious, an ABG and VBG (if available) should be obtained

ABG to determine severity of acidosisVBG to help determine if a hypermetabolic process is ongoing

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Intraoperative ManagementTreatmentThe earlier an MH episode is recognized and treated, the better patients doTurn 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)-417-3722If available, charcoal filters can be placed on the circuitTreat the patient with Dantrolene

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Intraoperative ManagementDantrolene (Dantrium, Ryanodex

)Hydantoin derivative that inhibits Calcium releaseDantrium packaged as a

lypholized powder with 20mg of Dantrolene and 3g of mannitolEach 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 doseAdministered preferably through a large veinRyanodex, a newer formulation, has 250mg of Dantrolene and 150mg of mannitolEach vial needs to be reconstituted with 5cc of sterile water –

1 minute reconstitution time for a single doseDosing Regardless of Dantrolene formulation, the dosing is the sameInitial Bolus 2.5mg/kgRepeat 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 wellAdministration may result in weakness, so appropriate airway management is recommendedIf Dantrolene is not available, symptomatic treatment is the best optionOther Calcium Channel blockers do not treat an MH episode

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Intraoperative ManagementSymptomatic TreatmentHyperthermiaIf doesn’t respond to Dantrolene, external or internal coolingFoley 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 necessaryArterial Line for blood pressure and labs (Creatine Kinase and Myoglobin)Metabolic AcidosisSodium Bicarbonate

HyperkalemiaCalcium, Bicarbonate, Insulin/Glucose, Beta Agonist, HyperventilationCardiac ArrhythmiasTreat per ACLS and PALS guidelinesWith the exception that calcium channel blockers in presence of Dantrolene may worsen cardiovascular collapse

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Postoperative ManagementAs 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 hoursDiuresis and Alkalization to prevent myoglobin accumulationIf patient has a known history of MH and undergoes an uneventful, triggering-agent free anesthetic, they can be discharged same day

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Counseling/TestingClinical 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 centerCaffeine-Halothane Contracture Test (CHCT)

Done in 5 locations in North AmericaIn-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

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MH PreparednessMHAUS websitewww.mhaus.orgMHAUS hotline international phone number1-(209)-417-3722

iPhone AppWeight based drug dosing for Dantrolene and symptomatic treatment$1.99Supposed to be used for educational purposes only

MH Cart DrugsDantrolene and drugs noted earlier for symptomatic treatment60 cc syringes and sterile waterEquipment for venous or central venous access, arterial accessIdeally, equipment for labs like ABG, Creatine Kinase, Myoglobin, Coagulation Profiles, and Lactate

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

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Sources1. Denborough, M., and Lovell, R., “Anesthetic Deaths in a Family”.

The Lancet, 1960; 2: 45-462. Kalow, W., Britt, B.,

Terreau, M., Haist, C., “Metabolic Error of Muscle Metabolism After Recovery from Malignant Hyperthermia”. The Lancet, 1970; 296(7679): 895-8983. Harrison, G., “Control of the Malignant Hyperpyrexic Syndrome in MHS Swine by Dantrolene Sodium”. British Journal of Anaesthesia

, 1975; 47(1): 62-654. 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): 9310-93155. 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;119:1359-667. Nelson, T., “Malignant Hyperthermia: A Pharmacogenetic Disease of Ca+2 Regulating Proteins”. Current Molecular Medicine, 2002; 2: 347-3698. Dirksen, S., Larach, M., Rosenberg, H., et al., “Future Directions in Malignant Hyperthermia Research and Patient Care”. Anesthesia & Analgesia, 2011; 113(5): 1108-11199. 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): 1078-108610. Schiemann, A., Paul, N., Parker, R., et al., “Functional Characterization of 2 Known Ryanodine Receptor Mutations Causing Malignant Hyperthermia”. Anesthesia & Analgesia, 2014; 118(2): 375-38011. Nelson, P., Litman, R., “Malignant Hyperthermia in Children: An Analysis of the North American Malignant Hyperthermia Registry”. Anesthesiology, 2014; 118(2): 369-37412. 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: 1363-137014. 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