Malignant Hyperthermia

Presenter: Sumit GuptaModerator: Dr. Anjolie Chhabra Additional Prof. Anesthesiology

AIIMS, New Delhi

Introduction

Malignant Hyperthermia Pharmaco-genetic disorder

In Genetically Susceptible. On exposure

Volatile inhalational agents & Sch. Abnormal ↑↑ intracellular Ca²⁺

Rapid ↑ Body Temperature: Hyperthermia Skeletal muscle activity

Rhabdomyolysis and metabolic acidosis → Death

Malignant

HISTORY• Ist case reported ~ 1960: Australia

• Danbourough And Lovell

– 21 year/M → malleolar # fixation

– George Locher (Wisconsin) and Beverly Britt (Toronto)

• Familial disorder

• Central loss of temperature control

– Disorder of skeletal muscle metabolism

• 1966: Wilson et al

• Ist coined the term “malignant hyperthermia”

• 2001: Punj et al (IRCH): Ist case of MH in India

History of 10 anesthesia related deaths in the family

PATHOPHYSIOLOGY• NORMAL PHYSIOLOGY

• STORE OPERATED CALCIUM ENTRY

1.Motor neuron

releases Ach

2.Ach binds to Ach receptors -opens Na⁺ channels & generates APs

3. AP reaches T

tubule

4. Voltage Sensor DHPR

receptors activated

5.Ca²⁺ is released from SER via Ryanodine receptor. (3isoforms: Cardiac, Skeletal, Brain). Biphasic response to Ca ²⁺ & Inhibited by Mg ²⁺

6. Ca²⁺ binds to Troponin

and promotes

actin-myosin

interaction

7. SERCA pumps propel Ca²⁺ back to the SR & cause relaxation when Ca²⁺ is <10 -7 M and require ATP

PATHOPHYSIOLOGYAbn Excitation contraction Coupling

1.Motor neuron releases Ach

2.Ach binds to Ach receptors & opens Na⁺ channels & generates APs

3. AP is propagated to the T tubule

4. Voltage Sensor DHPR

receptors activated 5.Ca ² ⁺ is released

from SER via Ryanodine rececptors

6. Ca ² ⁺ then binds to Troponin facilitates

actin-myosin complex

7. SERCA propel Ca²⁺ back to SR & causes relaxation when Ca²⁺ is <10 -7

M and require ATP

PATHOPHYSIOLOGY• Calcium releasing Unit (CRU)

– Key unit of Excitation Contraction Coupling

– Includes Ryanodine• Central component of CRU• Interacts with Ca²⁺ V1.1

and other proteins• Homer 1, calstabin, triadin,

junctin, junctophilin etc.– Predominantly affected by MH

mutations

PATHOPHYSIOLOGYMH Mutations: AD with Variable Penetrance

↑ sensitivity•Inhalational anesthetics •Caffeine•4-chloro-m-cresol• K⁺

↓ inhibition •Ca²⁺ >10-5 M

•Mg²⁺

MOST COMMON•RyR1 (50-70%): Chr. 19q •DHPR : CACNA1s (Chr. 1) •Calsequestrin

INHERITANCE CAN VARY

EVALUATION

• Indications– Individuals with “MH susceptible” contracture test

• Identify the mutation involved– Can be offered as first line test if “hyperthermic reaction

under anesthesia”– Ist degree relatives of an index case

• Risk of transmission: 50%– Family member of a person +ve mutation test– Contracture test

• Not available • Refusal by patient

GENETICS AND DNA TESTING

GENETICS AND DNA TESTING

DNA testing

Involves testing for Ryr1 and CACNA1s

Universal application is not possible

A negative test has to be confirmed with Contracture tests

Misses MH due to mutation of other genesMany mutations are not expressed. Can’t rule out MH susceptibility completely

CONTRACTURE TEST

• Gold standard– Sensitivity & Specificity • >90%

– Detects abnormal muscle response to Halothane and caffeine.

– Requires• Muscle Harvesting: Quadriceps(MC),Rectus abdominus.

– Specimen Length: 15-25 mm, Thickness: 2-3 mm and Weight 100-150 mg (max 2-4gm).

– Local infiltration or femoral and lat. Femoral cut. nerve block.– Weight>30 Kg and age > 4 years

It is 99 % sensitive and specific. BUT1. Inter laboratory variability.2. Averages are recorded3. Accuracy of caffeine and

halothane concentrations.

CONTRACTURE TEST• Indications

– History of hyperthermic reaction under GA

– Negative Genetic analysis in a suspected case

– Recurrent Rhabdomyolysis

• Record Contracture

– Caffeine > 2mmol/l and halothane >2%(IVCT)/3% (CHCT)

• Localized contracture test

– Microdialysis based– Infusion of caffiene or halothane

into muscle

– Acid base changes in muscle

+ve test: Contracture > 0.2 G Caffeine conc.<2mmol/L halothane conc. <2%

CONTRACTURE TEST

IVCT

• Used in Europe

• Both Incremental Halothane

(0.5-3%) and Incremental

caffeine 0.5 -32 m mol/l are

used (2X increments).

• MH equivocal → MHs/MHc

CHCT

• Used In USA

• Halothane is used at fixed 3

% and incremental caffeine

in 2X increments.

• MH susceptible

NO DIFFERENCE BETWEEN SENSITIVITY OR SPECIFICITY AND

SIMILAR RESULTS ARE OBTAINED WITH EITHER TEST.

IF RESULT IS POSITIVE FOR EITHER CAFFEINE OR HALOTHANE

CONTRACTURE TEST

MH SusceptiblePositive response to both halothane

and caffeine

MH EquivocalPositive response to either Caffeine

or halothane

MH Normal Contracture less than 2 g at Caffeine >3mmol/L or

Halothane>2%.

MH SusceptiblePositive response to both halothane

and caffeineMHc: Positive response to Caffeine MHH:Positive response to halothane.

MH Normal Contracture less than 2 g at Caffeine >3mmol/L or

Halothane>2%.

Porcine stress

syndrome

Exertional Rhabdom-

yolysis

Non anesthetic MH

Myopathy↑↑ CPK

NON ANESTHETIC MHAnimal model of

Human MHAR : InbreedingHomozygous for RyRMH like syndrome with stressors:Endogenous & exogenous stressor

Assoc. with Recurrent Exertional Heat stroke also

• All MH suspectible• King

Denbourough syndrome.

Abn facies with prox. Myopathy• Central Core

diseaseCPK may be normal.+ve IVCT• Evan’s myopathy

Awake MH•MH in the absence of classical triggers•Coexistent 2nd mutation• Higher susceptibility to exogenous trigger• Extreme Physical

activity in hot surroundings

• Infectious fever

NON ANESTHETIC MH

Genetic•Combined myopathy with RyR mutation.•Variable penetrance.

Diagnosis• Dilemma

• Unknown mutations• CHCT/IVCT

• Poor Sensitivity & Specificity.

• Diagnosis with different triggers/new tests.

Avoid•Heat exposure•Physical activity in Hot environment.•Febrile illness: Early t/t: Rapid Cooling •Prophlaxis: Dantrolene•Counseling to parents.NOT AUTOSOMAL

DOMINANTHeat,Oxidative stress Non invasive : P31 MRI

At Risk of MHHypertrophyMuscle HypotoniaSpasmOpthalmoplegia .

COMING BACK TO ELEPHANT IN THE ROOM

MH: Clinical presentation

• INCIDNCE– WORLD : 1: 10,000 – 1:220,000.– JAPAN : 1:60,000 →1:73,000.– INDIA: Under reported 16- 17 cases

Mortality:Intially: 70%.With Dantrolene: 1.4-5%

Clinical Presentations• Males> females• MC in young age, muscular• ENT/DENTAL/SQUINT• Most Rapid onset halothane + Sch

• MH can occur– Previously Uneventful anesthesia exposure

MAC requirement is highest in young age

Exposed to higher dose.

Fulminant MHImmediate onset

Rapid Course

Insidious MHDelayed Onset.

Can present even in Recovery Room

TYPES

PATHOGENESISTriggerSusceptibility

Absent inhibitory

factors

Persistent Ca2+Release From the SR→

Sustained Muscle

Contracture↑Skeletal Muscle

metabolic activity

HypercarbiaTachypnea.Metabolic

acidosis(↑lactate)

↑ O2 consumptionFall in SpO2Fall in SvO2.

↑ed sympathetic

activityTachycardiaArrhythmia

SweatingGeneralized

Muscle RigidityElevated Temp.

Muscle break down

CyanosisRhabdomyolyisi

sHyperKalemia

VT/VFDIC

CLINICAL FEATURES

HYPERCARBIA(92%)

SIN

US TACHYCARDIA(73%)

RAPID ↑ TEMP.(65

%)

ELEVATED TEMP. (53

%)

GEN. MUSCLE RIGIDITY(41%)

TACHYPNEA( 27.1%)

SWEATING (18

%)

CYANOSIS( 9.4

%)

VT/VF

DIC

•1. HYPERCARBIA IS ALSO EARLIEST SIGN OF MH• 2. MASSTER SPASM CAN

EVEN PRECEDE HYPERCARBIA BUT

PRESENT ONLY IN 27%.

CLINICAL FEATURES

• EARLY SIGNS

1. Inappropriately elevated CO2

production (↑EtCO2, ↑RR).

2. ↑O2 Consumption3. Mixed Metabolic

and Respiratory acidosis

4. Profuse Sweating.5. Mottling of skin.

1.Inappropriate tachycardia2.Cardiac arrhythmias (Ventricular ectopics &Bigemini).3.Unstabele arterial Pressure.

1.Masster Spasm with Sch.

2. Generalized Muscle rigidity

METABOLIC CARDIOVASCULAR MUSCLE

TEMPERATURE CAHANGES ARE LATE

SIGNS

CLINICAL FEATURES

1. Rapid rise in Core body temperature.

2. Severe Cardiac arrhythmias.

3. Cardiac arrest.

PHYSICAL

1. HyperKalemia.2. Grossly elevated

CPK.3. Grossly elevated

Blood Myoglobin.4. Dark Colored urine5. D.I.C.

LABORATORY

•Rapid rise in Temperature and high Temperature correlate with Mortality .•Core Temperature monitoring shows mortality benefit as time to administer Dantrolene is shortened.• No benefit of skin Temperature monitoring.

• Generalized Muscle Rigidity - 15 (R/o Hypothermia & Immediate awakening from GA)

• Masseter spasm after Sch - 15Rigidity

• ↑ CK after anesthesia with Sch(>20,000). - 15

• ↑CK after anesthesia w/o Sch(>10,000). - 15

• Myoglobinuria (>60mcg/ml) - 15

• Serum myoglobin > 170mcg/ml -15

• Serum K+ >6.0 meq/L(r/o renal failure.) -15

Muscle Breakdown

• EtCO2> 55 or Art. CO2> 60 with Controlled ventilation -15

• EtCO2> 60 or Art. CO2> 65 with Spont. Ventilation -15

• Inappropriate HyperCarbia. -15• Inappropriate tachypnea - 10

Respiratory Acidosis

Clinical Score

• Larach Score (1994)

Clinical Score• Larach Score (1994)

• Inappropriate rapid rise in temperature- 15

• Inappropriately raised temperature >38.8◦ C in periop period- 10

Rise in Temperature

• Inappropriate sinus tachycardia -3• VT or VF- 3

Cardiac Involvement

• +ve Family H/O in 1st degree relative. - 15

• +ve Family H/O in other relatives.- 5

Family History

• BE>-8meq/L -10• pH<7.25.- 10• +ve Family H/O with +ve anesthetic

History of MH.( exclude ↑ CPK).-5• +ve Family H/O with ↑ CPK -10

Other Indicators

Grading (only the Highest Score of a Process)

SCORE1. 0

2. 3-93. 10-194. 20-345 35-496. 50+

MH RANK123456

LikelihoodAlmost never

UnlikelySome what Less

than likelySomewhat more

likelyVery likely

Certain

Differential diagnosis for a “GREAT MIMIC”

• Anaphylactic reaction• Diabetic coma• Drug toxicity or abuse• Equipment malfunction with increased carbon dioxide (CO2)• Exercise hyperthermia• Hyperthyroidism• Hypoventilation or low fresh gas flow• Increased ETCO2 from laparoscopicsurgery• Insufficient anesthesia or analgesia (or both)• Intracranial free blood• Malignant neuroleptic syndrome• Muscular (Duchenne and Becker) dystrophies/Myotonias• Pheochromocytoma• Rhabdomyolysis• Sepsis

TREATMENTIMMEDIATELY

Declare emergency and call for Help.Inform surgeons

Termination of SurgeryStop all Inhalational agents

Switch to Non Trigger anesthesiaHyperventilation with flow 10 L

100% O2Disconnect circuit.Inform1800-MHHYPER Monitoring

•ECG, NIBP, EtCO2•Wide bore IV•Consider CVP, Arterial early• InvestigationK+, CPK, ABG, Myoglobin, Blood sugar

TREATMENT

• Dantrolene• Hydantoin derivative– 2.5 mg/kg – Max 10 mg/Kg– 20 mg/ ampoule

• 16-20 ampoules– Mixed with sterile water.

• NaOH(pH-9-10), Mannitol (isotonic)• Others solun. → precipitation.

– t1/2: 10 -15 hours– S/E: Respiratory muscle weakness, Cholestasis

TREATMENT

Hyperthermia2-3 L of ice

cold saline(4 Celsius)Surface cooling,

cold sheets, ice packs in axilla and

groinTemperatur

e<38 Celsius.

AcidosisHyperventilate→normocapnia

Soda Bicarb.

HyperKalemia

50 ml 50 % D WITH 50

UNITS INSULIN.

10 ML 10% CALCIUM

GLUCONATE

DIALYSIS

ARRYTHMIASAmiodarone

3mg/kg B blocker if Persistent

Urine outputHyper

hydrationFurosemid

e 1-2mg/kgMannitol 1g/kg.

Observe for at least 24 hours in ICU.

Recrudescence risk is 50%

AAGBI TEMPLATE MH

AAGBI SAMPLE MH KITCOMPARTMENT 1

Dantrolene•100 ml sterile water X 12• Dantrolene X12 vials.•50 ml syringe X 10•Location of Dantrolene

COMPARTMENT 2Treatment

•Amiodarone 300 mg•ẞ Blockers•Calcium chloride/luconate•Soda bicarb 50ml•Propofol vials•Glucose 20%

COMPARTMENT 3Investigations

•Blood vials: Biochem., FBC, Coagulation, Urine Sample, Grouping•Art & CVP Canula & Transducer

COMPARTMENT 4Fridge pack

• 2l NaCl 4 degree C• Insulin

COMPARTMENT 3Investigations

•Blood vials: Biochem., FBC, Coagulation, Urine Sample, Grouping•Art & CVP Canula & Transducer

Masseter Spasm• Usually seen after Sch• Jaw muscle Rigidity with whole body flaccidity > 2min.

– MH susceptibility: 30%.– Higher risk→ Jaw + whole Body rigidity

• “Jaws of steel”– Most severe variant– Ventilation and Intubation might not be possible.– Stop surgery

• Surgery– Controversial in others– To proceed or to stop

Slow Tonic fibers in Jaw muscle

GradingGrade 1: Jaw stiffness onlyGrade 2: Jaw stiffness interfering with intubationGrade 3: Jaws of Steel

Drugs causing MH

• Sch• Volatile agents– HAL>ISO>ENF>SEVO.

• ONDANSETRON

ANESTHESIA MH SUSCEPTIBLITY

• Avoid trigger agents• Flush the circuit with 10 L O2.• Use Charcoal filter in anesthesia machine• TIVA• Regional anesthesia.• Xenon (Case Report)

Thank you

PATHOPHYSIOLOGY

• SERCA pumps– Propel Ca ² ⁺ back to the SR– Relaxation

• Ca ² ⁺ is <10 -7 M– Requires ATP

• Ryanodine– SR Ca ² ⁺ release channel– 3 isoforms• Cardiac, Skeletal, Brain

– Biphasic response to Ca ²⁺– Mg ²⁺

GENETICS AND DNA TESTING

• Malignant Hyperthermia– Pharamacogenetic syndrome.– Ryanodine mutations 50-80%• Chr. 19q• Associated with Myopathies

– Central core disease, Evans Myopathy.• Vary

CLINICAL PRESENTATION