malignant hyperthermia is a muscle disorder

1. Malignant Hyperthermia
Presenter: Sumit Gupta
Moderator: Dr. Anjolie Chhabra
Additional Prof. Anesthesiology
AIIMS, New Delhi

2. 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

3. 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

4. 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 Mg²⁺
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

5. PATHOPHYSIOLOGY
Abn 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

6. 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

7. PATHOPHYSIOLOGY
MH 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

8. EVALUATION

9. • 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

10. 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 genes
Many mutations are not expressed.
 Can’t rule out MH susceptibility completely

11. 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.
BUT
1. Inter laboratory variability.
2. Averages are recorded
3. Accuracy of caffeine and
halothane concentrations.

12. 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%

13. 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 susceptibleIF RESULT IS POSITIVE FOR EITHER CAFFEINE OR HALOTHANE

14. CONTRACTURE TEST
MH Susceptible
Positive response
to both halothane
and caffeine
MH Equivocal
Positive response
to either Caffeine
or halothane
MH Normal
Contracture less than 2 g
at Caffeine >3mmol/L or
Halothane>2%.
MH Susceptible
Positive response to both halothane
and caffeine
MHc: Positive response to Caffeine
MHH:Positive response to halothane.
MH Normal
Contracture less than 2 g
at Caffeine >3mmol/L or
Halothane>2%.

15. Porcine
stress
syndrome
Exertional
Rhabdom-
yolysis
Non
anesthetic
MH
Myopathy
↑↑ CPK
NON ANESTHETIC MH
Animal model of Human MH
AR : Inbreeding
Homozygous for RyR
MH 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 disease
CPK 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

16. 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
DOMINANT
Heat,Oxidative stress
Non invasive : P31 MRI
At Risk of MH
Hypertrophy
Muscle Hypotonia
Spasm
Opthalmoplegia .

17. COMING BACK TO ELEPHANT IN THE
ROOM

18. 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%

19. 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 MH
Immediate onset
Rapid Course
Insidious MH
Delayed Onset.
Can present even
in Recovery Room
TYPES

20. PATHOGENESIS
Trigger
Susceptibility
Absent inhibitory
factors
Persistent Ca2+Release
From the SR→
Sustained Muscle
Contracture
↑Skeletal Muscle metabolic
activity
Hypercarbia
Tachypnea.
Metabolic acidosis(↑lactate)
↑ O2 consumption
Fall in SpO2
Fall in SvO2.
↑ed sympathetic
activity
Tachycardia
Arrhythmia
Sweating
Generalized Muscle
Rigidity
Elevated Temp.
Muscle break down
Cyanosis
Rhabdomyolyisis
HyperKalemia
VT/VF
DIC

21. CLINICAL FEATURES
•1. HYPERCARBIA IS ALSO EARLIEST SIGN
OF MH
•2. MASSTER SPASM CAN EVEN PRECEDE
HYPERCARBIA BUT PRESENT ONLY IN 27%.

22. CLINICAL FEATURES
• EARLY SIGNS
1. Inappropriately
elevated CO2
production
(↑EtCO2, ↑RR).
2. ↑O2 Consumption
3. Mixed Metabolic
and Respiratory
acidosis
4. Profuse Sweating.
5. Mottling of skin.
1.Inappropriate
tachycardia
2.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

23. 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 urine
5. 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.

24. • Generalized Muscle Rigidity - 15
(R/o Hypothermia & Immediate awakening from GA)
• Masseter spasm after Sch - 15
Rigidity
• ↑ 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)

25. 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)
SCORE
1. 0
2. 3-9
3. 10-19
4. 20-34
5 35-49
6. 50+
MH RANK
1
2
3
4
5
6
Likelihood
Almost never
Unlikely
Some what Less than likely
Somewhat more likely
Very likely
Certain

26. 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

27. TREATMENT
IMMEDIATELY
Declare emergency and call for Help.
Inform surgeons
Termination of Surgery
Stop all Inhalational agents
Switch to Non Trigger anesthesia
Hyperventilation with flow 10 L
100% O2
Disconnect circuit.
Inform1800-MHHYPER Monitoring
•ECG, NIBP, EtCO2
•Wide bore IV
•Consider CVP, Arterial early
• Investigation
K+, CPK, ABG, Myoglobin,
Blood sugar

28. 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

29. TREATMENT
Hyperthermia
2-3 L of ice cold
saline(4 Celsius)
Surface cooling,
cold sheets, ice
packs in axilla and
groin
Temperature<38
Celsius.
Acidosis
Hyperventilate
→normocapnia
Soda Bicarb.
HyperKalemia
50 ml 50 % D WITH 50
UNITS INSULIN.
10 ML 10% CALCIUM
GLUCONATE
DIALYSIS
ARRYTHMIAS
Amiodarone 3mg/kg
B blocker if Persistent
Urine output
Hyper hydration
Furosemide 1-2mg/kg
Mannitol 1g/kg.
Observe for at least 24 hours in ICU.
Recrudescence risk is 50%

30. AAGBI TEMPLATE MH

31. AAGBI SAMPLE MH KIT
COMPARTMENT 1
Dantrolene
•100 ml sterile water X 12
• Dantrolene X12 vials.
•50 ml syringe X 10
•Location of Dantrolene
COMPARTMENT 2
Treatment
•Amiodarone 300 mg
•ẞ Blockers
•Calcium chloride/luconate
•Soda bicarb 50ml
•Propofol vials
•Glucose 20%
COMPARTMENT 3
Investigations
•Blood vials: Biochem.,
FBC, Coagulation, Urine
Sample, Grouping
•Art & CVP Canula &
Transducer
COMPARTMENT 4
Fridge pack
•2l NaCl 4 degree C
•Insulin
COMPARTMENT 3
Investigations
•Blood vials: Biochem.,
FBC, Coagulation, Urine
Sample, Grouping
•Art & CVP Canula &
Transducer

32. 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
Grading
Grade 1: Jaw stiffness only
Grade 2: Jaw stiffness
interfering with intubation
Grade 3: Jaws of Steel

33. Drugs causing MH
• Sch
• Volatile agents
– HAL>ISO>ENF>SEVO.
• ONDANSETRON

34. 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)

36. 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⁺
– Mg²⁺

37. GENETICS AND DNA TESTING
• Malignant Hyperthermia
– Pharamacogenetic syndrome.
– Ryanodine mutations 50-80%
• Chr. 19q
• Associated with Myopathies
– Central core disease, Evans Myopathy.
• Vary

38. CLINICAL PRESENTATION