Malignant Hyperthemia - Relevance to anesthesia and emergency medicine and Dantrolene pharmacology

1. Malignant Hyperthermia and
Dantrolene Sodium
R.Srihari

2. Topics for Discussion
• Introduction
• Pathophysiology
• Triggering Agents
• Clinical Presentation
• Clinical Features
• Laboratory Findings
• Clinical Diagnosis
• Differential diagnosis
• Management

3. Introduction
• Malignant hyperthermia(MH) manifests
manifests clinically as a hypermetabolic crises
when an MH susceptible individual – exposed
to volatile anesthetic or succinyl choline
• Incidence – estimated to be 1:100000
anesthetics administered
– Males > Females
– Children less than 19 contribute to ~ 50%

4. Pathophysiology
• MH susceptible patients have genetic skeletal muscle
receptor abnormalities allowing excessive calcium
accumulation in presence of certain anesthetic
triggering agents
• Mechanism how anesthetic triggers MH by interacting
with the receptors – Unknown
• Due to an episode of MH  Clinical manifestations are
due to cellular hypermetabolism sustained muscle
contraction and breakdown( rhabdomyolysis) 
anaerobic metabolism  acidosis  sequelae

5. • Normal Muscle Physiology:
– Depolarization spreads throughout the muscle cell via t-tubule system
 Activates Dihydropyridine(DHP) receptors located in t-tubule
membrane
 These receptors are coupled to ryanodine receptors which are
calcium channels embedded In the wall of Sarcoplasmic reticulum
Calcium release through DHP receptor trigger RYR1 receptors to
release calcium from SR into intracellular space
Calcium combines with troponin to cross link actin and myosin
resulting in muscle cell contraction
Reuptake of calcium by Sarcoplasmic reticulum ATPase leads
to muscle cell relaxation

6. • Malignant Hyperthermia:
– MH susceptible patients have mutations for abnormal RYR1 or DHP
receptors
 unregulated passage of calcium from sarcoplasmic reticulum into
intracellular space
ACUTE MH CRISIS
Accelerated levels of aerobic metabolism sustain muscle for a time,
but produce CO2 and cellular acidosis and deplete oxygen and ATP
 Early signs: Hypercarbia + Respiratory/
Metabolic acidosis
A change to anaerobic metabolism worsens acidosis with
production of lactate

7. – Once energy stores are depleted , rhabdomyolysis
occurs and results in hyperkalemia and myoglobinuria
Hyperkalemia occurs early in Muscular patients
– Overtime sustained contractions generates more heat
than the body is able to dissipate
 Marked hyperthermia occurs minutes to hours
following onset of symptoms
 Core body temperature may increase rise 1 C
every few minutes
 Severe hyperthermia leads to increase in CO2
production and increased Oxygen consumption with
widespread organ dysfunction  DIC

9. Triggering Agents
• Vast majority of patients developed MH while
patient was receiving volatile anesthetic agent
with or without succinylcholine

10. Clinical Presentation

11. • Clinical signs present perioperatively in
several possible patterns
– Intraoperatively during any phase of anesthetic
manifested by gradually worsening hypercarbia,
tachycardia, metabolic acidosis and generalised
rigidity
– Perioperatively with isolated rhabdomyolysis in
otherwise asymptomatic patients

12. Clinical Features

14. • Early signs:
– Hypercarbia
– Sinus tachycardia
– Masseter muscle rigidity
– Generalised muscle rigidity
• Later signs:
– Hyperthermia
– ECG changes related to
hyperkalemia
– Ventricular ectopics/bigemini
– Ventricular
tachycardia/fibrillation
– Myoglobinuria (peak -14 hrs)
– Excessive Bleeding

15. Laboratory Findings

16. Clinical Diagnosis
• During an acute event, diagnosis of MH is
presumptive, based on 1 or more clinical findings
a/w MH
• Diagnosis must be considered in all patients
receiving triggering agents as 90% have negative
family history for MH
• Treatment is initiated emergently as soon as
diagnosis of MH is considered

17. • Clinical signs:
– Increased EtCo2
– Generalised muscle
rigidity
– Hyperkalemia related
arrhythmias
– Tachycardia
– Tachypnea
– Myoglobinuria
– Hyperthermia
• Lab Studies:
– ABG –pH <7.25
– K> 6
– CK >100000 units
– CK>20000 units (with
SCh)
– Serum myogoblin >170
mcg/L
– Urine Myoglobin >60
mcg/L

18. Differential Diagnosis
• Anesthesia/Surgery related:
– Insufficient anesthesia/ analgesia
– Insufficient ventilation/ fresh gas flow
– Overheating
– Increased CO2 absorption during laparoscopy
• Drug related:
– Anaphylaxis – low BP ; high PCO2; no muscle signs
– Transfusion reactions- fever; brown urine; hyperkalemia
– Drugs of abuse: Cocaine, Ecstasy,Metamphetamine- sudden cardiovascular collapse ;
tachypnea
• Alcoholic withdrawal syndrome – delirium, high HR, BP
• NMS- slow onset ; fever, rigidity, autonomic instability
• Serotonin syndrome – fever, high BP, muscle rigidity
• EPS sideeffects of antipsychotics – Rigidity
• Pheochromocytoma
• Thyroid storm

19. Management
• Approach to management of suspected MH crisis:
– Evaluate and manage hypercarbia
• Increase minute ventilation
• Eliminate obstruction of ventilation
• Seek sources of increased CO2
– Confirm other signs of MH:
• Generalised rigidity
• PVC (or other signs of hyperkalemia)
• Tachycardia
• Unstable hemodynamic stability (high or low)
• Masseter spasm
• Unexplained metabolic acidosis

20. • Initiate MH protocol:
– Optimize oxygenation and ventilation:
• Increase FiO2 to 100%
• Increase RR and TV to maximise ventilation and reduce
etCO2
• If not intubated  ETT done and NDMR given
– Discontinue triggering agents
• Inform surgeon of the diagnosis
• Surgical procedure should be terminated if not
possible to be finished under intravenous anesthesia
• Charcoal filter to be placed at expiratory and inspiratory
limbs of circuit  not necessary to change machine

22. • Administer Dantrolene:
– Skeletal muscle relaxant –directly acting at cellular level
– Chemical strucutre – consists of Hydantoin group
– Only known antidote for MH
– Dose :2.5mg/kg- continuous repeat dose of 1mg/kg until
symptoms subside or cumulative dose of 10mg/kg reached in
large iv line
– No renal/hepatic dose adjustments
– Paediatric and Geriatric dosing – similar to adult dose
– Brand –Ryanodex (newer) supplied as 250mg vial reconstituted
with 5ml sterile water
 as it is hyperconcentrated it will achieve higher
concentrations faster

23. • Older brands- Dantrium and Revonto
– Present as 20mg vial to be reconstituted with 0.9%
NS or 5%D to 60 ml
– After given iv – has to be flushed with saline

24. – Mechanism of action:
• Acts directly on skeletal muscle by interfering with release of
calcium ion from sarcoplasmic reticulum
Prevents or reduces increases in myoplasmic calcium ion
concentration that activates the acute catabolic process
associated with malignant hyperthermia
– Pharmacokinetics:
• Time to peak concentration : 1 min post iv
• Metabolism: Hepatic; metabolites – 5-hydroxydantrolene
• Half life elimination: 4-11 hours
• Excretion: Feces (50%) and Urine(25% as unchanged drug)

25. – Side effects:
• Flushing
• A-V block
• Tachycardia
• Voice disorder
• Dizziness
• Dysphagia

26. – Monitor and treat hyperkalemia:
Based on ECG changes to prevent life threatening
arrhythmias and cardiac arrest
USE OF CCBS – CONTRAINDICATED IN MH AS IT
CAN WORSEN HYPERKALEMIA AND
HYPOTENSION
– Check labs:
• Electrolytes, Blood gases, CK , serum myoglobin,
coagulation parameters and fibrin split products

27. • Initiate supportive care:
– Monitor and treat acidosis:
• Bicarbonate
– Treat cardiac arrhythmias as per ACLS protocol
– Treat hyperthermia  can precipitate DIC
• >39 C should be cooled  infuse cold saline intravenously, lavage
open body cavity, apply ice to surfaces till temp <38.5 C
– Insert bladder catheter to monitor urine color and volume.
• Urine dipstick test + for heme myoglobinuria
• Urine output >1ml/kg/hr
– Monitor muscle compartment for compartment syndrome
– Institute measures to prevent rhabdomyolysis induced renal
failure
• Hydration + Soda Bicarbonate + Diuretics

28. • Ongoing care:
– When surgery over, patient should be transferred to
ICU for ventilatory support and hemodynamic
monitoring for 24 hours
– Dantrolene can be stopped or interval between dosing
increased to every 8-12 hours if the following criteria
met:
• Metabolic stability for 24 hours
• Core temperature less than 38 C
• CK is decreasing
• No evidence of myoglobinura
• Muscle no longer rigid

29. • Counselling after acute MH:
– Not have anesthesia with triggering agents
– Avoid exercises in excessive heat or humidity as
they can trigger event
– Inform family members of possible MH episode
 MH- genetic

31. Thank You