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Malignant Hyperthermia and
Dantrolene Sodium
R.Srihari
Topics for Discussion
• Introduction
• Pathophysiology
• Triggering Agents
• Clinical Presentation
• Clinical Features
• L...
Introduction
• Malignant hyperthermia(MH) manifests
manifests clinically as a hypermetabolic crises
when an MH susceptible...
Pathophysiology
• MH susceptible patients have genetic skeletal muscle
receptor abnormalities allowing excessive calcium
a...
• Normal Muscle Physiology:
– Depolarization spreads throughout the muscle cell via t-tubule system
 Activates Dihydropyr...
• Malignant Hyperthermia:
– MH susceptible patients have mutations for abnormal RYR1 or DHP
receptors
 unregulated passag...
– Once energy stores are depleted , rhabdomyolysis
occurs and results in hyperkalemia and myoglobinuria
Hyperkalemia occu...
Triggering Agents
• Vast majority of patients developed MH while
patient was receiving volatile anesthetic agent
with or w...
Clinical Presentation
• Clinical signs present perioperatively in
several possible patterns
– Intraoperatively during any phase of anesthetic
ma...
Clinical Features
• Early signs:
– Hypercarbia
– Sinus tachycardia
– Masseter muscle rigidity
– Generalised muscle rigidity
• Later signs:
–...
Laboratory Findings
Clinical Diagnosis
• During an acute event, diagnosis of MH is
presumptive, based on 1 or more clinical findings
a/w MH
• ...
• Clinical signs:
– Increased EtCo2
– Generalised muscle
rigidity
– Hyperkalemia related
arrhythmias
– Tachycardia
– Tachy...
Differential Diagnosis
• Anesthesia/Surgery related:
– Insufficient anesthesia/ analgesia
– Insufficient ventilation/ fres...
Management
• Approach to management of suspected MH crisis:
– Evaluate and manage hypercarbia
• Increase minute ventilatio...
• Initiate MH protocol:
– Optimize oxygenation and ventilation:
• Increase FiO2 to 100%
• Increase RR and TV to maximise v...
• Administer Dantrolene:
– Skeletal muscle relaxant –directly acting at cellular level
– Chemical strucutre – consists of ...
• Older brands- Dantrium and Revonto
– Present as 20mg vial to be reconstituted with 0.9%
NS or 5%D to 60 ml
– After given...
– Mechanism of action:
• Acts directly on skeletal muscle by interfering with release of
calcium ion from sarcoplasmic ret...
– Side effects:
• Flushing
• A-V block
• Tachycardia
• Voice disorder
• Dizziness
• Dysphagia
– Monitor and treat hyperkalemia:
Based on ECG changes to prevent life threatening
arrhythmias and cardiac arrest
USE OF C...
• Initiate supportive care:
– Monitor and treat acidosis:
• Bicarbonate
– Treat cardiac arrhythmias as per ACLS protocol
–...
• Ongoing care:
– When surgery over, patient should be transferred to
ICU for ventilatory support and hemodynamic
monitori...
• Counselling after acute MH:
– Not have anesthesia with triggering agents
– Avoid exercises in excessive heat or humidity...
Thank You
Malignant hyperthermia and dantrolene sodium
Malignant hyperthermia and dantrolene sodium
Malignant hyperthermia and dantrolene sodium
Malignant hyperthermia and dantrolene sodium
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Malignant hyperthermia and dantrolene sodium

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

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Malignant hyperthermia and dantrolene sodium

  1. 1. Malignant Hyperthermia and Dantrolene Sodium R.Srihari
  2. 2. Topics for Discussion • Introduction • Pathophysiology • Triggering Agents • Clinical Presentation • Clinical Features • Laboratory Findings • Clinical Diagnosis • Differential diagnosis • Management
  3. 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. 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. 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. 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. 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
  8. 8. Triggering Agents • Vast majority of patients developed MH while patient was receiving volatile anesthetic agent with or without succinylcholine
  9. 9. Clinical Presentation
  10. 10. • 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
  11. 11. Clinical Features
  12. 12. • 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
  13. 13. Laboratory Findings
  14. 14. 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
  15. 15. • 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
  16. 16. 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
  17. 17. 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
  18. 18. • 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
  19. 19. • 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
  20. 20. • 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
  21. 21. – 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)
  22. 22. – Side effects: • Flushing • A-V block • Tachycardia • Voice disorder • Dizziness • Dysphagia
  23. 23. – 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
  24. 24. • 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
  25. 25. • 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
  26. 26. • 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
  27. 27. Thank You

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