Unraveling Malignant Hyperthermia: Clinical Insight & Management in ICU

1. Malignant Hyperthermia Catherine Maw 24/10/2012

2. OUTLINE • Define and discuss aetiology of thermal disorders • Relevance to ICU • Clinical Presentation of MH • Differential diagnosis and pitfalls • Treatment in theatre and ICU • Subsequent management

3. Thermoregulation • Balance between heat production and loss • Hypothalamic thermoregulatory centre • “Pyrexia” = resetting of thermoregulatory set point to a higher level by activation of heat conserving mechanisms • “Hyperthermia” = failure of effector mechanisms to maintain the normal set point

5. Fever in the ICU • Regulated hyperthermia • Endogenous pyrogens (IL6 and PGE2) act on the hypothalamus • Reset the thermoregulatory set point to higher temp • Effector organs prevent heat loss • May be protective • When pyrogens decrease, set point decreases • Deleterious effects (↑CO, O2 consumption, CO2 production)

6. Hyperthermia • Failure of effector mechanisms to maintain the hypothalamic set point (core ≥ 40°C) • Heat stroke • Drug induced hyperthermias (MH, NMS, Serotonin syndrome, sympathomimetic syndrome, anticholinergic syndrome) • Heat injury is the insult • Protein denaturation and lipid dissolution at 42°C (core)

7. Why is it fatal? • Direct cellular damage • Increases membrane permeability • Activation of Na-K-ATPase pump • ATP depletion • Tissue oedema • Cytokine activation, coagulation cascade activation • Cellular death (lactate, hyperkalaemia, acidosis) • Similar picture to sepsis

8. Why? • Metabolic acidosis • Hyperkalaemia • Rhabdomyolysis • Renal failure • DIC • Liver failure • Death

9. Australian History • 1960: Dr Jim Villiers at Royal Melbourne Hospital • Patient with 10 family members who died under GA • Patient had malignant hyperthermia (MH) • Villiers presented the successful anaesthetic outcome • 1972: Lancet. Denborough and Lovell. • Royal Melbourne (one of 3) centres for MH

10. Definition and Aetiology • Pharmacological disease of skeletal muscle • Hypermetabolic crisis • Induced by exposure to volatile anaesthetic agents or Suxamethonium • Loss of normal calcium homeostasis • Unregulated release of Calcium form the sarcoplasmic reticulum • Myocytehypermetabolism

11. Relevance • Anaesthetic complication • Ongoing patient care will always involve ICU • Insidious versus acute • True MH rare • Hyperthermia differentials more common

12. Epidemiology • 1 in 10,000 to 1 in 30,000 anaesthetics • Young adults (45-55% of cases in <19 years) • More frequent in minor ops • Male > Female 2:1 • Mortality previously 70-80% • Reduced to 2-3% now

14. Geneticsof MH • Majority of MH susceptible patients have mutations on RYR1 or DHP genes • Inherited or spontaneous • 50% Autosomal Dominant • 200 mutations identified • 29 have causality

15. Pathophysiology ctd • Sustained muscle contraction due to high levels of myoplasmic calcium • Heat generated (initial insult) • Cascade similar to sepsis/systemic inflammation • Initial aerobic metabolism generating CO2 and → cellular acidosis • Then Oxygen and ATP depletion → worsening acidosis and lactate production • Depleted energy → muscle death and rhabdomyolysis

16. Risk Factors • Positive family history • Previous exposure to Suxamethonium or volatiles • Exertional heat stroke • Exercise induced rhabdomyolysis • Central core disease • Scoliosis • Strabismus surgery

17. Diagnosis

18. Early • Prolonged masseter muscle spasm after Suxamethonium • Inappropriately ↑ ETCO2 or tachypnoea during spontaneous respiration (ETCO2 >60) • Inappropriately ↑ ETCO2 (ETCO2 >55) during controlled ventilation • Inappropriate tachycardia • Cardiac arrhythmias, especially ventricular ectopics

19. Developing • Developing rise in temperature (0.5 ◦C per 15 mins) • Progressive respiratory and later metabolic acidosis • Hyperkalaemia • Profuse sweating • Cardiovascular instability • Desaturation • Generalised muscle rigidity

20. Late • Myoglobinuria • Myalgia • Grossly elevated CK • Coagulopathy • Cardiac arrest

21. Differential diagnosis • Inadequate anaesthesia / machine issue / patient factor • Sepsis • Intracerebral infection or bleed • Recreational drugs • Neuroleptic malignant syndrome • Thyroid storm • Phaeochromocytoma

22. Management • ANZCA suggest MH Resource kit • Link to mhanz • Task cards based on the aviation safety model • If diagnosis is suspected: • Declare Emergency • Call for HELP and send for MH resource kit • Turn off the volatile and remove vaporisers • Hyperventilate on >15l/min fresh gas flows with 100% O2 • TIVA

31. Ongoing Care • ICU for ventilatory support, haemodynamic monitoring, renal support • CK peaks at 14 hours • Dantrolene does not effect cardiac or smooth muscle • Recrudescence in 25% • 1mg/kg Dantrolene every 6 hours for 48 hours

32. MH Susceptibility Testing • Gold standard is the contracture test • In vitro response of a fresh sample of muscle tissue to Caffeine or Halothane • Muscle strip in physiological solution is attached to a strain gauge and electrically stimulated to measure baseline tension • Repeat in Halothane and Caffeine • High sensitivity and specificity • Expensive and specialist referral needed • Genetic testing cheaper but sensitivity 30-50%

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