Malignant Hyperthermia Catherine Maw 24102012 OUTLINE Define and

Malignant Hyperthermia Catherine Maw 24/10/2012

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

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

Fever in the ICU • • Regulated hyperthermia Endogenous pyrogens (IL 6 and PGE 2) act on the hypothalamus Reset thermoregulatory set point to higher temp Effector organs prevent heat loss May be protective When pyrogens decrease, set point decreases Deleterious effects (↑CO, O 2 consumption, CO 2 production)

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)

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

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

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

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 • Myocyte hypermetabolism

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

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

Genetics of MH • Majority of MH susceptible patients have mutations on RYR 1 or DHP genes • Inherited or spontaneous • 50% Autosomal Dominant • 200 mutations identified • 29 have causality

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 CO 2 and → cellular acidosis • Then Oxygen and ATP depletion → worsening acidosis and lactate production • Depleted energy → muscle death and rhabdomyolysis

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

Diagnosis

Early • Prolonged masseter muscle spasm after Suxamethonium • Inappropriately ↑ ETCO 2 or tachypnoea during spontaneous respiration (ETCO 2 >60) • Inappropriately ↑ ETCO 2 (ETCO 2 >55) during controlled ventilation • Inappropriate tachycardia • Cardiac arrhythmias, especially ventricular ectopics

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

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

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

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 >15 l/min fresh gas flows with 100% O 2 TIVA

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% • 1 mg/kg Dantrolene every 6 hours for 48 hours

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%