Malignant hyperthermia





Background

Epidemiology

  • Incidence of MH reaction = 1 in 40,000 to 1 in 100,000

  • Prevalence of genetic susceptibility = 1 in 5,000 to 1 in 10,000

  • Difficult to gather data

  • Factors that complicate accurate figures

    • Apparently reduction in risk of reaction ... with increasing age
    • On average
      • Susceptible patients have had 3 previous uneventful GAs
      • 75% of MH have had previous anaesthesia

  • Male affected more frequently than female (approx 3:1)

  • Incidence decreased in patients ≥ 50 yo

  • Inherited as an autosomal dominant condition

May be associated with

  • Myotonia
  • Osteogenesis imperfecta
  • King-Denborough syndrome
  • Duchenne's muscular dystrophy

PP

Triggers

  • Volatile agents

    • Halothane is the most potent trigger

  • Suxamethonium

MOA

MOA = Loss of skeletal muscle cell calcium homeostasis
→ Increased intracellular calcium concentration

  • Leading to:
    • Muscle rigidity
    • Hypermetabolism
    • Rhabdomyolysis

Muscle rigidity

  • Due to continuous actin-myosin interaction

Hypermetabolism

Due to

  • (Directly) Calcium-calmodulin complex directly stimulating glycolytic enzymes
  • (Indirectly) Increased demand for ATP ... due to consumption by myofilament interaction and Ca2+ pumps

Rhabdomyolysis

Due to

  • Excessive contractile activity
  • Increased turnover of membrane phospholipids due to Ca2+ activation of phospholipase

It can also lead to leakage of potassium and myoglobin into blood

  • Hyperkalaemia
  • Renal failure

Other sequelae

  • Hyperthermia

    • Excessive heat from excessive muscle contraction and metabolic stimulation
    • Body temp may increase by ≥ 1ºC per 10 min

  • Decreased SpO2

    • Oxygen delivery may not meet the metabolic demand

  • Acidosis

    • Excessive production of CO2 and lactic acid

  • Hyperkalaemia

    • Due to rhabdomyolysis
    • Can lead to arrhythmia

  • Myoglobinuria

    • Due to rhabdomyolysis
    • Can lead to renal tubular damage and acute renal failure

  • Disseminated intravascular coagulation

    • Due to hyperthermia and ... necrosing tissues (which releases tissue clotting activators)

S&S

Sequence of events is quite consistent
... but onset time is quite variable

  • Fastest with halothane (less than 1/2 hour), then isoflurane
  • Usually within 1 to 2 hours
  • Rarely MH can develop 2 to 3 days postop

Early

  • Masseter muscle spasm
  • Increased metabolism
    • Increased CO2 production
      • Tachypnoea or rise in EtCO2
    • Tachycardia

NB

  • Hyperthermia and acidosis occur later

Followed by...

  • Unstable BP
  • Decline in SpO2

Late signs

  • Hyperthermia
    • Can be ≥ 1ºC per 10 min
  • Metabolic acidosis
  • Generalised muscle rigidity
  • Rhabdomyolysis
    • Hyperkalaemia
    • Raised CK
    • Myoglobinuria
  • Cardiac arrhythmia / arrest
  • DIC

Dx

DDx

  • Inadequate anaesthesia / analgesia
  • Inappropriate ventilation / fresh gas flow
  • Infection / sepsis
  • Tourniquet ischaemia
  • Phaeochromocytoma
  • Thyroid storm
  • Anaphylaxis
  • Neuroleptic malignant syndrome
  • Serotonin syndrome
  • Stimulant drugs
    • Cocaine
    • Amphetamine

Rx

Initlal Rx

Early diagnosis is most important

  1. Declare crisis and call for help

  2. Removal of triggering agent

    • Discontinue volatile anaesthetics
    • High flow 100% O2 (> 15L/min)
    • Hyperventilate

  3. Start MH protocol

NB

  • Do NOT waste time changing machine / circuit. Very time consuming and may not bring any benefit.

Definitive Rx

Dantrolene

Maintenance of anaesthesia

  • Propofol 30 to 50 mL/hr or TCI 4 mcg/mL
  • Midazolam 2.5 to 5 mg IV PRN

Active cooling

  • Cooling mattress
  • Application of ice
  • Removal of blankets
  • Lower OT temperature setting

NB

  • Avoid excessive cooling, which will cause peripheral vasoconstriction, preventing heat loss
  • Cease active cooling at 38ºC

Rx of complications

Rx of Acidosis

  • Dantrolene (i.e. treating primary cause)
  • Hyperventilation
  • Sodium bicarbonate 0.5 to 1 mmol per kg ... when pH < 7.2
    • 8.4% of NaHCO3 = 1 mmol/mL

Rx of hyperkalaemia

  • Hyperventilation
  • Insulin and dextrose
    • Adult: insulin 10 iu in 50 mL of 50% dextrose
    • Paed: Insulin 0.15 iu/kg + 50% dextrose 0.5 mL/kg
  • Calcium
    • Ca2+ chloride 0.1 mL per kg, or...
    • Ca2+ gluconate 0.3 mL per kg

Rx of arrhythmia

  • Amiodarone 3mg/kg slowly IV
  • Lignocaine 1 mg/kg IV
  • Procainamide 300mg over 15 min
  • Metoprolol 1 to 2 mg IV PRN
  • Treat hyperkalaemia

Renal protection

  • Maintain urine output ≥ 2 mL/kg/hr ... via maintaining IV volume with NS

Inotropic support

  • Consider adrenaline or noradrenaline

Other Rx adjuncts

  • Lines (Arterial line ± CVL)

  • Lab tests

    • ABG
      • esp for pH, K+, BSL, pCO2
    • U&E
    • Coag
    • Creatine kinase (CK)
    • Urine for myoglobin for rhabdomyolysis

  • ICU or transfer

Follow-up

Referral for confirmation of clinical diagnosis

  • in vitro contracture testing (IVCT)
  • DNA testing

In vitro contracture testing (IVCT)

  • Definitive test
  • Muscle biopsy from vastus muscle → Expose to halothane and caffeine
  • If European MH Group (EMHG) protocol used
    • Sensitivity of 99%
    • Specificity of 93.6%
    • Also uses muscle biopsies and exposure to halothane and caffeine

DNA testing

  • MH susceptibility inherited in classic autosomal dominant fashion
  • DNA testing checks ... 15 causative mutation in ... ryanodine receptor protein (RYR1) gene ... on chromosome 19
  • About 50% of susceptible patients do not have mutation on chromosome 19
  • Thus,
    • Positive result confirms MH susceptibility
    • Negative DNA does NOT rule out MH susceptibility
      • i.e. Muscle biopsy is still required

NB:

  • OHA3 says 70% are linked to RYR1 on chromosome 19q
    • i.e. 30% (instead of 50% do not)

Post-intervention

  • Mortality from MH = 2 to 3%

    • Used to be 70 to 80% (when dantrolene was not available)

  • Up to 25% of patients relapse in the first 24 hours

Others

Masseter muscle spasm (MMS)

  • Prior to onset of paralysis, suxamethonium induces MMS in most people

  • In patients susceptible to MH, the response is extreme

    • e.g. inability to open month 2 min after suxamethonium
    • e.g. resistance to mouth opening 4 min after administration

  • Jaw rigidity is more pronounced with inhalation induction than IV induction

  • Of patients referred for testing following an episode of jaw rigidity as the only feature ... about 25% to 30% are proved to be susceptible to MH ... even when anaesthesia had continued uneventfully with volatile agents

  • May be the first indication of an undiagnosed muscle disease, e.g. myotonia

Management

  • Abandon surgery if possible
  • Otherwise convert to MH safe technique