Malignant Hyperpyrexia

• Approximate UK MH incidence is 1 in 50,000 - 70,000
• MH susceptibility prevalence is higher; 1 in 1,500 - 10,000


• More common in males (62%) than females (38%)
• May represent a higher penetrance in male populations
• May represent the fact more men undergo surgery


• Age distribution of MH reactions skewed towards young adults and children

• MH is a rare, autosomal dominant condition
• Up to 75% of cases are due to mutations in the RyR1 receptor gene on chromosome 19 (of which fifty different mutations are known to cause MH)
• Approximately 1% result from mutations of the CACNA1S gene, which encodes the principal subunit of the dihydropyridine receptor


• Known triggers are:
• Volatile anaesthetics: halothane, isoflurane, sevoflurane, enflurane, desflurane, ether, and methoxyflurane
• Depolarising neuromuscular blocking agents: suxamethonium, decamethonium


• Exposure to the trigger agent(s) can lead to uncontrolled release of calcium from the sarcoplasmic reticulum in skeletal muscle via the ryanodine receptor and consequent profound, sustained muscle contraction

• Congenital myopathy
• The most well known association is autosomal dominant central core disease, with an RYR1 variant which cause gain of function in the receptor
• Others:

• Exertional rhabdomyolysis
• Some RYR1 gene variants associated with exertional rhabdomyolysis are implicated in MH susceptibility
• E.g. McArdle disease, Carnitine palmitoyltransferase type 2 deficiency
• Depending on the precise mutation, may need referral to a diagnostic MH unit for further assessment
• Patients carrying RYR1 gene mutations of unknown significance associated with exertional rhabdomyolysis should be considered at risk of developing MH


• Idiopathic hyper-CK-aemia
• Describes persistently increased CK levels 2x upper limit normal for ≥3months
• Should be referred to an MH unit and considered MH susceptible


• Exertional heat illness
• Those with a history of (recurrent) exertional heat illness requiring hospitalisation should be evaluated by an MH unit
• Patients carrying RYR1 gene mutations of unknown significance associated with exertional heat illness should be considered at risk of developing MH

• Excitation - contraction coupling is the transduction of electrical energy into the mechanical work of muscle contraction
• Exposure to trigger agents in MH susceptible individuals causes dysregulation of excitation - contraction coupling
• There is sustained, uncontrolled release of calcium from the sarcoplasmic reticulum via the RyR1 receptor in skeletal muscle


• This sustained calcium release causes an increased metabolic demand for ATP, in order to sequester calcium, leading to:
• Increased O₂ consumption → hypoxia
• Increased CO₂ production → sympathetic activation (i.e. tachycardia) and respiratory acidosis


• Continued calcium release, in excess of calcium sequestration, leads to sustained muscle contraction and consequent:
• Muscle rigidity
• Heat production → hyperthermia
• Compromised integrity of the sacrolemma, and release of:
• Potassium ions → hyperkalaemia
• Creatine kinase and myoglobin → rhabdomyolysis and AKI
• Hyperthermia and rhabdomyolysis predispose to development of DIC

• Signs of MH can occur at any point under anaesthesia and are described post-anaesthesia too
• Earlier occurrence tends to happen if suxamethonium and a volatile agent is used
• Earlier occurrence happens if a more potent volatile is used (e.g. isoflurane) vs. less potent (e.g. desflurane)


• Overall there is significant variability in both the temporal relationship of trigger and reaction, and the magnitude of MH reactions
• May not occur on the patient's first exposure to GA; some cases of patients having had tens of GAs prior to their first reaction

• Typically masseter spasm following suxamethonium use, although general rigidity may occur
• With ongoing rigidity there is rhabdomyolysis, causing raised CK, AKI, hyperkalaemia ± arrhythmia and DIC
• Masseter spasm may occur as the only clinical feature

• Hypoxia → lactic acidosis
• Persistent rising EtCO₂ → respiratory acidosis
• Tachypnoea if the patient is spontaneously ventilating
• Unexplained tachycardia or other arrhythmia
• Hypertension
• Hyperthermia with up to 1'C rise in temp every 10mins

• Consider using local, regional or neuraxial technique rather than GA


• If GA necessary;
• Use trigger-free anaesthetic
• Change anaesthetic machine circuits, remove vaporisers
• Flush circuits with 100% O₂ at maximal flows for 20 - 30mins; aim is for concentrations of volatile to be <5ppm
• Charcoal filters


• No role for prophylactic dantrolene
• Environmental exposure is unlikely to trigger MH, as the required concentration of volatile is double that of the COSHH standards
• Consider avoiding multiple serotonergic drugs as at increased risk of serotonin syndrome

MH is an anaesthetic emergency, and I would seek senior anaesthetic support as well as making a rapid but thorough assessment of the patient

• Ask surgeon to stop (/finish)
• Call for immediate anaesthetic help and the MH trolley
• One needs lots of actions occurring simultaneously, so it makes most sense to designate a (senior) member of the theatre team as coordinator, to delegate the various tasks described below

1. Disconnect patient from anaesthetic machine (and source of volatile agent), removing the vaporiser


2. Hand ventilate using high flow 100% oxygen from an alternative source e.g. cylinder
• Use new circle system, soda lime and activated charcoal filters


3. Secure adequate IV access
• Insert arterial line and central line
• Manage arrhythmias with amiodarone (5mg/kg) or β-blockers; avoid calcium channel blockers which can cause severe myocardial depression if used alongside dantrolene
• Administer dantrolene
• Bolus dose 2.5mg/kg
• Repeat boluses of 1mg/kg every 5-10mins
• Theoretical maximum dose 10mg/kg
• Target reducing heart rate, EtCO₂ <6kPa and a temperature of <38.5°C


4. Maintain anaesthesia using IV agents e.g. propofol


5. Insert temperature probe and actively cool
• Ice packs in groin/axilla
• Cold IV fluid
• Cold body cavity lavage
• Cooling blankets
• Animal models suggest targeted hypothermia (34.5°C) may antagonise the MH reaction if there is no response to dantrolene


6. Insert urinary catheter and monitor UO
• Treat AKI and rhabdomyolysis expectantly; aim UO 2ml/kg/hr ± use of furosemide
• Manage hyperkalaemia and acidosis expectantly
• Treat with insulin/dextrose and bicarbonate infusions
• Calcium as indicated
• May need haemofiltration




8. Monitor for DIC with clotting profiles + VHA, treating as standard

• Transfer to ICU for ongoing management
• Symptoms can recur up to 14hrs (- 24hrs) later


• Inform patient and relatives about events and implications
• Document in clinical notes
• Clinical incident form
• Replenish dantrolene stocks
• Formal referral to St James University Hospital MH centre in Leeds

• Hyperkalaemia
• Metabolic acidosis
• Rhabdomyolysis and renal failure
• DIC
• Compartment syndrome
• Death (UK mortality 4%, although this was 80% before advent of dantrolene)

• Referral to St James University Hospital MH centre in Leeds


• Genetic testing, which can confirm a diagnosis of MH if an abnormal gene is identified (40% sensitivity)


• Formal diagnosis based on the response of biopsied muscle with in vitro contracture testing
• Vastus muscle biopsy
• Performed under LA
• Exposed to 0.5 - 2% halothane or 2mmol/L caffeine within 5hrs of biopsy
• MH demonstrated by characteristic contracture pattern
• Can be susceptible (positive), equivocal or negative
• Not suitable for paediatric patients <10yrs old or <30kg in weight
• Not validated in pregnancy