Malignant Hyperthermia

Malignant hyperthermia (MH) is a rare (incidence of 1 in 50,000–70,000 in the UK), autosomal dominant condition, affecting males (62%) more than females (38%) and may occur after many previous anaesthetics.

Mechanism 

The exact mechanism has not been fully elucidated but the ryanodine receptor located on the membrane of the sarcoplasmic reticulum and encoded on chromosome 19 is intimately involved. There are three isoforms of the ryanodine receptor encoded by three distinct genes. Isoform 1 (RYR1) is located primarily in skeletal muscle, isoform 2 (RYR2) is located primarily in heart muscle and isoform 3 (RYR3) is located primarily in the brain. The RYR1 receptor functions as the main Ca2+ channel allowing stored Ca2+ from the sarcoplasmic reticulum into the cytoplasm, which in turn activates the contractile mechanisms within muscle. Abnormal RYR1 receptors allow excessive amounts of Ca2+ to pass, resulting in generalised muscle rigidity. ATP consumption is high as it is used in the process to return Ca2+ to the sarcoplasmic reticulum and as a result there is increased CO2, heat and lactate production. Cells eventually break down resulting in myoglobinaemia and hyperkalaemia.

Treatment 

This requires intravenous dantrolene (increments of 1 mg.kg−1 up to 10 mg.kg−1), aggressive cooling (using ice-cold saline to lavage bladder and peritoneum – if open) and correction of abnormal biochemical and haematological parameters. Treatment should continue on the ICU and should only stop when symptoms have completely resolved, otherwise it may recur. Before the introduction of dantrolene in 1979 the mortality rate was as high as 70% but is now less than 5%.

Diagnosis 

The diagnosis of MH is based on the response of biopsied muscle to 2% halothane and caffeine (2 mmol.l−1). Patients are labelled either ‘susceptible’ (MHS) – when positive to both halothane and caffeine, ‘equivocal’ (MHE) – when positive to either halothane or caffeine, or ‘non-susceptible’ (MHN) – when negative to halothane and caffeine.

Safe Drugs

 These include opioids, thiopental, propofol, etomidate, ketamine, benzodiazepines, atropine, local anaesthetics and N2O. Patients suspected of having MH should be referred to the UK malignant hyperthermia investigation unit in Leeds.

Dantrolene 

Dantrolene is used in the treatment (and prophylaxis) of MH, neuroleptic malignant syndrome, chronic spasticity of voluntary muscle and ecstasy intoxication. It is available as capsules and in vials as an orange powder containing dantrolene 20 mg, mannitol 3 g and sodium hydroxide. Each vial should be reconstituted with 60 ml water producing a solution of pH 9.5. It is highly irritant when extravasated and a diuresis follows intravenous administration reflecting its formulation with mannitol. Treatment of suspected MH starts with a dose of 2.5 mg.kg−1, followed by 1 mg.kg−1 every 5 minutes until the metabolic signs start to resolve. Although there is no upper dose limit, little benefit is seen with doses above 10 mg.kg−1. Chronic use is associated with hepatitis and pleural effusion.

Mechanism of Action

Dantrolene uncouples the excitation contraction process by binding to the ryanodine receptor, thereby preventing the release of Ca2+ from the sarcoplasmic reticulum in striated muscle. As vascular smooth muscle and cardiac muscle are not primarily dependent on Ca2+ release for contraction, they are not usually affected. It has no effect on the muscle action potential and usually has little effect on the clinical duration of the NDMRs. It may, however, produce respiratory failure secondary to skeletal muscle weakness. Kinetics Oral bioavailability is variable and it is approximately 85% bound in the plasma to albumin. It is metabolised in the liver and excreted in the urine.