Pharmacology for Anaesthesia and Intensive Care

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9780521704632c11 CUFX213A/Peck 9780521618168 December 28, 2007 12:5

Section IICoredrugs in anaesthetic practice

to involve contraction of tonic myofibrils and transient dilation of choroidal blood

vessels.


Intragastric pressure – rises by about 10 cmH 2 O,but as the lower oesophageal

sphincter tone increases simultaneously there is no increased risk of reflux.


Anaphylaxis – suxamethonium makes up a significant proportion of the cases of

anaphylaxis caused by muscle relaxants.


Malignant hyperthermia (see below).


Prolonged neuromuscular block (see below).

Malignant hyperthermia (MH)

MH is a rare (1 in 200 000 in the UK), autosomal-dominant condition.

Mechanism

The exact mechanism has not been fully elucidated but the ryanodine receptor

located on the membrane of the sarcoplasmic reticulum and encoded on chromo-

some 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 is the brain. The RYR1 receptor functions as the main Ca^2 +chan-

nel allowing stored Ca^2 +from the sarcoplasmic reticulum into the cytoplasm, which

in turn activates the contractile mechanisms within muscle. Abnormal RYR1 recep-

tors allow excessive amounts of Ca^2 +to pass, resulting in generalized muscle rigidity.

ATPconsumption is high as it is used in the process to return Ca^2 +to the sarcolplas-

mic reticulum and as a result there is increased CO 2 ,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 ITU 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.