Onset of the MH in humans is extremely variable; in initial symptoms and in the time of onset of syndrome. There have been instances where fulminant MH has occurred in patients who have previously tolerated potent triggers without difficulty. Reason is unknown. Timing
Increased creatine kinase, myoglobinuria
Triggers
Succinylcholine Safe drugs
All intravenous anaesthetics including ketamine All benzodiazepines All non-depolarising neuromuscular blocking drugs All local anaesthetics,including preparations containing vasoconstrictors All analgesics,including opioids Neostigmine Atropine Glycopyrrolate Metoclopramide Droperidol ‘Safe drugs’ have been evaluated in the laboratory and safely used in patients known to be susceptible to malignant hyperthermia.Other drugs used in the context of anaesthesia have not necessarily been so thoroughly tested.Readers are advised to seek expert opinion from the Leeds MH Investigation Unit should they consider using other drugs in susceptible patients. Malignant hyperthermia
• uncommon pharmacogenetic disorder of skeletal muscle, a
syndrome triggered in susceptible individual by commonly-used volatile anaesthetics + suxamethonium
• Clinical diagnosis, high mortality rate (early days 80%, recently
with dantrolene + better monitoring ~ 5%)
Genetics
• autosomal dominant inheritance w/ variable penetrance +
o only 5% of all MH showed chromosome 19 abnormalities
o Occurs on 2nd or later triggering anesthetic in 1/3 of
o But all thought to be picked up by contracture testing
o MHS1: Ryanodine Receptor; 19q13, 50% of family and
Incidence
Anywhere from 1:60,000 anaesthetics to suspected in 1:4000
Most families - dominant pattern of inheritance
Occurs on second or later triggering anaesthetic in 1/3
But all thought to be picked up by contracture testing
Best defined is the Ryanodine receptor on 19q13
overall 1:16,000 (if only volatile / sux
• Characterize by accelerated hypermetabolism • incidence of approx 1:40,000 GA in adults and 1:15,000 in
Diseases Associated with Malignant Hyperthermia RYR1 mutations have been found in 50-80% of patients and relatives who are labeled MH susceptible by positive contracture tests and in almost all families with Central Core Disease and King- Denborough syndrome. Etiopathology
• condition is a result of a rapid accumulation of Ca in striated
muscle cytoplasm due to a defect in calcium-release channel of sarcoplasmic reticulum
• ↑ iCa stimulate metablism both directly + indirectly
o Directly through activation of phosphorylase to ↑glycolysis
o indirectly b/c of high demand for ATP production ( ATPase
are important components of myofilament relaxation + Ca sequestration pumps of SR and sacrolemma)
Fig:Schematic representation of the triad junction of skeletal muscle shows the junctional foot protein(RYR1) and its associated proteins. In skeletal muscle, the αis-subunit of the dihydropyridine receptor participates in excitation-contraction coupling. These physical links transmit essential signals across the narrow gap of the triadic junction that activate the RYR1 and release Ca2+from the sarcoplasmic reticulum
Dantrolene
• direct-acting muscle relaxant • blocking Ca release from SR
o neuromuscular transmission + electrical properties of
o little / no effect on smooth / cardiac muscle
• total paralysis cannot be obtained ( attribute to its poor water
• lyophilized orange powder 20mg/vial + mannitol 3g
(isotonicity) + NaOH (increase solutbility) – diluted with 60ml H2O for injection
• Incompatibilities:
Dantrolene is incompatible with acidic solutions, including 5% dextrose injection and 0.9% sodium chloride injection.
• rate of dissolution increase by heat • Stability: - After reconstitution, protect from temperatures
below 15°C or above 30 °C Protect from direct light. Use within 6 hours
• Give them through blood filters (avoid problems with crystals
o Precipitate formation has occurred after transfer of
reconstituted dantrolene solutions to large glass bottles for preparation of an intravenous infusion. It is recommended that intravenous infusions be prepared in sterile plastic bags, immediately prior to the time of anticipated use. Also, the prepared infusion should be inspected for cloudiness and/or precipitation prior to use, and discarded if either is present.
• given ivi / PO (20% bioavailability) • Vd ~ 1L/kg • metabolized by liver microsomes by hydroxylation to weakly
active metabolite and excreted in urine (and bile)
• 2-2.5mg/kg iv every 15 mins until 10mg/kg or until sx resolved
o Mannitol – diuresis may occur (? Good)
• Side effect related to dantrolene itself
• Skeletal muscle weakness – usually does not affect
• GI upset – nausea / vomiting / diarrhea • Uterine atony • Hepatitis + pleural effusion in chronic PO uses • Drug interaction (see below)
Intravenous Dantrolene & Ca blocker
• Avoid concurrent use of verapamil with iv dantrolene ( shown to
cause VF + CVS collapse from severe hyperK in anaesthetized swines)
• also retriggers MH • profound myocardial depression
∴ don’t use CCB concurrently with iv dantrolene in mx of a malignant hyperthermic crisis
QMH dantrolene stock: F3 recovery room and K11 recovery room contains 6 vials for initial resuscitation. Early additional Dantrolene should be mobilized from pharmacy (23 vials stock)
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