Malignant Hyperthermia

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Malignant Hyperthermia
April 9th, 2008

• Paris Balfour-Ducharme (paris.balfour.ducharme_at_uto
  ronto.ca)
• Brent Ferris (brent.ferris_at_utoronto.ca)
• Nigel Noronha (nigel.noronha_at_utoronto.ca)
• Cory Twinney (cory.twinney_at_utoronto.ca)

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What is it?

• A genetically-determined reaction to general
  anaesthesia, resulting in an uncontrolled
  increase in skeletal muscle respiration
• - abnormal increase in body temp
• - fatal if not treated immediately
• Can be triggered by all volatile anaesthetics
  (ie. halothane) and the muscle relaxant
  succinylcholine

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The Ryanodine Receptor!

• Ryanodine receptor (RyR1)
• Ca2 channel on the sarcoplasmic reticulum of
  skeletal muscle cells
• has two Ca2 binding sites (one high-affinity,
  one low)

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How its supposed to work

• Action potential
• propagates through T-tubule, activates
  dihydropyridine receptor (DHP)
• DHP releases small amount of Ca2 into the
  cytosol
• Ca2 binds to high-affinity RyR1 site ? channel
  opens ? positive feedback
• excitation-contraction coupling
• high intracellular Ca2 activates low-affinity
  site and channel closes

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The RyR1 Gene

• long arm of chromosome 19
• 90 mutations identified, at least 25 causal for
  MH
• Autosomal dominant inheritance
• Mutation clusters in central region and
  N/C-termini destabilize closed state of channel
• Mutation causes trigger agents (caffeine,
  anaesthetics, succinylcholine) to alter affinity
  of Ca2 binding sites
• Closed state of channel is destabilized

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Incidence / Risk Factors

• 15000-150000 (depending on anaesthetic)
• all ethnic groups
• twice as common in males
• majority of patients with central core disease
  (inherited myopathy) are susceptible
• Biopsy susceptibility testing can confirm, but
  not rule out, MH in those with a family history

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Signs/Symptoms

• Hypermetabolism
• Muscle rigidity
• Cell damage
• leakage of potassium, creatine kinase, myoglobin
• Increased ventilation/cardiac output
• ?PaCO2 ?PaO2, lactic acidosis
• Hyperthermia
• typically temperature rises by 1-2oC every 5
  minutes

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Lethal Consequences!

• Cardiac arrhythmias (hyperkalemia)
• Hemorrhage (acidosis)
• Disseminated Intravascular Coagulation (gt41oC)
• Renal failure (rhabdomyolysis/myoglobinuria)

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Treatment

• Dantrolene sodium the only current treatment
• Reduced mortality from 80 (1960s) to lt10
  (present day)
• Must be administered immediately
• Mechanism
• Binds antagonistically to RyR and blocks release
  of Ca2
• Ca2 will be pumped back into SR and ATP
  expenditure will decrease

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Future Research

• Dantrolene administration can be problematic due
  to low water-solubility
• Large fluid volumes must be infused, rapid IV
  preparation is difficult
• Azumolene is 30x more water-soluble and equally
  potent, but has not yet entered clinical use.

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Malignant Hyperthermia - Summary

• Definition
• uncontrolled increase in skeletal muscle
  metabolism due to mutation in ryanodine receptor
  (RyR)
• autosomal dominant mutation causes trigger agents
  (anaesthetics, succinylcholine) to destabilize
  closed state of RyR channel
• Release of Ca2 into cytosol causes massive
  energy expenditure and hyperthermia
• Symptoms hypermetabolism, hyperthermia, muscle
  rigidity, respiratory/metabolic acidosis, cell
  damage/leakage (potassium, creatine kinase,
  myoglobin)
• Diagnostic Criteria
• Respiratory acidosis (End tidal CO2 gt 55mmHg)
• Unexplained tachycardias, ventricular
  fibrillation
• Rhabdomyolysis (CK gt 20,000/L units, cola
  coloured urine, potassium gt 5mmol/L)
• Rapidly increasing temperature (gt38.8oC)Family
  history
• If untreated, death results from cardiac
  arrhythmias, hemorrhage, renal failure and
  disseminated intravascular coagulation (DIC).
• Treatment Dantrolene sodium antagonizes RyR1 and
  halts Ca2 efflux from sarcoplasmic reticulum
  (problematic due to low water-solubility).

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References

• Bryant S.H. et. al. The mechanism of action of
  dantrolene sodium, Journal of Pharmacology and
  Experimental Therapeutics, 1977
• http//jpet.aspetjournals.org/cgi/reprint/201/1/1
  38
• Davis, M. et. al. Malignant Hyperthermia,
  Orphanet Journal of Rare Diseases, 2007
• http//www.pubmedcentral.nih.gov/articlerender.fc
  gi?artid1867813
• Krause, T. et. Al. Dantrolene - A review of its
  pharmacology, therapeutic use and new
  developments. Anaesthesia. 59(4), 364373.
• Lenhart S.E. et. al. Modulation of the ryanodine
  receptor and intracellular calcium, Annual Review
  of Biochemistry, 2007
• http//arjournals.annualreviews.org/doi/full/10.1
  146/annurev.biochem.76.053105.094237