(09) Clin Corr: Malignant Hyerpthermia

Question 1

What went wrong after giving the anesthesia?

Answer 1

• increased end tidal CO2 (110 mmHG)
• Hyperthermia (107)
• Tachycardia HR 108 bpm (vs 32-48)
• premature ventricular contractions
• Blood pH at 6.7, PaCO2 137 mmHg, PaO2 110 mmHg
• Hypertension
• High hemoconcentration

Question 2

What did they treat the ventricular tachycardia with?

Answer 2

• magnesium sulfate and lidocaine

Question 3

Voltage potential propagates into the T-tubule

Activates _____ (_____)

Activates \_\_\_\_\_ (\_\_\_\_\_) in the
 sarcoplasmic reticulum (SR)

_____ release into the cytoplasm

Ca2+ unbinds calsequestrin and binds to _____, uncovering myosin crossbridge binding sites on _____

Concentric contraction initiated

SERCA Ca2+-ATPase actively pumps Ca2+ back into the SR

Ca2+ is no longer bound to troponin C, the
troponin complex goes back to blocking binding
sites on actin.

Answer 3

• dihydropyridine receptors, DHPR
• ryanodine receptors, RYR
• Ca2+
• Troponin C

Question 4

Mutation of what gene leads to Malignant Hyperthermia? (in what)?

What does this cause in humans?

MH in humans has also been associated with mutations in _____.

Answer 4

• gene encoding the skeletal muscle ryanodine receptor (RYR1)
• pigs, humans, dogs, horses
• central core disease, multi-mini core disease
• DHPR

Question 5

• MH crisis results from uncontrolled muscle _____ release

• In vitro contracture test:
– Increased sensitivity to
_____ and _____

• SR calcium channels form MH pigs:
– Increased ______
release
– Enhanced activation by
______, ______
– Enhanced t-tubule
______
– Reduces inhibition by high
concentrations of _____ and
_____

Answer 5

• Ca2+
• caffeine, halothane
• calcium-induced-calcium
• caffeine, halothane
• depolarization
• calcium,

Question 6

What type of disease is malignant hyperthermia?

List the types of anesthesia?

• How many RYR1 mutations have been identified in humans?

What domain are RYR1 found in in pigs? dogs? horses?

Answer 6

• autosomal dominant pharmacogenetic disease
• halothane > isoflurane > sevoflurane > desflurane
• > 80
• 1, 1, 2

Question 7

What is particular is the fuck up in malignant hyperthermia?

What results due to this?

Answer 7

• abnormally induced or prolonged open state of RYR
• increased intracellular Ca2+
• sustained muscle cell activation and contraction
• increased aerobic and anaerobic metabolism

Question 8

look at this for a spell

Question 9

What induces the ventricular fibrillation?

Another thing I forgot to mention….

• Markedly increased ________ ventilation during ______ ventilation.

Answer 9

• hyperkalemia (high K)
• minute, spontaneous

Question 10

(Clinical Findings During General Anesthesia)

Muscle rigidity-

• Initially _______ muscle spasm, contraction of _____
• Generalized muscle ______
• Protraction of the _________ and _______ of the globe
• _______ (brown, coffee-colored urine)

Answer 10

• masseter
• rigidity
• third eyelied, retraction
• myoglobinuria

Question 11

(Laboratory Findings During General Anesthesia)

List them (there are 7)

-reminder PRAMHHH

Answer 11

• poor oxygenation depsite mechanical ventilation
• respiratory acidosis
• acidemia
• metabolic (lactic) acidosis
• hypertension
• hemoconcentration
• hyperproteinemia

Question 12

(Laboratory Findings During general anesthesia) PART 2

List them (CHARE)

Answer 12

• hyperglycemia
• azotemia (increased blood urea nitrogen and creatinine)
• rhabdomyolysis
• Electrolyte abnormalties (high K, Phosphate, low chloride, low or high natremia, calcium)
• coagulopathy

Question 13

What is used as treatement for malignant hyperthemry?

Answer 13

• Dantrolene (only specific treatment), abolishes excitation-contraction coupling, decreases intracellular calcium (by actin on ryanodine receptor)
• Supportive care (fluids, acid/base, hyperkalemia)

Question 14

What is the combo that she talks about?

Question 15

(Polysaccaride Storage Myopathy) LOOK AT TITLE

• A common inherited _____ in horses
• A dmoinant mutation in _____
• Unregulated _____ activity
• Accumulation of excess ____ and _____
• What percentage of horses are hetero and homo?

Phenotype?

• what can it cause?

Answer 15

• glycogenolysis
• GYS1
• glycogen synthas
• glycogen - abnormal, less branched polysaccharide
• 6%, 94% (quarter horses)
• varies widely
• exertional rhabdomyolysis, recumbency resulting in euthanasia

Question 16

What are some environmental factors that affect phenotypic expression of polysaccharide storage myopathy?

Answer 16

• decreased consumption of starch (helps) - consistent daily exercise (these reduce exertional rhabdomylosis 75%)
• Allelic heterogeneity
• modifying genes

Question 17

What was her hypothesis about the phenotypic variation?

Answer 17

• phenotypic variation in PSSM may be due in large part to presence of modifying genes

Question 18

What are the three steps of identifying a modifying gene?

Answer 18

1. genetic assocation (identifying a candidate gene)
2. exercise trial (demonstrate clinical significance)
3. retrospective analysis

Question 19

Where is the GYS1 locus?

Answer 19

• ECA10

Question 20

What was her hypothesis about the combo?

What did she notice when fed fat vs starch?

How did they meausre this?

Answer 20

• RYR1 mutation results in a more sever clinical phenotype in this family
• The affected horses fared much better on a high fat diet than on a high starch diet.
• creatinine kinase in the blood

Question 21

• Horses with both GYS1 and RYR1 were more likely to have _____ rhabdomyolysis

Answer 21

• non-exertional

Question 22

• What is the prevalence of RYR1 mutation in quarter horse and related?

Answer 22

• 0.5 to 1%