Inherited diseases relevant to anaesthesia

Question 1

What are the 2 key inherited diseases relevant to anaesthesia?

Answer 1

1. Malignant hyperpyrexia (/hyperthermia)
2. Pseudocholinesterase deficiency

Question 2

What is malignant hyperpyrexia/ hyperthermia?

Answer 2

• Life-threatening condition resulting from a genetic sensitivity of skeletal muscles to volatile anaesthetics and depolarising neuromuscular blocking drugs
• Often seen following administration of anaesthetic agents, during or after

Question 3

What is the physiological/genetic cause of malignant hyperpyrexia?

Answer 3

• Excessive release of Ca²⁺ from the sarcoplasmic reticulum of skeletal muscle
• This is associated with defects in a gene on q (long) arm of chromosome 19, encoding the ryanodine receptor, which controls Ca²⁺ release from the sarcoplasmic reticulum
• In malignant hyperpyrexia, the ryanodine receptor doesn’t close properly following a stimulus, which leads to excessive calcium release, reabsorbed in the SR in a futile cycle

Question 4

What type of inheritance pattern does malignant hyperpyrexia follow?

Answer 4

• Autosomal dominant with variable penetrance
• shows vertical transmission
• (50% chance child will have it if you have it if you’re heterozygous, 100% if you’re homozygous)

Question 5

What type of condition may have a similar aetiology/ be related to malignant hyperpyrexia?

Answer 5

Neuroleptic malignant syndrome

Question 6

How common is malignant hyperpyrexia and who is affected?

Answer 6

• Occurs in 1 in 4500 to 1 in 60 000 patients, depending on how close to affected group you are geographically
• Can affect all races and occurs worldwide
• Children and younger patients more commonly affected (perhaps because know it exists in affected older adults already?)

Question 7

Why might it appear that a generation has been skipped rather than the usual vertical transmission for malignant hyperpyrexia?

Answer 7

If penetrance is low and parents have only 1 or 2 children, this can happen

Question 8

What are 6 features of the presentation of malignant hyperpyrexia?

Answer 8

1. Muscular rigidity
2. Hyperthermia
3. Rhabdomyolisis
4. Hypermetabolic state
5. Increased oxygen consumption
6. Increased carbon dioxide production

Question 9

What are the 4 substances produced due to rhabdomyolysis, and which is the most lethal?

Answer 9

1. Myoglobin
2. Creatine kinase
3. Creatine phosphate
4. Potassium - this is the most lethal

Question 10

What are the 2 key causative agents for malignant hyperpyrexia?

Answer 10

1. Halothane
2. Suxamethonium
3. (antipsychotics can also cause ⇒ neuroleptic malignant sydrome)

Question 11

Does the causative agents of malignant hyperpyrexia lead to a reaction every time?

Answer 11

No

Question 12

Why do hyperpyrexia and muscle damage result from lack of closure of the ryanodine receptor and release of calcium, in malignant hyperpyrexia?

Answer 12

• The process consumes large amounts of ATP and generates excessive heat
• Muscle cell damaged by depletion of ATP and possibly also the high temperature, and cellular constituents leak into circulation (potassium, creatine, creatine kinase, myoglobin)

Question 13

What are the first 6 steps to take when someone is suffering from malignant hyperpyrexia?

Answer 13

1. Call for help - too difficult for one person
2. Stop triggering agents
3. Hyperventilate with 100% oxygen
4. Finish or abort procedure
5. Treat with dantrolene
6. Cool patient

Question 14

What is the drug used to treat malignant hyperpyrexia and what is the dose?

Answer 14

• Dantrolene
• 2mg/kg bolus; may repeat 2mg/kg every 5 minutes, then 1-2mg/kg each hour

Question 15

How does dantrolene work to treat malignant hyperpyrexia?

Answer 15

Prevents Ca²⁺ release from the sarcoplasmic reticulum

Question 16

1. Cold IV normal saline
2. Cold body cavity lavage
3. Ice bags to body
4. Cold nasogastric lavage
5. Cooling blanket

Answer 16

What are 5 ways to cool a patient down who is suffering from malignant hyperpyrexia?

Question 17

What are 6 further things to treat or monitor when a patient is suffering from malignant hyperpyrexia?

Answer 17

1. Change to clean breathing system not exposed to volatile agents
2. Monitor and treat acidosis
3. Promote urine output
4. Treat hyperkalaemia urgently and effectively
5. Treat dysrythmias
6. Monitor creatine kinase, urine myoglobin, and coagulation for 12-24 hours

Question 18

How should acidosis during malignant hyperpyrexia be monitored and managed?

Answer 18

Monitor with serial ABGs, give sodium bicarbonate

Question 19

What urine output should be aimed for following malignant hyperpyrexia, and what are 2 drugs that can be given to achieve this?

Answer 19

• maintain >2ml/kg/hour with conscientious fluid management
• Furosemide and mannitol as appropriate

Question 20

What are 2 drugs that can be used to treat dysrhythmias during malignant hyperpyrexia?

Answer 20

Procainamide, calcium chloride

Question 21

What is another drug currently under investigation to treat malignant hyperpyrexia?

Answer 21

Azumolene

Question 22

What is the test for malignant hyperpyrexia and what does it involve?

Answer 22

• Caffeine-halothane contracture test (CHCT)
• Muscle biopsy taken from front of thigh at an approved centre (only a few in UK)
• fresh biopsy bathed in solution containing caffeine and halothane, observed for contraction

Question 23

What are the sensitivity and specificity of the caffeine-halothane contracture test for malignant hyperpyrexia?

Answer 23

97% sensitivity, 78% specificity

Question 24

What are 8 things that should be done for a patient undergoing surgery who is known to be susceptible to malignant hyperpyrexia?

Answer 24

1. Clean machine: remove vaporisers, replace CO₂ cannisters, bellows and gas hose
2. Flush machine for 20 minutes with oxygen, 10L/min
3. Make sure the MH ‘pack’ is available: drugs and sheet for management, enough in-date dantrolene
4. Schedule patient as first case of day, arrange ICU/HDU post-op
5. Consider dantrolene and sedation as pre-medication
6. Check creatine kinase, FBC, U&E pre-operatively - baseline values to compare
7. Considered anaesthetic alternatives: monitored anaesthetic care with sedation and local anaesthesia, or GA using non-triggering agents. TIVA can be given
8. After surgery, check lab values for CK and ABG, monitor patient in an appropriate setting

Question 25

What is pseudocholinesterase deficiency?

Answer 25

* **Inherited enzyme abnormality (pseudocholinesterase)**, in which there is abnormally **slow degradation** of exogenous choline ester drugs, such as succinylcholine * other pathological conditions, physiological alternations, and medications can also lower plasma pseudocholinesterase activity

Question 26

What is the presentations of pseudocholinesterase deficiency and what are 3 examples of drugs that can cause it?

Answer 26

* Prolonged duration of action with: * suxamethonium * mivacurium * ester local anaesthetics: procaine, cocaine

Question 27

What is the normal action of pseudocholinesterase enzyme on suxamethonium?

Answer 27

* hydrolysis and inactivation of approximately 90-95% of an intravenous dose of succinylcholine occurs before it reaches the NMJ. * Remaining 5-10% of succinylcholine acts as a receptor agonist at the NMJ

Question 28

How does suxamethonium's effects on the NMJ usually wear off?

Answer 28

By diffusion

Question 29

By how long can the effects of suxamethonium be prolonged in a patient with pseudocholinesterase deficiency?

Answer 29

up to 8 hours (vs normal effect of about 2 minutes)

Question 30

In which ethnic groups is inherited suxamethonium deficiency more common?

Answer 30

People of European descent (rare in Asians)

Question 31

What genetic mutation can cause pseudocholinesterase deficiency?

Answer 31

Gene at E1 locus on the long arm of chromosome 3

Question 32

What proportion of the population is homozygous for the normal pseudocholinesterase genotype, and how is this designated?

Answer 32

96%, EuEu

Question 33

What are the 3 types of atypical alleles that 4% of the population carry one or more of?

Answer 33

1. **Ea**: atypical dibucaine-resistant variant point mutation 2. **Ef**: fluoride resistant variant point mutation 3. **Es**: silent variant frameshift mutation

Question 34

What will be the phenotype of a single atypical allele involved in pseudocholinesterase deficiency (E1 locus on chromosome 3)?

Answer 34

partial deficiency in enzyme activity - slightly prolonged duration of paralysis, longer than 5 minutes but shorter than 1 hour

Question 35

What proportion of the population carry 2 pseudocholinesterase gene allele mutations, and what is the effect of this?

Answer 35

Less than 0.1%; will produce clinically significant effects from succinylcholine lasting **longer than 1 hour**

Question 36

What are 7 causes of apparent pseudocholinesterase deficiency?

Answer 36

1. chronic infections (e.g. tuberculosis) 2. extensive burn injuries 3. liver disease 4. malignancy 5. severe malnutrition 6. severe uraemia 7. some drugs e.g. chlorpromazine, bambuterol, cyclophosphamide, glucocorticoids (high ose)

Question 37

How is pseudocholinesterase deficiency diagnosed?

Answer 37

* Plasma assays of pseudocholinesterase enzyme activity * Sample of **patient's plasma** incubated with **substrate** butyrulthiocholine along with **indicator chemical** 5,5'-dithiobis-(2-nitrobenzoic acid). Assayed using **spectrophotometry**

Question 38

What are the 3 key aspects of treatment of a patient with pseudocholinesterase deficiency, who has been given suxamethonium?

Answer 38

1. **Sedation and ventilation:** make sure suxamethonium worn off before giving non-depolarising muscle relaxant. _Keep *anaesthetised*,_ _*sedated* to point of unconsciousness_ 2. **FFP** 3. **Blood transfusion**

Question 39

Should you try to wake up a patient while paralysed who is experiencing prolonged suxamethonium action?

Answer 39

no

Question 40

How can you check if a patient with pseudocholinesterase deficiency is still paralused?

Answer 40

use nerve stimulator

Question 41

Why are FFP and blood transfusions given in pseudocholinesterase deficiency reactions?

Answer 41

FFP contains some pseudocholinesterase, which can help reverse these patients

Question 42

When should FFP be used to treat pseudocholinesterase deficiency?

Answer 42

in serious conditions in which there is no pseudocholinesterase at all