2018B

2018 (2nd sitting)

Question 1

Question

Describe the surface anatomy of the anterior neck (30% of marks) and the underlying structures relevant to performing a tracheostomy (70% of marks).

Example answer

Structure

Fibromuscular tube ~10cm long
Supported by 16-20 incomplete cartilaginous rings which joined by fibroelastic tissue and are connected posteriorly by smooth muscle (the trachealis)
Divided into cervical and thoracic parts

Course

Trachea begins approximately C6 where it is continuous with the larynx
Trachea travels inferoposteriorly
Enters thoracic cavity through the superior thoracic aperture, at the level of the jugular notch
Ends approximately at level of sternal angle (T4/5) where it divides into left and main bronchi

Relations

Posterior: oesophagus
Anterior: thyroid gland (isthmus), cervical fascia, manubrium, thymus remnants,
Right lateral: thyoid gland (lobe), carotid sheath ( common carotid, vagus, IJV), RLN
Left lateral: thyroid gland (lobe), carotid sheath ( common carotid, vagus, IJV), RLN

Neurovascular supply

SNS: sympathetic trunks
PSNS: recurrent laryngeal and vagus nerves
Arterial supply: Branches from inferior thyroid arteries
Venous drainage: Inferior thyroid veins

Surface anatomy of anterior neck (superior --> inferior)

Hyoid bone (C3)
Thyroid cartilage
Cricothyroid membrane
Cricoid cartilage (C6)
Thyroid gland
Sternohyoid muscle just lateral to the midline structures, overlies sternothyroid and thyrohyoid

Layers of dissection in tracheostomy (from anterior --> posterior)

Skin
Subcutaneous tissue
Fat
Pretracheal fascia
Fibroelastic tissue between tracheal cartilage rings
Trachea

Examiner comments

79% of candidates passed this question.

Answers required a description of the surface anatomy outlining the midline structures including
the hyoid bone and cartilages. The tissue layers should have been mentioned as should the
relevant tracheal anatomy. The anterior, posterior and lateral relations of the trachea should
also have been included along with the relevant nerves and blood vessels. Diagrams were not
essential but could have been included.
Candidates should note that marks were not awarded for a description of how to perform a
tracheostomy.

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Question 2

Question

Compare and contrast amiodarone and digoxin.

Example answer

Name	Digoxin	Amiodarone
Class	Cardiac glycoside (antiarrhythmic)	Antiarrhythmic (Class III), though other class (I, II, IV) activity
Indications	tachyarrhythmias (e.g. AF, SVT), heart failure	Tachyarrhythmias (e.g. SVT, VT, WPW)
Pharmaceutics	62.5mcg/250mcg (PO tablets) 25/250 mcg/ml (IV)	100-200mg tablets Clear solution in ampoules (150mg) for dilution in dextrose
Routes of administration	IV and PO	IV and PO
Dose	Generally load with 250-500mcg, then 62.5-125mcg daily thereafter. Digoxin level (0.7 - 1.0) for most conditions.	IV: 5mg/kg, then 15mg/kg infusion / 24hrs. Oral: 200mg TDS (1/52) > BD (1/52) > daily
pKA	7.2	6.6 (highly lipid soluble)
Pharmacodynamics
MOA	Direct cardiac: inhibits Na/K ATPase > increased Ca > positive inotropic effect + increased refractory period Indirect cardiac: increased PSNS release of ACh at M receptors > slowed conduction at AV node/bundle	- Blocks K channels (Class III effects) prolonging repolarisation and therefore refractory period. - Decreases velocity of Phase 0 by Blocking Na channels (Class I effects) - Non-competitive inhibition of Ca channels prolonging depolarisation + AV nodal conduction time (Class IV effects) - Slows AV/SA nodal conduction via anti-adrenergic activity (Class II effects)
Side effects	CVS: May worsen arrhythmia (lead to VF), AV block, shortened QT interval, scooped ST, TWI, bradycardia GIT: nausea, anorexia, vomiting CNS: dizziness, drowsiness	Side effects worsen w. time! RESP: pneumonitis, fibrosis CVS: bradycardia, QT prolongation CNS: peripheral neuropathy Thyroid: hypo/hyperthyroidism LIVER: cirrhosis, hepatitis DERM: photosensitivity, skin discolouration
Pharmacokinetics
Onset	2-3 hours (PO), 10-30mins (IV), duration of action 3-4 days	Immediate (IV), 4 hours (PO)
Absorption	80% oral bioavailability	PO bioavailability 40-60%
Distribution	Protein binding 25% VOD 6-7L/kg	Highly protein bound (>95%) VOD: ~70L /kg
Metabolism	Minimal hepatic metabolism (15%)	Hepatic (CYP3A4) with active metabolites (desmethylamiodarone)
Elimination	T 1/2 48 hours urine excretion (70% unchanged)	T 1/2 = 1 month Faces, urine, skin
Special points	Reduce dose in renal failure, monitor with dig level. not removed by dialysis	Amiodarone increases digoxin level (by preventing renal excretion and lowering protein binding)

Examiner comments

82% of candidates passed this question.

Most candidates had a good structure for answering this question; a table was commonly used.
Marks were awarded for indications and an explanation of the mechanism of action of both
drugs, which was generally well explained. The pharmacodynamic effects were often listed in a
general manner and more detail would have achieved a higher mark, including a list of the ECG
effects. Some detail on the pharmacokinetics and adverse effects of the drugs was expected
and this section was generally well answered. Better answers noted digoxin levels and potential
drug interactions.

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Question 3

Question

Explain the causes of the differences between measured end tidal and arterial partial pressures of carbon dioxide (CO2).

Example answer

ETCO2 - PaCO2 gradient

There is normally a gradient between PaCO2 and ETCO2 of 0-5mmHg (where ETCO2 is lower)
The difference between the values is due to alveolar dead space
- Alveolar dead space is due to alveoli which are ventilated but not perfused (e.g. west zone 1 lungs)
- These alveoli do not participate in gas exchange (there is no perfusion), thus contain very little CO2 and a lot of O2 (the same amount as in inspired air)
- This relatively CO2 deplete gas mixes with the rest of the expired gas, diluting the ETCO2 reading, thus leading to an observed discrepancy
- Note: It is not due to anatomical dead space as this gas has already been washed out in the early stages of exhalation and thus does not contributed to ETCO2
Healthy/awake patients have near zero alveolar dead space, so near zero gradient

Factors affecting ETCO2 - PaCO2 gradient

Changes in pulmonary perfusion
- Global reduction in pulmonary perfusion
  - e.g. pHTN, heart failure, Cardiac arrest, Severe shock
- Regional decreases in pulmonary perfusion
  - e.g. pulmonary embolism, fat embolism
Changes in ventilation
- Excessively high PEEP --> increased West Zone 1
Measurement error
- Inline HME filters
- Timing of measurement (measuring before end-expiration)
- Poor / loss of ETCO2 calibration
- Interference from other gases (e.g. N2O and collision broadening)
Physiological factors
- Increasing age > increased gradient

Examiner comments

29% of candidates passed this question.

The answer required an explanation of the causes of the difference between the PaCO2 and ETCO2. This required recognising how the end point of phase 3 of the capnograph trace corresponds with end tidal CO2. The difference is caused by the alveolar dead space. The difference is normally very small in healthy adults with the ETCO2 being lower than the PaCO2. It is increased with increasing alveolar dead space. Many incorrectly attributed anatomical dead space as a contributor to the PaCO2-ETCO2 gradient. Discussion of the various types of dead space did not score marks. Marks were awarded for the processes that cause an increased gradient e.g. low cardiac output and pulmonary embolism. Recognising physiological factors such as increasing gradient with increasing age scored marks. Marks were not awarded for descriptions on how dead space is measured.

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Question 4

Question

Compare and contrast ketamine and midazolam.

Example answer

Name	Midazolam	Ketamine	Notes
Class	Benzodiazepine (sedative)	Anaesthetic (phencyclidine derivative)
Indications	Anaesthesia, sedation, treatment of seizures, anxiolysis	induction GA, conscious sedation, analgesia,
Pharmaceutics	IV: clear solution, pH 3.5. Diluted in water.	100mg/ml. Clear colourless solution. Racemic mixture of S and R enantiomers, or S+ enantiomer alone. Water soluble.
Routes of administration	IV, IM, S/C, intranasal, buccal, PO	IV/IM/PO/SC/PR
Dose	Dose depends on many pt. factors. 1-5mg premedication. 2.5-10mg seizures. Infusions.	0-0.25mg/kg/hr (analgesia), 1-2mg/kg (GA), 0.5mg/kg (sedation)
pKa	6.5	7.5
Pharmacodynamics
MOA	Midazolam (BZD) binds to GABA_A receptors (ionotropic ligand gated channel) in the CNS. Cl enters > hyperpolarisation.	NMDA antagonism, weak opioid receptor agonism, weak Ca ch inhibition	- Ketamine has weak GABA effects
Effects	CNS: sedation, amnesia, anticonvulsant effects, decreased cerebral O2 demand	CNS: dissociative anaesthesia and analgesia. CVS: increased HR/BP, decreased pulmonary and systemic vascular resistance RESP: bronchodilation	- Ketamine has analgesic and bronchodilator properties - Midaz has anticonvulsant properties
Side effects	CVS: bradycardia, hypotension CNS: confusion, restlessness RESP: respiratory depression/ apnoea	CNS: emergence reactions including hallucinations, unpleasant dreams. May increase ICP in non vent. pts. CVS: may increase HR/BP, increased myocardial O2 req. GIT: Nausea, vomiting, increased salivation	- Ketamine does not cause respiratory depression and preserves airway reflexes
Pharmacokinetics
Onset	peak effect 2-3 minutes (IV)	30s IV, duration of effect 10-20mins
Absorption	~40% oral bioavailability Absorbed well, but sig. 1st pass metabolism	Lipid soluble > readily absorbed. But poor OBA (16%) due to 1st pass metabolism	Both have poor PO bioavailability
Distribution	95% protein bound, very lipid soluble Vd = 1L / kg	Large (5L/kg) VOD. Small protein binding (25%). Crosses placenta.	- Midaz will rapidly accumulate with infusions, ketamine will not
Metabolism	Hepatic metabolism by hydroxylation Active (1-a hydroxymidazolam) and inactive metabolites	Metabolised by CYP450 > majority inactive metabolites (norketamine active 33% potency)	Similar
Elimination	Renal excretion T 1/2 = 4 hours	Elimination T1/2 = 2 hours. Kidneys (95%), faeces (5%)	Both predominately renal excretion
Special points	Flumazenil - antagonist (reversal agent)	Nil reversal agent	No reversal agent for ketamine - Midaz exhibits tolerance, withdrawal, dependence, ketamine does not.

Examiner comments

62% of candidates passed this question.

In addition to the key PK and PD properties of each drug, a clear comparison was required to score well (why choose one drug over the other?). When a table was used the addition of a comparison column was helpful. A good answer covered the following: ketamine has analgesic properties whilst midazolam does not; ketamine preserves airway reflexes and does not cause respiratory depression unlike midazolam; whilst ketamine increases cerebral blood flow and CMRO2, midazolam decreases t; ketamine has a direct myocardial depressant effect which is often offset by an increase in sympathetic tone, whilst midazolam has no direct cardiac depressant effects but may reduce BP due to reduced SVR; midazolam has anticonvulsant properties, ketamine does not; ketamine is a bronchodilator; both drug effects are offset by redistribution; midazolam is lipophillic at body pH and will accumulate with prolonged infusions, ketamine will not; both are metabolised in the liver; midazolam can be reliably reversed by flumazenil, whereas there is no reliable complete reversal of ketamine; midazolam exhibits tolerance, dependence and withdrawal, whereas patients will only experience tolerance to the analgesic properties of ketamine. â€œDrugs in Anaesthesia and Intensive careâ€ chapters on midazolam and ketamine outline the key facts to include in this answer; interpretation and comparison of these facts will help achieve a good mark.

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Question 5

Question

Describe the carriage of carbon dioxide (CO2) in the blood.

Example answer

Overview

CO₂ is constantly produced as a by-product of metabolism and needs to be cleared
CO₂ content of blood
- Mixed venous: 52mls/100mls blood, at PaCO₂ of ~45mmHg
- Arterial: 48mls/100mls blood, at PaCO₂ of ~40mmHg

CO₂ is transported in three main forms in the blood:

Dissolved CO₂

Accounts for
- ~5% of the total carbon dioxide in the blood
- ~10% of the CO₂ evolved by the lung
The amount dissolved is proportional to the partial pressure (Henry's Law)
20x more soluble than O₂, so dissolved CO₂ plays a more significant role in transport

Bicarbonate

Accounts for
- ~90% of the carbon dioxide in the blood
- ~60% of the CO₂ evolved by the lung
Bicarbonate is formed by the following sequence
<math display="block">CO_2 + H_{2}O \leftrightarrow H_{2}CO_{3} \leftrightarrow H^+ + HCO_3^-</math>
Process
- CO2 dissolves into RBC and leads to H+ and HCO3 (per above equation)
- HCO3 moves into plasma, H+ binds to reduced (deoxy) Hb
- Cl moves into the cell to maintain electroneutrality (chloride shift)
- When Hb is oxygenated in the lungs, H+ dissociates and coverted back to CO2 by the above equation and is exhaled
- Haldane effect accounts for the increased capacity of Hb to carry CO2 when poorly oxygenated

Carbamino compounds

Accounts for
- ~5% of the CO₂ in the blood
- ~30% of the CO₂ evolved by the lung
Formed by the combination of CO₂ with terminal amine groups in blood proteins
Haemoglobin is the most abundant protein and has most imadazole side chains (greatest carrier capacity)
- The reaction occurs faster with deoxHb than oxy-Hb (Haldane effect)

Examiner comments

65% of candidates passed this question.

A definition of arterial and venous CO2 content (mls and partial pressure) and an outline of the 3 forms of CO2 in the blood and their contribution to the AV difference, followed by a detailed explanation of each form of carriage was required for this question. A good answer included a table of the contribution of each form of carriage to arterial and venous content and the AV difference; explained the concepts of chloride shift when describing carriage as HCO3 -; detailed the Haldane effect and its contribution to carbamino carriage and referenced Henryâ€™s law when describing dissolved CO2. Westâ€™s Chapter 6 on gas transport details the key information to score well on this question

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Question 6

Question

Outline the determinants of venous return to the heart

Example answer

Venous return

Rate of blood flow back to the right atrium
In healthy state: venous return = cardiac output (else pathological pooling of blood occurs)
Can be defined by following eqns:
- VR = CO
- VR = MSFP - RAP / resistance to venous return
Therefore factors effecting venous return are those that affect
- MSFP
- RAP
- Resistance to venous return
- Cardiac output

Cardiac output

Normally ~5L/min
Increased CO = increased venous reutn
CO is effected by
- Afterload (reduced afterload = increased cardiac output = increased VR)
- Contractility (increased contractility = increased CO = increased VR)

MSFP

Normally ~7mmHg
Increased MSFP = increased VR
Affected by venomotor tone and blood volume
Increased VR (= increased blood volume and increased venomotor tone)

RAP

Normally 2-6mmHg
Increased RAP = reduced driving pressure = reduced venous return
Factors which increase RAP
- Positive intrathoracic pressure (e.g. PPV)
- Reduced pericardial compliance (e.g. effusion)
- Reduced RA compliance/contractility (e.g. AF)
- TVR

Resistance to venous return

Increased RVR = reduced VR (due to ohms law)
Factors effecting RVR
- Autonomic tone
- Intrabdominal pressure
- IVC Obstruction (e.g. pregnancy) reduces VR
- Posture (decreased VR with erect posture)
- Vasoactive drugs
- skeletal muscle pump

Examiner comments

31% of candidates passed this question.

Answers should have included a description of the need for a pressure gradient for flow and a discussion on right atrial pressure, mean systemic filling pressure and resistance to blood flow. The discussion of each of these factors included definitions, normal values, factors affecting them and the direction of change on venous return. Diagrams were not essential, but their use assisted some candidates in explaining the effects of RAP on venous return.

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Question 7

Question

Describe protein binding and its significance in pharmacology.

Example answer

Protein binding

Drugs in blood can exist in two forms (protein bound, protein unbound)
Protein binding of drugs involves the formation of reversible drug-protein complexes
- Protein + drug <-> protein-drug complex
Drugs vary greatly in degree of plasma protein binding
- e.g. warfarin and phenytoin which are >95% protein bound
- e.g. rocuronium which is approx. 10% protein bound
Types of proteins
- Drugs can bind to proteins in the plasma (e.g. albumin, globulins) or tissue
- Albumin is the most sig. drug binder and binds neutral/acidic drugs (e.g. barbiturates)
- a-1 glycoproteins and globulins bind basic drugs (e.g. morphine)
- Haemoglobin can bind some drugs e.g. phenytoin
Effect of protein binding
- Only unbound fraction exerts can interact with receptors and exert its pharmacologic effect
- Only unbound drug in plasma can freely cross cell membranes
- Only unbound drugs can undergo filtration or metabolism
- For drugs which are highly protein bound (>90%), small changes in degree of protein binding can have sig. clinical effects. I.e. protein binding from 99% to 98% doubles to unbound (active) drug concentration (from 1% to 2%)
- Highly tissue bound drugs have long duration of action, high volume of distribution and readily build up in the body
Protein binding is affected by
- Protein factors
  - Concentration of protein (decreased protein > increased unbound drug)
  - Number of available protein binding sites
- Drug factors
  - Protein affinity
  - Concentration of drug - higher drug concentration > saturation of protein > higher unbound (free) drug
- Patient factors
  - temperature and pH
  - Inflammation, infection, surgery > increased acute phase reactants > increased protein binding
  - Age

Examiner comments

19% of candidates passed this question.

Descriptions of protein binding were generally too brief (e.g. a statement saying that drugs and hormones bind to proteins in the plasma rather than a description of usually reversible binding with a drug-protein equilibrium). It was expected that the factors which determine protein binding would be described. Marks were attributed if proteins, along with characteristics of the drugs they bind, were named. Candidates achieved better marks if they named the pharmacological parameters affected by protein binding and explained how and why change occurs along with the significance of those changes. Few candidates differentiated between tissue and plasma protein binding and the different effects on the volume of distribution.

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Question 8

Question

Describe gastric emptying (40% of marks) and outline its regulation (60% of marks).

Example answer

Gastric emptying

The coordinated emptying of chyme from the stomach to the duodenum
Regulated by food, local mechanical, neural, hormonal and drug factors
Mechanism
- During fasting
  - Migrating motor complexes (Slow peristaltic waves that originate in fundus) sweep through stomach at regular intervals
  - Role is to keep the stomach empty of secretions and food debris
  - Interrupted by food consumption
- During fed state
  - Receptive relaxation of stomach following swollowing
  - Tonic contraction / peristalsis > propelling food towards pylorus > mixing
  - Small food particles <2mm are pushed through pyloric sphincter at a stable rate
    - Half time of solids is ~2 hours
  - Liquids empty more rapidly and the rate of emptying is dependant on the antral-duodenal pressure gradient.
    - Half time of liquids <30 minutes

Regulation

Food factors
- Fluids have half time of 30 mins, solids have half time of 2 hours
- Carbohydrates (fastest) > proteins > fatty acids (slowest)
- Tonicity: increased tonicity = decreases emptying rate
Local factors
- Increased gastric volume > increased gastric emptying
- Duodenal stretch / wall irritation / acidity >reflex inhibition > decreased gastric emptying
Neural factors
- Increased SNS stimulation > decreased contractility + gastric emptying
- Increased PSNS (vagal) activity > increased contractility + gastric emptying
Hormonal factors
- secretin (stimulated by low duodenal pH) > decreased emptying
- Cholecystokinin (stimulated by fatty acids) > decreased emptying
- Somatostatin > decreased emptying
- Gastrin (stimulated by stretch, amino acid content) > increased emptying)
- Motilin: stimulates migrating motor complex > increased emptying
Drugs factors
- e.g. opioids > decreased empyting
- eg. metoclopramide > increased emptying

Examiner comments

24% of candidates passed this question.

Candidates were required to provide a description of gastric emptying (40% marks). Although
the question showed the allocation of marks, many candidates did not provide sufficient detail
for this section. This required some description of what gastric emptying is (the co-ordinated
emptying of chyme from the stomach into the duodenum).
Better answers provided detail regarding the process of gastric emptying in the fed and fasted
state and differentiated between liquids, solids, carbohydrate, protein and fats. Factors
regulating emptying included an outline of peristaltic waves, the basal electrical rhythm and its
modulation, the migratory motor complex (MMC) and its modulation, neural input, stretch and
hormonal control.
Many candidates erred by answering the question "the regulation of gastric secretions" rather
than the question (the regulation of gastric emptying). Although they scored well for hormonal
control, they missed out on marks for the other factors relevant to the regulation of gastric
emptying.

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Question 9

Question

Describe the renal handling of water including the modulation of water excretion

Example answer

Renal handling of water

Glomerulus
- Water is freely filtered at the glomerulus (~180L / day)
- The amount filtered will depend on the GFR and starlings forces
Proximal convoluted tubule (PCT)
- Approximately 60-70% of the filtered water is reabsorbed
- Secondary active transport of Na in the PCT creates an osmotic gradient which allows passive absorption of water via osmosis
Loop of Henle (LOH)
- Approximately 10-15% of the filtered water is reabsorbed in the descending LOH
  - Iso-osmotic absorption due to the increased medullary concentration gradient
- The ascending LOH is relatively water impermeable
Distal convoluted tubule (DCT)
- Approximately 0-5% water reabsorbed in DCT
- Relatively impermeable
Collecting duct (CD)
- Reabsorbs 5-20% of the remaining water (depending on the level of ADH)
- ADH inserts luminal aquaporins in collecting duct cells which allows increased reabsorption of water down the osmotic concentration gradient

Regulation

There is an obligatory water loss of ~500mls a day needed for waste clearance
The body also needs to maintain fluid and osmolality homeostasis
The main site of water regulation in the nephron is in the collecting ducts via the action of ADH
Mechanism
- Primary:
  - Osmoreceptors in hypothalamus detect increased osmolality > increased production of ADH > increased release of ADH from posterior pituitary > increased luminal aquaporins in CD > increased water reabsorption
- Secondary
  - Baroreceptors detect reduced blood pressure > increased ADH secretion
  - ANP/BNP secretion is reduced with decreased BP (stretch) > decreased GFR + activation of RAAS

Examiner comments

37% of candidates passed this question.

This question required a brief introduction of the role the kidney plays in water balance; a more
detailed description of how water is handled as it passes through the various segments of the nephron (glomerulus, PCT, Loop of Henle, DCT and Collecting Duct); the modulation of water excretion by the kidney due to ADH (vasopressin) and how this operates; and the stimuli (osmotic and non-osmotic) for ADH secretion. Although worth mentioning in the context of the effect they have on water movement through the kidney, detailed explanations of Starling's forces in the glomerulus, and of the operation and maintenance of the counter-current mechanism, were not required. More important was describing the control of water reabsorption in the collecting ducts (and thus modulation of water excretion by the kidney) under the influence of ADH

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Question 10

Question

Compare and contrast the pharmacology of vancomycin and flucloxacillin.

Example answer

Name	Vancomycin	Flucloxacillin
Class	Glycopeptides (antibiotic)	Penicillins (antibiotic)
Indications	Severe gram positive infections,MRSA, C.diff	Gram positive infections (particularly staph)
Pharmaceutics	White powder for reconstitution	Capsule, tablet or white power for reconstitution
Routes of administration	PO, IV, PR, intrathecal	PO, IV,
Dose	Dose/interval adjusted according to desired peak/trough levels	250-1g, every 6 hrs
Pharmacodynamics
MOA	Inhibits cell wall synthesis by binding to D-ala-D-Ala portion of growing cell wall	Beta-lactam ring binds to penicillin binding protein > prevents crosslinking > impaired cell wall synthesis
Microbial coverage	Gram positives, including MRSA. C diff coverage	Narrow spectrum Gram positive bacteria Does
Side effects	CNS: ototoxicity RENAL: nephrotoxicity HAEM: thrombocytopaenia, leukopenia IMMUNO: red man syndrome	GIT: diarrhoea, nausea, cholestatic hepatitis IMMUNO: penicillin allergy CNS: neurotoxicity Haem: blood dyscrasias
Pharmacokinetics
Absorption	PO bioavailability <1%. Only given orally for C. diff infections.	PO bioavailability 70%
Distribution	Poor CSF penetration (requires higher dosing) VOD = 0.5L / kg 50% protein bound	95% protein bound VOD = 0.3 L /kg CNS penetration with meningitis only
Metabolism	No metabolism	Hepatic metabolism
Elimination	Unchanged in the urine T 1/2 = 6 hrs	Renal elimination (predominately unchanged) T 1/2 = 1 hour
Monitoring	Renal function	Monitor LFTs, renal function
Resistance	Cannot treat VRE (VanA/B resistance genes)	Can treat b-lactamase producing bacteria, but not MRSA (mecA gene)

Examiner comments

49% of candidates passed this question.

Most candidates structured their answers well. Expected information included: the class of antibiotic of each agent, their respective pharmaceutics, pharmacodynamics, pharmacokinetics, indications and adverse effects. Better answers provided pharmacodynamic and pharmacokinetic information relevant to each drug rather than generic statements. Good answers also included the common resistance mechanisms for both agents.

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Question 11

Question

Describe the anatomy relevant to the insertion of an intercostal catheter.

Example answer

Surface anatomy

Lateral approach
- ICC is inserted in the 'triangle of safety' based off surface landmarks
  - Anterior border: lateral border of the pectoralis major
  - Posterior Border: lateral border of latissimus dorsi
  - Inferior border: 5th intercostal space
  - Superior: base of axilla
Anterior approach
- Second intercostal space, midclavicular line

Layers of dissection / path of needle

Skin
Subcutaneous tissue
Pectoralis muscle (in anterior approach only)
External intercostal muscle
Internal and innermost intercostal muscles
Parietal pleura
Pleural space

Important anatomical considerations

Intercostal neurovascular bundle
- Sits in the inferior aspect of the rib, between innermost and internal IC muscles
- Vein > artery > nerve (from superior to inferior)
- Care to avoid this by aiming for the rib below, and guiding over the top of the inferior rib
Anterior approach
- Variable degrees of breast/subcutaneous tissue
- Will also contain the pectoralis major muscle (variable thickness) between subcutaneous tissue and intercostal muscles
5th intercostal space
- The reason it is important to place above the 5th intercostal space as this reduces of inadvertently placing the ICC into intrabdominal structures (e.g. liver, spleen) or penetration of the diaphragm (as the diaphragm can go as high as 5th intercostal space during expiration / pregnancy)
Deeper structures
- Beneath pleural space is the visceral pleura and lung parenchyma, which should be avoided..obviously
Internal mammary artery / lymphatic ducts
- Too far medial on anterior approach risks damage to these structures

Examiner comments

56% of candidates passed this question.

An anatomy question expects the use of anatomical nomenclature to describe relationships. Good answers defined the â€œsafe triangleâ€ for the lateral approach, soft-tissue layers passed through from skin to pleura and relationship of the neurovascular bundle to the ribs and intercostal muscles. Additional marks were gained for describing the anterior approach and related structures. Common omissions included description of deeper structures (relations) including intrathoracic and intra-abdominal organs and level of the diaphragm with regard to rib space. No marks were awarded for a description of intercostal catheter insertion.

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Question 12

Question

Outline the control of blood glucose.

Example answer

Overview

Normal blood glucose levels (BGLs) are ~4-6mmol/L
BGL will rise following carbohydrate consumption
Regulation of BGL is via short and long term mechanisms
Insulin and glucagon are the main regulatory hormones

High BGL

Increased BGL (>6.0mmols) is sensed directly by the pancreas
The increased glucose is taken up by GLUT receptors > undergoes glycolysis > increased ATP/ADP ratio > depolarisation > exocytosis of insulin from pancreatic B-islet cells
There is an initial rapid release, followed by a prolonged slow release
The increased insulin results in
- Increased glucose uptake into cells and Glycogenesis (liver)
- Decreased gluconeogenesis, glycogenolysis and lipolysis
The net effect is reduced BGL

Low BGL

Decreased BGL (or during times of fasting) is sensed by pancreas
Leads to
- Increased glucagon secretion from a-islet cells in pancreas (<3.0 mmols)
- Decreased insulin secretion from the B-islet cells in pancreas (<4.0 mmols)
Glucagon acts via GPCR (Gs) to
- Increased glycogenolysis and gluconeogenesis in the liver
- Increased lipolysis and ketoacid formation
Hypoglycaemia also directly stimulates the hypothalamus (with prolonged hypoglycaemia, starvation)
- Stimulates GHRH release > decreased glucose uptake + increased fat utilisation
- Stimulates ACTH release > increased cortisol > decreased glucose uptake + increased fat utilisation
- Stimulates TRH release > increased TSH > increased GIT absorption of glucose
- Stimulates "hunger" centre in the lateral hypothalamus > seek food
- Direct SNS stimulation of adrenal medulla > increased adrenaline > increased catabolism
The net effect is increased BGL

Other factors

BGL control is interconnected to liver function
- Involved in glycogenolysis/glycogenesis functions regulated by insulin/glucagon
- Hence liver dysfunction can impair its glucostat function and BSL control
BGL control is interconnected to renal function
- Can help modulate BGL control through control of absorption of glucose
Other
- Insulin and glucagon also affected by: cholecystokinin, somatostatin, food intake

Examiner comments

53% of candidates passed this question.

A definition of normal glucose levels was expected, mentioning how it is regulated despite variable intake. Most answers incorporated the roles of insulin/glucagon and the glucostat function of the liver. Sufficient detail regarding the mechanism of insulin release was often lacking. Extra marks were awarded for description of the role of the satiety centre in the hypothalamus, glucokinase and processes in fasting and starvation that maintain blood glucose levels. Marks were not awarded for describing effects of insulin and glucagon unrelated to glucose control.

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Question 13

Question

Compare and contrast rocuronium and cisatracurium

Example answer

Name	Rocuronium	Cisatracurium
Class	Aminosteroid NMB	Benzylisoquinolinium derivative (NMB)
Indications	NMB (e.g. RSI)	NMB (i.e. RSI)
Pharmaceutics	Clear colourless solution (50mg/5ml vials) Shelf life increased in fridge.	Clear colourless solution (10mg/5ml vials) stored at 4 degrees
Routes of administration	IV (can also be given IM)	IV (can also be given IM))
Dose	0.6 - 1.2mg/kg (RSI dose)	0.15-0.2mg/kg (RSI) Used more commonly as an infusion (titrated to desired TOF)
Pharmacodynamics
MOA	Non depolarising NMB Inhibits the action of ACh at the NMJ by competitively binding to alpha subunit of nAChR on pre and post junctional membrane	Non-depolarising NMB Inhibits the action of ACh at the NMJ by competitively binding to alpha subunit of nAChR on pre and post junctional membrane
Effects	NMB > paralysis	NMB > muscle paralysis
Side effects	Histamine release: none ANS: vagolytic (inc HR) OTHER: anaphylaxis (<0.1%), pain on injection	Histamine release: none ANS: no vagolysis OTHER: anaphylaxis (very rare)
Pharmacokinetics
Onset	Onset: 45-90s Duration: ~30 mins	Onset: 1-3 minutes Duration: 30-45 minutes
Absorption	IV only	IV only
Distribution	VOD = 0.2 L /kg Protein binding = 10% Doesn't cross BBB	VOD = 0.15 L/kg Protein binding = 15%
Metabolism	Minimal hepatic metabolism (<5%)	Organ independent Hoffman elimination (70-90%) > laudanosine and acrylate
Elimination	Bile 70%, Renal 30% elimination Unchanged drug T 1/2 = 90 mins	Renal and biliary elimination (10-30%) Inactive metabolites T 1/2 - 30 mins
Special points	Reversible with sugammadex	Not reversible with sugammadex

Examiner comments

32% of candidates passed this question.

This question was best answered using a tabular format outlining class of drug, pharmaceutics, pharmacokinetics, reversibility and side effects. Better answers commented on the significance of the differences between the two agents and its relevance to ICU practice. Many candidates confused these muscle relaxants with each other and with depolarising muscle relaxants.

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Question 14

Question

Explain the detection and response to hypoxaemia

Example answer

Hypoxaemia

Abnormally low concentration of oxygen in arterial blood
Usually defined clinically as a PaO2 < 60mmhg or SaO2 < 0.9

Hypoxia

Oxygen deficiency at the tissues which is typically, but not always, due to hypoxaemia
Prolonged hypoxaemia may often result in hypoxia

Detection of hypoxaemia

Stimulus
- Decreased PaO2
Sensors
- Peripheral chemoreceptors located in the carotid body and aortic arch
Afferents
- CN IX (carotid body receptors)
- CN X (aortic arch receptors)
Integrator/controller
- Medullary and pontine respiratory control centres
- Includes nucleus retroambiualis, parambigualis, ambigualis, PreBotzinger and Botziner complexes
Efferents and effectors
- Phrenic nerve (diaphragm) - predominant
- UMN nerves to the other muscles of respiration
Effector muscles
- Diaphragm and intercostal muscles
- Accessory muscles of respiration (SCM, pectoral, scalene, pharyngeal, abdominal muscles )

Response to hypoxaemia

Ventilatory response
- Increased minute ventilation (hyperbolic relationship with rapidly increasing MV when PaO2 <50-60)
Cardiovascular response
- Hypoxic vasoconstriction of pulmonary circulation
- Hypoxic vasodilation of systemic circulation
Autonomic response
- Relative increase in sympathetic tone
  - Leads to tachycardia, increased CO, increased SVR
  - BP stable / slight increase
Metabolic changes
- If concurrent hypoxia there will be a switch from aerobic to anaerobic metabolism
Hypoxia inducible factors (HIF)
- With tissue hypoxia, hypoxia inducible transcription factors are no longer broken down.
- HIFs > increased erythropoiesis (increased EPO), cell differentiation and angiogenesis

Examiner comments

34% of candidates passed this question.

A logical approach to answering this question included a definition of hypoxaemia and then a
discussion of the sensors, integrators and effectors involved. It was expected that candidates
would cover the peripheral chemoreceptor response (including the respiratory, cardiovascular
and autonomic effects), time course of the ventilatory response, hypoxia-inducible factors,
vascular effects (hypoxic vasoconstriction in the pulmonary circulation and vasodilatation in the
systemic circulation) and metabolic changes (switch to anaerobic metabolism). No marks were
awarded for discussing the causes of hypoxaemia. Many candidates incorrectly stated that
hypoxaemia is detected by the central chemoreceptors.

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Question 15

Question

Outline the production / absorption (30% of marks), composition (30% of marks) and function of cerebrospinal fluid (CSF) (40% of marks).

Example answer

CSF

ECF located in the ventricles and subarachnoid space
~2ml/kg of CSF
Divided evenly between the cranium and spinal column

Production

Constantly produced
~550ml produced per day (~24mls/hr)
Produced by
- Choroid plexus (70%) - located in ventricles of brain
- Capillary endothelial cells (30%)
Produced by a combination of ultrafiltration (via fenestrated choroidal capillaries) and active secretion
- Na actively transported out. Gradient drives co-transport of HCO3 + Cl
- Glucose via facilitated diffusion, water by osmosis

Composition relative to plasma

Similar: Na, osmolality, HCO3
Increased: Cl, Mg, CO2
Decreased: pretty much everything else (protein, potassium, calcium, glucose, pH)

Circulation

Circulation is driven by
- Ciliary movement of ependymal cells
- Respiratory oscillations and arterial pulsations
- Constant production and absorption
CSF flows from
- Lateral ventricles > foramen of Monro > 3rd ventricle > Sylvian aqueduct > 4th ventricle > cisterna magna (via foramen megendie and luschka) > spreads between spinal/cranial subarachnoid spaces

Reabsorption

Rate of ~24mls/hr
By the arachnoid villi
- Located predominately in the dural walls of the sagittal + sigmoid sinuses
- Function as one way valves, with driving pressure leading to absorption.

Functions

Mechanical protection
- The low specific gravity of CSF > decreased effective weight of the brain (1500g > 50g)
- With the reduced weight
  - Less inertia = less acceleration/deceleration forces
  - Suspended > no contact with the rigid skull base
Buffering of ICP
- CSF can be displaced / reabsorbed to offset any increase in ICP
Stable extracellular environment
- Provides a constant, tightly controlled, ionic environment for normal neuronal activity
Control of respiration
- The pH of CSF is important in the control of respiration (CO2 freely diffuses into CSF and can activate central chemoreceptors)
Nutrition
- Provides a supply of oxygen, sugars, amino acids to supply the brain

Examiner comments

71% of candidates passed this question.

This question was generally well answered. Better answers noted production including an
amount, site and mechanism. Similarly, absorption included the site, the rate and factors which
affect the rate. The electrolyte and pH and how they compare to extracellular fluid should have
been included in the section on composition.

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Question 16

Question

Describe the forces that result in fluid exchange across capillary membranes

Example answer

Fluid exchange across membranes

Bulk flow of fluid across a semi-permeable membrane is a balance of Starling forces
Can be expressed using the following formula
- <math display="inline">Bulk \: flow \: = \: \kappa[(P_c \; - \; P_{if}) \; - \; \delta(\pi_p \; - \pi_{if})]</math>
Where:
- Kappa = membrane filtration constant
  - Accounts for membrane permeability and surface area
- Delta = reflection constant
  - Takes into consideration protein leakage
  - Values range from 0-1
- Capillary hydrostatic pressure (P_c)
  - Main factor determining bulk flow under physiological conditions
  - Normally ~35mmhg at arterial end, 15mmHg at venous end of capillary.
  - Determined by
    - The ratio of resistances between pre/post capillary arterioles
    - Arterial and venous blood pressure and gravity
- Interstitial hydrostatic pressure(P_if)
  - Normally ~0mmhg (there is minimal interstitial fluid which is draining away)
  - Affected by anything that modifies lymphatic drainage (e.g. immobility, tourniquet)
- Plasma oncotic pressure (Ï€_p)
  - The osmotic pressure attributed to by large insoluble proteins (e.g. albumin) within plasma
  - Normally ~28mmHg. Does not rapidly change
  - Affected by plasma protein concentrations and intravascular fluid status
- Interstitial oncotic pressure (Ï€_if)
  - Osmotic pressure attributed to by small amounts of insoluble proteins which have leaked into interstitial space
  - Normally ~3mmHg. Does not rapidly change
  - Affected by membrane integrity
Using the above values at venous/arterial ends, it is demonstrated that bulk flow occurs
- OUT of the vessel at arterial end
- IN to the vessel at venous end
Main factor as described is the Capillary hydrostatic pressure gradient (Pc - Pif)

Examiner comments

57% of candidates passed this question.

The expected answer included a clear explanation of Starlingâ€™s forces, including an understanding of the importance of the relative difference along the length of the capillary, with approximate values and examples of factors that influence them. Some explanation of what contributed to the hydrostatic or osmotic pressure gained more marks than merely stating there was a pressure. Several candidates digressed to Fickâ€™s law of diffusion or intracellular flow of ions which was not directly relevant to capillary flow.

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Question 17

Question

Describe ketone bodies including their synthesis and metabolism

Example answer

Ketone Bodies

Water soluble molecules, derived from fatty acids, that contain ketone groups
Three main compounds: acetoacetate, 3-Î²-Hydroxybutyrate, and acetone
Normal plasma level is <0.6mmol/L

Ketogenesis

Ketone bodies can only be produced in the liver
Î²-oxidation of fatty acids in the liver produces acetyl-CoA
Acetyl-CoA usually enters the citric acid cycle to produce ATP
When large amounts of acetyl CoA are produced they condense to form acetoacetate
Acetoacetate is then reduced in the mitochondria to 3-Î²-hydroxybutyrate (majority) or acetone (minority).

Regulation

The body constantly produces small amounts of ketone bodies (even during fed states)
When carbohydrate stores are available the main pathway for energy utilisation is glycogenolysis
Ketogenesis is accelerated by decreased insulin levels and increased glucagon levels (e.g. in times of starvation or carbohydrate restriction). This leads to increased activity of hormone sensitive lipase and acetyl Coa Carboxlyase which drive ketogensis
As the lack of insulin is the main driver of ketogenesis, it explains why Type 1 diabetics develop diabetic ketoacidosis

Metabolism/utilisation

Ketone bodies can be used as an energy substrate by
- Kidney, skeletal muscle and cardiac muscle cells (under physiological conditions)
- Nervous tissue (during times of starvation)
Process
- Ketone bodies enter mitochondria
- Ketone body reconstituted to Aceto-acetyl CoA (by SCOT)
- Cleavage of acetyl group by MAT to form Acetyl CoA
- Acetyl CoA enters the Citric acid cycle

Examiner comments

35% of candidates passed this question.

Whilst most candidates understood that ketones provided an alternative source of substrate for energy production, many lacked a basic understanding of their synthesis and metabolism Important facts included what ketone bodies are, where they were synthesised, where they were taken up and used as fuel, under what circumstances they are used and the integral role of insulin. Many candidates accurately reproduced the glycolytic and/or the TCA cycle, but this was not being examined, and did not score additional marks. Many candidates incorrectly stated that ketone production was the result of anaerobic metabolism.

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Question 18

Question

Describe the factors affecting left ventricular function

Example answer

Not 100% if this answer is exactly what they want tbh.

Factors affecting LV systolic function

Preload
- Frank starling mechanism
  - Increased preload > increased sarcomere length > increased force of LV contraction > increased SV
Afterload
- LV is afterload independent (due to compensatory mechanisms)
Contractility
- Anrep effect
  - Means of autoregulating contractility with changes in preload
  - Increase in afterload > increased ESV > increased sarcomere stretch > increased force of subsequent contraction > increased SV
- Bowditch effect
  - A means of compensating for decreased diastolic filling time with fast heart rates
  - Increased HR > decreased time to expel intracellular calcium > accumulation > increased inotropy
- Integrity of myofilaments
  - Damaged myocardial tissue > impaired LV contraction (e.g. in ischaemia/infarction)
- Coordinated depolarisation
  - Suboptimal myocardial depolarisation in the LV > impaired coordination of LV contraction
  - e.g. in heart block, sinus node dysfunction
- Substrate supply
  - Adequate supply of ATP (derived from glucose,fat, protein) to ensure ability of LV to function as needed
- Hormones
  - e.g. catecholamines --> increased inotropy/chronotropy/lusitropy
- Autonomic tone
  - Increased SNS activity / decreased PSNS activity > increased chronotropy and inotropy
- Drugs
  - E.g. B agonists --> increased chronotropy and inotropy
- Electrolytes
  - E.g. Calcium: too little = impaired systolic function, too much = impaired diastolic function

Factors affecting LV diastolic function

LV diastolic function is determined by it compliance
- LV systolic function
  - Poor LV systolic function > high end systolic volume > impedes diastolic filling
- Heart rate
  - Increased HR > shorter time in diastole > reduced compliance; filling is time dependant
- Lusitropic properties of the ventricle
  - Increased by SNS tone and catecholamines
- Wall thickness
  - Increased thickness = reduced compliance

Examiner comments

12% of candidates passed this question.

Candidates often misinterpreted the question and described determinants of cardiac output. The answer should have focussed on factors affecting/contributing to normal LV function - not pathological states. Some answers showed a lack of appreciation that normal left ventricular function is afterload independent, due to compensatory reflexes. Answers needed to consider intrinsic and extrinsic factors affecting LV function - the latter (e.g. SNS, PSNS, hormones, drugs) was often left out. Answers needed to consider both systolic and diastolic function. An excellent answer included physiological phenomena such as the Treppe effect, Anrep effect and baroreceptor and chemoreceptor reflexes. Mention of normal conduction and pacing as well as blood supply limited by diastole scored additional marks.

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Question 19

Question

Describe toxicity of local anaesthetic agents

Example answer

Local anaesthetic toxicity

Typically occurs ~3mg/kg (without adrenaline) ~6-7mg/kg (with adrenaline) when used regionally
CNS and CVS side effects are most evident
CNS effects occurring at lower plasma drug concentrations
CNS side effects
- Lower doses: Visual disturbances, perioral numbness, tremors
- Higher doses: Slurred speech, confusion, decreased level of consciousness
- Highest doses: Seizures, coma, apnoea
CVS side effects
- Lower doses: Hypertension, tachycardia
- Higher doses: Hypotension, bradycardia,
- Highest doses: Cardiovascular collapse, arrhythmias
Other effects
- Methemoglobinemia
- Allergy

Factors affecting toxicity

Patient factors
- Acidosis: decreases protein binding > increased unbound fraction
- Increased age: decreased clearance
- Pregnancy: decreased protein levels > increased unbound fraction
- Hyperkalaemia: decreased dose required for toxicity
- Hepatic dysfunction: reduced metabolism > increased risk of toxicity
- Renal dysfunction: reduced clearance > increased risk of toxicity
Drug factors
- Increasing dose = increased risk of toxicity
- Type of local anaesthetic
  - e.g. bupivacaine has lower CC/CNS ratio than lidocaine (more likely to be cardiotoxic than CNS toxic)
- Site of administration: more vascular areas > higher risk
- Coadministration with vasoconstrictors (e.g. adrenaline) > slower absorption > reduced risk toxicity
- Drug interactions: displacement from protein binding sites by highly protein bound drugs e.g. phenytoin > increased unbound fraction > increased risk of toxicity

Management of local anaesthetic toxicity

Alkalinise
- Decreases the unbound (active) fraction of the drug
Give intralipid
- Increases the lipid bound fraction (decreases active unbound fraction)

Examiner comments

28% of candidates passed this question.

Most questions lacked a systematic approach to the question and specific detail. The relationship between systemic toxicity (CNS and CVS) and plasma levels should be described. Many candidates did not clearly state that CNS toxicity occurs at lower plasma levels that CVS toxicity. Factors that affect toxicity (e.g. drug factors, patient factors, interactions) needed to be elaborated with some detail. Patient factors such as age, pregnancy, acidosis, hyperkalaemia, hepatic failure were often omitted. Finally, marks were also awarded for noting methaemoglobinaemia as possible toxicity and the existence of specific therapy (intralipid).

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Question 20

Question

Describe the pharmacology of heparin highlighting important differences between unfractionated and fractionated (low molecular weight) heparin

Example answer

Name	HMWH (heparin)	LMWH (enoxaparin)
Class	Anticoagulant	Anticoagulant
Indications	Prophylactic and therapeutic anticoagulation (e.g. AF, DVT, PE, ACS etc)	Prophylactic and therapeutic anticoagulation (e.g. AF, DVT, PE, ACS etc)
Pharmaceutics	MW = 5,000-25,000 Da Clear solution for injection	MW = 5,000 Daltons Clear solution for injection
Routes of administration	IV, SC	SC (main), can also be given IV
Dose	Prophylactic: 5,000 IU BD-TDS Therapeutic: infusion (APTT target)	Therapeutic: 1mg/kg BD or 1.5mg/kg OD Prophylactic: 20-40mg OD
pKA
Pharmacodynamics
MOA	Heparin binds to antithrombin 3 > conformational change > increases affinity for inactivating thrombin (factor IIa) and Factor Xa	Enoxaparin binds to AT-3 > conformational change > increases affinity for inactivating factor Xa (and weakly factor IIa - 4x less activity)
Effects	Anticoagulation	Anticoagulation
Side effects	HAEM: increased risk of haemorrhage, bruising, HITTS (higher than LMWH)	HAEM: increased risk of haemorrhage, bruising, HITTS (lower than HMWH)
Pharmacokinetics
Onset	Immediate (IV), 30 mins (SC)	Peak effect 3-4 hrs post SC injection
Absorption	PO bioavailability - 0% Variable SC absorption	PO bioavailability - 0% >90% bioavailability post SC injection
Distribution	VOD = 0.1L/kg Lipid solubility: low Protein binding: high Does not cross BBB / placenta	VOD = 4.3L Protein binding: does not bind to heparin binding proteins
Metabolism	Reticuloendothelial system	Minimal hepatic metabolism
Elimination	Renal elimination (very minimal) - hence preferred in renal failure T 1/2 = 1 hrs	Renal elimination of active and inactive metabolites T 1/2 = 6-12 hours
Special points	Reversal: protamine (1mg = 100IU) - 100% Monitoring: APTT level	Reversal: protamine (<75% efficacy) Monitoring: Anti-Xa level

Examiner comments

71% of candidates passed this question.

Better answers were tabulated and included sections on pharmaceutics, indications and an explanation on how the difference in molecular weight influenced pharmacodynamics and pharmacokinetics. Knowledge of adverse effects was limited to bleeding and HITTS, often without consideration of relative risk from LMWH. Many candidates did not know the t1/2 of UFH or LMWH.

2018 (2nd sitting)

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