CO₂

• End-product of aerobic metabolism
• Produced almost entirely in mitochondria
• Normal production approx. 200ml/min
• Total CO₂ in blood
  • Venous 52mL/dL
  • Arterial 48mL/dL

CO₂ Carriage in 4 forms:

Gladwin / Sakurai 2016

2020A 01: 68% of candidates passed this question.
A detailed understanding of the carriage of carbon dioxide (CO2) in the blood is essential to the practice of intensive care medicine. Comprehensive answers classified and quantified the mechanisms of CO2 carriage in the blood and highlighted the differences between the arterial and venous systems. An explanation of the physiological principles surrounding these differences and the factors which may affect them was expected. The changes that occur at the alveolar and peripheral tissue interfaces with a similar explanation of process was also required. Candidate answers were often at the depth of knowledge required for an ‘outline question’ and a more detailed explanation was required to score well.

2020A 02: 69% of candidates passed this question.
GTN is a commonly used ‘level 1’ drug. The most comprehensive answers included information on available drug preparations, indications, mechanism of action, pharmacodynamics and pharmacokinetics and its side-effect profile. It was expected that significant detail be included in the pharmacodynamic section (e.g. preferential venodilation, reflex tachycardia, effects on myocardial oxygen demand etc). Common omissions included tachyphylaxis, dosing and its metabolism. Many answers didn’t mention the first pass effect.

Adverse Consequences of Blood Transfusion

1. Acute (<24 hours)

1a) Immune-mediated

1b) Non-immune mediated

2. Delayed (>24 hours)

2a) Immune-mediated

2b) Non-immune mediated

3. Storage Lesions

A storage lesion refers to the changes that occur to a sample of blood during storage. (Note: Australian Red cross anti-coagulates Whole blood with CPD, but washes and stores Red Cells in SAGM).

Massive Transfusion

• Replacement of >1 blood volume in 24 hours
• 50% of blood volume in 4 hours

Adverse consequences of massive transfusion

JC / Sakurai 2019

2020A 03: 43% of candidates passed this question.
As only an outline was asked for, a brief statement about each complication was sufficient. Better answers were structured using a classification of: Acute Immunological, Acute Non Immunological, Delayed Immunological and Delayed Non-immunological. Examples of expected detail would include the following:
E.g. Bacterial infection – a statement outlining the incidence of bacterial infection, a common causative organism or why bacterial infections are more commonly associated with platelet transfusions than red cells would have scored the marks allocated to ‘bacterial infection’.
E.g. Acute Haemolytic Transfusion Reaction – a statement about red cells being destroyed due to incompatibility of antigen on transfused cells with antibody of the recipient and an approximate incidence scored the marks allocated to AHTR.
An excellent resource is the Australian Red Cross transfusion website as listed in the suggested reading section of the syllabus

Medullary concentrating gradient

• physiological process which sets up a concentration gradient from cortex through to medulla
• allows formation of concentrated urine
• Mechanisms:
  • Counter current Multiplier: creates concentrated medullary interstitium
  • Counter current Exchange (vasa recta): maintains intersisital osmotic gradient
  • Recycling of urea: contributes to high osmolarity of medullary interstitium
• Normal cortico-medullary gradient 300-1400mOsmol.

Counter-current Mechanism in Kidney

Counter Current Multiplier:

Set-up

1. Descending limb LoH Permeable to water only 
2. Ascending limb LoH Permeable to NaCl only
   • Thin passive NaCl reabs
   • Thick NaCl via active NKCCT cotransport and paracellular 

Generation

1. Enters LoH osmolarity throughout = 300mOsm
2. Max effort of NKCCT = 100mOsm/kg
   • Tubular OSM = 200/kg
   • Interstitial Osm = 400/kg
3. Descending limb diffuses water down gradient
   • Descend limb OSM now 400
4. Process repeats (flow, pump salt, equilibrate water)

Counter Current Exchange:

• Hairpin loop arrangement of the vasa recta in the juxta-medullary nephrons.
• Provides blood flow to medullary tissue without impact of the cortico-medullary gradient.
• Relies on slow flow of blood.
• Mechanism
  • On descent, water is lost from capillaries and NaCl is absorbed into capillaries increasing osmolarity
  • On ascent water is reabsorbed and solute is lost

Role of Urea in Medullary Concentration Gradient

• 900mmol/day filtered
• 350-550mmol/day reabsorbed.
• Comprises 50% of osmolality (300-650 mOsm/kg)
• Freely filtered at the glomerulus
  • Secreted by thin limbs of LoH down concentration gradient from medullary interstitium to tubular fluid.

• As water and Na are reabsorbed, tubular [Urea] increases
• [Urea] = >500mmol/L at collecting ducts
• Equilibrates with interstium due to slow flow rates.
• ↑ADH
  • urea transporters UT1 and UT3 insertion → ↑ CD permeability to urea
  • → ↑ medullary gradient (further 10% reabsorption if required)

Gladwin / JC 2020

2020A 04: 63% of candidates passed this question.
Higher scoring candidates described the counter-current multiplier mechanism, the countercurrent exchanger and the contribution of urea cycling to the medullary osmotic gradient. Detailing the mechanisms as to how they may be established, maintained and or regulated. Descriptions of the multiplier (LOH) alone did not constitute a passing score. Values for osmolality at the cortex & medulla and within the different parts of the LOH was required.
A description of the countercurrent exchanger system where inflow runs parallel to, counter to and in close proximity to the outflow was expected. This could have been achieved by describing the anatomical layout of the loop of Henle and the vasa recta.

MECHANISMS OF ANTIBIOTIC RESISTANCE

• Mechanisms of Antibiotic Resistance can be classified broadly:
  • Efflux Pumps
  • Blocked Penetration / Alteration in access to target site
  • Target Modification
  • Modification of Drug or pathways
• There might be multiple resistance mechanisms at play in the same organism

Spread of Bacterial Resistance

• Selective pressure selects for favourable mutations of resistance
• mosaic genes (from other bacteria eg strep pneumo from strep mitus) or uptake of DNA from environment
• transfer of resistant bacteria from person to person
• horizontal gene transfer;
• transduction – acquisition of bacterial DNA from a phage (a virus that propagates in bacteria);
• transformation – uptake and incorporation of free DNA released into the environment by other bacterial cells;
• conjugation – gene transfer (usually on plasmids), by direct cell-to-cell contact through a bridge.

Sources:
Microbiology Lippincott Williams & Wilkins
https://courses.lumenlearning.com/microbiology/chapter/drug-resistance/
https://www.encyclopedie-environnement.org/en/health/antibiotics-antibiotic-resistance-and-environment/

Gladwin / Sakurai / JC 2019

PHARMACOLOGY OF CIPROFLOXACIN

2020A 05: 71% of candidates passed this question.
Most candidates had a structured answer to mechanisms of resistance that covered the major categories (alter target protein, prevent entry, efflux, degrade drug) and provided an example of a bacteria and the affected antibiotic, as was required to answer the question in full. Ciprofloxacin, whilst perhaps not a first line drug in the ICU, was not well known by many candidates. Better answers included a brief outline of class, mechanism of action (action on DNA gyrase to inhibit replication), spectrum (Gram negatives particularly mentioning Pseudomonas, lesser Grampositive cover, not anaerobes, some atypical), PK (with correct dose, wide penetration into tissues including bone/prostate etc., predominantly renal excretion), side effects/toxicity (common or specific to cipro e.g. QT, tendinitis, arthropathy) and an example of resistance.

Anatomical and Mechanical Differences

• Relatively larger head
• Prominent occiput
• Short neck
• Neonates do not have dentition
• Relatively larger tongue
• Higher larynx (C3-4 in infant, C4-5 in adult)
• Larynx lies more cephalad and anteriorly
• Epiglottis is narrower, omega shaped, more floppy and relatively larger
• The narrowest part of the airway is the subglottic area at the level of the cricoid cartilage
• Infants are obligatory nasal breathers until 3-5 months of age, the narrow nasal passages can easily be obstructed by secretions
• Shorter compressible trachea
• Increased risk of laryngospasm with inappropriate instrumentation.
• The smaller the patient the harder it is to position a LMA appropriately and maintain the correct position
• More compliant tissues and reduced muscle tone
• Main carina also lies more cephalad
• Small peripheral Airways (50% are < 2 mm diameter)
• ↓↓↓ bronchial muscle → so bronchospasms uncommon and bronchodilator drugs have minimal response
• Alveoli immature, and number <10% of adult total
• Reduced mucociliary clearance
• ↓ % type I muscle fibres (highly oxidative/slow contraction) in diaphragm (25% in neonate vs 55% in adults) and IC muscles (45% vs 65%) → ↑ risk of muscle fatigue

Lung Volumes

• FRC (30 mL/kg) → same as adult (as FRC remains 40% of TLC) BUT ↓ stable and ↑ risk of atelectasis due to following reasons:
  • Significant ↓ in outward recoil of CW (as rib is cartilaginous and contains very little respiratory muscles)
  • Mild ↓ inward recoil
• TLC (75-80 mL/kg) → same as adult
• VC (45 mL/kg) → lower cf. adult (60 mL/kg)
• TV same as adult (7 mL/kg)
• ↑ CC due to low elastic recoil of lungs → in fact, CC > FRC such that there is small AW closure during tidal ventilation → results in gas trapping and hypoxaemia

Lung Physiology

Gladwin / JC 2019

2020A 06: 20% of candidates passed this question.
This question required an outline of the anatomical, mechanical and functional differences. It was expected that factors leading to an increased work of breathing and oxygen cost would be mentioned. The mechanics of expiration were not often included in candidates’ answers. Immaturity of the alveoli and peripheral chemoreceptors were common omissions. Inaccuracies regarding upper airway anatomy and compliance of the chest wall cost some candidates marks. The question did not call for an explanation of the relative difficulty of intubation. Discussion of pathophysiology due to airway obstruction, causes of central apnoea or sensitivity to drugs was not required. Many answers included inaccurate information. Points which were often missed were difference in bronchial angles, number of alveoli, number of type 1 fibres in diaphragm, ciliary function and peripheral chemoreceptors.

Systemic Vascular Resistance
(Total Peripheral Resistance)

Systemic vascular resistance (peripheral vascular resistance, SVR) is the resistance in the circulatory system that is used to create blood pressure, the flow of blood and is also a component of cardiac function.

• Majority of resistance in systemic system results from arterioles – state of contraction and relaxation of smooth muscle cells of arterioles which determines distribution of blood to organs
• The % of each organ blood flow is dependent on the organ vascular resistance
• Systemic vascular resistance is the resistance of several circuits in parallel, which have both common and independent factors in their regulation.
  • As they are in parallel the sum of reciprocals is used to determine the overall value.

Control

• As per Hagen Poiseuille Equation:

where: η = blood viscosity
L = length of vessel
r = radius of vessel

• radius is the most important factor

Extrinsic Control

• Extrinsic SNS control
  • Arterioles have profuse SNS supply → NAd from nerve endings act on α1-adrenoceptors to cause vasoconstriction (and β2-adrenoceptors to cause vasodilation – but effect is weaker!)
  • Due to the tonic SNS outflow from medullary vasomotor centres, arterioles have a basal level of vasoconstriction → the degree of basal vasoconstriction (and arteriolar resistance) can be varied by altering SNS outflow
• Extrinsic PNS control
  • PNS control of arterioles is less important → vessels of external genitalia have dual ANS supply with PNS dilator nerves and SNS constrictor supply; PNS activation in heart, brain and lungs have an uncertain role
• Extrinsic hormonal control
  • Adrenaline (from adrenal medulla) → effect on organ blood flow depends on the relative % of α1- and β2-adrenoceptors present in the arteriole
  • AII (from RAAS) → vasoconstriction (via AT2R)
  • ADH (from posterior pituitary) → vasoconstriction (via V1R)
  • ANP (from RA) → vasodilation (via ANPR)

Intrinsic Control

• Autoregulation
  • Ability of an organ to maintain relatively constant blood flow across variations in perfusion pressure
  • flow = pressure/ resistance → as the P changes, the R also changes to maintain flow
  • Outside limits of autoregulation: flow = dependent on driving pressure
  • Kidneys, brain, heart
• Autoregulation is dependent on 2 mechanisms:
  • Pressure autoregulation: myogenic stretch response to ↑ and ↓ in pressure → vasoconstriction, and vasodilation
  • Metabolic or vasoactive autoregulation: direct action of locally derived metabolites and vasoactive substances e.g. platelets release thromboxane A2 → constriction in damage

Bianca / Kerr 2016

2020A 07: 21% of candidates passed this question.
This question invited a detailed discussion of the physiological control mechanisms in health, not pathophysiology nor drug-mediated effects. The central and reflex control mechanisms that regulate SVR over time are distinct from the local determinants of SVR. There was often confusion between dependent and independent variables. Cardiac output is generally depended upon SVR, not vice versa, even though SVR can be mathematically calculated from CO and driving pressures. The question asked about systemic vascular resistance and did not require a discussion of individual organs except for a general understanding that local autoregulation versus central neurogenic control predominates in different tissues. Emotional state, temperature, pain and pulmonary reflexes were frequently omitted. Peripheral and central chemoreceptors and low-pressure baroreceptors were relevant to include along with high pressure baroreceptors.

Lactate is the conjugate base of lactic acid (an organic 3-C acid)

Production:

• It is produced by anaerobic metabolism of pyruvate either:
  • Physiologically → in RBC (no mitochondria), renal medulla (↓ PO2), cornea/ lens (↓ PO2) → hence, normal plasma [lactate] is 0.5-2 mmol/L (and NOT zero!)
  • Pathologically → reduced tissue perfusion and/or O2 delivery (Eg. shock, hypoxaemia) → thus, plasma [lactate] ↑↑↑ (> 2 mmol/L)
• Plasma [lactate] is 0.5 – 2 mM (and NOT zero) due to physiological production → it can be measured clinically as an indicator of anaerobic metabolism (Ie. ↑ anaerobic metabolism due to pathological situations lead to ↑ [lactate])

Fate of lactate:

• Persistent anaerobic metabolism (Ie. ongoing hypoxia) causes an accumulation of cellular lactate → this diffuses out of the cell into plasma along its [ ] gradient → lactate can then be:
  • Used as a fuel source by the heart and brain
  • Transported to the liver where it is:
    • Converted back to glucose via gluconeogenesis (requires 6x ATP), which is then transported back peripherally for use → “Cori cycle”
    • Converted to pyruvate intermediate → utilised locally in TCA cycle for ATP production via oxidative phosphorylation
• Resolution of hypoxia (Ie. tissue O2 tension restored) → intracellular lactate can be oxidised back to pyruvate for use in local tissue aerobic metabolism (Ie. fed into TCA cycle)

Functions of Lactate:

Lactate Sink:

• Lactate acts as a sink in heart, liver, muscle etc, allowing a period of ongoing ATP production from glycolysis when:
  • cells become oxygen deplete
  • Kreb’s cycle is inhibited
  • Other causes of pyruvate accumulation: circulating catecholamines, exercise, sepsis or lack of mitochondria (RBCs)

Lactate Shuttle:

• Intracellular shuttle:
  • Lactate may be shuttle out of:
    • mitochoncrial membrane
    • peroxisomes
  • into cytoplasm of myocytes, neurons, astrocytes
  • Ixydised by cytoplasmic LDH to pyruvate, generating NADH for energy use
• Intercellular shuttle:
  • Excess lactate, formed within fast-twitch fibres, is transported to other cells within the body with the oxidative capability to metabolize lactate, such as type I (slow-twitch) muscle cells, enhancing their excitability and limiting fatigue
  • Furthermore, once in circulation, lactate attaches to red blood cells (RBCs) and is disassociated in the liver where inter-conversion via gluconeogenesis facilitates glucose formation, providing an alternative aerobic energy source.

Lactate as a signaling molecule:

• Redox signaling by intracellular shuttles
• Gene expression
  • Increased intracellular levels of lactate can act as a signalling hormone, inducing changes in gene expression that will upregulate genes involved in lactate removal, and stimulates mitochondrial biogenesis.
• Control of lipolysis
  • the shuttle regulates FFA mobilization by controlling plasma lactate levels.
  • lactate functions to inhibit lipolysis in fat cells through activation of an orphan G-protein couple receptor (GPR81) that acts as a lactate sensor, inhibiting lipolysis in response to lactate

Bianca / JC 2021

2020A 08: 16% of candidates passed this question.
Better answers used the categorisation in the question as a structure for their answer. Many candidates gave a good description of lactate production from glycolysis, increasing with accumulation of NADH and pyruvate, when these are unable to enter Krebs cycle. There were however, many vague and incorrect descriptions as to what lactate is and its physiological role. Many candidates suggested that its presence is abnormal or pathological. Most answers demonstrated a superficial understanding and physiological detail of lactate’s role as an energy currency in times of oxygen debt. Higher scoring candidates often mentioned non-hypoxic causes of pyruvate accumulation which include; circulating catecholamines, exercise, sepsis or lack or mitochondria (RBCs). Mention of the relative ATP production of the two fates of pyruvate was also noted in more complete answers. The Cori cycle was generally superficially described. A key role of lactate is the ‘lactate sink’, allowing a period of ongoing ATP production from glycolysis when cells become oxygen deplete or the Kreb’s cycle is inhibited; few candidates detailed or highlighted this.

PHARMACOKINETICS

Absorption

• ↓ Oral absorption
  • ↑ N/V
  • ↓ gastric emptying during labour
  • ↓ gastric motility 2° to intestinal compression
  • ↑ gastric absorption
  • ↓intestinal absorption due to ↓ intestinal blood flow
• ↑ IM/SC/transdermal absorption
  • ↑ skin blood flow
    • ↑ C.O. (by 30-40%)
    • ↓ SVR
• IV (↑ onset)
• Neuraxial
  • ↓ epidural space 2° to EDVs
  • ↓ spinal and epidural doses
• Inhalational
  • Progesterone-mediated ↑ MV (by 50-70%)
  • ↑ FA/FI ratio (= uptake

Distribution

• ↑ VD (↑ TBW/ECF and fat)
  • ↑ TBW/ECF (by 50%) (important for polar/ionized drugs)
  • ↑ body fat % (important for lipid soluble drugs)
• ↓ plasma protein 2° to dilutional effect
  • ↓ albumin →
    • ↑ free % of acidic drugs (Eg. STP, propofol)
    • ↓ dose required
    • ↑ transplacental transfer of drug.
  • ↓ A1AGP (by 30%) →
    • ↑ free % of basic drugs (Eg. LA, β blockers)
    • ↓ dose required
    • ↑ transplacental transfer of drug
• Ionisation (mild ↑pH alters ionisation based on pKa)
  • ↑ MV = mild respiratory alkalosis
    • ↑ transplacental transfer of basic drugs as they will have ↑ % in unionized form
      • (Base in base is less ionised)
      • ↑ ion trapping in more acidotic foetal circulation

Metabolism

• Progesterone:oestrogen ratio
  • Progesterone → induces hepatic enzymes
  • Oestrogen → inhibits hepatic enzymes
• ↓ plasma cholinesterase (30%)
• Placenta metabolises some drugs
• Foetal liver has functioning CYP450
  • Can metabolise drugs
  • But requires transfer back to maternal circ for conjugation

Excretion

• ↑ RBF/GFR (50%)
  • ↑ clearance/↓ elimination t1⁄2 of water-soluble drugs
• ↑ MV/↓FRC
  • ↑ washout of volatile agents

PHARMACODYNAMICS

• Decreased MAC – Increased sensitivity to volatile anaesthetics
• Increased LA sensitivity due to decreased α1-glycoprotein
• Increased sensitivity to IV anaesthetics

Gladwin 2016

2020A 09: 7% of candidates passed this question.

Answers framed around absorption, distribution, metabolism and excretion performed better. Some brief comments on physiology are required as the basis for pharmacokinetic change, but discussion of physiology that was not then specifically related to pharmacology did not score marks. Specific ‘real life’ examples necessitating change in practice or prescribing were well regarded e.g. reduction in spinal/epidural local anaesthetic dosing. Vague statements about possible or theoretical changes were less well regarded.

2020A 10: 49% of candidates passed this question.
These are both level 1 drugs regularly used in intensive care. Significant depth and detail of each drug were expected. Overall knowledge was deemed to be superficial and lacked integration. Better answers identified key points of difference and overlap in areas such as structure, pharmaceutics, pharmacokinetics, pharmacodynamics, mechanism of action, adverse effects and contraindications. A tabular list of individual drug pharmacological properties alongside each other did not score as well as answers which highlighted key areas of difference and similarities.

STRUCTURE

Structure

• Globular proteins which contain a haem moiety which binds O₂.
• Haem is an protoporphryin ring derivative with a central Fe2+ molecule that binds O₂
• Haemoglobin: MW ≈ 65000 daltons
  • Hb contains 65-70 % of total body iron
  • Globular molecule made up of four subunits, each containing a haem moiety conjugated to a polypeptide.
  • Polypeptides collectively = globin → two pairs 2α + 2β → 4 haem moieties (Tetramer)
  • Can bind a total of 4 O₂ and also exhibits cooperative affinity (each subsequent O₂ binding takes less energy → sigmoid shaped OHDC

Location

• Hb is located in large concentrations (≈15g/L) in red blood cells that circulate throughout the blood stream.

Synthesis

• Haeme is synthesised in mitochondria and cytosol of immature RBCs, Globin is synthesized by ribosomes in cytosol.
• Production continues till RBCs lose their RNA after entering vasculature

Degradation

• RBCs at the end of their life cycle get phagocytosed by macrophages in liver or spleen, or get hemolysed in circulation.
• Haemoglobin is then broken up
  • Haeme gets degraded into bilirubin
  • iron gets recycled

FUNCTION

• O2 carrier:
  • O2 loading exhibits positive cooperativity:
    • α1ß1 & α2ß2 contacts stabilise Hb molecule as O2 reacts with it
    • reaction of O2 with each subunit occurs sequentially with each facilitating the next
    • ∴ ↑ing affinity as O2 loads ⇒ sigmoid OHDC
• O2 unloading – vice versa:
  • ß chains pulled apart
  • 2,3-DPG enters molecule ⇒ ↓affinity of Hb for O2
• Protein buffer in RBC:
  • Haemoglobin exists as a weak acid (HHb) as well as its potassium salt (KHb)
  • In acidosis:
    • Additional H⁺ ions are bound to Hb molecules
    • HCO₃^– diffuses down its concentration gradient into plasma
      • Electroneutrality is maintained through the inwards movement of Cl^–.
    • Dissolved CO₂ will also form carbamino compounds by binding to the terminal amino groups
• Ligand Binding:
  • Competitive inhibitors such as carbon monoxide (CO) and allosteric ligands such as carbon dioxide (CO2) and nitric oxide (NO).
  • The carbon dioxide is bound to amino groups of the globin proteins to form carbaminohemoglobin; this mechanism is thought to account for about 10% of carbon dioxide transport in mammals.
  • Nitric oxide can also be transported by haemoglobin; it is bound to specific thiol groups in the globin protein to form an S-nitrosothiol, which dissociates into free nitric oxide and thiol again, as the hemoglobin releases oxygen from its heme site. This nitric oxide transport to peripheral tissues is hypothesized to assist oxygen transport in tissues, by releasing vasodilatory nitric oxide to tissues in which oxygen levels are low.

2020A 11: 57% of candidates passed this question.
Marks were awarded for the two components of this question – structure and function. The structure component was often only briefly described with a cursory overview provided; however, this component contributed around half of the available marks. Many candidates were unable to accurately describe the structural components of the haemoglobin molecule. The functional component was handled better – however much time was wasted with detailed drawings of the oxyhemoglobin curve (not many marks awarded for this). The basic function of haemoglobin carriage of oxygen and carbon dioxide was known, but detail was often missing about its role as a buffer or its role in the metabolism of nitric oxide

Definitions

Natural frequency: the frequency at which a system oscillates when not subjected to a continuous or repeated external force.

Resonance describes the phenomenon of increased amplitude that occurs when the frequency of a periodically applied force (or a Fourier component of it) is equal or close to a natural frequency of the system on which it acts.

Resonant frequency:  The frequency of a dynamic system at which the amplitude of response to an oscillating force is a relative maximum is known as a resonant frequency (OR) A natural frequency of vibration determined by the physical parameters of the vibrating object.

Damping:  the property of a system that diminishes resonance.

Critical Damping: Occurs when the damping coefficient (DC or γ gamma) is equal to the undamped resonant frequency of the oscillator.

Optimum Damping: Level of damping which provides a compromise between the speed of the system with its accuracy

Undamped simple harmonic oscillator

• obeys hooke’s law
• motion is sinusoidal in time
• demonstrates a single resonant frequency.

Resonance

Invasive arterial blood pressure is a driven harmonic oscillator

• An external force (pulsations of the heart) adds to the oscillations of the system (the tubing/transducer etc).
• If the frequency of the driving force is similar to, or a harmonic of, the natural frequency of the system then the result is amplification

Arterial waveform is a complex summation of multiple simple sinusoidal waveforms (a fourier series)

• The frequency of the arterial wave (i.e., the pulse rate) is known as the natural or fundamental frequency
• The sine waves used to reproduce it must have a frequency that is a multiple (or harmonic) of the fundamental frequency
  • Increasing the number of harmonics allows better reproduction of high-frequency components, such as a steep systolic upstroke

In most clinical systems

• Natural resonant frequency is 10 to 15 Hz
• Primary frequency of the arterial waveform (the heart rate is 60 to 120 bpm or 1 to 2 Hz)
• However the higher frequency components of the more complex arterial waveform are closer to the natural resonant frequency and are amplified to a larger degree.

To minimize the potential of amplification and improve the dynamic accuracy of the real arterial pressure, system should have resonant frequency  >> than 6-8 times frequency of the system being measured:

• Should have noncompliant (i.e. stiff) tubing
• Total mass of liquid in the system should also be minimized (shorter/thinner tubes)
• air bubbles or blood clots or occlusion should be eliminated

Damping

the property of a system that diminishes resonance.

• Damping:
  • decreases the magnitude of the oscillations
  • allows the system to come to rest at a new value.
• Degree of damping determines the rate at which the system achieves that new value.

System can be:

• Underdamped (DC < 0.7):
  • Reaches the zero position quickly
  • Oscillates around it
  • Causes falsely ↑ SBP and falsely ↓ DBP
• Critically damped (DC = 1):
  • Quickest approach to zero amplitude for a damped oscillator without overshoot.
  • Occurs when the damping coefficient (DC or γ gamma) is equal to the undamped resonant frequency of the oscillator.
• Optimal damping (DC = 0.64):
  • Provides a compromise between the speed of the system with its accuracy
  • Minimises overshoot of oscillations, phase and amplitude distortion, and provides maximal frequency response
• Overdamped (DC > 1):
  • The approach to zero is slower
  • Very slow to respond
  • Causes falsely ↓ SBP, falsely ↑ DBP and loss of fine details of waveform (Eg. dichrotic notch)

Bedside Flush Test:

• The degree of damping in an invasive arterial line system can be determined by the bedside flush test
  • Briefly open the continuous flush device to produce a square wave

Gladwin / Sakurai / JC 2020

2020A 12: 23% of candidates passed this question.
Many candidates gave detailed answers that involved the set up and components of the arterial line system that was not asked for in the question and did not attract marks. There was confusion around the correct use of the terms natural frequency, resonance frequency and harmonics – candidates that were able to describe these frequencies correctly went on to achieve a good mark – the graphs and discussion around optimal dampening, over and underdamped traces were often drawn poorly or without sufficient detail, and at times were not used within in the context of the answer. Descriptions of the clinical effect seen with over / under dampened traces on blood pressure was well described.

Respiration

• Normal RR ~ 10 breaths per minute
• Normal tidal volume ~ 500ml/kg (in 70kg male)
• Therefore normal minute ventilation approx 5l/min

Afferents / Sensors

Chemoreceptors

• Central
  Located in retrotrapezoidal nucleus
  • Sensitive to changes in CSF [H⁺]
    • CO₂ readily diffuses across BBB and converted to H⁺ and HCO₃^– via carbonic anhydrase
    • Increased [H⁺] (and therefore CO₂) stimulated respiration
• Peripheral
  Located in aortic bodies (innervated by vagus nerve) and carotid bodies (innervated by glossopharyngeal nerve)
  • Sensitive to PO₂, [H⁺], PCO₂ and blood flow
    • O₂ dependent K⁺ channels
      • Respiration increases as O₂ drops below 50mmHg
  • CO₂
    • Linear increase in respiration as CO₂ increases

Baroreceptors:

• Located in aortic arch and carotid sinuses
  • Responds to stretch
    • As MAP drops → less stretch on vessel walls → increased sympathetic outflow from medullary vasomotor centre → triggers increase in respiration

Pulmonary receptors

• Stretch receptors
  • Increased stretch of pulmonary parenchyma triggers inflation reflex → inhibits inspiration to prevent overdistention
  • Collapse of pulmonary parenchyma triggers deflation reflex → inhibits expiration to prevent atelectasis and loss of FRC
• J fibres
  • Nociceptive mechano-chemoreceptors
    • On stimulation → Bronchospasm, apnoea, bradycardia and hypotension

Others

• Joint and muscle receptors stimulate ventilation
• Pain and temperature sensation can alter ventilation via the cortex and limbic system

Central control of breathing

Central input

• There is input from the hypothalamus and cortex, with the ability of the cortex to override the medulla and bring ventilation under voluntary control

Controller

• Medullary Respiratory Centre
  • Dorsal respiratory group (DRG)
    • Located in and adjacent to Nucleus Tractus Solitarus
    • Associated with inspiration and timing
    • Works as an ‘integrating centre’ with VRG
  • Ventral respiratory group (VRG)
    • Including Pre-Botzinger and Botzinger complex → Central Pattern Generator
    • Associated with control of expiration, airway dilation and central pattern generation
    • sends inhibitory impulses to Apneustic centre
• Pontine respiratory group (PRG)
  • Pneumotaxic centre
    • controls both the rate and the pattern of breathing
    • Sends inhibitory impulses to the inspiratory area
    • Antagonist to apneustic center
    • decreases tidal volume
  • Apneustic centre:
    • sends signals for inspiration for long and deep breaths
    • controls the intensity of breathing and is inhibited by the stretch receptors of the pulmonary muscles at maximum depth of inspiration, or by signals from the pnuemotaxic center
    • increases tidal volume.

• Inspiratory phase:
  • Gradual ramping up of nerve activity – ↑muscle contraction
• Expiratory phase I:
  • Gradual reduction of nerve activity – ↓muscle contraction
• Expiratory phase II:
  • Inspiratory muscles inactive
  • If increased respiratory drive, expiratory muscles are activated

Efferents

• Phrenic nerve (C3, 4, 5) → Innervates diaphragm – Main inspiratory muscle
• Spinal nerves to intercostal muscles (external intercostal → inspiration, internal intercostal → expiration)
• Brachial plexus → Pectoralis major (forced breathing inspiration)
• Accessory muscle → Sternocleidomastoid (forced breathing inspiration)
• Spinal nerves to abdominal muscles (forced expiration)

Mooney / Sakurai / JC 2020

2020A 13: 53% of candidates passed this question.
Most candidates provided a structured answer based around a sensor / central integration / effector model with appropriate weighting towards the sensor / integration component. Better answers provided an understanding of details of receptor function, roles of the medullary and pontine nuclei and how these are thought to integrate input from sensors. Marks were awarded to PaCO2 ventilation and PaO2 ventilation response when accurate, correctly labelled diagrams or descriptions were provided.

2020A 14: 51% of candidates passed this question.
Most candidates presented a well-structured answer and provided a basic understanding. Answers that provided accurate indications and details of the mechanism underlying the actions of frusemide attracted more marks. Those recognising the increased delivery of sodium and chloride to the distal tubule (exceeding resorptive capacity) were awarded more marks that those answers that attributed the diuretic action solely to reduction in the medullary gradient. Frusemide has many potential adverse effects and a reasonable list was expected. Conflicting information was common (e.g. highly bound to albumin – Vd 4 L/kg) and better answers avoided this.

DEFINITION

The fraction of drug that reaches the circulation compared with the same dose given intravenously. (%)

(or)

The ratio of the area under the stated concentration–time curve (AUC) divided by the area under the i.v. concentration–time curve. (%)

FACTORS AFFECTING BIOAVAILABILITY

• Pharmaceutical factors
  • Preparation: Decreasing order: Solutions > Suspensions > Capsule > Tablet > Coated tablet
  • Particle Size
  • Salt form
  • Crystal forms have better availability compared to amorphous forms
  • Degree of ionization: – Non-ionised, lipid soluble drugs – higher bioavailability

• Pharmacological factors
  • Gastric Emptying and GI Motility
  • GI Diseases: Coeliac, Crohn’s
  • Timing in relation to food intake
  • First pass metabolism: The degree of metabolic breakdown of an orally administered drug that occurs in the intestine or liver before it reaches the systemic circulation.
  • Drug-Drug interactions
  • Pharmacogenetic factors

• Other factors:
  • Area of absorptive surface
  • State of circulation (shock, tissue perfusion)
  • Hepatic Insufficiency, Poor renal function
  • Route of administration

Sources: Cross and Plunkett. Physics, Pharmacology, Physiology for Anaesthetists. Goodman & Gilman’s Pharmacological Basis of Therapeutics. Katzung Clinical Pharmacology

JC 2020

49% of candidates passed this question.

Many candidates spent time defining and describing aspects of pharmacokinetics which were not relevant to the question. E.g. clearance, volume of distribution and half-life. Candidates who scored well utilised a structure which incorporated the headings of the factors which affect the bioavailability of medications with a simple description as to the nature of the effect. These factors included: the physical properties of the drug, the preparation, patient factors, the route of administration and metabolism amongst others.

Formation / Production of CSF

• 60-70% of the CSF is formed by the choroid plexuses
• 30-40% by the cerebral vessels lining the ventricular walls
• Normal rate is 20mL/hour
• Formation independent of ventricular pressure
• Mechanism
  • From Coroid Plexus by net transport of Na+, K+, Cl-, HCO3- and water, from plasma to ventricles
  • Na down Conc grad
  • Others down electro chem grads

Distribution / Circulation of CSF

Absorption of CSF

• Absorbed through the arachnoid villi into the cerebral venous sinuses
  • Absorption by bulk flow, is proportional to ventricular pressure
  • If pressure < 7 cmH2O, CSF absorption ceases
  • Above 7cmCSF absorption is linear
  • At approximately 11 cmH2O, CSF Absorption = Formation

Composition of CSF

IDENTICAL to brain ECF, but differs in several manners from plasma

Compared with plasma:

• ↑ pCO2 (50 mmHg)
  • ↓ pH (7.33)
• ↓ protein content
  • 0.5% of plasma; 20 mg/dL
  • poor acid-base buffering capacity
• ↓ content of glucose (by 60%) and cholesterol
• ↑ [Cl-] (by 7-14%) and ↑ [Mg2+] (by 40%)
• ↓ [K+] (by 40%), ↓ [Ca2+] (by 50%) and ↓ [Pi] (by 20-30%)
• ↑ creatinine (by 25%) but ↓ urea
• IDENTICAL osmolality (295), [Na+] (145), and [HCO3] (25)

Role / Functions of CSF

• Protective role (main function)
  • Water bath effect
    • Attributed to the low specific gravity of CSF (1.007)
    • Causes brain to be buoyant
    • ↓ its effective net weight from 1400 g to 50 g
    • Mechanical cushion against acceleration/deceleration forces
  • Buffer ↑ ICP by CSF translocation to extracranial subarachnoid space
    • Abrupt ↑ ICP buffered by translocation of CSF within the vault to extracranial compartments
• Maintains constant ionic environment conducive to neuronal electrical activity CSF
• Supply role of nutrients (Eg simple sugars, amino acids) and O2 to brain
• Excretion of toxic substances, metabolic by-products, and CO2 from brain
• “Lymph-type” function → interstitial proteins in brain ECF return to circulation by
• CSF absorption across arachnoid villi
• Acid-base regulation → due to content, CSF allows for tight respiratory control
• Endocrine transport function → transports hormones to other brain regions

Gladwin / JC 2020

2020A 16: 81% of candidates passed this question.
This is a three-part question and was marked as such. The circulation and functions of CSF was generally well answered. Formation of CSF, however, was answered poorly, with many candidates listing its composition instead. The examiners were looking for an understanding of the physiological processes of formation not the composition.

2020A 17: 27% of candidates passed this question.

These are both level 1 drugs commonly used as an infusion in daily practice. This question specifically asked the candidates to frame their answers around an intravenous infusion of fentanyl in comparison to morphine. A tabular listing of general properties of the two drugs highlighting the differences between the drugs would not score well. The question asks for a considered response that should focus on context sensitive half-life, compartments and metabolism, instead many focused on the speed of onset and potency, which are minor considerations when drugs are given for long periods by infusion. Candidates often demonstrated a superficial knowledge of key pharmacokinetic concepts with limited application of these principles in the context of an intravenous infusion. Better answers also related the above to various relevant pharmacodynamic influences such as age, liver and renal impairment.

Respiratory Changes In Pregnancy

Anatomical

• Diaphragm ascends ~4cm due to foetus
• AP and lateral diameters of thorax increase 2~3cm due to relaxin effect on chest
  wall
• Thoracic circumference increases 5~7cm (AP and lateral diameters increased 2~3cm)
• Airway dilatation → decreased resistance (35%) and increased deadspace (45%)
• Increased cardiac output, intravascular volume, and decreased oncotic pressure
  • Increased plasma volume → increased pulmonary blood volume → decreased compliance
  • Venous engorgement → Upper airway oedema

Mechanical

• Lung volume changes occur from 20 weeks
• TLV decreases 5% from baseline
• FRC decreased 20% due to both ERV and RV
• Significant postural change in FRC of 70%
• Progesterone → increased sensitivity to CO2 → Minute ventilation increases 50%
  • TV increases (25%)
  • RR increases
  • Results in hypocarbia and compensated respiratory alkalosis
    • pCO2 ~ 26-32mmHg
    • HCO3 ~ 18-20mmol/l
  • Further increase in MV during contractions
• Inspiratory capacity increased by 10%
• Closing capacity unchanged
• Increased O2 consumption during labour (60%)

After birth

• FRC and RV return to normal within 48 hours
• TV returns to normal within 5 days

Sakurai 2016

2020A 18: 31% of candidates passed this question.
The question asked for a description of the respiratory changes throughout pregnancy, which includes labour. Simple lists of changes did not score highly. A straightforward structure including; first, second and third trimester delineation would have elevated many answers from below par to a pass. Many good answers gave succinct detail on both mechanical respiratory changes and the hormonal mechanisms behind them. Higher scoring answers also described the overall effect of individual changes to spirometry, geometry or respiratory control.

Factors that determine venous return back to the heart

The factors that influence VR are captured in 2 formulae:

The three variables that influence venous return are:

• Mean Systemic Filling pressure (MSFP)
  • MSFP is the theoretical pressure present in the systemic circulation at equilibrium
  • MFSP is the main driving pressure moving blood back towards the RA – It is the MAIN factor determining venous return (and thus CO)
  • MSFP can be used to assess the degree of filling of systemic circulation: It is normally 7 mmHg (0-20 mmHg)
  • Two factors influence MSFP:
    • Blood volume ↑ → ↑ ­MSFP
    • Venomotor tone (venous capacitance) ­ ↑ → ↑ ­MSFP
• RA pressure (RAP)
• Resistance to venous return (RVR)

Therefore, the factors that affect venous return influence one or more of the aforementioned variables:

• Blood volume
  • Blood volume is proportional to MSFP and thus venous return
• Venomotor tone
  • ↑ venomotor tone (Eg. due to SNS activity) ↓ vein compliance and capacity → ↑ MSFP → ↑ venous return
  • ↓ venomotor tone (Eg. due to SAB) ↑ vein compliance and capacity → ↓ MSFP → ↓ venous return
  • This has a greater effect on venous return when
    • (i) venous pressures are normal, and
    • (ii) veins are circular (not collapsed and contain large volumes of blood)
• Venous valves
  •  Veins have one-way valves that prevent retrograde flow
• Skeletal muscle pump
  •  Alternating contraction and relaxation of limb skeletal muscle forces blood out of the veins towards the heart (thus, increasing MSFP)
  • During contraction, veins compress to expel blood towards the heart, then during relaxation, veins distend and fill with blood
  • With exercise, this pump function enhances net venous return
• Respiratory pump
  • During inspiration, venous return is ↑ due to
    • (i) ↓ RAP (associated with fall in P_INTRAPLEURAL), and
    • (ii) ↑ IAP (due to diaphragmatic contraction)
  • During expiration, the effects are reversed
  • Note that if RAP is < 0 mmHg, the respiratory pump will NOT have any effect on venous return as the thoracic veins would have collapsed at subatmospheric pressures
• Posture
  • When going from supine to erect, there is ↓ venous return due to venous pooling in the lower extremities
  • Normally, there is reflex vasoconstriction to prevent this BUT this reflex is delayed and less effective in the elderly
• Effect of ventricular contraction and relaxation
  • During rapid ejection phase of ventricular systole, atrial pressure falls sharply (to zero or –ve values) as the ventricle contraction pulls the atrioventricular fibrous ring downwards and increases the atrial volume – This causes net blood flow into atria and increases venous return
  • During early diastole, ventricles fill rapidly causing both ventricular and atrial pressures to decline – This facilitate blood flow into atria and increases venous return
• Intrapericardial pressure
  • ↑ intrapericardial pressure (Eg. tamponade) can ↑ RAP, thus impeding venous return
• Afterload
  • Changes in the dimension of the resistance vessels (arterioles) has a small effect on MSFP as only 2% of blood volume is in arterioles (cf. venous capacitance vessels) – Instead, it has an impact on “Resistance to venous return”
  • ↓ afterload (such as decreased SVR due to arteriolar vasodilation) → ↓ RVR → ↑ VR
  • ↑ afterload (such as increased SVR due to arteriolar vasoconstriction) ↑ RVR → ↓ VR

Bianca 2020

2020A 19: 67% of candidates passed this question.
The factors that influence VR are captured in 2 formulae; VR = CO, and VR = (MSFP-RAP) / Venous Resistance. Candidates that used these as the backbone structure of their answer scored well. Quite a few candidates failed to consider factors that affect left heart CO also effect VR.
Recognising that CO does = VR appeared to elude some candidates.

Phosphate

• Most abundant anion, approx. 1% of total body weight
• Normal serum level 0.8 to 1.3 mmol/L in adults
• daily requirement = 0.4mmol/kg/day

Distribution

• Mostly intracellular.
• Bone & teeth (85%), tissue (14%), ECF (1%)
• In skeleton with calcium, as hydroxyapatite crystals or amorphous calcium phosphate
• In tissue and ECF:
  • 2/3 is tied up in molecules like ATP
  • 1/3 in inorganic phosphate
  • pH dependent

Absorption

Dietary intake 20mg/kg/day → Proximal intestine absorbs 16mg/kg/day

Elimination

• Feces:
  • 3mg/kg/day secreted into intestine via pancreatic, bile, intestinal secretion
  • unabsorbed 4mg/kg/day from dietary intake
• Kidney:
  • 100mg/kg/day in UF.
    • 80% reabsorbed in proximal tubule
    • 5% in DCT
  • rest excreted (~15mg/kg/day)
• Net Intake-Excretion of Phosphate
  • modulated based on physiological needs such as bone remodelling, bone growth, etc
    • bone resorption ~300mg/day
    • absorption ~300mg/day

Regulation

GI – Bone – Renal axis

Regulators:

• Dietary phosphate intake and absorption
• Calcitriol
  • which increases phosphate absorption from the gut and bone
• Parathyroid hormone (PTH)
  • directly causes phosphate resorption from bone and decreases its reabsorption in the proximal tubule
  • indirectly by stimulating the production of calcitriol.
• Phosphatonins, such as fibroblast growth factor-23 (FGF-23):
  • Inhibit renal phosphate reabsorption
  • inhibit synthesis of calcitriol

Factors that alter renal regulation of phosphate:

Physiological Role

• Bone and teeth formation
• Cell wall structure (phospholipids)
• Nucleic acid generation
• Glucose metabolism
• High energy bonds
• O2 transport (2,3 DPG)
• Phosphate Buffer
• intracellular signalling

• Sources
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3743361/
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686387/
  • https://cjasn.asnjournals.org/content/10/7/1257

JC 2020

2020A 20: 29% of candidates passed this question.
The answer structure should have utilized the headings provided in the question. Many candidates described the physiology of calcium, which while related, did not attract marks. The distribution section required not only the sites of distribution but also the percentages found in each. The regulation should have included both primary and secondary mechanisms and an outline on the factors affecting renal excretion, intestinal absorption and release from bone etc. An outline of the physiological role of phosphate required a broad knowledge of physiological processes.