O₂

• Total body O2 content ~ 1.55L
  • ~850mls – blood (20.4ml/100ml blood) (O2 Carriage)
    • 20.1ml/100ml – bound to Hb
    • 0.3ml/100ml – dissolved
  • ~200ml – bound to myoglobin
  • ~450ml in FRC
  • ~50ml dissolved in tissue
• O2 Content
• O2 Delivery
  • Determinants
• O2 Extraction / Extraction Ratio

Carriage of O₂

• Normal arterial blood has a PO2 of 100mmHg and is 97.5% saturated
• Venous blood has a PO2 of 40mmHg and is 75% saturated
• O2 is carried either bound to Hb or dissolved in solution
  

• Dissolved O2 (2%)
  • obeys Henry’s Law: amount dissolved ∝ the partial pressure.
  • For each mmHg of PO2, there is 0.003ml O2/100ml blood
  • therefore normal arterial blood with PO2 of 100mmHg contains 0.3ml O2/100ml

• Bound to Hb (98%)
  • each gram of fully saturated Hb can bind 1.34ml of O2 (= Hufners constant)
  • 98% O2 in blood = bound to Hb, a protein tetramer with an iron-porphyrin ring attached to each chain
  • O2 coordinates with each Fe atom → inducing a conformational change → promotes binding of O2 to the other Fe atoms.
  • total O2 binding capacity of Hb in blood (at normal p, temp, and PCO2) = 1.34ml/g → giving a total O2 carrying capacity of blood which an Hb of 150g/l of 20.1ml/100ml

O₂ content

• 1.34 = Hufners constant at 37 degrees
• 0.03 = solubility coefficient for O2 in water
• O2 content per 100mL:
  

Relevant Anatomy (for O2 Carriage)

• RBCs
  • small, flexible, biconcave discs
  • cell membrane contains carbohydrate based antigens (ABO) and transmembrane proteins (Rhesus)
  • No nucleus; no mitochondria (therefore aerobic metabolism not possible – entirely dependent on glucose and glycolytic pathway)
• Hb: large, ion containing protein contained within RBCs
• HbA
  • Most common form of adult Hb (95%)
  • Quaternary structure comprising 4 polypeptide globin subunits (2 alpha and 2 beta chains) in tetrahedral arrangement
  • 4 globin chains held together with weak electrostatic forces
  • each globin chain has its own haem group – an ion containing porphyrin ring with iron in the ferrous state (Fe²⁺)
  • O₂ molecules are reversibly bound to each haem group through a weak coordinate bond to the Fe ion
  • In total: 4 O2 molecules can be bound to each Hb molecule – one for each heme group
• Different Hb types have different structures of globin chains
  • HbA: 2 alpha, 2 beta (Adult)
  • HbF: 2 alpha, 2 gamma (Foetal – replaced by HbA by 6/12 age)
  • HbA2: 2 alpha, 2 delta (2-3% adults)
  • Different O2 carriage and dissociation curves
• Disorders of Hb synthesis:
  • Decreased production of normal globin change: Thalassaemia
  • Abnormal globin chains: Sickle cell anaemia
  • Affects O₂ Carriage

O₂ Delivery, Uptake

O₂ Delivery and Uptake

• Normal O₂ Delivery = 1000ml/min
• Determinents of tissue O₂ delivery
  • Diffusion from alveolus to blood: Fick’s law of diffusion and factors affecting rate
  • Diffusion from capillaries into tissues and cells: partial pressure difference
• O₂ER: O₂ Extraction ratio = % of oxygen removed = O₂ extraction / C_aO₂

Determinants of O2 Delivery

• Cardiac output = HR x SV
  • Pathological states like low output or hyperdynamic states can alter CO
• Oxygen content dependent on Hb, Sats, PaO2
• O₂ delivery decreased in:
  • decreased cardiac output (decreased preload, contractility, HR or increased afterload)
  • decreased saturations (V/Q mismatch, decreased V, decreased PiO2, Shunt, increased CO2)
  • decreased Hb (blood loss, iron deficient anaemia, anaemia of chronic disease, etc)
• O₂ Uptake increased in:
  • increased metabolic activity (sepsis, exercise, malignancy, pregnancy)
  • right shift of HbO2 curve (­CO2, ¯pH, ­2,3 DPG)

HR

affected by automatic rhythmicity of cell and balance between sympathetic & parasympathetic systems

Stroke Volume

• = Amount of blood pumped into the circulation per contraction
• dependent on preload, contractility, afterload
• Preload
  • ~ Venous return
  • (MSFP-RAP)/RVR
    • MSFP – Mean Systemic Filling Pressure
      Equilibration of pressures in the systemic circulation if cardiac output was abolished
      Describes the filling state of the circulation and tone of capacitance vessels
    • RAP – Right atrial pressure
    • Resistance to venous return
      • Calibre of transmitting venous system according to Poisuille-Hagen equation (where resistance ∝ 1/r⁴ )
      • Physical obstructions to venous return: Mechanical obstruction, Valvular stenosis
  • Thoracic pump (negative intrathoracic pressure created during inspiration)
  • Skeletal muscle pump
  • One way valves
  • Pump function of the ventricle
  • Venous tone
  • Skeletal muscle pump
  • One way valves
  • Pump function of the ventricle
  • Venous tone
• Afterload
  • Proportional to aortic pressure and ventricular size
  • Inversely proportional to ventricular wall thickness
  • Affected by obstruction to the LVOT
• Contractility
  • Affected by adrenergic or muscarinic stimulation
  • Availability of Ca

O2 diffusion into blood:

• Fick equation:
  • Describes Diffusion through tissues
  • Rate of movement of solute across semi-permiable membrane J is

where

C = concentration (or partial pressure for gasses)
A = cross-sectional area
T = thickness of the membrane or distance over which diffusion takes place.

• Thickness of membrane (normal: 0.3μm)
• Surface area of membrane (normal: 50-100m²)
  • Age, posture, degree of inflation (1 mark for any)
• Partial pressure gradient across membrane
  • Rate of blood flow through lungs
  • (no points for mentioning diffusion constant of gas – question relates to only oxygen)
• Rate of oxygenation of reduced Hb
  • Shift of oxygen dissociation curve (pH, temperature, PCO2, 2,3-DPG)
  • Haematocrit
  • Abnormalities of haemoglobin

Kerr / JC 2020

2018A 01: 32% of candidates passed this question.
Better answers divided oxygen carriage into that bound to haemoglobin and that carried in the dissolved form. A reasonable amount of detail on the haemoglobin structure and its binding of oxygen was expected, including an explanation of co-operative binding and the oxygen carrying capacity of haemoglobin. Better answers mentioned Henry’s law in the description of dissolved oxygen, along with an estimation of the amount of oxygen that is normally in the dissolved form.
It was expected that answers include the equation for oxygen delivery, a brief description of the components of that equation and the normal value, which a large number of candidates omitted.

2018A 02: 45% of candidates passed this question.
This question was best answered using a table. Better answers included: the mechanisms of action, the pharmacokinetics and pharmacodynamics, indications for use and adverse effects. To complete the answer, the two drugs should have been compared and contrasted. There are many areas which could be contrasted e.g. different indications, different mechanisms of action, different half-lives and duration of action, different metabolism and different pharmacodynamic effects, in particular the effects on the cardiovascular system and the pulmonary circulation. Similarities should also have been highlighted.

Dead space

• Ventilated lung volume in which no gas exchange occurs
• Anatomical dead space
  • Dead space volume of conducting airways
    • Oropharynx, nasopharynx and first 16 divisions of the tracheobronchial tree
    • Approx 2ml/kg
  • Measured by fowlers method (N₂ washout)
• Alveolar dead space
  • Dead space volume of parts of the respiratory airways that are ventilated but not perfused
    • West Zone 1 (P_A > P_a)
      • Low cardiac output
      • Positive pressure ventilation
      • Posture
    • Disease states
      • Pulmonary Embolism
  • Measured by subtracting anatomical deadspace from physiological dead space
• Physiological dead space
  • Alveolar + anatomical dead space
  • Calculated from Bohr equation
  • Normal arterial to end-tidal CO₂ gradient is approx 5mmHg
    • Increases if increased dead space
• Apparatus dead space
  • Dead space contributed by artificial airway devices (endotracheal tubes, LMA, HME filters)
  • Usually reduces anatomical deadspace (due to bypass of oropharynx)

Calculation / Measurement of Dead Space

Bohr’s Method

• Bohr’s Equation:

• Based on the principle that all CO₂ exhaled must come from ventilated alveoli

• PĒ_CO2 is mixed-expired CO2 in an expired tidal breath
• Alveolar PCO2 is difficult to measure, so the Enghoff modification is used
  • which assumes P_ACO₂ = P_aCO₂

Fowler’s Method

Single-breath nitrogen washout test

• Single Vital Capacity Breath – 100% O2 → Exhales to Residual volume
• Expired Nitrogen concentration and volume is measured
• Plot of concentration by volume generated
  • Phase I: Pure dead space. No Nitrogen present.
  • Phase II: Midpoint is volume of Anatomical dead space.
  • Phase III: Expired N2 plateaus
  • Phase IV: Closing capacity. Sudden Increase in Nitrogen.

Consequences of increasing dead space

• Alveolar ventilation
  • RR x (tidal volume – dead space)
  • Therefore, as dead space approaches tidal volume, alveolar ventilation approaches zero, and cannot be compensated by increasing respiratory rate
• P_aCO₂ is inversely proportional to alveolar ventilation → P_aCO₂ increases as alveolar ventilation decreases
  • Decreased pH
  • Increased central and peripheral stimulation of ventilation → Reduction in P_aCO₂
    • Central chemoreceptors activate medullary vasomotor centre → increased sympathetic discharge
  • If P_aCO₂ increases, alveolar CO₂ in non-dead space alveoli will increase
    • P_AO₂ will decrease according to alveolar gas equation

Sakurai / JC 2016

2018A 03: 59% of candidates passed this question.
Some candidates failed to provide a correct definition of dead space. An outline of anatomical, alveolar and physiological dead space was expected. The Bohr equation was commonly incorrect, and many did not comment on how to measure the components of the Bohr equation. Fowler’s method was generally well described though some plotted the axes incorrectly. The impact of increased dead space was not often well explained. Very few people stated the major impact of increased dead space is reduced minute ventilation and how this would affect CO2.

NORMAL SODIUM

• Total Sodium (Na) = 4000 mmol (60 mmol/kg) 
• Distributed:
  1. Bone (45%)
  2. ECF (50%)
     • 1°ly found in ECF (major EC cation)
  3. ICF (5%)
     • 10-15 mmol/L maintained by
     • Na⁺/K⁺ ATPase
     • low g_Na → prevents influx of Na
• Role of Na
  1. Main determinant of ECF osmolality and tonicityNa/Cl ~ 90% ECF osmotic solute load
  2. Main determinant of ECFV
  3. Depolarisation in action potential 2° to ↑Na conductance
  4. Co-transport of substances across membranes (Eg. Glucose)
  5. Involved in Na+/K+ ATPase in cell membranes
• Total output =Total input
  • 1-1.4 mmol/kg/day
  • ~100-300 mmol/day in 70 kg adult
  • 10.5 g/day
• Sodium Control – Lost via:
  1. Kidneys (main) ~ lose 150 mmol/day
     • Filters 25000 mmol Na+/day
     • 99.5% reabsorbed
     • 65% PCT, 25% TAL of LoH, 5% EDCT, 4-5% LDCT and CD
  2. Sweat and GIT loss in faeces ~ lose 10 mmol/day (0.25 g/day each)

Sodium Reabsorption in Kidney

Overview of renal Na⁺ regulation:

• Thus, renal Na⁺ regulation depends on:
  • Degree of glomerular filtration of Na+ → GFR (minor)
    • Changes in GFR due to hyper or hypovolaemia will (indirectly) adjust sodium elimination. Increased plasma volume increases GFR, and vice versa.
  • Degree of tubular reabsorption of Na⁺ (major)
    This is the main mechanism for controlling sodium in euvolaemia.
    In terms of long term Na excretion; Na reabsorbed is more impt than GFR because:
    • (i) GFR is heavily autoregulated
    • (ii) Glomerulotubular balance blunts any major changes in Na+ excretion that would have resulted from minor changes in GFR changes that actually occurs
  • Na reabsorption through GIT/sweat/salivary glands:
    • Varies with diet and exercise
    • Mainly action of Aldosterone via Na/K ATPase

• Normal values
  • Na⁺ filtration: 140mmol/L x 180L/day = 25000mmol Na/day
  • Na⁺ excretion: 140mmol excreted
    • rest reabsorbed
    • Fractional excretion = 0.5%

Na+ regulation: Control of GFR

1. Intrinsic autoregulatory factors (tubuloglomerular feedback and myogenic mechanism)
   • MAP has minor effect on GFR over MAP range 70-175 mmHg → BUT changes
     in BP that invoke baroreceptor reflexes (BRR) can override these autoregulatory
     mechanisms → alter GFR and amount of Na+ filtered
2. Extrinsic factors: Body Na+ content (via ECFV)
   • Direct renal effects – ↓ [Na⁺] (or ↓ ECFV) → results in ↓ GFR due to a ↓ glomerular capillary P(HYDROSTATIC) and ↑ glomerular capillary P(ONCOTIC) → ↓ GFR and Na⁺ filtered
   • Indirect renal effects – ↓ [Na⁺] (or ↓ ECFV) → stimulates arterial, venous and cardiac BRR → neurohormonal response → to ↓ GFR and Na⁺ filtered via:
     • (i) ↑ SNS and RAAS activity → cause afferent and efferent arteriolar constriction and mesangial cell contraction
     • (ii) ↑ ADH → cause afferent arteriolar constriction and mesangial cell contraction
     • (iii) ↓ ANP → inhibit afferent arteriolar dilation and mesangial cell relaxation

Na+ Regulation: Control of Reabsorption

1. Glomerulotubular balance:
   • Intrinsic autoregulatory mechanism that minimises the effect of changes in GFR on Na⁺ and H₂O excretion
   • It functions on the basis that the PCT reabsorbs a constant proportion of glomerular filtrate (65% of filtered Na⁺ /H2O), rather than a constant amount
   • In effect – ↑ GFR = ↑ filtration of Na+/H2O = ↑ Na+/H2O reabsorption
   • Mechanism:
     • With ↑ GFR → large amount of plasma is filtered at the glomerulus → leads to ↑ π(ONCOTIC) of plasma in peritubular capillaries
   • This results in an ↑ gradient that –
     • (i) Favours tubular reabsorption, and
     • (ii) Counteracts the effect of ↑ GFR on fluid leaving the PCT
2. Renal interstitial hydrostatic pressure (Intrarenal physical factors)
   • ↓ ECFV (and ↓ Na⁺) results in ↓ MAP → leads to (i) ↓ P_HYDROSTATIC and (ii) ↑ π_ONCOTIC of peritubular capillaries → thus, ↑ Na⁺ (and ↑ H2O) reabsorption from tubular interstitium into peritubular capillaries
3. Hormonal Influences:
   • Renin
     • Released by ↓ Na delevery to macula densa or β1 stimulation secondary to volume underload
     • Tubular effects:
       • increased PCT Na/Cl reabsorption, increased tubular K secretion
       • Direct PCT effect
       • Aldosterone release
   • Aldosterone
     • Most important regulator of Na⁺ reabsorption
     • Alters protein translation (inducing production of tubular basolateral Na+/K+ATPase and luminal ENaC and K+channels) → causes ↑ Na+ reabsorption by DCT and Principal cells of CCD
     • Increased Na reabsorption throughout the GIT/sweat and salivary glands via Na/K ATPase
     • Increased H2O reabsorption and increased Na via solvent drag
   • Angiotensin II
     • Negative feedback on renin release
     • Increased aldosterone release
     • Decreased RBF and GFR
       • Direct renal arteriole constriction (efferent = afferent)
       • Mesangial cell contraction thus decreased Kf and GFR
     • Direct stimulation of Na⁺ reabsorption at PCT, and
     • Indirect stimulation of Na⁺ reabsorption via SNS, AII, and aldosterone
   • SNS
     • Direct stimulation of Na+ reabsorption at the PCT (α1 and β1 receptors), and
     • Indirect stimulation of Na⁺ reabsorption via RAAS
   • ADH
     • → ↑ Na⁺ reabsorption at the CCD (principal cells) → acts synergistically with aldosterone here
   • ANP
     • Inhibition of Na⁺ reabsorption (blockage of ENaC) in the CDs
     • ↓ RAAS and ↓ ADH activity
4. Other causes ↑Na reabsorb:
   • Cortisol
   • Oestrogen
   • GH
   • Thyroid hormone
   • Insulin
   • Dopamine
5. Other cause ↓Na reabsorb:
   • PGE2 inhibits NaK ATPase to reduce Na reabsorption
   • Glucagon
   • Progesterone
   • PTH
   • Renal vasoDilators:
     • PGs
     • Kinins
6. Pressure natriuresis & diuretics
   • renal compensatory mechanism that maintains long-term regulation of arterial BP by controlling the kidney’s excretory ability of Na⁺and H2O
7. Pharmacological agents:
   • Ouabain (a cardiac glycoside) inhibits NaK ATPase decreasing excretion
   • Loop Diuretics → ↑ Na loss

Gladwin / Bianca / JC 2019

2018A 04: 6% of candidates passed this question.
A description of filtration and reabsorption, including amounts was required. Better answers described sodium handling in a logical sequence as it progressed through the nephron including the percentages reabsorbed in each segment. In addition to the amounts reabsorbed, the mechanisms of transport across the tubular luminal and basolateral membranes into interstitial space should have been described.

• aldosterone = stimulates Na+ reabsorption at the collecting tubules
• intra renal factors such as interstitial pressure which is lowered during hypovolaemia and reduced renal perfusion, thus promoting Na+ reabsorption gradient
• sympathetic nervous system – influences interstitial pressure and increases renin production
• angiotensin II – stimulates reabsorption at proximal tubule
• Atrial Naturetic Peptide/Factor – inhibits Na+ reabsorption
• Others – dopamine, cortisol, insulin => increase Na+ reabsorption, but minor factors

Syllabus – D1, 2f
Reference – Textbook of medical Physiology, Guyton, Chp 28

PK and PD of Fentanyl and Remifentanil

Context sensitive half-time

• Defined as the time for plasma concentration to fall to half of its value at the time of stopping an infusion
• A method to describe the variability in plasma concentrations after ceasing an infusion
  The “context” is the duration of infusion.
• Used because terminal elimination half-life has little clinical utility for predicting drug offset
  Half-lives are often misleading when discussing drug infusions.
• Dependent on:
  • Duration of infusion
    During an infusion, drugs distribute out of plasma into tissues. When the infusion ceases, drug is cleared from plasma and tissue drug redistributes back into plasma.
    • The longer an infusion, the more drug has distributed out of tissues, and the longer the redistribution phase
    • The longest context-sensitive half time occurs when an infusion is at steady-state
  • Redistribution
    The maximal CSHT reached depends on the:
    • V_Dss
      Drugs with a larger V_Dss have a longer CSHT, as only a small proportion of the drug in the body will be in plasma and able to be cleared.
    • Rate constant for elimination
      Drugs with a smaller rate constant for elimination have a longer CSHT.

Drugs with longer context-sensitive half-times will wear off less predictably.

Context sensitive half time – Fentanyl vs Remifentanil:

• Fentanyl shows variable CSHT – Has high redistribution, with VdSS 3-5L/kg, and a terminal half life of 3 hours. Hence, prolonged infusion may lead to increased duration of action and SE
• Remifentanil has little redistribution and a small Vd (0.2-0.3L/kg) in the peripheral compartments, and a very short elimination half life of 3 minutes. Hence, it has a very short, context-insensitive half time
  It wears off reliably and quickly following cessation of infusion.

Courtesy: icuprimaryprep.com

2018A 05: 66% of candidates passed this question.
Well-constructed answers were presented in a table to compare pharmacokinetics and pharmacodynamics with a separate paragraph to discuss the concept of context sensitive halftime. Important pharmacokinetic points included: the differences in lipid solubility, ionised fractions and onset, and differences in metabolism. Marks were awarded for a definition of context-sensitive half-time. A discussion of these two drugs’ context-sensitive half-times should have included the differences in re-distribution into other compartments and rates of elimination.

Buffer

• Weakly ionised acid or base in equilibrium with its full ionised salt
• A buffer can “resist” change in pH by absorbing or releasing H+ ions
• Works best when pKa is closest to the target pH (7.4)
• Isohydric Principle
  • All buffer systems which participate in defence of acid-base changes are in equilibrium with each other. There is after all only one value for [H⁺] at any moment. This is known as the Isohydric Principle.

Effectiveness:

• buffer pKa (most effective if pKa = pH of carrying solution)
• pH of carrying solution
• amount of buffer present
• open (physiological) vs closed (chemical) system

Buffer Systems by site

Buffer Systems

Protein (Intracellular)

• pKa of imidazole group is 6.0
• pKa of the histadine residues themselves = 6.8
• Protein buffer ability is proportional to Histadine residue content.

Haemoglobin (Blood)

• Protein buffering system
• Important intracellular buffer in RBC
  • Exists as weak acid – HHb and potassium salt KHb.
  • Hb a pK_a of 8.2 in deoxy form and 6.6 in oxyHb
  • Buffering capacity due to imidazole residues on 38 histidine residues on Hb molecule
    • pKa of residues 6.8 à close to physiological pH

• Also important in extracellular buffering (following bicarbonate buffer system)
  • Due to fast equilibration of HCO₃^– (Hamburger Shift)
  • Band3 Transporter (HCO₃^–/Cl^– antiporter)
  • Allows carbonic anhydrase reaction to take place by limiting build-up of HCO₃^– (la chatelier principle)

• Formed in erythrocytes as a tetramer of 4 subunits
• Hb ~ 6 times the number of histadine (38) residues compared with albumin. (3-6x buffering capacity)
• Hb is in much greater concentrations than any other protein (15 g/dL vs 7 g/dL)
• For each mmol OxyHb, 0.7mmol H⁺ is buffered and 0.7mmol of CO₂ can enter circulation without a change in pH
• Available at high concentrations in RBC
• Isohydric exchange
  • the buffer system (HHbO₂-HbO₂-) is converted to another more effective buffer (HHb-Hb-) exactly at the site where an increased buffering capacity is required
  • Deoxyhaemoblobin is a much more effective buffer
  • oxygen unloading increases the amount of deoxyhaemoglobin and this better buffer is produced at exactly the place where additional H⁺ are being produced because of bicarbonate production for CO₂ transport in the red cells.

Bicarb (Plasma, Interstitium, Urine (minimal))

• Catalysed by carbonic anhydrase (slow where CA is absent (plasma))
• Open at both ends
• Bicarb regulation at kidneys
• CO₂ regulation at lungs

Ammonia (Urine)

Equlibrium between ammonia and ammonium

Steps:

• Glutamine enters PCT cells
  • 20% from filtrate
  • 80% from peritubular capillaries
• Ammonia (NH3) produced from glutamine in PCT by glutaminase secreted into lumen
• Reabsorbed in TAL of LoH
• Diffuses into peritubular cells of CD down conc Grad
• H+ secreted into lumen of CD
• Combines with ammonia to form ammonium
• Ammonium positive charge prevents reabsorption
• Thus “excess hydrogen can be secreted with ammonium”

Phosphate (Urine, Bone)

Effect in urine is limited due to:

• Minimal urinary pH is 4.5 → equation B is >99% ionised → of little use.
• Requires filtered PO4 → Normally low levels.
• Depends on Diet and PTH.
• Where H is secreted in distal tubules, there is minimal PO4 excretion

CaCO3 (Bone)

• Important in chronic metabolic acidosis
• Release of calcium carbonate from bone is the most important buffering mechanism involved in chronic metabolic acidosis.

Please Note: This answer is viewed from the Traditional approach to Acid-Base theory. Alternative (physicochemical approaches) deemphasise bicarb due to its equilibrium with water and relatively low concentration compared with the strong ions.

Gladwin / Sakurai / JC 2020

2018A 16: 45% of candidates passed this question.
Few candidates defined a buffer making it difficult to award 25% of the marks for this question.
The three main buffers in blood should have been described: bicarbonate system, haemoglobin and proteins. The pKa, the buffering mechanism and the capacity of the system should have been described. The Henderson Hasselbach equation was sometimes incorrect. Marks were only awarded for buffers in blood and unfortunately some candidates described non-blood buffers.

Blood supply to the Gastrointestinal system

• Portal circulatory system + arterial blood flow into liver
• 1100ml of portal blood + 400ml from hepatic artery = 1500ml (30% CO)
• Oxygen consumption – 20-35% of total body needs

Arterial Supply

Venous Drainage

Portosystemic Anastomosis

• Areas:
  • Lower end of oesophagus
  • Upper part of anal canal
  • Umbilicus
  • Retroperitoneal Bare area of liver
• The gastroesophageal junction around the cardia of the stomach-where the left gastric vein and its tributaries form a portosystemic anastomosis with tributaries to the azygos system of veins of the caval system.
• The anus-the superior rectal vein of the portal system anastomoses with the middle and inferior rectal veins of the systemic venous system. 
• The anterior abdominal wall around the umbilicus-the para-umbilical veins anastomose with veins on the anterior abdominal wall.

2018A 07: 7% of candidates passed this question.
An outline of the blood supply from the oesophagus down to the anus was expected. Very few candidates knew the branches of the main 3 arteries and which portion of the gastrointestinal system they supplied. Concepts related to control of blood flow and autoregulation of blood flow were not asked and therefore marks were not awarded for this information.

Pulse oximeters assumes that only oxy-Hb and deoxy-Hb are present in the blood. It cannot differentiate other species of haemoglobin such as carboxyhaemoglobin (carboxy-Hb) or methaemoglobin (met-Hb) because it only uses two wavelengths of light (660 nm and 940 nm).

Co-oximeter:

• A co-oximeter is a blood gas analyzer that, in addition to the status of gas tensions provided by traditional blood gas measurements, measures concentrations of oxygenated hemoglobin (oxyHb), deoxygenated hemoglobin (deoxyHb or reduced Hb), carboxyhemoglobin (COHb), and methemoglobin (MetHb) as a percentage of the total hemoglobin concentration in the blood sample
• Use of co-oximetry is indicated:
  • when a history is consistent with toxin exposure
  • hypoxia fails to improve with the administration of oxygen
  • there is a discrepancy between the Pao2 on a blood gas determination and the oxygen saturation on pulse oximetry (Spo2)
  • clinician suspects other dyshemoglobinemias such as methemoglobinemia or carboxyhemoglobinemia.
• Different haemoglobin species have different absorption spectra.

Mechanism / Measurement

• Uses Beer-Lambert law to detect different Hb species.
  • “Incidence of light is inversely proportional to the path distance and concentration of light absorbing particles within the path”
• multi-wavelength spectrophotometry (measures the absorption of light passing through blood from several dozens of wavelengths)
• Complex, but straightforward internal computations
• enables the instrument to distinguish between oxy-Hb, deoxy-Hb, and carboxyhemoglobin,-COHb, methemoglobin -metHb, other hemoglobin moieties and ‘background’ light-absorbing species
• This is reported as the fractional oxyhaemoglobin content (FO₂Hb), which is defined as:

• The FO2Hb measure provides a more accurate picture of the availability of oxygen to the tissues in the presence of haemoglobin variants.
• If the original blood sample contained no carboxy-Hb or met-Hb, then the values for FO2Hb and SaO2 would be identical.

Advantages:

• Accurate measure of oxygen saturation: low readings indicate true hypoxia, and high readings always represent true hypoxia
• Able to detect different Hb species, like deoxy-Hb, carboxy-Hb, met-Hb
• Not confused by ambient light,  absence of pulsatile flow, tricuspid regurgitation, methylene blue dye.

Limitations of co-oximetry:

• Expensive (depending on device
• Invasive (Blood sample needed)
• Variations with different devices, especially due to Limitations on Quality control
• Possible false values with severe hypoxemia, and extremes of Hb concentrations (better with newer generation devices)
• Not available in all blood gas analyzers
• Continuous monitoring not commercially availabe yet

Limitations of pulse oximetry:

JC 2020

2018A 08: 32% of candidates passed this question.
Most candidates confused co-oximetry with other methods of measuring oxygenation of blood. Whilst there were a number of excellent descriptions of pulse oximetry, these attracted no marks for the first two sections. Structuring the answer based on the three parts asked, would have improved answers ensuring all aspects of the question were addressed.

Functions of the Placenta

• Organ of foetal + maternal origin; supports developing foetus
• Low pressure, low resistance AV shunt that provides metabolic nutrients necessary for growing foetus
• Functions
  • Transfer: gas exchange; nutrient + waste exchange; drugs; heat
  • Immunological barrier
  • Metabolic
  • Endocrine

1. Transfer

a. Gas Exchange

• Diffusion dependent on Fick’s Principle

• Maternal placental flow ~600ml/min at term (2x foetal flow) → ↑diffusion by ↑concentration gradient for solutes
• Molecules <600Da more readily diffuse down concentration gradient
• O2 diffusion
  • PO2 entering placenta via uterine artery = 18mmHg (SpO2 45%)
  • PO2 leaving placenta via uterine vein 28mmHg (SpO2 70%)
  • Foetus able to absorb large enough vol O2 despite low PO2 because:
    • Foetal Hb
      • 2 y subunits cf β → prevent binding of 2,3-DPG → L shifted OHDC → favours O2 loading at ↓PaO2
      • [FHb] 50% > maternal [Hb]
    • Double Bohr effect
      • Describes Bohr effects happening on either side of placental gas exchange in mother + foetal circulations
      • Accounts for 2-8% of O2 transfer
      • Bohr effect 1: placenta: foetus unloads CO2 in placenta → ↑placental CO2 → RIGHT shift HbA OHDC → ↓HbA affinity for O2 → ↑placental O2 unloading
      • Bohr effect 2: foetus: foetus unloads CO2 → ↓foetal CO2 → LEFT shift HbF OHDC → ↑HbF affinity for O2 → ↑foetal O2 binding/ uptake
• CO2 diffusion
  • Foetal PaCO2 50mmHg; intervillous PCO2 37mmHg
  • CO2 offloading favoured in foetus by:
    • High foetal [Hb] ↑s amount of CO2 that can be carried as carbaminoHb
    • Double Haldane effect
      • Haldane effect: describes how ∆O2 sat of Hb affect CO2 transport: deoxyHb has ↑affinity for CO2 than oxyHb
      • Double Haldane: describes Haldane effects happening across the placenta
      • Accounts for 45% of CO2 transfer between maternal and foetal circulation
      • Haldane 1: placenta: placenta unloads O2 → ↓placental O2 → deoxyHbA has ↑affinity of CO2 → ↑placental CO2 uptake from foetus
      • Haldane 2: foetus: foetus takes up O2 → ↑HbF O2 → ↓HbF affinity for CO2 → ↑HbF CO2 release to placenta

b. Nutrient delivery

• Nutrient diffusion
  • High foetal caloric requirements in late pregnancy
  • Facilitated diffusion of glucose via carrier molecules in trophoblasts
  • Active transport for amino acids, Ca2+, Fe, folate, vit A and C

c. Waste removal – Urea, Uric acid, Creatinine, Br

d. Heat transfer

2. Immunological function

• permeable to IgG via pinocytosis → allows maternal abs to provide passive immunity to foetus
• Trophoblast cells lose many cell surface MHC molecules → making them less immunogenic; also cells cover themselves in mucoprotein which
  disguises them from maternal immunie system
• Chorionic cells act as immunological barrier – preventing maternal T cells and abs from reaching foetal circulation
  • Some bacteria (listeria) and viruses (rubella, parvovirus B19, HIV) can cross into foetal circulation
• Progesterone + alpha-foetoprotein produced by yolk sac act as maternal immunosuppressive agents

3. Metabolic

• synthesis of glycogen, cholesterol, FA, enzymes

4. Endocrine function

• synthesis of 4 main hormones:
  • bHCG
  • hPL: human placental lactogen (human chorionic somatomammotrophin)
  • Oestriol
  • Progesterone
• Synthesis of other hormones and growth factors
  • Placental corticotrophin
  • Human chorionic somatostatin
  • Human chorionic thyrotropin
  • Epidermal growth factor
  • Somatomedin

Placenta

• Placenta:
  • temporary fetal organ that begins developing from the blastocyst shortly after implantation
  • ~22cm length, 2.5cm thickness. ~500gm
  • Connects to fetus by umbillical cord
• “Chorionic villus” is the basic structural unit of the placenta → it is a vascular projection of foetal tissue that is bathed by maternal blood within the “Intervillous space”. It consists of:
  • Foetal connective tissue containing foetal capillaries
  • Chorion → outermost layer of foetal tissue that is made of 2 layers →
    • (a) Syncytiotrophoblast (directly contacts maternal blood in intervillous space) and
    • (b) Cytotrophoblast (b/t syncytiotrophoblasts and foetal CT)

Placental Circulation

• Placental circulation = Two circulation systems in parallel – maternal and the fetal
• Maternal circulation system
  • Uterine Arteries (600ml/min, 100mm Hg) → arcuate arteries → radial arteries → spiral arteries (70 mm Hg) & basal arteries (myometrium and deciduas)
  • Spiral arteries → intervillous spaces (10mm Hg) → uterine veins that are arranged in the periphery of the intervillous space.
  • Blood in the intervillous space is exchanged 2-3 times per minute.
• Fetal circulation system:
  • Two villus Umbilical Arteries (50mmHg) → finer vessels that cross through the chorionic plate → villus capillaries (30mmHg) → leaves placenta through umbillical vein (20mmHg)
  • Their supply amounts to approximately 40% of the fetal heart blood volume per minute.
  • The pressure in the fetal vessels and their villus branches always lies over that of the intervillous space. This protects the fetal vessels from collapse.
• Substances traverse between foetal and maternal blood via the following layers:
  • Maternal blood (intervillous space) ↔ Chorion (2x layers of trophoblasts) ↔ Foetal connective tissue ↔ Endothelium of foetal capillaries ↔ Foetal blood

Determinants of Placental Blood Flow

Uteroplacental blood flow

• At term → uteroplacental BF is 500-700 mL/min (10% maternal C.O.) of which:
  • 70-90% of this BF enters the intervillous space (via the spiral arteries) → NOT autoregulated as blood flow is “pressure-dependent” (see factors below)
  • 10-30% of this BF supplies the myometrium/deciduas (via the basal arteries) → autoregulated blood flow
• Blood flow to the intervillous space (which participates in substance exchange with foetal blood) is affected by the following factors:

• Uterine arterial pressure (UAP):
  • Maternal arterial BP → ↓ MABP (Ie. due to SNS block 2° neuraxial block,
    hypovolaemia, supine hypotension syndrome, Etc.) causes ↓ UAP → ↓ UBF
• Uterine venous pressure (UVP):
  • Uterine tone and contractions → ↑ tone/contractions (Ie. due to contractions,
    oxytoxics, ketamine, Etc.) causes ↑ UVP → ↓UBF
• Uterine vascular resistance (UVR):
  • Uterine arteriolar tone → ↑ vasoconstriction (Ie. a/w essential HT and PET, α-adrenoceptor stimulation (by endogenous SNS innervation, catecholamines or sympathomimetics), and vasopressin) causes ↑ UVR → ↓ UBF

Umbilical blood flow

• At term → umbilical BF is 360 mL/min (25-50% of foetal C.O. (≈ 1000 mL/min))
• It is “autoregulated” (cf. uterine BF) → involves vasodilators (PCI-2/NO) derived from vascular endothelium
• BF is ↓ with severe hypoxia, ↑ BGL, catecholamine and cord compression

Kerr / Bianca 2020

2018A 09: 32% of candidates passed this question.
Many candidates provided a broad overview of functions of the placenta but lacked detail.
Placental blood flow has maternal and foetal components, though most only considered the maternal circulation to the placenta and didn’t mention the foetal vessels. Many were not specific as to what blood vessels were described.
Many stated that uterine blood flow is not autoregulated, however went on to describe myogenic and neuro-humoral mechanisms of autoregulation

• Suxamethonium is the dicholine ester of succinic acid which acts as an ultrashort acting depolarising muscle relaxant.
• It is used in rapid sequence induction and to modify seizures caused by ECT.
• Mechanism of Action:
  • mimics the actions of Ach by binding to the nicotinic Ach receptor and causing membrane depolarization.
  • However, because its hydrolyzing enzyme is not present at the NMJ, the effect lasts longer than for Ach.
  • The persistent depolarization renders the voltage sensitive Na channels inactive within 1-2 mins.
  • This prevents the transmission of further APs. Initially causes fasciculations, then muscle relaxation.

• Partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist
• A partial agonist is unable to achieve a maximal biological response following active site binding, despite increasing doses

• A non-competitive antagonist binds to an allosteric (non-agonist) site on the receptor to prevent activation of the receptor
• Since it induces a lower biological response on active site binding than acetylcholine, it is a non-competitive antagonist of acetylcholine at the nicotinic receptor
• No matter how high levels of acetylcholine are at the neuromuscular junction, maximal response will not be reached

Advantages and Disadvantages of Sux in ICU

Mooney / JC 2020

2018A 10: 46% of candidates passed this question.
This commonly used drug should be very well-known. The question asked for an outline, hence long explanations of various aspects of pharmacology (e.g. pseudocholinesterase deficiency) were unnecessary.
Headings should have included: advantages (e.g. rapid onset, rapid offset, short acting, IV or IM administration, not end organ dependent for metabolism, premixed, safe in pregnancy and neonates). The disadvantages section should have included the following headings: pharmaceutical, adverse drug reactions (including several potentially fatal ones), numerous contraindications, unpleasant side-effects and potential problems with repeat dosing.

2012B 02: 13 (59.1%) of candidates passed.
For a good answer candidates were expected to mention that an agonist is a drug that elicits a maximal response on binding to a receptor. A partial agonist has intrinsic affinity with only  partial efficacy and hence is unable to elicit a maximal response. A competitive drug acts at  the same binding site of a receptor as an endogenous ligand (e.g. acetylcholine at the  neuromuscular junction) and its action therefore is surmountable with increasing  concentrations of drug and how this concept relates to suxemethonium. For the remainder  of the question, Candidates were expected to mention the advantages and disadvantages of  suxamethonium within Intensive Care practice. Good answers included a systematic  approach and use of tables and/or well organised lists.

Regional Supply

Coronary Blood Flow

• 80 mL/min/100 g
• or 200-250 mL/min
• 5% of CO at rest
• Can increase by 3-4 times (up to 400mL/min/100g)

High Extraction Ratio

High at rest (55-65%) body average of 25% 

• Extraction ratio can only rise by factor of < 2 to 90%
• AV Δ O₂ = 11 mL/dL 
• Coronary venous O₂ content = 5 mL/dL
• Coronary sinus SpO₂= 20mmHg

Coronary perfusion pressure (CPP)

• ADP = Ao Diastolic Prssure
  • It is different throughout the cycle and b/w ventricles

Phasic Supply as per diagram.

Determinants of Coro BF

• Physical Factors
  • Extravascular compression (CPP factors)
• Neural and Neurohumoral Factors
  • ↑ SNS tone →
    • α receptor mediated vasoconstriction
    • β receptor mediated vasodialtion 
    • ↑ force and rate of contractions → ↑ vasodialtor metabolite release
    • Overall effect is dilation
  • ↑ PSNS tone → KACh stimulation → mild ↓ Coronary vascular resistance
• Metabolic Factors (main)
  • Vasodilatory
    • ↑ Adenosine, H, K, CO2, Lactate
    • NO → GTP 
    • ↑ O2 demand → ↓ ATP → ↑KATP channel activation → hyperpolarisation → vasodilation
• Myogenic autoregulation (keep CPP 60-180 mmHg)

Gladwin 2016

2018A 11: 46% of candidates passed this question.
Some answers suffered from listing things rather than describing things as the question required.
Better answers included a description of metabolic, physical and neuro-humoral factors and the relative importance of each.
Many described detailed anatomy which was not necessary.

Diastole in the cardiac cycle corresponds with cardiac myocyte relaxation, and includes periods of isovolumetric relaxation and ventricular filling.

Isovolumetric relaxation

• As aortic pressure overcomes ventricular pressure, and the inertia of forward flow of blood out of the LVOT, the aortic valve closes
• The ventricular myocytes relax, while both the mitral (or tricuspid) and aortic (or pulmonary valves) remain closed
• The volume of blood within the ventricle remains constant (LV End-Systolic Volume ~50mls) , however ventricular pressure decreases from 120mmHg to close to 0mmHg (or 20 to 0mmHg in R ventricle

Ventricular filling

• Passive phase
  • As ventricular pressure decreases below the atrial pressure, the mitral (or tricuspid) valve opens allowing forward flow of blood from the atria to the ventricles leading to a progressive increase in ventricular volume and pressure.
  • The first two-thirds of the ventricular filling is due to passive filling
• Active phase
  • 20% of ventricular filling is provided by the atrial kick during the final quarter of ventricular filling resulting in a slight increase in ventricular pressure
  • Ventricular pressure overcomes atrial pressure and the mitral (or tricuspid) valves close

Electrochemical events

• The cardiac action potential is tied to contraction via excitation-contraction mechanism.
• Diastole corresponds to phase IV where voltage gated L and T-type Ca channels close, ceasing Ca influx, and ongoing K efflux repolarizes the myocyte.
• ECG
  • The T wave corresponds with ventricular repolarization and occurs immediately prior to ventricular diastole.
  • The QRS complex corresponds with ventricular depolarization and occurs immediately prior to ventricular systole
  • Diastole corresponds with the terminal part of the T wave to immediately after the QRS complex
• Electrical current through cardiac cycles
  • During depolarization, current runs from the base of the heart to the apex (corresponding to flow down bundle of His) the just before the end of depolarization, the direction of flow reverses (corresponding to flow down Purkinje fibres)
  • During repolarization, the order reverses, from Purkinje system → Bundle of His

Coronary artery perfusion

• Due to the high ventricular pressures impeding blood flow during systole in a starling-resistor model, left ventricular perfusion (or right ventricular perfusion during pressure-overloaded states) occurs predominantly during diastole.
• As right ventricular pressures are significantly lower than aortic pressures even during systole, perfusion continues (in a normal right ventricle)

Sakurai 2016

2018A 12: 29% of candidates passed this question.
Many answers lacked structure and contained insufficient information. Better answers defined diastole and described the mechanical events in the 4 phases of diastole. A common error was the ECG events in diastole. The electrical events and coronary blood flow should have been mentioned.

DEFINITIONS

Viscosity (η)

Used to indicate a fluid’s internal resistance to flow. Also thought of as a measure of the friction of a fluid.
e.g. honey has a high viscosity than water and as such moves much slower if poured

Density (ρ)

relates the mass of a substance to its volume such that ρ = kg/m3
Although some gases may have similar viscosity, their densities may be different (eg. O2 and He)

Flow

measure of volume of fluid / gas moved per unit of time (e.g. ml/min).

FLOW

TYPES OF FLOW

Laminar

Turbulent

Transitional

Reynold’s Number

• The Reynolds Number is defined as the ratio of inertial forces to viscous forces in a flowing fluid.
• It is used in many fluid flow correlations and is used to describe the boundaries of fluid flow regimes (laminar, transitional and turbulent).
• Reynold’s number can predict the likelihood of turbulent flow occurring.

Flow	Reynold’s Number
Laminar	<2300
Transitional	2300-4000
Turbulent	>4000

• Density (ρ) is the major determinant of Re: ↑ρ (N2 v He) → ↑prob of turbulent flow
• Viscosity (η) has a much smaller contribution to the determination of Re: ↓η → ↑probability of turbulent flow

Laminar Flow

• Laminar flow is the flow that corresponds with low velocities and Reynolds numbers less than 2300.
• In this type of flow, the fluid flows in parallel layers, with no disruption between the layers.
  • At low enough velocities, the fluid will tend to flow without lateral mixing, while adjacent layers simply slide past one another
  • The movement of substance in the centre is twice the velocity of the movement of substance at the walls (there is no flow at the walls)
• For flow to be laminar, the tube in which it is travelling must have smooth, parallel sides with no branches in the system

• There is a linear relationship between pressure and flow
• Viscosity of the gas / fluid is directly proportionate to resistance:
  • ↑η → ↑R → ↓flow
  • Density has no effect on the flow of gas during laminar flow
• Altering the other variables will change R as seen

Turbulent Flow

• Turbulent flow is the most common form of flow in nature, and corresponds to the Reynolds numbers higher than a value of 4000
• chaotic and unpredictable, and is often seen with fluids at high velocities
• undergoes irregular fluctuations, or mixing, and continuously changes magnitude and direction
• Flow is disorganised with small eddies forming → creates a square wavefront

• Flow is inversely proportional to √ρ
• Pressure is proportionate to flow²
• Resistance proportional to density and not viscosity

Transitional Flow

• Transitional or Transient flow  is the phase of flow that occurs between laminar and turbulent flow, and corresponds to Reynolds numbers that land between 2300 and 4000.
• In this type of flow, there is a mixture of laminar and turbulent flows present.
• As Reynolds number increase from 2300 to ~4000, there are an increasing amount of disturbances appearing within the flow.
• Transition can occur in either direction, that is laminar–turbulent transitional or turbulent–laminar transitional flow.

Sources: cfdsupport.com, cvphysiology.com

JC 2019

2018A 13: 46% of candidates passed this question.

Whilst most candidates defined density correctly, there was a lot of uncertainty regarding viscosity. Most candidates recognised that flow may be laminar, turbulent or transitional. Most accurately recounted Reynolds number and applied this correctly. Additionally, the Poiseuille equation was correctly stated by most candidates and correctly related to laminar flow. Few candidates recalled the equation describing turbulent flow

Background

• Acetylcholinesterase (AChE) is an enzyme that hydrolyse acetylcholine (ACh) into choline & acetate
• AChE is found in synaptic clefts and is responsible for the termination of synaptic transmission
• Common action of anti-cholinesterases = allow build up of Ach and prevent it from being destroyed.

Naturally Occuring Cholinesterases

Two types of naturally occurring cholinesterases:

1. Achesterase – nerve endings & in RBCs
2. Non-specific or pseudocholinesterases – destroy other esters – tissues & plasma

Anticholinesterase drugs

AntiAchE drugs are administered in anaesthesia when spontaneous recovery from NDNMB is occurring to accelerate it.

Classification:

Drugs are classified by the way in which they inhibit the activity of AchE.
3 main types of anticholinesterase:

1. Reversible antagonist via electrostatic binding
   • ie. edrophonium
   • causes electrostatic attachment to the anionic site of the enzyme -> stabilising the H+ bond at the esteratic site -> edrophonium-AchE complex prevents Ach from binding
2. Reversible antagonist via covalent bonding [Formation of carbamyl esters (carbamates)]
   • ie. neostigmine, physostigmine & pyridostigmine
   • antagonise AchE enzyme by being competitive substrate for Ach -> forms a carbamyl-ester complex at the esteratic site of enzyme.
   • longer lasting bond (15-30min)
3. Irreversible antagonist via covalent bonding
   • ie. organophosphate anticholinesterase drugs (echothiopate), insecticides & nerve gases
   • combine with Ach at the esteraic site to form a stable covalent bond -> does not undergo hydrolysis.
   • synthesis of a new AchE is required.

Pharmacodynamic effects

Anticholinesterase drugs inhibit AChE, thereby increase the concentration of ACh at both nicotinic and muscarinic ACh receptors
Muscarinic effects occur at lower doses than nicotinic effects

Muscarinic effects

• CVS – bradycardia ± hypotension
• RESP – bronchoconstriction ± bronchospasm
• CNS – miosis, cholinergic syndrome – confusion, agitation, nausea/vomiting
• GIT – hypersalivation, ↑GIT motility, nausea/vomiting, diarrhoea
• GUT – urination, incontinence
• OTHER – lacrimation, diaphoresis

Mnemonic: SLUDGE-BM: Salivation/Sweating, Lacrimation, Urination, Diaphoresis/Diarrhoea, GI upset, Emesis, Bradycardia/bronchospasm, Miosis

Nicotinic effects

• Reversal of non-depolarising neuromuscular blockers
• Prolongs effect of suxamethonium (depolarising NMB)
• Anticholinesterase overdose → excess synaptic ACh → depolarisation block ± fasciculation

Clinical uses

1. Reversal of non-depolarising neuromuscular blocker
   • Mechanism – anticholinesterase drugs ↑ synaptic ACh → competes with ND-NMB in synapse for nAChR → reversal of neuromuscular block
   • Drugs – usu. neostigmine, administered together with glycopyrrolate or atropine
2. Diagnosis and treatment of myasthenia gravis
   • Mechanism – anticholinesterase drugs ↑ synaptic ACh → competes with myasthenia auto-antibodies for post-synaptic nAChR → ↑muscle strength
   • Drugs – e.g. edrophonium for diagnosis, pyridostigmine for maintenance
3. Treatment of cognitive impairment in neurodegenerative diseases (e.g. Alzheimer’s disease, Lewy body dementia, etc)
   • Mechanism – ↑ synaptic ACh in CNS → ↑ cholinergic transmission
   • Drugs – e.g. rivastigmine, galantamine, donepezil
4. Treatment of glaucoma
   • Mechanism – constriction of sphincter pupillae and ciliary muscles → miosis → facilitate outflow of aqueous humor → IOP decreases
   • Drugs – e.g. echothiophate eye drops, physostigmine
5. Treatment of anticholinergic syndrome
   • Anticholinergic syndrome caused by: anti-histamines, anti-parkinsonians, atropine, anti-spasmodics, mydriatics, skeletal muscle relaxants, plants
   • CLINICAL FEATURES: delirium, tachycardia, dry and flushed skin, dilated pupils, myoclonus, hyperthermia, urinary retention, bowel sounds, seizures, dysrhythmias(tachy)
   • Mechanism – increase synaptic ACh
   • Drugs – e.g. physostigmine (tertiary amine + lipophilic → readily crosses BBB)

JC 2019

2018A 14: 32% of candidates passed this question.
Many candidates who scored poorly confused anticholinesterase drugs with anticholinergic drugs. Some described pharmacokinetics when it was not asked. Similarly, treatment of organophosphate poisoning and/or cholinergic crisis was not asked for in the question.

Definition:

• ICP: hydrostatic pressure within the cranial vault
• Normal value is 5-15 mmHg
• focal ischaemia when ICP > 20 mmHg
• global ischaemia when ICP > 50mmHg

Munro-Kellie Doctrine

• The rigid and closed cranial vault forms a fixed brain volume containing
  • Brain parenchyma (80%, 1400 g)
  • CSF (10%; 75 mL)
  • Cerebral blood and vessels (10%; 75 mL)
• Δ’s in volume of any components → Δ’s in others or and increase in ICP

CSF Production / Absorption

CSF Production:

• 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

CSF Absorption:

• 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

Control of ICP

• ICP is regulated via volume buffering
  • i.e. increase in volume of one intracranial component leads to compensatory decrease in volume of other intracranial components
• When volume buffering mechanism is exhausted → rapid increase in ICP (decompensation)
  • Movement of cerebral venous blood = rapid compensation, lower capacity
  • Movement of CSF = gradual compensation, larger capacity

Determinants of ICP:

• Brain
  • Age / Mass
  • Space occupying lesions
  • Cerebral Oedema
• CSF
  • CSF production
  • CSF Absorption
• Cerebral Blood Volume
  • Cerebral autoregulation: Flow-metabolic coupling
  • Cerebral metabolic rate
  • Increase in systemic blood pressure / flow
  • Venous Outflow obstruction
  • Vasoactive agents
• Monro-Kellie Doctrine
  • Loss of above – e.g. Fractures, surgery

Compensation for Elevated ICP (Intracranial Pressure)

Early compensation

• Δ CSF distribution and flow
• CSF is displaced to spinal subarachnoid space
• ↑’d resorption rate

Late compensation

• ↑ ICP → ↓ CBF → ↓ in cerebral blood volume → cerebral ischaemia

Decompensation

• ↑ICP → ↓ in cerebral tissue volume → brain herniation
• Cushing Reflex
  • Hypertension, bradycardia and abnormal breathing associated with raised ICP
• Mechanism:
  • Stage 1:
    • ↑ ICP → ↓ blood supply to vasomotor area → Local hypoxia/hypercarbia → ↑ SNS >> ↑ PSPS vasomotor stimulation
    • ↑ TPR → ↑ MAP
    • ↑ HR → ↑ CO
    • → compensatory ↑CBF
  • Stage 2:
    • ↑ CO → Baroreceptor stimulation → ↑ Vagus nerve stimulation → Bradycardia and ↓ contractility.

Gladwin / JC 2020

2018A 15: 45% of candidates passed this question.
A definition and a normal value were expected. A description of the Monro-Kellie doctrine was expected. Better answers divided into the various components of the cranium with the answer focussing on cerebral blood volume and CSF volume as the brain tissue as no capacity to change its volume.

2018A 16: 30% of candidates passed this question.
The use of a table assisted with both clarity and the ability to compare the two drugs. Writing separate essays about each makes it difficult to score well. It was expected that candidates would follow a standard pharmacology format and discuss pharmaceutics, pharmacokinetics, pharmacodynamics and adverse drug reactions. Both of these drugs are ‘Level A’ in the syllabus and a suitable level of detail was expected.
It was expected candidates would discuss in detail the mechanism of action, electrolyte and acid-base effects. Pharmacokinetic values were poorly answered. Qualitative terms such as ‘moderate, good and some’ are vague and should be avoided. Only correct numerical values (or ranges) attracted full marks.

Definitions

Osmolality is a measure of solute concentration as defined as the number of osmotically active particles per kilogram water.

Tonicity is the effective osmolality and is equal to the sum of the concentrations of the solutes which have the capacity to exert an osmotic force across the membrane.

Pharmacology

CICMWrecks Table – NS | 5% Dex (Click to Open)

2018A 17: 29% of candidates passed this question.
Most candidates gave an adequate definition of osmolality and tonicity. A single concise sentence for each attracted full marks. Some candidates drew diagrams & equations, which added few marks. Some candidates confused osmolarity (mOsm/L) and osmolality (mOsm/kg).
Tonicity was best defined as the number of ‘effective’ osmols (those that cannot cross the cell membrane) in a solution relative to plasma. The use of a table greatly facilitated the comparison of 0.9% saline and 5% dextrose solutions. Values for composition, osmolarity and osmolality were poorly done. Some manufacturers state calculated values and some approximate values on the bags – both were accepted.
No candidate correctly pointed out the fluids respectively have 9g NaCl and 50g dextrose per litre.

JC 2019

2018A 18: 52% of candidates passed this question.
There were some good answers, though invasive BP measurement was better answered than oscillometry. Many candidates provided extensive detail in one area i.e. the workings of a Wheatstone bridge, to the detriment of a balanced answer. Few seemed to have a structure consisting of “equipment, method, sources of error, advantages, disadvantages” or similar and missed providing important information as a result. Several described auscultatory non-invasive blood pressure measurement, rather than oscillometry, which although related in principle is a different process.

Definitions

• Temperature – average kinetic energy of the atoms and molecules that make up a substance
• Temperature setpoint is the level at which the body attempts to maintain its temperature.
• Core body temperature:
  • Refers to deep body temperature of main internal organs (in head, trunk, abdomen) →
    sites where metabolic activity occur (Ie. heat production)
  • Kept constant at 37 +/- 0.4 °C (“Normothermia”) → displays normal variations:
    • Diurnal variation – ↑ in evening (37.3 °C) and ↓ in early morning (35.8 °C)
    • Menstrual variation – ↑ 0.5 °C in latter half of cycle
• Variations in core body temperature:
  • Normothermia → core body temperature 37 +/- 0.4 °C
  • Hypothermia → core body temperature < 36 °C
  • Hyperthermia → core body temperature > 37.5 °C
• Peripheral body temperature:
  • Refers to body temperature peripherally (Ie. skin, arms, legs, superficial tissues of core
    sites) → sites where heat loss occur
  • Temperature varies widely → always LESS than core body temperature
• Regulation of body temperature is done by balancing heat loss and heat production, predominantly through behavioural mechanisms and skin

Regulation of Body Temperature

Temperature sensors are central and peripheral, whilst regulation occurs centrally, and has multiple
effectors

Sensors:

• Central
  • Deep tissues/viscera (Eg. in intestinal wall)
  • Brain (anterior hypothalamus and extra-hypothalamic areas)
  • Spinal cord
• Peripheral
  • Dermis (main)
  • Corneas

Central Controller:

Hypothalamus is the main body temperature regulatory centre

• Posterior hypothalamus responds to cold
  • inputs from peripheral afferents
  • responsible for the temperature set point
  • ACh is the major neurotransmitter here.
• Anterior hypothalamus responds to heat
  • both peripheral input and change in blood temperature
  • Major neurotransmitters are Nad, 5HT, dopamine and prostaglandins.

Effector Mechanisms:

1. Skin
   • Sweating (evaporation)
     • Secrete plasma-like fluid Na142, Cl- 104 (urea/K, etc v low amounts) osmolality controlled by rate of secretion and aldosterone
     • loss via evaporation (latent heat of vapourisation of water)
     • 1-2L in extreme exercise up to 10 L max per 25 hours.
     • 0.54 kcal/gram of H2O evaporated
     • Degree of evaporation determined by ambient temperature and relative humidity
   • Blood Flow (radiation)
     • 8 (300 mL/min) – 30% CO skin
     • Vasodilation up to 30 fold increase
     • Vasoconstriction up to 10 fold decrease
     • vasoconstriction/dilation controlled by SNS (α1-mediated) vascular SM contraction and hypothalamic feedback
   • Fat/Clothing
     • Fat conducts heat 1/3 as readily as other tissues (decreased radiation)
     • Clothes reduce conductive heat loss via private zone of air adjacent to skin and decreased convection air currents -50% and more if specialised
2. Non-Skin
   • Non-shivering thermogenesis
     • Predominantly in brown fat
     • Uncoupling of oxadative phosphorylation
     • Increased heat gain without oxygen consumption/ATP production
   • Shivering
     • Increased heat gain by metabolism
   • Behaviour
     • For gain (exercise) or loss (submerging in water)
     • Voluntary muscle contraction (Ie. ↑ activity with cold stress; ↓ with hot stress) – Affects heat production
     • Body posturing (Ie. ↓ BSA with cold stress;↑ with hot stress) – Affects heat loss
     • Clothing (Ie. ↑ clothing with cold stress; ↓ with hot stress) – Affects heat loss
   • Appetite
     • Cold stress stimulates food-induced thermogenesis → ↑ metabolic rate and heat production
   • Thyroid hormone secretion
     • Cold stress stimulates thyroid hormone secretion → long-term ↑ metabolic rate and heat production

Gladwin / JC 2019

2018A 19: 52% of candidates passed this question.
The best answers were systematic, using a sensor, integrator, effector approach, while also mentioning physiological variations i.e. diurnal, with ovulatory cycle etc.
Few candidates raised the concept of central and peripheral compartments. The differentiation of the concepts of set point, interthreshold range and thermoneutral zone was often confused.

Hypothalamus

• Hypothalamus
  • organ that regulates large number of autonomic/ endocrine processes
  • acts as control centre
• Cells
  • magnocellular neurosecretory cells in the paraventricular nucleus and the supraoptic nucleus of the hypothalamus produce neurohypophysial hormones, oxytocin and vasopressin. These hormones are released into the blood in the posterior pituitary.
  • Much smaller parvocellular neurosecretory cells, neurons of the paraventricular nucleus, release corticotropin-releasing hormone and other hormones into the hypophyseal portal system, where these hormones diffuse to the anterior pituitary.
• Location
  • Part of the fore brain. Considered part of the diencephalon
  • Located below the thalamus and forms the floor and lower part of the lateral walls of the third ventricle
  • Anteriorly extends up to the optic chiasma
  • Posteriorly continuous with the tegmentum of midbrain
• Structure
  • formed by gray matter conglomeration of neurons that organize in nuclei and also by white-matter substance formed by myelinated nervous fibers.
  • Nuclei send and receive fibers to other parts of brain
  • divided by the anterior horns of the fornix in a lateral, medial, and periventricular (median) region and by a coronal plane passing through the infundibulum in an anterior and posterior region.
• Regions
  • Anterior / Prechiasmatic / Supraoptic
    • located above the optic chiasm
    • contains: supraoptic, preoptic and medial preoptic, the suprachiasmatic and the anterior hypothalamic nucleus, alongside with the paraventricular nucleus
  • Infundibular / Tuberal
    • located above tuber cinereum (between anterior and posterior)
    • composed of two parts, anterior and lateral
    • contains: dorsomedial, ventromedial, paraventricular, supraoptic, and arcuate nucleui
  • Posterior / Mamillary
    • formed by medial and lateral area
    • medial area contains mamillary nuclei and posterior nucleus
    • lateral area contains lateral nucleus and tuberomammillary nucleus
• Connections: Nervous, Endocrine, CSF, Direct to pituitary
• Blood supply
  • mainly hypophyseal artery (branch of anterior cerebral artery)
  • Detailed arterial supply:
    • Anterior: branches of ACA and ACOM
    • Tuberal: branches of PCOM and superior hypophyseal artery
    • Posterior: branches of PCA
    • Infundibulum: superior hypophyseal arteries from the ophthalmic branch of ICA (C6)
  • drains into hypothalamohypophyseal system of veins to anterior pituitary → hypophyseal vein

Function of Hypothalamus

Autonomic nervous system activity

• CVS:
  • Ant hypothalamic stimulation → ↓BP + ↓HR
  • Post hypothalamic stimulation → ↑BP + ↑HR
• Thermoregulatory: integrates thermoreceptor input + controls activity of heat loss + heat gain mechanisms
• Satiety: hunger modulated by glucose, CCK, glucagon, and leptin
• Water balance:
  • Osmoreceptors: control ADH release from posterior pituitary
  • ATII: stimulates thirst + ADH release via subfornical organ + organum vasculosum
• Circadian rhythm
• Behaviour
• Sexual function

Endocrine/ hormonal activity

• Direct neural control of posterior pituitary gland
• Pituitary neurosecretory neurons
  • Magnocellular neurons:
    • consists of SON + PVN
    • synthesise and secrete ADH and oxytocin
  • Parvocellular neurons:
    • form tuberoinfundibular tract → secrete hypophysiotropic hormones
    • release controlled by Nad, dopamine, 5-HT
• Hypothalamic hormones → action in pituitary
  • Anterior pituitary by hormone secretion into long portal vein
    • GnRH → stimulates FSH + LH release
    • CRH → stimulates ACTH release
    • GHRH → stimulates GH release
    • TRH → stimulates TSH release
    • Somatostatin (GH inhibiting hormone) → inhibits GH, TSH, ACTH, and PRL release
    • PRL releasing hormone (PRH) → stimulates PRL release
    • Dopamine → inhibits PRL release
  • Posterior pituitary by neuronal innervation
    • ACh → stimulates release of ADH + oxytoxin
    • NAd → inhibits ADH + oxytocin secretion

(See next tab for detailed table of nuclei with functions, and communications of hypothalamus)

Sources: https://www.intechopen.com/chapters/63258
https://human-memory.net/hypothalamus/#Structure

JC / Kerr 2022

Nuclei and functions

Communications of Hypothalamus

• Nervous connections: divided into afferent and efferent fibers
  • Afferent fibres: carry somatic and visceral sensations as well as from special senses
    • Somatic and visceral afferents via lemniscal afferent fibers and nucleus of tractus solitarius, that reach the hypothalamus via reticular formation
    • Visual afferents from the optic chiasma reach the suprachiasmatic nucleus
    • Olfactory afferents are received through medial forebrain bundle
    • Auditory afferents though not identified completely but are influenced by the hypothalamus
    • Hippocampo-hypothalamic afferents reach via fornix to mamillary bodies
    • Tegmental fibers from midbrain
    • Thalamo-hypothalamic fibers from the midline and dorsomedial nuclei of the thalamus
    • Amygdalo-hypothalamic fibers from the amygdaloid complex reach the hypothalamus via stria terminalis
  • Efferent fibers: complex and numerous
    • To brain stem and spinal cord: The hypothalamic nuclei send efferent fibers to nuclei present in the brainstem and spinal cord. In this way, they control the autonomic nervous system.
    • Mammillothalamic Tract: This tract consists of fibers arising in the mamillary body and terminating in the anterior nucleus of thalamus.
    • Mammillotegmental Tract: These fibers terminate in the reticular formation, present in the tegmentum of the midbrain.
    • Limbic System: The nuclei in the hypothalamus also send efferent fibers to the various nuclei of the limbic system.

• Endocrine:
  • regulating factors or hormones released by hypothalamus → reach pituitary via the hypophyseal portal system of veins → cells of pituitary release hormones
• Direct:
  • Cell bodies present in hypothalamus → axonal terminals in posterior pituitary gland
  • Bodies synthesise oxytocin and vasopressin, stored in axonal terminals in posterior pituitary and released on demand
• CSF:
  • clear metabolic waste
  • distribute glucose, amino acids, lipids, and neurotransmitters

2018A 20: 21% of candidates passed this question.
Most candidates understood the endocrine functions of the hypothalamus, and to some degree its interactions with the pituitary. Fewer candidates mentioned the importance of the hypothalamus as an integrator for the autonomic nervous system, or its roles in arousal/emotions.
Many candidates had only a vague idea of the structure of the hypothalamus, while the best candidates were able to relate function to structure quite accurately