2021A 01: 90% of candidates passed this question.
Adrenaline is a level 1 drug and is commonly used in intensive care. A comprehensive explanation of the drugs MOA, PK, PD and side effect were expected. Candidates who scored well generally provided a factually accurate, detailed and well-structured answer. Overall, the quality of answer provided for this question was of a high standard.

Work of Breathing

• WOB = Energy used by the respiratory muscles during ventilation
• Work = Pressure x Volume (measured in Joules)
• represented as area on pressure-vol loop (dynamic compliance curve)
• Tidal breathing at rest: <2% BMR; O2 requirement = 3ml/min

Components of Work of Breathing

WOB can be divided into:

1. Inspiratory work
   • Active
   • Elastic + resistive work
2. Expiratory work
   • Usually passive (uses potential energy stored during inspiration)
   • Resistive work

Inspiratory elastic work

• ~65% of total work
• work done on inspiration to overcome:
  • surface tension of lung (70%)
  • elastic properties of lung/ lung elastic recoil (30%)
• stored as elastic potential energy → used on expiration

Inspiratory + expiratory resistive work

• ~35% of total work; lost as heat
• energy required to overcome frictional forces: includes
  • Airway resistance: between gas molecules
    • depends on type of flow + airway calibre
    • turbulent flow (↑RR; upper airway obstruction, ↑airway density)
      → ↑ airway resistance than laminar flow
    • ↓ airway calibre (radius) (e.g. bronchoconstriction, dynamic airway compression, ETT)
      → ↓ calibre → ↑ WOB
  • Tissue resistance e.g. interstitial lung disease
• Usually potential energy stored from insp work is sufficient to perform expiratory resistive work → expiration can become active in pathological conditions e.g. COPD, asthma

Minimising WOB:

• Elastic work:
  • PEEP: keep lung vol at FRC and maximise number of ventilated alveoli
  • Positioning: optimise lung volume
  • Surfactant: minimise surface tension
  • Optimise RR: elastic WOB ↓s with ↑ RR
• Resistive work
  • ↓RR: RR directly proportional to resistive work
  • ↑laminar flow: more efficient than turbulent flow; can be ↑ by ↓gas density e.g. heliox
  • ↑radius: ↑lung vol; bronchodilators

Kerr

2021A 02: 24% of candidates passed this question.
This is a core topic within respiratory physiology. There was a very low pass rate for this question. Expected components of the answer included: a definition of WOB as a product of pressure and volume or force and distance including the units of measurement; followed by a detailed explanation of the following three broad components – elastic resistance, viscous resistance and airflow resistance. Further marks were awarded to situations where the energy for expiration increases beyond stored potential energy as well as the impact of respiratory rate and tidal volume on different aspects of the WOB. For example, the changes in TV will have relatively greater impact on the elastic component, whereas RR will impact the resistance component. Additional marks were awarded for describing the efficiency of breathing. A common area where candidates missed out on marks was producing a diagram of WOB without a description; many diagrams were often incorrectly drawn or had no axes labelled. There were many incorrect definitions or respiratory equations provided without any link to the written answer. Factual inaccuracy and limited depth of knowledge were also prevalent in poorly performing answers. Marks were not awarded for a description of the control of breathing.

PLATELET

Formation

• produced during hematopoiesis in a sub-process called thromopoiesis, or production of thrombocytes.
• Bone marrow: Common myeloid progenitor cells → promegakaryocytes → megakaryocytes
• Megakaryocytes produce protoplatelets within their cytoplasm → released in cytoplasmic extensions upon cytokine stimulus
  • Protoplatelets break up into hundreds of platelets that circulate throughout the bloodstream
  • The remaining nucleus of the ruptured megakaryocyte is consumed by macrophages.
• Megakaryocyte and platelet production is regulated by thrombopoietin (hormone produced by the liver and kidneys)
• Thrombopoietin stimulates differentiation of myeloid progenitor cells into megakaryocytes and causes the release of platelets.
• Thrombopoietin is regulated by a negative feedback mechanism based on platelet levels
• Each megakaryocyte produces between 5,000 and 10,000 platelets
• Altogether, around 10¹¹ platelets are produced each day in a healthy adult

Fate

• Average lifespan of a platelet is 5 to 10 days
• Old platelets are destroyed by macrophage phagocytosis in the spleen and by Kupffer cells in the liver
• Up to 40% of platelets are stored in the spleen as a reserve, released when needed by sympathetically-induced splenic muscle contractions during severe injury.

Structure

• Small anucleated cells derived from megakaryocytes which originate from haematopoietic stem cell
• Normally 150~300 x 10³ /μl

• Actin and myosin
• Remnants of the ER, SR storing calcium
• Mitochondria
• Enzyme systems → production of prostaglandins
• α granules
  • Thrombin
  • PDGF
  • P-selectin
  • Fibronectin
  • vWF
• Dense granules
  • ADP
  • ATP
  • Ca²⁺
  • Serotonin
  • Histamine

Function

• Haemostasis
  • Formation of platelet plug
    • Interact with collagen exposed at damaged endothelium by GPIa
    • Activated by PAF, Thrombin
      • Morphological change → irradiating pseudopods
      • Degranulation
      • Aggregation
        • Expression of GPIIb/IIIa → binds fibrin and vWF
• Immunomodulation
  • Deployed to sites of inflammation and infection and secrete cytokines and chemokines

Sakurai / JC 2019

2021A 03: 79% of candidates passed this question.
This question was divided in three sections to help candidates formulate an answer template. The first section required a brief outline of the formation of platelets from pluripotent stem cells via megakaryocytes. The second section required an outline of platelet structure highlighting the special features such as, an absence of a nucleus, the presence of an external glycocalyx layer, specific surface receptors, contractile proteins, dense tubular system and granules. The third section was about platelet function where the expected focus was on the role of platelets in haemostasis. This required outlining the mechanism of platelet plug formation by adhesion-activation-aggregation, interactions with the coagulation cascade and role of platelets in clot contraction as well as fibroblast invasion. Although many candidates were able to answer the first section reasonably well, there was a noticeable knowledge deficit in the latter two sections. A significant proportion of answers had missing information on platelet structure and lack of structure in outlining platelet function.

Overview of parental nutrition

• Parental nutrition is the delivery of nutrients into venous circulation (peripherally or centrally) instead of the enteral route → it can be used to supplement nutrient delivery via enteral route, or supplement nutrient delivery in its entirety (total parental nutrition)
• It is prepared by sterile technique → typically a 3L bag of hyperosmolar solution (containing glucose, amino acids, lipids, H2O, electrolytes, vitamins and trace elements)
• It can only be administered by CVC due to its ↑ tonicity (Nb. issues with irritation and thrombosis if given via PIVC) → infused over 24 hrs
• It also requires multidisciplinary team involvement

Indications for parental nutrition

• Indicated for those unable to ingest or digest nutrients or to absorb them from GI tract for a prolonged period of time (> 3-4 days) → includes those who have:
• A failed trial of enteral feeding
• Contraindications to enteral nutrition:
  • GI obstruction
  • Upper GI strictures and fistulae (Eg. enterocutaneous fistulae)
  • Severe pancreatitis
  • Prolonged ileus (Eg. major abdominal surgery where feeding not anticipated for days, paralytic ileus)
  • Inflammatory conditions (Eg. IBD or mucositis due to chemotherapy)
  • Short gut syndromes (Eg. major SB resection)

Daily nutritional requirements for parental nutrition

BUT these vary according to:

• Physiological factors:
  • Age, gender, body size
  • Pregnancy
  • Activity level
  • Hydration status
• Pathological factors
  • Burns and sepsis → ↑ protein and caloric intake
  • Renal failure → ↓ volume, protein and electrolyte (esp K+) content
  • CCF → fluid reduction
  • Hepatic failure → ↓ a.a/protein content to prevent encephalopathy
  • Respiratory failure → ↓ glucose to minimise CO2 production

Components of parental nutrition

• (1) Energy source → glucose:lipid mixture (60:40 or 50:50)
  • Glucose (as 50% dextrose)
    • Used as an energy substrate → provides 50% of daily caloric needs
    • Glucose has ↓ energy density → 3.4 kcal/g only (cf. 4 kcal/g for carbohydrates) → 50% dextrose needs to be given (1 L = 940 kcal) → BUT this is hypertonic (1900 mosm/L) and requires delivery via CVC
    • Insulin can be given to aid glucose utilisation (esp in stressed patients)
    • Need to avoid excess glucose delivery → risk of ↑ BGL, lipogenesis (liver disease), ↑ MR and ↑ CO2 production (delayed ventilatory wean)
  • Lipid (as 10% or 20% intralipid)
    • Used as (i) an energy substrate (provides 30-40% daily caloric needs), and (ii) provision of essential FAs (vital for cell membranes and PG synthesis)
    • ↑ energy density cf. glucose → 1.1 kcal/mL (10%) and 2 kcal/mL (20%) → thus 1000 kcal can be achieved by 500 mL of 20% or 1L of 10%
    • Can be infused separately (Ie. not mixed with glucose/a.a. solution) → can be given 1x/week BUT usually given daily to aid caloric delivery in the smallest volume of solution –
• Nitrogen-source (as symthamin 17)
  • Used for (i) tissue protein synthesis (Eg. enzymes) and (ii) caloric needs
  • Includes > 50% essential a.a.’s (isoleucine, leucine, valine, lysine, methionine, phenylalanine, threonine, tryptophane) and > 25% branched chain a.a
  • Nb. A.a. are all L-isomers (as the body cannot use D-isomers)
• H2O → to maintain body H2O balance and replace losses (Eg. dehydration, bleeding)
• Electrolytes (Na+ /K+ /Cl- /PO4 3-/Mg2+, Ca2+) → to maintain and replace losses
• Vitamin/trace elements → vital to enzyme systems and metabolic pathways in body
  • Vitamin solutions – both H2O and fat-soluble vitamins (esp folic, thiamine, vitamin K)
  • Trace elements (Zn, Fe, Cu, Mn, Co, Se, I, Cr, Mb)

Monitoring of parental nutrition

• Needed to assess for (i) progress of nutritional state and (ii) complications of therapy
• Involves:
  • Clinical r/v (Eg. fluid balance, weight, nutritional assessment, infections)
  • Frequent ward glucose testing (until BGL stabilises)
  • Investigations → daily EUC, CMP, BGL; weekly FBC, LFT (incl albumin), Coags, Lipid studies, and plasma/urine osmolality

Complications of parental nutrition

• Catheter-related (MOST common) → PTX, chylothorax, embolism (air/thrombus), infection, Etc.
• Fluid/electrolyte disturbances
  • Fluid overload or hyperosmolar dehydration
  • Electrolyte disturbances
  • Normal AG metabolic acidosis (due to ↑ Cl- content)
• Metabolic disturbances
  • Hyperglycaemia (initially) → delay in ↑ endogenous insulin (thus supplemental insulin required)
  • Rebound hypoglycaemia (with abrupt cessation of TPN) → due to ↑ levels of endogenous insulin
  • Metabolic bone disease
• Others:
  • Immune suppression (due to fat component)
  • Liver disease → initially deranged LFTs → later fatty liver/steatohepatitis
  • ↑ PaCO2 (due to excessive glucose metabolism)

Bianca

2021A 04: 59% of candidates passed this question.
The pharmacology of enteral and parenteral nutrition is a level 1 topic in the first part syllabus. The TPN dose in terms of daily calorie and other nutritional requirements were key expectations in first part of the question. A detailed list of all macro and micronutrients was required under TPN composition. Expected information about macronutrients were their forms in the TPN solution (e.g., carbohydrate in the form of glucose, protein in the form amino acids), their relative calorie contributions and their essential components (e.g., the names of the essential amino acids). Identification of potential variability in composition and dose based on specific patient factors scored extra marks. Side effects included metabolic derangements (refeeding syndrome, over or under-feeding, hyperglycaemia, hyperlipemia), biochemical disturbances (fluid and electrolyte imbalances), organ injury (liver, pancreas) and vascular access related complications. Limited breadth and depth of information as well as incorrect facts were prevalent in the answers that scored lower marks.

CVP

• Central venous pressure (CVP) is mean vena caval or right atrial pressure
• In the absence of tricuspid stenosis, equals right ventricular end-diastolic pressure.
• expressed in mmHg or cmH2O (1.36 cm water = 1.0 mm Hg)
• Normal 0-6mmHg in spontaneously breathing non-ventilated patient

• Venous Return, VR = (MSFP – RAP or CVP) / Resistance to venous return
• CVP is a major determinant of RV filling pressure (RV Preload)
  • This regulates stroke volume through Frank-Starling mechanism
• CVP increased in disorders that increase Rt sided diastolic pressures
  • left heart disease, lung disease, primary pulmonary hypertension, and pulmonic stenosis
• CVP is determined by an interplay of various factors
  • Mainly influenced by volume of blood and compliance of central compartment

Factors affecting the measured CVP:

• Central venous blood volume (Inc volume à inc flow à inc CVP)
  • Venous return/cardiac output
    • Vena cava compression (Obesity/Valsalva/pregnancy/inc IAbd pressure – dec VR à dec CVP)
  • Total blood volume
  • Regional vascular tone
• Compliance of central compartment (inc Comp à inc return and venous pressure)
  • Vascular tone
  • Right ventricular compliance
  • Myocardial disease
  • Pericardial disease
  • Tamponade
• Tricuspid valve disease
  • Stenosis (inc mean CVP)
  • Regurgitation (transient inc CVP)
• Cardiac rhythm (dec CVP with no atrial contraction, inc CVP when RA contracting against closed TV)
  • Junctional rhythm
  • AF
  • A-V dissociation
• Reference level of transducer (inc or dec)
  • Positioning of patient
• Intrathoracic pressure (inc pressure à inc CVP)
  • Respiration (Inspiration makes intrathoracic pressure more negativeà increases CVP)
  • Intermittent positive pressure ventilation (IPPV)
  • Positive end-expiratory pressure (PEEP)
  • Tension pneumothorax

Measurement

• Invasive:
  • by inserting central venous catheter into Internal Jugular or Subclavian Vein
• Non-Invasive:
  • Height of JVP provides visual estimate
  • peripheral vein collapse on the dorsum of the hand or antecubital fossae
  • Bedside ECHO and doppler techniques: IJV, Hepatic veins, IVC assessment

Invasive Measurement:

Complications of CVP Monitoring

• Mechanical complications:
  • Arterial puncture and cannulation, Hematoma, Hemothorax, Surrounding nerve injuries, Pneumothorax, Embolization of broken catheter or guide wire, Air embolus, Arrhythmias, Lymphatic system injury
• Infectious complications:
  • Sepsis, Endocarditis
• Thrombotic complications:
  • Venous thrombosis, Pulmonary embolism

CVP Waveform

(not required for this answer)

Changes in waveform:

AF	a wave lost, c wave more prominent. If coarse AF, fibrillation waves may be visible
A-V dissociation / Junctional rhythm	tall canon a waves (due to atrial contraction against closed Tricuspid valve)
TR	large fused c-v wave (due to blood ejected back during ventricular systole)
TS	attenuated a-wave and y-descent (increased pressure required to overcome TS)
RV compliance decreased	a wave accentuated
Pericardial constriction	short steep y-descent
Cardiac tamponade	CVP monophasic with a single x-descent

Sources:
Daniel Saddawi-Konefka, Critical Care Secrets
Shay McGuinness Cardiothoracic Critical Care 2007
Richard E. Klabunde, CVphysiology.com
T. Smith, Central Venous Pressure: Uses and Limitations

JC 2019

2021A 05: 57% of candidates passed this question.
This question examined a core area of cardiac physiology and measurement. Considering this, candidates overall, scored poorly in this section. There was a common misunderstanding around the relationship between cardiac output and CVP. A decrease in cardiac output (e.g. due to either decreased stroke volume or heart rate) will cause an increase in CVP as blood backs up in the venous circulation, increasing venous volume as less blood moves through to the arterial circulation; the resultant increase in thoracic volume increases central venous pressure. Several candidates confused the direction of their arrows, for example “increased right atrial compliance increases CVP”. Double negatives were used by several candidates which then resulted in the incorrect relationship described. (e.g., “arrow down compliance and arrow down CVP”). The measurement section should have included an explanation of the components of an invasive pressure monitoring system relevant to the measurement of CVP.

FACTORS

The factors which alter the response (number of receptors occupied) may be separated into: pharmacodynamic factors, pharmacokinetic factors, pharmaceutical and drug interaction factors

Pharmacodynamic Factors

• decreased pH increases the affi¬nity of non depolarising NMB
• electrolyte disturbances
  • Ca disturbances affect the release of ACh from the presynaptic terminal (triggered by Ca)
  • hypercalcaemia results in shortened blockade
  • hypocalcaemia potentiates blockage
  • magnesium
    • stabilise membranes and decrease release and sensitivity to ACh
  • potassium
    • hypokalaemia leads to membrane hyperpolarisation (decreased drug effect)
    • hyperkalaemia has the reverse effect
• pathology
  • myasthenia gravis patients have defective nACh receptors
  • eaton-lambert syndrome patients have decreased ACh release
  • burns – leads to receptor mediated resistance to non depolarising NMBD

Pharmacokinetic factors
(affect the amount of drug reaching the receptor)

• absorption
  • dose given (higher dose – more receptors occupied)
• distribution
  • lipid soluble drugs such as vecuronium may accumulate in lipid rich tissue (esp infusion)
  • women have higher lipid content which may lead to reduced effect site conc
• metabolism
  • hepatic failure may lead to decreased metabolism of a drug – pancuronium
• excretion
  • renally excreted drugs, especially minimally metabolised vecuronium, rocuronium

Pharmaceutical / Drug Interactions

• Increase effect
  • aminoglycosides – decreased prejunctional ACh release
  • volatile anaesthetics – mechanism not well understood
  • frusemide – potassium effect, may interfere with cAMP and ACh release
• decrease effect
  • anticonvulsants – may develop resistance to pancuronium, vecuronium

JC 2019

2021A 06: 13% of candidates passed this question.
Vecuronium is a commonly available and regularly used amino-steroid neuromuscular blocking agent. It is a level 1 drug in the 2017 syllabus. A simple template utilising the headings; pharmaceutics, PK, PD, uses in ICU and adverse reactions with associated relevant important facts would have scored well. Expected information regarding the factors prolonging neuromuscular blockade included electrolyte abnormalities, drug interactions and patient factors. Overall, the level of understanding and knowledge demonstrated in the answers was below an expected standard for a level 1 drug.

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.

2021A 07: 48% of candidates passed this question.
This question was answered best if the main arteries and veins were discussed first and then their corresponding supply outline in reasonable detail. Very few candidates were able to achieve this. Listing the names of vessels with no context and in a random non-sequential order did not attract many marks. The physiology of the blood supply to the liver also did not attract marks.

Potassium

• Predominany intracellular cation
• Total Stores: Approx 3200mmol (50mmol/kg)
• Key Functions:
  • Main determinant of ICF osmolality and tonicity
  • Responsible for RMP of excitable cells via Goldmann-Hodgkin-Katz due to ↑↑gK relative to other species
  • Role in action potential → repolarisation phase
  • Secretion of insulin and multiple other KATP dependant processes
  • Regulation of IC processes (protein/glycogen synthesis)
  • Involved in Na+/K+ ATPase in cell membranes

Potassium Elimination

• Faecal – 8mmol/day
• Renal – 92mmol/day (See next heading for details)
  • Urinary K+ excretion = [K+ filtered by glomerulus] + [K+ secreted by CCD/LDCT] – [K+ reabsorbed by renal tubules]
  • Glomerular filtration: Freely filtered = 756mmol/day (180L x 4.2mmol/L)
  • PCT: 65% reabsorption
  • LoH: 25~30% reabsorption
  • DCT/Collecting Ducts – variable
    • Determined by Aldosterone, Plasma [K+], Tubular Flow rate
    • Secreted by principal cells
    • Reabsorbed by intercalating cells

K+ handling within the tubular system:

• PCT (55% of filtered K+ is reabsorbed):
  • K+ is reabsorbed passively via the paracellular route due to:
    • Solvent drag → coupled to flow of Na+ and H2O
    • [ ] gradient → created by reabsorption of H2O
    • Electrical gradient → due to +ve luminal charge in late PCT
• TAL of LoH (30% of filtered K+ is reabsorbed):
  • K+ is reabsorbed by 2° active transport via paracellular route → +ve charged lumen generated by ion flux created by NKCCT transporter causes K+ to be reabsorbed by diffusion down its electrical gradient
• LDCT and CCD (0 to > 15% K+ is secreted):
  • Principal cells of CCD and LDCT → 2° active secretion K+ → via:
    • Basolateral Na+ /K+ ATPase → (i) generates an electrochemical gradient that draws Na+ intracellularly from the tubular lumen (via the ENaC channel), and (ii) pumps K+ from peritubular capillaries into tubular cell
    • The –vely charged lumen generated by influx of Na+ across ENaC channel → favours tubular secretion of K+
  • o Type A intercalated cells of CCD and LDCT → 2° active reabsorption of K+ :
    • H+ is produced within tubular cell by hydration of CO2 (using CA) → H+ is then exchanged for tubular K+
• MCD (5% of filtered K+ is reabsorbed)

Renal K⁺ regulation:

• Renal K+ regulation occurs MAINLY via control of K+ secretion at the distal nephron (CCD and LDCT) via the following factors:
  • Circulating factors:
    • Plasma [K+ ]
      • ↑ [K+ ] causes ↑ K+ secretion by → (i) Directly stimulating Na+ /K+ ATPase in principal cells, and (ii) Directly stimulating Aldosterone release from adrenal cortex
    • Aldosterone
      • ↑ aldosterone causes ↑ K+ secretion by → ↑ production of Na+ /K+ ATPase, K+ channels and ENaC Na+ channels in the principal cells
    • Plasma pH
      • Alkalosis via ↓ plasma [H+ ] causes ↑ K+ secretion by → stimulating Na+ /K+ ATPase in principal cells
  • Luminal factors:
    • Flow of tubular fluid in DCT and CCD
      • ↑ tubular fluid flow causes ↑ K+ secretion by → maintaining ↓ luminal [K+ ] (Ie. continuously washing it away) → permits passive diffusion of K+ ↓ its [ ] gradient into tubular lumen
    • ↑ Na+ delivery rate to DCT and CCD → ↑ K+ secretion
    • -ve lumen potential difference → ↑ K+ secretion

JC / Gladwin / Sakurai / Bianca 2020

2021A 08: 33% of candidates passed this question.
This question covers a core physiology topic. The detail required is well described in the recommended reference texts. Generally, this question was poorly answered. From an answer template perspective, a “describe question” in this context involves both the stating the relevant potassium handling mechanism and then giving a description of how it occurs and how this system is regulated. Many answers that scored poorly simply listed sites of potassium handling but excluded the details surrounding the specific receptors and channels involved as well as the processes that exist to perpetuate and regulate these biological processes. Simple identification as to whether the potassium was being secreted or reabsorbed as well as the location as to where this may occur within the nephron, were often not specifically detailed or used interchangeably. Such answers scored poorly.

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

2021A 09: 59% of candidates passed this question.
This question was relatively well answered by most candidates. There was significant variation in the temperatures expressed as normal and few candidates mentioned CORE temperature as a concept. Several candidates gave a detailed description of thermo-neutrality for which there were no marks.

Warfarin Pharmacology

Warfarin Reversal

The following reversal strategies may be either used alone or in combination:

1. Stopping warfarin
   • S-warfarin is eliminated via oxidation predominantly by CYP2C9 (and to a lesser extent by CYP3A4 and 1A2) → inactive metabolites
   • Elimination half-life of S-warfarin is 29 hours
     • ∴ in patients with normal hepatic metabolic and synthetic functions  take 4 ~ 5
   • days for INR to normalise
2. Vitamin K
   • Can be given either enterally or parenterally (IV, IM) (bioavailability ≈ 100%)
     • Requires few hours to work
     • Enteral administration Requires presence of bile salts to be absorbed by gut
     • Parenteral administration has rare but life threatening complication of hypersensitivity probably related to its preservative, benzyl alcohol
   • Low dose vitamin K (1 ~ 2.5 mg) will slowly reduce INR over 24 hours
     • but often will not result in complete reversal and would not significantly affect re-establishment of anticoagulation with warfarin
   • High dose vitamin K (10 mg) will slowly reduce INR over 12 hours
     • ∴ often given together with clotting factors (e.g. FFP)
3. Fresh frozen plasma
   • Plasma from donated blood, which contains all clotting factors
   • ∴ immediately reverses coagulopathy
   • However, short duration of action (24 ~ 48 hours) ∴ reserved for active bleeding
   • Used when PCC not available
   • Dose 2 ~ 4 units (10-15ml/kg) depending on INR and bleeding risk
   • Disadvantages = relatively large fluid volume, possible transfusion reactions (e.g. immune reaction, TRALI, infection, etc)
4. PCC – Prothrombin complex concentrates (Prothrombinex)
   • Human plasma derivative containing concentrates of factors II, IX and X
   • 500IU PCC has 500IU of II, IX, X each in a vial
   • ∴ immediately reverses coagulopathy
   • Dose 25 ~ 50 IU/kg
   • Advantages = reliable reversal, smaller fluid volume, avoids transfusion
   • complications associated with FFP
   • Disadvantages = expensive
5. Recombinant activated factor VII (NovoSeven)
   • Controversial treatment, present in some guidelines
   • Indication = life threatening bleed with significantly elevated INR
   • Given together with vitamin K and FFP
   • Disadvantage = thromboembolic complications

2021A 10: 43% of candidates passed this question.
Warfarin is listed as a level 1 drug in the 2017 syllabus and as such a detailed knowledge of its mechanism of action would be expected from candidates sitting the exam. The reversal agents for warfarin are collectively classed as level 2 drugs and hence the knowledge required would be at a write short notes level. The following topics were expected: what drugs may be used, how they work, in what dose, any common side effects, why/when would one be used in preference to others etc. The use of reversal agents for warfarin is a common practice in ICU. Generally, answers demonstrated a lack of a precise and detailed knowledge with respect to warfarin’s mechanism of action and had a very superficial knowledge with incorrect facts regarding the reversal agents.

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

2021A 11: 57% of candidates passed this question.
This is a core physiology topic; a detailed knowledge of buffering and the available buffer systems is crucial to ICU practice. A candidate presenting for the first part exam should have a detailed understanding of all aspects of the buffer systems. Higher scoring answers provided both technical details of the buffer systems, the context for their normal function and their relative importance. Efficient answers dealt with the buffers by chemical rather than by site, but many answers categorising buffers by site also scored well. Many low scoring answers simply failed to provide detail, some provided incorrect information. Very few candidates demonstrated an understanding of the isohydric principle.

2021A 12: 54% of candidates passed this question.
There were many exceptional answers which provided extensive detail on the drug. The best of these gave context for the drug characteristics, such as by referring to oxycodone relative to other opioid drugs that might be chosen, or to considerations for safe and effective administration. Some answers, however, provided generic information on opioid drugs, which could not gain all the available marks.

Anterior Pituitary Gland

• Anterior lobe of pituitary gland (aka. adenohyophysis) → forms 80% of pituitary gland → consists of 3 parts:
  • Pars tuberalis
  • Parts intermedius (intermediate lobe)
  • Pars distalis (anterior lobe) → produces most anterior pituitary hormones
• Derived from buccal ectoderm → it extends upwards from the epithelial lining of the primitive mouth cavity (as Rathke’s pouch), then fuses with the downward growing infundibulum of the hypothalamus (which forms the posterior pituitary)
• Consists of non-neural secretory epithelial cells connected INDIRECTLY to the hypothalamus via the “hypothalamic-hypophysial portal system”:
  • Non-neural secretory epithelium:
    • Granular secretory cells (chromophils)
      • Acidophils (80%) → red-staining cells → synthesise and store large peptide hormones in secretory granules
        • Lactotropes → PRL
        • Somatoropes → GH (somatotropins)
      • Basophils (20%) → blue-staining cells → synthesise and store glycoprotein hormones in secretory granules
        • Gonadotropes → FSH and LH
        • Thyrotropes → TSH
        • Corticotropes → ACTH (and MSH)
    • Agranular secretory cells (chromophobes)
      • Weakly staining cells → inactive or degranulated secretory cells → does not synthesise any hormones
  • Hypothalamic-hypophysial portal system
    • Branches of superior hypophysial artery → forms “1° capillary plexus” near median eminence of hypothalamus → then forms lesser portal veins that gives rise to “2° capillary plexus” in anterior lobe of pituitary gland
    • Functions of portal venous system
      • Blood supply of 90% of anterior pituitary (and infundibulum)
      • Pathway for hypophysiotropic hormones (from median eminence of hypothalamus) to reach the anterior pituitary gland, and
      • Allows hormones secreted by anterior pituitary gland to enter systemic circulation
• Blood supply → 90% supplied by hypothalamic-hypophysial portal system (from superior hypophysial artery)

Hypophysiotrophic hormones: Control of anterior pituitary gland

• Hypophysiotrophic hormones are small peptides (EXCEPT for DA) produced by cell bodies (containing “parvocellular neurons”) in the hypothalamus located near the median eminence → small amounts are secreted from the tuberoinfundibular tract into the hypothalamic-hypophysial portal system → reaches anterior pituitary where it exerts either an “excitatory” or “inhibitory” effect on non-neural secretory epithelial cells

Nb. Only trace levels of these hormones are found in systemic circulations b/c → (i) small amounts are secreted, and (ii) they are secreted into the hypothalamic-hypophysial portal system

• Nature of release from hypothalamus:
  • Pulsatile manner → can vary with circadian rhythm, but induced in the presence of specific stimuli (Eg. cold, stress, Etc.)
  • Regulated by –ve feedback (esp from hormones secreted by peripheral organs) EXCEPT PRL (see below)
• Types of hormones:
  • Thyrotrophin-releasing hormone (TRH) → tripeptide (3 a.a.) → stimulates TSH secretion from thyrotropes
  • Corticotrophin-releasing hormone (CRH) → 41 a.a. peptide → stimulates ACTH secretion from corticotropes
  • Gonadotrophin-releasing hormone (GnRH) → 10 a.a. peptide → stimulates LH and FSH secretion from gonadotropes
  • Growth-hormone releasing hormone (GHRH) → 43 a.a. peptide → stimulates GH secretion from somatoropes
  • Somatostatin (GHIH) → 14 a.a. peptide → suppresses GH secretion from somatotropes (also ACTH, TSH and PRL release; also inhibits insulin/glucagon)
  • Prolactin releasing factor (PRF) → stimulates PRL secretion from lactotropes
  • Dopamine (DA) → suppresses PRL secretion from lactotropes

Bianca 2016

2021A 13: 40% of candidates passed this question.
Few candidates described cell types as chromophils and chromophobes. There were many errant references to chromaffin cells which are found mainly in the adrenal medulla, and to staining on H&E. Chromophil cells stain by absorbing chromium salts. Few candidates mentioned that the hormones secreted by the anterior pituitary are peptides. Most candidates outlined the hypophyseal-portal system well. Knowledge of TSH and ACTH control and target organ effects were good. Similar knowledge for LH, FSH, PRL and GH was much more sporadic.

2021A 14: 29% of candidates passed this question.
This question was best answered with a structured approach as per any pharmacology question. It nonetheless required good understanding of various aspects of physiology. Many candidates failed to gain marks by omitting to mention facts which could have been prompted by a defined structure. A good response mentioned the pharmaceutic features including formulation and the hypertonicity of IV bicarbonate, pharmacodynamics including indications for use, mode of action, adverse effects (systemic and local), pharmacokinetics and dose. Pleasingly a few candidates stated that sodium bicarbonate’s mechanism of action to cause alkalosis involved increasing the strong ion difference in plasma. Credit was also given for stating the mechanism of action as providing bicarbonate ions to augment the extracellular buffer system.

Fick’s law of diffusion

• 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.

The rate of diffusion of a gas through a tissue is:

Directly ∝:

• Surface area of the barrier
  Affected by:
  • Parenchyma volume: Changes with Body size and in disease states
  • V/Q mismatch: reduced in shunt and dead space
  • Pulmonary Blood Volume: changed with vascular distension and recruitment
    • Cardiac output: increased recruitment in high output states, decreased recruitment and increased V/Q mismatch in shock states
    • Posture: Increased surface area while supine (compared to sitting or standing)
• Solubility of the gas
  • CO₂ is ~20 times as soluble as O2 in blood
• Concentration gradient (partial pressure difference)
  • Rate of blood flow through lungs
    • Transit time of blood across capillary (not part of Fick’s Equation) – based on HR
    • alters total gas exchange across alveolus
    • Can potentially change perfusion limited gas exchange to diffusion limited
  • Alveolar partial pressure affected by:
    • Atmospheric pressure
    • Ventilation: Alveolar hypoventilation → ↑ P_ACO₂ , ↓ P_AO₂
  • Partial pressure in blood affected by:
    • Binding of gas to protein:
    • Rate of oxygenation of reduced Hb:
      • Shift of oxygen dissociation curve (pH, temperature, PCO2, 2,3-DPG)
      • Haematocrit
      • Abnormalities of haemoglobin
    • Formation of carbamino compounds
    • Anaesthetic agents to plasma contents, e.g Albumin, cholesterol
    • Enzymatic Action
      • carbonic anhydrase (conversion of HCO3 to CO2)

Inversely ∝:

• Membrane thickness
  • Increased thickness impedes gas exchange – Pathological states like pulmonary edema and cardiac failure
• Square root of Molecular Weight
  • smaller substances diffuse more quickly

Diffusion vs. perfusion limited

Transfer of gases can be diffusion or perfusion limited dependent on the rate limiting step

Is the transfer of O2 perfusion or diffusion limited?

• Can behave as both perfusion and diffusion limited
• O₂ diffusion takes 0.25s; pulmonary capillary transit time is 0.75s
• Normal conditions
  • Transfer of O₂ across the alveolar capillary barrier is perfusion limited
  • Equilibrium is reached between alveolar and capillary PO2 before the RBC has traversed the pulmonary capillary
• Conditions where transfer of O₂ may become diffusion limited
  • Disease of the alveolar capillary barrier
    • Pulmonary fibrosis: thickening of alveolar-capillary barrier → ↓ rate of diffusion
    • Exercise: ↑ ­CO → ↓ RBC transit time
    • Altitude: ↓ PaO2

Diffusion of O2 and CO2

Kerr / JC 2020

2021A 15: 36% of candidates passed this question.
This question required detail on those factors affecting gas exchange at the level of the alveolus. A description of the components of the Fick equation was expected – and how this related to oxygen and carbon dioxide transfer at the alveolar capillary membrane. The rapid rate of equilibration (developed tension) was the limiting factor in of blood/alveolar exchange that rendered some gases perfusion limited (examples – N2O, O2 under usual conditions but not all) and the slower rate of others diffusion limited (examples CO and O2 under extreme conditions e.g., exercise, altitude). Estimates of time taken for each gas to equilibrate relative to the time taken for the RBC to travel across the interface was also expected for full marks. CO2 despite rapid equilibration and higher solubility was correctly described as perfusion limited (unless in disease states). Better answers described CO2 as ventilation limited. Some answers also correctly included the component of interaction with the RBC and haemoglobin. Ventilation/perfusion inequalities over the whole lung were not asked for and scored no marks.

2021A 16: 62% of candidates passed this question.
Most candidates used a structured approach with the usual major pharmacology headings. Mechanism of action was well described by most, with better answers including mechanisms of resistance. Higher scoring candidates included an explanation as to the combination of the drugs. Likewise, better answers included detailed information on spectrum of activity beyond “gram positive and gram negative”, including relevant groups of organisms which are not covered. There also seemed to be some confusion about coverage for anaerobes, which piperacillin tazobactam covers well. Specific detail about adverse reactions, other than ‘allergy, rash, GI upset, phlebitis, etc’, is expected for commonly used antibiotics.

Principles

Beer-Lambert Law

• Incidence of light is inversely proportional to the path distance and concentration of light absorbing particles within the path.

Hb absorbance at 660nm and 940nm utilized

• 660nm maximally absorbed by deoxyhaemoglobin
  • Ratio of absorbance at 660nm and 940nm utilized to calculate SpO₂

using healthy volunteers derived R values
Sats 100% R = 0.4
Sats 85% R = 1.0
Sats 50% R = 2
Sats 0% R = 3.4

Pulse oximeter

• Light emitter
  • Produces infra-red light at 660nm and 950nm
• Light detector
  • Detects light at 660nm and 950nm
• Processor
  • Calculates SpO₂ using the ratio of absorbance at 660nm and 950nm
  • Light detected (incidence) represents light passing through both pulsatile (arterial) blood and non-pulsatile elements (venous blood and other tissues)
  • Processor differentiates light incidence during maxima and minima of pulse wave and calculates SpO₂ from pulsatile blood only giving SaO₂

Limitations

Absorption spectra confounded by:

• Carboxyhaemoglobin
  • Absorbs 660nm, not at 940nm
  • R closer to 0.4
  • causes the pulse oximeter to read artificially high
• Methemoglobin
  • though it absorbs 660nm light, it also absorbs 940nm light to a greater degree
  • R closer to 1
  • causes the SpO2 to trend towards 85%

Sakurai 2016

2021A 17: 74% of candidates passed this question.
Most candidates provided a reasonable structured sequence of how a pulse oximeter generates a value. Nearly all candidates described the Beer-Lambert laws correctly, but few specifically described the basic principles of absorption spectrophotometry. Most candidates had a reasonable list of extrinsic factors that can interfere with pulse oximeter performance, but few described the intrinsic/inherent limitations of the device that can cause SpO2 to be different to SaO2, such as functional versus fractional saturation.

2021A 18: 57% of candidates passed this question.
The best answers appropriately addressed the pharmacology of magnesium sulphate, rather than diverting into physiology. They noted that the question concerned intravenous magnesium sulphate and did not discuss other routes. They included pharmaceutics, important examples of the wide-ranging indications, listed potential modes of action and considered the full range of body systems affected including potential adverse effects. Drug interactions, such as potentiation of neuromuscular blocking agents, and pharmacokinetics (including stating that magnesium is not metabolised) were described.

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

2021A 19: 62% of candidates passed this question.
Good candidates described normal blood flow to the coronary circulation, including differences between the right and left ventricles. Coronary artery anatomy was outlined, including the regions of the heart supplied and the concept of dominance. In addition to epicardial vessels, strong answers also outlined penetrating arteries, subendocardial supply and venous drainage. Regulation of coronary blood flow required an explanation of flow-dependence of the heart given its high oxygen extraction rate. Metabolic autoregulation and its mediators needed to be described, along with the physical factors driving coronary blood flow. Less important mechanisms such as the role of the autonomic nervous system were also described, with an emphasis on indirect effects over direct effects.

Cerebral Blood Flow

• CBF = CPP / CVR (Cerebral Perfusion Pressure / Cerebral Vascular Resistance)
• CBF 15% resting CO → ~750ml/min or 50ml/100g brain tissue/min
  • CBF<50ml/100g/min → cellular acidosis
  • CBF<40ml/100g/min → impaired protein synthesis
  • CBF <30ml/100g/min → cellular oedema
  • CBF <20ml/100g/min → failure of cell membrane ion pumps, loss of transmembrane electrochemical gradients
  • CBF <10ml/100g/min → cell death

Determinants of CBF

• CPP
  • Net pressure gradient driving blood flow through the cerebral circulation
  • CPP = MAP – ICP
    • MAP = CO x SVR; CO = HR x SV; SVR = MAP / CO
    • ICP dependent on: brain, blood, CSF
• CVR

Regulated by 4 primary factors:

• Cerebral metabolism
  • flow-metabolism coupling: ­
    ↑ metabolic demand → ↑ CBF + substrate delivery
  • Controlled by vasoactive metabolic mediators:
    H+ ions, K, CO2, adenosine, glycolytic intermediates, NO
• CO₂ and O₂
  • CO₂
    • At normotension: relationship between PaCO₂ and CBF = almost linear
    • ↑ ­PaCO₂ → cerebral arteriolar vasodilation → ↓ CVR + ­↑ CBF
      • 2~4% increase for every 1mmHg increase in CO2
    • ↓ PaCO₂ → cerebral arteriolar vasoconstriction → ­↑ CVR + ↓ CBF
    • Initial stimulus = ↓ brain ECF pH
    • Effects regulated by: NO, prostanoids, K channels, intracellular [Ca²⁺]
  • PaO2
    • little effect at normal PaO₂
    • PaO₂ <60mmHg → cerebral arteriolar vasodilation → ­­↑ CBF
    • Mechanism: hypoxia acts on →
      • cerebral tissue to promote release of adenosine → cerebal vasodilation
      • cerebrovascular smooth muscle → hyperpolarisation → ↓ Ca²⁺ uptake → vasodilation
• Autoregulation
  • Constant across CPP 50-150mmHg
    • CPP >150mmHg: CBF µ CPP
    • CPP <50mmHg: CBF <50ml/100g brain tissue/min → ischaemia
  • Stimulus to autoregulation = CPP (not MAP)
  • autoregulation curve R shifted in HTN; L in neonates
  • Mechanism:
    • Myogenic mechanism: arterioles vasoconstrict in response to ↑ ­wall tension + vasodilate in response to ↓ wall tension → ↓ or ↑­ CVR
    • May involve adenosine
    • Can be impaired in SAH, tumour, stroke, head injury
• Neurohumeral factors
  • Relative lack of humoral + autonomic control on normal cerebrovascular tone
  • Main action of SY nerves = vasoconstriction
• Other factors
  • Blood viscosity: directly related to HCt; ↓ viscosity → ↑ ­CBF as per Hagen-Poiseuille law
  • Temperature: ↓ CMRO₂ by 7% for each ↓ 1°C in temp
  • Drugs
    • E.g. barbiturates ↓ cerebral metabolism
    • Volatile agents → ↓ tension cerebral vascular smooth muscle → vasodilation + ­CBF

Kerr 2018

2021A 20: 19% of candidates passed this question.
Overall, this question was poorly answered with a high failure rate. A good answer gave a normal value, iterated that CBF is held relatively constant by autoregulation, and proceeded to divide factors affecting CBF into categories with an explanation/description of each. Those factors with the greatest influence were expected to have more accompanying information (e.g., pressure/myogenic autoregulation, metabolic). Systemic factors such as MAP, O2, CO2 were expected to be mentioned with detail of the impact (i.e., key values, relationships demonstrated with a description and/or labelled graph). Local factors within the brain such as H+ concentration/pH, metabolic activity (including the impact of temperature, inclusion of mediators, regional variation based on activity & grey versus white matter) were also expected to be mentioned. Few answers mentioned impact of pH change independently of CO2. Few answers mentioned how CO2 changes the pH of CSF and that over time, this impact is buffered/reduces. The role of the sympathetic nervous system was required to be mentioned although not explored in detail (although many answers overstated the importance of the SNS on CBF or gave a simplistic concept such as increased SNS activity increases CBF).
Many answers focussed on descriptions of the Monro-Kelly doctrine and ICP to the exclusion of the aforementioned factors or included detail on factors influencing MAP which were not required (and irrelevant when within the autoregulation range). Many answers were simplistic: e.g., increase MAP increase CPP therefore increase CBF, or by stating CO2/O2 without mentioning a relationship or the limits/patterns of the relationship. Many answers failed to separate the effect of systemic PaO2 and PaCO2 from metabolic autoregulation.