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Physiol-06A12 Classify and describe the main cellular and molecular mechanisms by which chemical neurotransmitters exert their effects. Use examples from cholinergic and adrenergic neurotransmission to illustrate the answer. 42%
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Neurotransmitter: substance released by a presynaptic cell on excitation that crosses a synapse to stimulate or inhibit the postsynaptic cell. Fast action, localised and tissue specific.
As opposed to hormones which are slow and diffuse action.
Act on cell membrane membranes. highly specific interaction
Mechanism of activation/inactivation:
1. those that act directly on ion channels.
2. those that act via heterotrimeric G proteins.
3. tyrosine kinase
Ligand gated Ion Channels
-protein pores in cell membrane allowing flux of ions (electrochemical gradients)
eg. nAChR and skeletal NMJ.
superfamily of pentameric ligand gated ion channels
-binding of two ACh to receptor causes conformational change that opens the channel to conduct Na+ and K+ , causes depolarisation of the sarcolemmal membrane to threshold leading to an action potential, and ultimately to Ca2+ release from the sarcoplasmic reticulum and thus the initiation of muscle contraction.
Action via G Proteins
Heterotrimeric guanine nucelotide binding proteins (cf. small G proteins) bind GTP, found on intracellular membrane, associated with ligand receptor, second messenger system : transduce. Amplifiy and diversify ligand receptor signal
form a large superfamily of proteins composed three subunits - α, β, and γ – (several isoforms )- and five families - Gs, Gi, Gt, Gq, G12.
eg receptors
a1 Gq IP3 DAG NA and vasocontriction
a2 Gi cAMP Ca K NA vasocontriction
b1 Gs cAMP Adr and inotropy
b2 Gs cAMP Salbutamol and bronchodilation
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Physiol-04B15 Describe the mechanism of action of G-proteins in the cell (60% pass rate)
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G Proteins
Intracellular membrane bound proteins
-Heterotrimeric
-bind guanine nucelotide
-extremely common proteins
-large superfamily of proteins composed three subunits - α, β, and γ - of which there are several isoforms
Subtypes Gs, Gi, Gt, Gq, G12.
The α subunits of G proteins have intrinsic GTPase activity.
-ligand receptor causes α subunit binds GTP.
-dissociation of the G protein into Gα-GTP and a Gβγ dimer. Both components may activate second messenger systems downstream
-Gα eventually hydrolyzes GTP to GDP allowing reassociation of the G protein into the trimeric form and the cycle can begin again.
Coupling to an Ion Channel
The effect of the M2 AChR in the sinoatrial node of the heart is an example of this mechanism:
* ↑ vagal tone causes ↑ ACh release via the vagus at the SA node.
* ACh binds to M2 and its associated Gs protein is activated.
* GDP exhanged for GTP on the α subunit of the Gs.
* Gs dissociates into Gα-GTP and Gβγ.
* Gβγ then activates the inwardly rectifying K+ current slowing depolarisation of the SA node membrane
* HR is slowed.
The fact that a second messenger system isn't involved is reflected in tha fact that this effects is also very rapid - slower than a ligand gated ion channel but still measured in milliseconds.
Coupling to a Second Messenger System
G proteins most commonly couple to second messengers systems. The two most common are the inositol 1,4,5-triphosphate/diacyl glycerol (IP3/DAG) system and the cyclic adenosine 3,5-monophosphate system (cAMP).
Heterotrimeric guanine nucelotide binding proteins (cf. small G proteins) bind GTP, found on intracellular membrane, associated with ligand receptor, second messenger system : transduce. Amplifiy and diversify ligand receptor signal
form a large superfamily of proteins composed three subunits - α, β, and γ – (several isoforms )- and five families - Gs, Gi, Gt, Gq, G12.
eg receptors
a1 Gq IP3 DAG NA and vasocontriction
a2 Gi cAMP Ca K NA vasocontriction
b1 Gs cAMP Adr and inotropy
b2 Gs cAMP Salbutamol and bronchodilation
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Physiol-01B5 Describe the structure and function of voltage gated ion channels
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Voltage-gated ion channels : transmembrane ion channels, activated by changes in electrical potential difference near the channel; these types of ion channels are especially critical in neurons,
Composed of several subunits arranged in such a way that there is a central pore through which ions can travel down their electrochemical gradients.
Examples include:
* the sodium and potassium voltage-gated channels of nerve and muscle.
* the voltage-gated calcium channels that play a role in neurotransmitter release in pre-synaptic nerve endings.
Structure
-made up of subunits : usually tetramers
- Each domain contains 6 membrane spanning alpha helices
-central pore : specific size and electrostatic bonds allow ion selectivity, narrowest part of the transmembrane pore
- the voltage sensing helix. It has many positive charges such that a high positive charge outside the cell repels the helix - inducing a conformational change
-each subunit has a paddles which cover or uncover central pore allowing movement of ion due to electrochemical gradient
Ion Channels and their function
Inwardly rectifying K+ channels,
-located in cardiac myocytes
-actively by depolarization of sarcomella
-slow to respond, but eventually open to allow K+ efflux with chemical gradient
-resulting in repolarization (phase 3 of AP)
Voltage Sensitive Na+ channels
-located in ubiquitously in all nerves, muscle cells
-activation (-65mV) cause conformational change and influx Na
-depolarizing cell membrane
-important in AP transmission
-blocked by tetratoxin and local anaesthetic agents
Voltage Sensitive Ca+ channels
-2 types : T and L type
-L type important in phase 2 of cardiac AP
-resulting in excitation contraction coupling
-can be blocked by Beta blockers
-also important in exocytosis
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Physiol-98B7 Briefly describe structure of mitochondria. Outline the metabolic processes that occur in mitochondria 64%
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Definition
Mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. Described as "cellular power plants", generate most of the cell's supply of adenosine triphosphate (ATP)
Structure
0.5–10 micrometers (μm) in diameter
-outer and inner membrane composed of phospholipid bilayers and proteins
-there are five distinct compartments:
-outer mitochondrial membrane : enclose entire organelle, containing porins for movement of ions and proteins
-the intermembrane space : space between the outer membrane and the inner membrane.
-the inner mitochondrial membrane :
1. Those that perform the redox reactions of oxidative phosphorylation
2. ATP synthase, which generates ATP in the matrix
3. Specific transport proteins that regulate metabolite passage into and out of the matrix
4. Protein import machinery.
-the cristae space (formed by infoldings of the inner membrane), increase surface area of inner membrane
- the matrix (space within the inner membrane). contains a highly-concentrated mixture of hundreds of enzymes, special mitochondrial ribosomes, tRNA, and several copies of the mitochondrial DNA genome. Of the enzymes, the major functions include oxidation of pyruvate and fatty acids, and the citric acid cycle.
Function
Role in metabolism
-breaking down of ingested complex energy sources to simpler molecules, then stripping the electrons (hydrogen) off and using these to generate the driving force for ATP synthesis.
Breakdown of energy molecules
First is the generation of Acetyl CoA from energy sources.
* Fatty Acid oxidation in the cytoplasm generates Acyl CoA and then Acetyl CoA.
* Glucose is converted to Pyruvate by glycolysis in the cytoplasm, and the pyruvate enters the mitochondria where it is irreversibly oxidised to Acetyl CoA
* Glycogen is converted to glucose by the presence of phosphorylase in liver and skeletal muscle cells, and via the gycolytic pathway is generated pyruvate and then Acetyl CoA.
3: The Citric Acid Cycle
Occurs in the mitochondrial matrix. Acetyl CoA is used to generate reductive equivalents by the removal of hydrogens (electrons) in several steps (or say, the reduction of the carrier molecules FAD and NAD generate FADH and NADH, which are used to ferry the hydrogens along the election transport chain)
4: Oxidative Phosphorylation
On the Inner Mitochondrial Membrane the ETC is a series of enzymes (NADH Dehydrogenase complex, B-Cl Complex, Cytochrome Oxidase Complex) that catalyze multiple reactions (oxidation of the reductive equivalents FADH and NADH) to free the hydrogens and transport them from the Matrix across the Inner Membrane to the Intermembrane space. This generates an electrochemical gradient across the membrane. The flow of hydrogen extruded across the inner mitochondrial membrane and then reentering the matrix is coupled to ATP production (by the membrane enzyme ATP-synthase).
Other functions
*Heat production
*Storage of calcium ions
* Regulation of the membrane potential
* Apoptosis-programmed cell death
* Calcium signaling (including calcium-evoked apoptosis)
* Cellular proliferation regulation
* Regulation of cellular metabolism
* Certain heme synthesis reactions
* Steroid synthesis
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Physiol-97B2 Describe mechanism of action in G proteins 47%
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G Proteins
Intracellular membrane bound proteins
-Heterotrimeric
-bind guanine nucelotide
-extremely common proteins
-large superfamily of proteins composed three subunits - α, β, and γ - of which there are several isoforms
Subtypes Gs, Gi, Gt, Gq, G12.
The α subunits of G proteins have intrinsic GTPase activity.
-ligand receptor causes α subunit binds GTP.
-dissociation of the G protein into Gα-GTP and a Gβγ dimer. Both components may activate second messenger systems downstream
-Gα eventually hydrolyzes GTP to GDP allowing reassociation of the G protein into the trimeric form and the cycle can begin again.
Coupling to an Ion Channel
The effect of the M2 AChR in the sinoatrial node of the heart is an example of this mechanism:
* ↑ vagal tone causes ↑ ACh release via the vagus at the SA node.
* ACh binds to M2 and its associated Gs protein is activated.
* GDP exhanged for GTP on the α subunit of the Gs.
* Gs dissociates into Gα-GTP and Gβγ.
* Gβγ then activates the inwardly rectifying K+ current slowing depolarisation of the SA node membrane
* HR is slowed.
The fact that a second messenger system isn't involved is reflected in tha fact that this effects is also very rapid - slower than a ligand gated ion channel but still measured in milliseconds.
Coupling to a Second Messenger System
G proteins most commonly couple to second messengers systems. The two most common are the inositol 1,4,5-triphosphate/diacyl glycerol (IP3/DAG) system and the cyclic adenosine 3,5-monophosphate system (cAMP).
Heterotrimeric guanine nucelotide binding proteins (cf. small G proteins) bind GTP, found on intracellular membrane, associated with ligand receptor, second messenger system : transduce. Amplifiy and diversify ligand receptor signal
form a large superfamily of proteins composed three subunits - α, β, and γ – (several isoforms )- and five families - Gs, Gi, Gt, Gq, G12.
eg receptors
a1 Gq IP3 DAG NA and vasocontriction
a2 Gi cAMP Ca K NA vasocontriction
b1 Gs cAMP Adr and inotropy
b2 Gs cAMP Salbutamol and bronchodilation
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Physiol-93B3 Briefly describe role of intercellular tight junctions
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Physiol-93B3 Briefly describe role of intercellular tight junctions
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Physiol-05B12 Briefly discuss the physiological roles of plasma proteins. 29%
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Plasma: the fluid medium of the intravascular compartment which transports substances between body tissues.
Plasma proteins: globular molecules from simple unconjugated proteins(eg. albumin) to complex proteins (eg. glycoproteins, lipoproteins) which are mostly synthesised in the liver and circulate in the plasma.
Major classes of plasma proteins
1. Albumin (45g/L)
2. Globulins (25g/L) Four subgroups are; alpha-1, alpha-2, beta, gamma
3. Fibrinogen (3g/L)
* Plasma proteins exist in equilibrium with the tissue proteins as an exchangeable pool.
Major functions of plasma proteins
1. Oncotic pressure
Maintenance of body water compartments is assisted by plasma proteins because capillary walls are relatively impermeable to plasma proteins (cf. all other solutes), causing the proteins to exert a force of 25mmHg accross the capillary wall which prevents extravasation of the intravascular volume into the interstitial fluid. This force is opposed by the hydrostatic pressure gradient across the capillary wall according to Starling's forces:
NFP = (Pc - Pi) -σ (π c - πi)
where:
NFP = net filtration pressure
P = hydrostatic pressure
π = oncotic pressure
C = capillary
I = interstitium
σ = reflection co-efficient.
Interestingly, while albumin exists in the highest concentration in plasma, quantatatively more albumin exists outside the circulation at any given time (but is distributed in a much larger volume thus is at a low concentration).
2. Transport Functions
* Plasma proteins bind to many substances (eg. hormones and drugs) and transport them around the body.
* Many ligands can bind to albumin including; free fatty acids, bilirubin, Ca++, cortisol, thyroxine, copper, drugs.
* Also minor contribution to transport of CO2 from tissues to lungs as carbamino compounds. (NB: haemoglobin is much more important than plasma proteins for forming carbamino compounds).
3. Acid-base Balance
* Plasma proteins are responsible for 15% of the buffering capacity of blood due to weak ionisation of the imidazole groups (average pKa about 6.8) in the histidine residues.
* CO2 can combine chemically with the terminal amine groups in blood proteins, forming carbamino compounds.
4. Proteolytic Systems
* Complement: involves >25 plasma proteins,
* Kinins: circulating vasodilator hormones eg. bradykinin.
* Coagulation system: antithrombin III, protein C (clot inhibition), fibrinogen (haemostasis), clotting factors II, VII, IX, X,
* Fibrinolytic system: protein C, Protein S, Plasminogen.
5. Role in Immunity
Cytokines, antibodies, complement.
6. Enzyme Activity
Pseudocholinesterase, alpha-1 antiprotease, alpha-1 antitrypsin.
7. Metabolism
Provides amino acids to tissues for synthesis or catabolism.
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Physiol-01A7 Describe how the body detects and responds to a water deficit 50%
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* Water deficit causes contraction of total body water, including intracellular and extracellular compartments.
* A water deficit causes a relative increase in serum Na+.
* Na+ (and it's obligatory associated anions) account for 92 % of ECF tonicity.
* Total body water is 600mls/kg, or 42L for a 70kg man.
* TBW is 2/3 intracellular and 1/3 extracellular.
* A large water deficit of 4 litres will cause a moderate drop in intravascular volume by around 10%.
Water balance in the body can be considered as a feedback system.
Sensors: osmoreceptors, baroreceptors (low pressure and high pressure), macula densa.
Central controller: hypothalamus
Effectors: thirst, ADH, ANP, renin angiotensin system.
Effectors feed back to the sensors to change the output.
[edit]
Osmoreceptors
* specialised cells in the hypothalamus which respond to changes in CSF tonicity.
* very sensitive to changes in tonicity, essentially monitors of ECF Na.
[edit]
Low pressure baroreceptors / Volume receptors
* stretch receptors located in the walls of the large veins and right atrium.
* monitor effective intravascular volume by assessing central venous presure.
[edit]
High pressure baroreceptors
* found in the carotid sinus and aortic arch.
* monitor arterial BP, so detect BP changes that occur with very large changes in total body water.
* less sensitive than osmoreceptors but more potent.
* hypovolaemia is a more potent stimulus for ADH than is hyperosmolarity or hypertonicity.
* rate of ADH secretion is inversely proportoinally to baroreceptor firing.
* 10-25% decrease in blood volume causes ADH release.
[edit]
Hypothalamus
* Thirst centre
* osmoreceptors located in hypothalamus
* OVLT (organum vasculosum of the lamina terminalis), The organum vasculosum of the lamina terminalis regulates noradrenaline release in the anterior hypothalamic nucleus. Changes in either plasma sodium concentration or arterial pressure can differentially affect hypothalamic neurons.
* SFO (subfornical organ), responds to angiotensin II
* Contains supraoptic and paraventricular nuclei for ADH systhesis.
[edit]
Thirst
* physiological urge to drink
* thirst centre in hypothalamus responds to hypertonicity, hypotension, hypovolaemia, AGII.
* also behavioural aspects of water intake.
[edit]
ADH
* adjusts water output through effect on the kidney.
* hormone produced in the supraoptic and paraventricular nuclei in the hypothalamus.
* a nonapeptide
* secreted from the hypothalamus and moves down via axonal transport to the posterior pituitary where it is secreted into the circulation.
* secretion is stimulated by: incr plasma tonicity, hypotension, stress, hypovolaemia, AG II, drugs (eg.barbiturates, chlorpropamide).
* acts on renal cortical and medullry collecting ducts via two cell types: principal cells (water reabsorption, Na/K excretion) and intercalated cells (H+ secretion).
* combines with V2 receptors on basolateral membrane of principal cells, adenyl cyclase activated, cyclic AMP formed, cytoplasm vessicles fuse with luminal mambrane, water channels "aquaporin 2" in vesicles allow water reabsorption down osmotic gradient.
* half life of 15 minutes
* inactivated in liver and kidney
* in absence of ADH the cortical and medullary collecting ducts have low permeability to water
[edit]
ANP and the renin angiotensin system
* hormone isolated from the right atrium
* increases GFR
* increases urinary sodium and water excretion
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Physiol-01A1 Outline the determinants and regulation of extracellular fluid volume 68%
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* ECF: that portion of total body water outside body cells, including intravascular, interstitial, and transcellular fluid volumes.
* ECF is 35% of total body water, or 15L in a 70kg male.
* Na+ (and its associated anions - mainly Cl-) is responsible for ~90% of extracellular tonicity.
* Cl- usually passively follows Na+ and as such regulation of Na+ balance is the major factor in determination of ECF volume.
* Na+ balance:
o Input: 100-300mmol/day in average western dietary intake.
o Output: Kidney (most), also sweat, faeces (small amount)
Regulation
Control of Na+ balance is a negative feedback control system.
Sensors
* Major role:
o Osmoreceptors: Organum vasculosum of the Lamina Terminalis (OVLT) and Subfornical Organ (SFO) - both circumventricular organs associated with the hypothalamus. Sensitive to a 1% change in ECF osmolarity.
o Low pressure (stretch) baroreceptors in the atria and great vessels. Senistive to ~10% change in intravascular volume, however once stimulated dominate over osmoreceptor input.
o Intrarenal mechanisms: intra-renal baroreceptors at juxtaglomerular cells, macula densa cells.
* Minor role:
o High pressure baroreceptors in carotis sinus and aortic arch which respond to arterial pressure - very large changes in ECF volume will be reflected in blood pressure. Travel via vagal nerves to brain.
Effectors
1. Renin-angiotensin-aldosterone system
2. Intrarenal mechanisms
3. ADH
4. ANP
1. Renin-angiotensin-aldosterone system
Renin:
* acid protease secreted by juxtaglomerular cells - specialised cells in the media of the afferent arteriole.
* released primarily in response to
1. intrarenal baroreceptors: ↑ arteriolar pressure at JG cells.
2. decreased chloride sensed at macular densa due to decreased GFR.
3. ↑ symapthetic tone.
* Angiotensin II and ADH inhibit renin secretion.
* stimulates the conversion of angiotensinogen to angiotensin I
* angiotensin I then converted to active angiotensin II by agiotensin conerting enzyme - principally (70%) in the lungs.
Angiotensin II:
* 8 amino acid peptide hormone.
* T½ 1-1½ minutes.
* direct effect on Na+ (and biacarb)reabsorbtion in the proximal tubule.
* indirect effect on Na+ reabsorbtion through ↑ aldosterone release, and through ↑ ADH and ACTH release.
* stimulates thirst centre.
Aldosterone:
* a corticosteroid produced by zona glomerulosa cells of adrenal cortex.
* most important regulator of Na+ excretion/reabsorbtion.
* acts on intracellular receptors to produce changes in protein expression (30-60 minute latency).
* stimulated principally by ATII (also minor stimulation by ACTH, Na, K).
* promotes reabsorption of Na+ (& K+ secretion) in a variety of tight epithelia - principally in the distal portion of the nephron but also in sweat/ salivary glands, colon and rectum.
* in DCT and CD acts by insertion of Na+ channels in luminal epithlial membrane, and up regulation of sodium potassium ATPase on basolateral membrane.
2. Intra-renal mechanisms
Glomerulotubular balance (GTB):
* Overall renal Na+ excretion = filtered load - tubular reabsorption.
* Filtered load ∝ GFR.
* GTB is a form of intrarenal autoregulation.
* Works by an unknown mechanism.
* Causes a constant proportion (~65%) of Na+ is reabsorbed in the PCT in the face of changes in GFR.
* Mitigates the effect of changes in GFR on Na+ (and thus water) reabsorbtion.
Tubuloglomerular Feedback (TGF):
* autoregulates GFR and to a lesser extent renal blood flow (RBF) within a single nephron.
* if GFR ↑ macula densa cells somehow detect an ↑ NaCl delivery to DCT (probable mediator is Cl-.
* this causes release of an unknown mediator or mediators (possibly adenosine) which causes
o afferrent arteriolar constriction → ↓ GFR & RBF.
o ↓ prostagladin release which normally cause arteriolar dilatation ↓ GFR & RBF.
o ↓ renin release.
* sensitivity of TGF is increased when ECF volume is decreased.
Renal Sympathetic Nerves:
* direct effect on Na+ reabsorbtion by action of α1 and β1 receptors on renal tubular cells.
* indirect effect on Na+ reabsorbtion by:
o renal vasoconstriction → ↓ GFR
o ↑ renin secretion by action of JG cells, and ↑ gain for renin release to non-sympathetic stimuli for renin release.
3. ADH
* hormone produced in the supraoptic and paraventricular nuclei in the hypothalamus.
* moves down via axonal transport to the posterior pituitary where it is secreted into the circulation.
* secretion is stimulated by:
o ↑ plasma tonicity.
o hypotension.
o stress, pain, emotion.
o Nausea & vomiting.
o exercise.
o change in posture.
o hypovolaemia.
o ATII.
o drugs (eg.barbiturates, chlorpropamide).
* half life of 15 minutes.
* inactivated in liver and kidney.
Direct effect on Na+ reabsorbtion by:
* synergistic action with aldosterone - Na+ channels inserted into luminal membrane of principal cells of cortical CD.
Indirect effect on Na+ balance by:
* combination with V2 receptors on basolateral membrane of principal cells → adenyl cyclase activated → cyclic AMP formed → cytoplasmic vesicles fuse with luminal membrane → water channels "aquaporin 2" in vesicles allow water reabsorption down osmotic gradient. In absence of ADH the cortical and medullary collecting ducts are impermeable to water.
* stimulates thirst centre.
* ↓GFR by mesangial cell contraction and renal vasocontriction (V1 receptors).
* inhibits renin release.
4. Atrial Naturetic Peptide
* released from the cardiac atria in response to stretch (↑ volume).
* also found in hypothalamus and other brain regions.
* increases excretion of Na by:
1. increasing GFR: relaxation of mesangial cells and afferent arteriolar vasodilation.
2. Probable direct inhibition of Na+ reabsorption in medullary CD.
3. reduction of renin (and thus ATII), aldosterone, and ADH release.
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Physiol-95B5 Outline the effects of IV administration of 500 mls of 20% mannitol, and the potential problems associated with its use.
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20% Mannitol (MW 182)
=200 g/L
=1098 mmol/L
Therefore hypertonic (3.5 times tonicity of plasma)
Uses
1. cerebral dehydration to decrease ICP
2. renal protection - protect again renal failure eg rhabdomyloysis
Osmotic effect on plasma volume: draws fluids from ICF to ECF.
Effects
1. reduced haematocrit via plasma expansion and reduced RBC size
-decreases SVR
-decreased viscocity
-increase CO and O2 delivery
2. intracellular dehydration
3. osmotic diuresis
-freely filtered
-not secreted or reabsorbed
-retains fluid in tubules
-reduction of plasma fluid volume
4. cerebral effects
-mannitol does not cross BBB
-therefore hyperosmolar solution is effective in removing fluid from brain
-0.5-1.5g/kg as 20%solution
-rapid effect
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Physiol-07A11 Discuss how the body handles a metabolic acidosis. 57%
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The main points to be covered were a definition of a metabolic acidosis, discussion of extracellular and intracellular buffering systems, respiratory compensation, the renal mechanisms to excrete non-volatile acids (titratable acidity, ammonium and ammonia), and resorption and regeneration of bicarbonate.
Extra marks were awarded for the mechanism of respiratory compensation, explaining that respiratory compensation does not lead to acid excretion, description of buffering by long as well as short term mechanisms, specific details of ammonia and ammonium production and bicarbonate regeneration, understanding that H+ ions can not be excreted unbound, the amount of acid that can be excreted by different renal mechanisms, and aldosterone’s effect on H+ excretion.
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Physiol-06B15 Explain how a metabolic acidosis develops in hypovolaemic shock. Describe the consequences of this metabolic acidosis for the body. 53%
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Shock is a life threatening condition that occurs when delivery of oxygen to tissue in adequate to meet demands.
Hypovolaemic shock results from inadequate circulating volume. Can be the result of
1. decreased plasma volume : haemorrhage, dehydration, 3rd space
2. increased capacitance : venodilation from sepsis or spinal cord transection
Hypovolaemia results in decreased perfusion of tissue
-decreased O2 delivery
-switch to anaerobic metabolism
glucose to pyruvate produces 4 ATP
pyruvate to lactate uses 2 ATP but oxidizes NADH to NAD+
Lactate is a marker of tissue hypoperfusion
Consequences of increased H+ load
1. buffering
2. compensation
3. correction
ng from inadequate delivery of nutrients
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Physiol-05A15 Discuss how the body handles a metabolic acidosis. 38%
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Physiol-05A15 Discuss how the body handles a metabolic acidosis. 38%
Metabolic acidosis is an abnormal primary process if left unchecked will result in an academia due to fixed acids.
An acid is a substance which donates protons. Eg HCl, H2CO3.
Causes
High Anion-Gap Acidosis
1. Ketoacidosis
Diabetic ketoacidosis
Alcoholic ketoacidosis
Starvation ketoacidosis
2. Lactic Acidosis
Type A Lactic acidosis (Impaired perfusion)
Type B Lactic acidosis (Impaired carbohydrate metabolism)
3. Renal Failure
Uraemic acidosis
Acidosis with acute renal failure
4. Toxins
Ethylene glycol
Methanol
Salicylates
Normal Anion-Gap Acidosis (or Hyperchloraemic acidosis)
1. Renal Causes
Renal tubular acidosis
Carbonic anhydrase inhibitors
2. GIT Causes
Severe diarrhoea
Uretero-enterostomy or Obstructed ileal conduit
Drainage of pancreatic or biliary secretions
Small bowel fistula
Body handles fixed acid load by
1. buffering : bicarbonate, phosphate, proteins, RBC
2. compensation : volatile acids CO2, ketones
3. correction : bicarbonate reabsorption, excretion of fixed acids, ammonia secretion
Effect of acidaemia
CVS: tachy, reduce inotropy
Resp : kussmuls breathing
Endo : adrenergic stim, cortisol
CVS : agitation, confusion, coma, seizure
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Physiol-03A9 Explain the role of haemoglobin as a buffer. 38%
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Buffer is a solution that contains a weak acid and its conjugate base or a weak base and its conjugate acid. It has the ability to minimise changes in pH when acid or base is added to it.
Hb is the most important noncarbonic buffer in ECF.
Hb is present in RBC as a weak acid(HHb) and a potassium salt(KHb).
* H+ + KHb--->HHb + K+
* H2CO3 + KHb----> HHb + Hco3-
Haemoglobin is capable of buffering both volatile and fixed acids unlike bicarbonate system which cannot buffer CO2
Though present in RBC's it serves as a important buffer for CO2 because of
* 1. High solubility of CO2
* 2. Presence of high concentration of Carbonic anhydrase in RBC
* 3. High buffering capacity of Hb- (a) Rich in Histidine residues which act as buffer from pH 5.7-7.7(pk-6.8) (b) Large amount of Hb in blood(150g/l) (c) Deoxy Hb is a better buffer as it is a weaker acid-accounts for 30% of haldane effect
Examiner's Comments
Only 38% of candidates passed this question.
A definition of a buffer was required, and also that buffering capacity or effectiveness depends on the concentration of the buffer relative to the ambient pH of the solution.
Haemoglobin, although intracellular (within the erythrocyte), functions mainly as an "extracellular" buffer for CO2 (volatile acid) formed from aerobic metabolism.
The solubility of CO2, the presence of carbonic anhydrase within the erythrocyte and the buffering capacity of haemoglobin all contribute to make the haemoglobin buffering system extremely efficient.
Haemoglobin is a quantitatively important buffer because there is a large amount present in blood - 150gm/L.
Also the imidazole groups of the histidine residues of the globin chains are an effective buffer as their pKa of 6.8 is close to the pH within the erythrocyte.
The buffering capacity of haemoglobin is greatest when it is needed most, that is when haemoglobin is deoxygenated in venous blood with a higher CO2 content.
Deoxygenated haemoglobin is a better buffer than oxyhaemoglobin as it is a weaker acid, and the pKa of its imidazole groups are higher at 7.9.
This information was deficient in most answers.
The increased buffering capacity of deoxygenated haemoglobin contributes approximately 30% of the Haldane effect.
Many candidates incorrectly stated that haemoglobin functioned as a buffer by the formation of carbamino compounds.
The dissociation of carbamino compounds within the erythrocyte actually adds hydrogen ions that need to be buffered by haemoglobin and other buffers.
Better answers mentioned the fact that the bicarbonate buffer system cannot buffer carbonic acid (CO2) as they form part of the same weak acid - conjugate base pair.
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Physiol-98B5 Explain how metabolic acidosis develops in hypovolaemic shock. Describe the consequences of metabolic acidosis to the body. 55%
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Physiol-98B5 Explain how metabolic acidosis develops in hypovolaemic shock. Describe the consequences of metabolic acidosis to the body. 55%
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Physiol-95A6 Describe the effects of intravenously administered sodium bicarbonate (8.4%) 100ml used in asystolic cardiac arrest in a 70 kg man 46%
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Physiol-95A6 Describe the effects of intravenously administered sodium bicarbonate (8.4%) 100ml used in asystolic cardiac arrest in a 70 kg man 46%
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Physiol-06A10 List the physiological factors which increase respiratory rate. Include a brief explanation of the mechanism by which each achieves this increase. 62%
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The 3 most important physiological factors:
* Hypercapnoea: very sensitive, minute-to-minute control by central (85%) and peripheral (15%) chemoreceptors that works synergistically with hypoxia (the lower the PaO2, the greater the increase in alveolar ventilation for incremental increases in PaCO2). The central chemoreceptors have a more powerful effect on ventilation, but the peripheral receptors have a faster response, and are thought to be important in regulating ventilation from breath to breath.
* Hypoxia: Not as important in acute control. PaO2 needs to drop to 60mmHg before alveolar ventilation increases. Is important in chronic lung disease where chronic tolerance to increased PaCO2 has developed and pH has returned to normal by compensatory mechanisms.
* Acidosis: An effect mediated mainly by peripheral chemoreceptors (carotid body), but if pH drops low enough, BBB becomes permeable to H+ and central chemoreceptors respond.
Other factors:
* Exercise: Unclear exact mechanism - severe exercise causes decreased pH.
* Voluntary control
* Pregnancy - causes greater change to tidal volume than respiratory rate
* Depression of central control (respiratory centre)- e.g. by opioid analgesics
* Pulmonary stretch reflex
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Physiol-08B13 Explain the concept of time constants and relate these to "fast" and "slow" alveoli.
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One time constant (tau) is the time taken for a system to reach 63% of maximum.
In the lung, a time constant is the time taken for an alveoli or alveolar unit to fill/empty 63%.
T=R*C
Resistence in mmHg/L/min
Compliance in L/mmHg
Normal healthy individuals time constants all the same
Disease
regional differences in compliane and resistence
asthma : bronchoconstriction + mucus plugs
compliance : increased
regional differences in ventilation
-quick vs slow time constant
-dynamic vs static compliance
-capnography, fowlers method
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Physiol-06B10 Describe the determinants of work of breathing in an adult human at rest. 62%
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Work of Breathing:
Measured in L/cmH2O [ sould be cm ( pressure) .ml( volume) ], or the Joule.
Work is Pressure x Volume (work = force x distance)
WoB is divided into Elastic and Resistance work.
Elastic work is divided into 1. surface tension (50 – 70%) 2. lung tissue (up to 50%)
Resistance work is divided into 1. viscous tissue resistance (20%) 2. airway resistance (80%)
Resistance work is performed in both inspiration and expiration.
Elastic work is performed in inspiration. The energy for expiration in quiet breathing comes from the elastic work performed in inspiration, which deforms the elastic tissue.
Expiration is said to be passive, meaning that the energy for expiration has already been outlaid in inspiration and stored elastically. Some energy is also lost as heat.
WoB will increase with an increase in any of the elements of Elastic work or Resistance work.
Surface tension is reduced by surfactant. Surfactant is decreased in premature neonates, prolonged ventilation, and ARDS- these conditions increase WoB.
Lung tissue elasticity is increased (ie compliance is decreased) in pulmonary fibrosis, which increases WoB.
Viscous tissue resistance is the friction from lungs sliding over chest wall and diaphragm sliding over abdominal organs. This is reduced by pleural fluid and peritoneal fluid.
Airway resistance is the resistance to gas flow in the airways. It is increased in turbulent (cf laminar) flow (eg in incr RR) and in a/ways with decreased radius (eg due to decr lung vol, oedema, secretions, mscle tone, extrinsic compression). It is decreased by laminar flow, incr lung volume, bronchodilation, decreased gas density.
In COAD, Raw is increased. By increasing FRC, the lung volume at which breaths are made is increased, and Raw (therefore WoB) is decreased.
In pulmonary fibrosis, compliance is decreased (increased elasticity of lung tissue), and Elastic work is increased. By increasing respiratory rate and decreasing tidal volume, although Raw is increased, there is a decrease in elastic work performed (because tidal volume is smaller, less elastic work is performed). Therefore WoB is decreased
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Physiol-03B13 Describe the factors that affect airways resistance. 64%
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Definition: Airway Resistance
The frictional resistance to gas flow throughout the airways. Calculated as driving pressure (i.e. the differential between mouth pressure and alveolar pressure) divided by flow rate. An expression of Ohm's Law.
This can be written as R = P/F
where
* R is airway resistance cmH2O/L/sec
* P is the driving pressure (mouth to alveoli) cmH2O
* F flow rate L.sec-.
Factors which affect airway resistance:
1. Nature of Flow
(i) Reynolds number (Re) is used to predict the likelihood of turbulent flow (>2000 indicates likely turbulence): Re = (density x velocity x diameter) / viscosity - From this, factors which increase likelihood of turbulent flow:
a) increased density of gas (eg deep diving because incr barometric pressure)
b) increased velocity (eg incr RR, large airways eg trachea)
c) increased diameter of tubing (eg large airways such as trachea)
converse also true; decr likelihood turb flow in:
a) decreased density of gas (heliox, altitude)
b) decreased velocity (eg decr RR, small airways)
c) decreased diameter (small airways)
- True turbulent flow may be seen in trachea (esp in exercise because incr velocity). True laminar flow may be seen at level of terminal bronchioles. in between probably experiences transitional flow.
(ii) laminar flow: described by Hagen-Poiseuille eqn:
R=8nl/pi.r^4
R = resistance, r = radius, l = length, η = viscosity.
This equation illustrates:
* flow increases proportionally with increased driving pressure
* a doubling of radius gives 16 fold decrease in resistance (because radius is to the fourth power; 2 x 2 x 2 x 2 = 16)
Despite decreased radius, the small airways offer comparatively little Raw, because they are greatly increased in number and are in parallel. Most airways resistance is in the larger airways (to the level of the medium sized bronchi).
(iii) turbulent flow: resistance much increased. - because of incr resistance, much greater pressure needed for an incr in flow, and relationship btwn pressure and flow is no longer linear. - radius has less effect on resistance - in turbulent flow, decr density of gas (eg heliox) gives greater flow rate for given driving pressure, because of decr resistance
2. Radius of tube
(i) small airways contribute less to resistance than large airways, despite decreased radius, because many more in number (as stated above)
(ii) airway calibre is affected by:
a) lung volume (incr lung vol leads to incr radial traction on airway leads to incr calibre leads to decr resistance)
b) incr smth mscle tone (eg incr PNS activity, decr SNS activity) leads to decr calibre)
c) incr secretions (eg asthma, irritation 2 smoking) leads to decr calibre leads to incr resistance
d) incr oedema (eg asthma, irritation 2 smoking) leads to decr calibre
e) extrinsic compression (eg forced expiration, tumour) leads to decr calibre
3. Anatomic site - bronchi main site of resistance despite a greater calibre than small airways due to comparitively smaller X sect area.
4. Lung volume - lung vol inversely related to AWR - When lung vol exceeds FRC radial traction opens bronchi causing decr AWR
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Physiol-03A14 Describe the factors that affect lung compliance. 39%
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Compliance: change in volume per unit change in pressure. mL/cmH2O. Compliance may be measured for the lungs alone, chest wall alone, or for the two together (total thoracic compliance, 100 mL/cmH2O, as 1/total compliance = 1/lung compliance + 1/chest wall compliance).
Compliance may be:
* static (measured at fixed lung volumes with no air flow), or
* dynamic (measured during breathing).
Factors which affect lung compliance
1. lung volume - On the pressure-volume curves for the lung and for the lung and chest wall together, compliance is the slope of the curve. As can be seen from the pressure-volume curves, compliance is greatest around FRC (around the volumes at which normal tidal breathing takes place) and decreases at very low and very high lung volumes.
2. lung size- there is an enormous difference between volumes of neonatal and adult lungs, but the pressures involved in breathing are much less different. specific compliance corrects for this by dividing compliance by FRC (Cs = C / FRC). A normal value is around 0.05 cm H2O.
3. posture- affects lung volume, therefore compliance.
4. pulmonary venous congestion- decreases compliance (makes lung 'stiffer').
5. disease states-
* Asthma leads to hyperinflation, and moves lung up on pressure volume curve, decreasing compliance.
* Fibrosis, collapse and consolidation all decrease distensibility of the lung and decrease compliance.
* Emphysema is unique amongst pulmonary diseases as compliance is increased. The lung is easier to distend due to destruction of lung parenchyma.
6. surfactant- 2 effects:
* firstly, opposes the effect of Law of LaPlace (P = 2T / R) which describes collapse of smaller alveoli into larger alveoli (collapse decreases compliance, see point 5 above).
* secondly, even without collapse, the effect of surfactant on decreasing surface tension leads to decreased 'stiffness' of the lung and increased compliance.
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Physiol-05B16 Explain the changes on Functional Residual Capacity (FRC) that take place with the administration of anaesthesia. 48%
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* FRC is the volume of gas remaining in the lungs at the end of normal expiration.
* FRC is the balance point betwen tendency of chest wall to spring outwards, and tendency of lung to collapse inward
Changes During General Anaesthesia
* Rapid drop in FRC of 15-20% with induction of anaesthesia.
* Considerable individual variation.
* Maximal drop in first few minutes and then remains steady throughout anaesthesia (i.e not progressive throughout anaesthesia).
* May remain for several hours after waking.
* Degree of reduction has a weak but significant correlation with age.
* Reduction occurs whether or not patient is paralysed.
Regional anaesthesia does not produce decrease in FRC other than related to supine position.
Application of PEEP may restore FRC to normal.
Causes of Changes in FRC
1: Supine position
* in change from erect to supine position (without anaesthesia) there is a decrease in FRC of approx. 0.5L due to cephalad displacement of diaphragm by abdominal contents.
* exagerated by obesity and trendelenburg position.
2: General Anaesthesia
* main effect appears to be due to reduction in the cross sectional area of the thoracic cage leading to a decrease in volume of about 200ml. Possible cause: combination of decreased muscle tone, change in diaphramatic position or spinal curvature.
While intuitively muscle paralysis would exacerbate these effects, this hasn't been demonstrated convincingly, most studies showing the FRC decrease with GA unaffected by muscle paralysis
3: Increased pulmonary blood volume and medistinal mass during GA may further decrease FRC although this hasn't been convincingly demonstrated.
Effects of Decreased FRC
1. decreased potential oxygen store
2. increased risk of atelectasis
3. increased work of breathing in non-paralysed patients
4. increased pulmonary vascular resistance
5. increased airway resistance.
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Physiol-03B11 Briefly describe the potential causes of a difference between measured end-tidal and arterial partial pressure of carbon dioxide. 43%
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Measuring end tidal CO2
* Measured using samples obtained from expired air. Utilises infrared analyser/capnograph to measure CO2 levels continously.
* Values are generally plotted as PeCO2 concentration over unit time.
* In a normal patient it produces a typical waveform: fig 10.12 Nunn's
* Alveolar concentration of CO2 generally taken at the peak of the graph, at the end of the alveolar plateau, which corresponds to alveolar CO2 concentration.
Factors Causing Measurement Errors
* Inadequate calibration of infrared sensor
* Inadequate tidal volume
* Blockage of sampling line
* Air entrainment into sampling line (leaks)
* Patient factors
* Delayed alveolar emptying with failure to obtain plateau reflecting alveolar CO2 concentration
* Smoker
* Increasing age
* Anaesthesia
* Increased anatomical dead space
Measuring PaCO2
* Measured by CO2 sensitive electrode via arterial blood sample.
* Based on H+ measurement based on reversible reaction of CO2 with H20
* - Uses Severinghaus CO2 electrode
Factors Causing Error
* Damage to Severinghaus electrode - damage to semi-permeable membrane
* Delay of 2-3 minutes while CO2 diffuses for measurement
* Not calibrated to pressure and temperature
* Air bubble in blood sample
* Excess heparin (acid) resulting in reduced measure PCO2
* Delay of sample being measured and not placed on ice
* Patient factors
* Venous sample taken instead of arterial sample
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Physiol-00B3 Draw an expiratory flow volume curve for a forced expiration from total lung capacity. Describe its characteristics of a normal lung as well as in obstructive and restrictive lung disease
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Physiol-00B3 Draw an expiratory flow volume curve for a forced expiration from total lung capacity.
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Physiol-98A2 Draw a flow/volume curve for a maximum forced expiration in a person with healthy lungs from: (a) Total lung capacity; (b) Function Residual capacity. Explain your curves 61%
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Physiol-98A2 Draw a flow/volume curve for a maximum forced expiration in a person with healthy lungs from: (a) Total lung capacity; (b) Function Residual capacity. Explain your curves 61%
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Physiol-97B7 Explain the factors influencing the distribution of ventilation during the inhalation of 500ml of air from Functional Residual Capacity in the erect posture 56%
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Define FRC
500ml is a normal tidal breath
Anatomical differences
-right greater than left
-therefore gets more
Ventilation differences
-gravitation traction on lung
-intrapleural pressure more negative at apex than base
-draw volume-intrapleural pressure curve
-apex alveoli subject to more negative intrapleural pressure, therefore more inflated, less compliant
-base alveoli subject to less negaive intraplerual pressure, therefore less inflated and more compliant
-therefore ventilation more at bases than apex
Time constants
-time taken to fill or empty alveoli 63% of maximum
-product of resistence and compliance
-fast alveoli : low reistence and low compliance
-slow alveoli : high resistence and high compliance
-fast alveoli fill first : then redistribution from fast to slow during breath hold
-time constants in healthy young person is the same
-but in elderly or patients with parenchymal lung disease (empysema, regions of different compliance) or airways obstruction (asthma) : varying time constants
Airway closure
-hypoventilation and actelecatasis
-recruitment/reopening of these at end of inspiration (high volumes)
Pathological considerations
-Extrinic compression : cancer
-pleural effusions
-pneumonthorax
-collapse/consolidation
-oedema, left heart failure
-chest wall defects : flail chest, kyphosis
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Physiol-96B6 Draw a respiratory flow/volume loop and outline how it is obtained. Briefly explain the physiological mechanisms involved in the concept of flow limitation. 51%
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How is it generated
-patient takes repeated maximal forced inspiratory and expiratory breathes into a pneumotachograph
-flow is measured against time
-volume is integrated
-time is disregarded and the flow vs volume is recorded
Draw and label normal
-draw loop of COAD and pul fibrosis
Effort independent limb
-includes most of descending part of expiration
-maximal flow possible at any particular voume.
-due to dynamic airways compression
Dynamic Airways Compression
-forced expiration requires positive intrapleural pressures (produced by contraction of expiratory muscles)
-alveolar pressure greater than mouth pressure
-gas flows out of lung through airways down a pressure gradient
-drop is pressure is proportional to length
-increased intrapleural pressure exerted on alveoli as well as airways
Diagram x 2
-initially airway held open by intralumenal pressure (luminal pressure > intrapleural pressure)
-bc of airway resistence, pressure inside airway will decrease
-if intrapleural pressure>luminal pressure, airway will collapse
STARLING RESISTOR
Factors that increase DAR
-increased airways resistence (athsma)
-increased compliance (emphysema)
COAD differences
-total lung volume is higher (over expanded chest)
-maximal flow is reduced
-expiratory independent curve is concave
Pulmonary fibrosis
-smaller lung volume
-decreased maximal flows
-more diamond shaped
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Physiol-07A9 Define 'Venous Admixture'. Briefly explain how venous admixture influences arterial 02 tension and how an increase in inspired 02 concentration may affect this. 43%
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Main points expected for a pass included:
* definition,
* sources of venous admixture with brief description of each,
* appreciation that venous admixture is a concept which may be expressed by the
shunt equation,
* statement of effect on PaO2 of venous admixture with reference to the
oxyhaemoglobin dissociation curve (demonstrating relation of oxygen tension to haemoglobin saturation), and
* the effect of increased inspired oxygen concentration on venous admixture.
Additional marks were allocated for more detail with respect to sources of venous admixture (e.g. relative contribution, magnitude effect), demonstration that small and large amounts of venous admixture affect PaO2 differently, explanation of relative effect of high versus low V/Q units, reference to isoshunt diagram and quantifying effect of increased inspired oxygen.
Mistakes commonly made included:
* imprecise or interchangeable use of terms (e.g. oxygen content for PaO2 and shunt or mixed venous blood for venous admixture); and
* use of oxyhaemoglobin dissociation curve to justify arguments regarding the effect of increased PaO2 on oxygen content.
Credit was not given for vague, non-directional statements of effect, or for discussion of carbon dioxide or factors which affect mixed venous PO2.
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Physiol-97A7 Compare the effect on arterial blood C02 and 02 levels of ventilation/perfusion inequalities
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Physiol-97A7 Compare the effect on arterial blood C02 and 02 levels of ventilation/perfusion inequalities
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Physiol-09A16 Outline the effects of acute exposure to air at an altitude where barometric pressure is 347mmHg. What compensatory mechanisms occur with gradual exposure to increasing altitude?
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Physiol-09A16 Outline the effects of acute exposure to air at an altitude where barometric pressure is 347mmHg. What compensatory mechanisms occur with gradual exposure to increasing altitude?
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Physiol-07B10 Discuss factors which affect the partial pressure of carbon dioxide in mixed venous blood.
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The partial pressure of carbon dioxide in mixed venous blood depends on the carbon dioxide content of the blood and represents a balance between CO2 production in the tissues and content in the arterial blood. Good answers demonstrated an understanding of this and provided details about these aspects
The partial pressure is related to the content by the carbon dioxide dissociation curve the position of which is determined by the state of oxygenation of haemoglobin, the Haldane effect. Carbon dioxide is present in the blood in three forms, dissolved, bicarbonate and carbamino compounds.
Carbon dioxide production is related to aerobic metabolism in cells and the total production is defined by the metabolic rate. Production may be increased (e.g. exercise, fever, MH, pregnancy) or decreased (e.g. anaesthesia, hypothermia).
The partial pressure of carbon dioxide in mixed venous blood is related to the pressure or content in arterial blood. This is determined by alveolar ventilation and normally controlled by chemoreceptor and the brainstem respiratory centre.
Other relevant material included definitions of mixed venous blood, normal values, the effect of temperature and cardiac output.
The most common error was discussing PCO2 without making it clear whether it was venous or arterial. The Fick equation was often used but required “solving” for CvCO2 to demonstrate the factors or importance to this question.
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Physiol-04B9 Describe how carbon dioxide is produced in the body. How does it move from the site of production to the pulmonary capillary? 60%
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Carbon dioxide is an end product metabolism of sugars (RQ 1.0) , fats (RQ 0.68) and amino acids (RQ 0.8) with oxygen ,in a process known as cellular respiration. Therefore all metabolically active cells. CO2 production is related to metabolic rate. Increased metabolic rate : exercise, hyperthryoidism, sepsis. Decreased metabolic rate : hypothermia, rest, hypothyroidism (big list but no time)
-glycolysis no CO2 produced
-pyruvate is converted to acetyl-CoA and CO2 (glucose : 2 pyruvate, a-a: pyruvates)
-fatty acids catabolised to produce acetyl-CoA
-acetyl CoA enters KREB cycle produces 2 CO2
Total amount of CO2, 10000mmol per day
Transport of CO2 from cells to atmosphere
Cell to blood : Fick’s law of diffsion, down concentration gradient from mito to cytosol to interstitium to capillaries. CO2 is very lipid soluable and freely diffuses down gradient
Blood : 3 forms; dissolved, bicarb, carbaminocompounds. Relative contributions of each in arterial and venous blood, Haldane effect
Blood to lungs : Fick’s law of diffusion, increase CO distention and recruitment
Lung s to atmosphere : alveolar ventilation, control via CO2 chemo receptors (central and peripheral)
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Physiol-04A11 What is 2,3, DPG? How is it produced in the red blood cell and how does it interact with haemoglobin? What is its relevance in altitude exposure, anaemia and stored blood? 84%
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2,3 DPG is 2,3 diphosphoglycerate. It is a highly charged anion which is present in high concentrations inside the red blood cell.
Produced in RBC from Rapoport-Luebering Shunt which is an offshoot from the main glycolytic pathway (Embden-Meyerhoff pathway)
Production:
* Glucose-6-phosphate
* 3, diphosphoglyceraldehyde
* 1,3 diphosphoglycerate -- enzyme 2,3 DPG MUTASE (acitivity increased with high pH)
* 2,3,DPG -- enzyme 2,3,DPG phosphatase (activity decreased with acidosis ie decreased RBC glycolysis)
* 3, phosphoglycerate
* pyruvate
T1/2 - 6hrs
Increased production:
* alkalosis
* exercise
* high altitude
* pregnancy
* chronic hypoxaemia
* anaemia
* increased thyroid hormone
* androgens
* growth hormone
Binds to beta (globin)chain of Hb - especially deoxyHB
ie HbO2 + 2,3,DPG = HB-2,3DPG + O2
Increased concentration shifts oxygen dissociation curve to right
* liberates O2 to tissues
* have conformational change in Hb
* increases P50
Poor binding to HbF HbF has greater O2 affinity because HbF is made of alpha2 gamma2 and 2,3 DPG binds to beta chain.
Altitude increased 2,3 DPG production -increased concentration in RBC - Increased P50 -Shifts O.D.C. to right - increased O2 availability to tissue - decreased O2 affinity for Hb
-stimulus: - chronic hypoxaemia - hyperventilation - low PiO2 due low barametric pressure
Anaemia - increased production due tissue hypoxia - increased O2 tissue unloading -increased PO2 at which O2 released - P50~ 3.8mmHg higher than normal
Stored Blood Decreased concentration - negligible after 2 weeks - due to cold storaage (<6 degrees) - decrease glycolysis
concentration returns to normal ~ 48 hrs post transfusion - glycolytic enzyme reactivation in RBC during storage have left shift of O.D.C.
Additives aim to decrease 2,3 DPG depletion rate -dextrose - substrate for glycolysis -phosphate/adenine - maintain ATP levels -citrate- anticoag + buffers lactic acid
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Physiol-03B12 Explain the difference between perfusion limitation and diffusion limitation in the transfer of gas between alveolus and pulmonary capillary. Outline the factors that determine whether gas transfer is perfusion or diffusion limited. 45%
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Determinants of Diffusion
Fick's Law of Diffusion
The rate of diffusion of a gas from alveolus (A) and pulmonary capillary (a) is described by Fick's law of diffusion:
V=DA(P1-P2)/T
( V =diffusion rate, A = area for diffusion (in the normal lung 50-100 m2), T = thickness of diffusion path (thickness of alveolar & capillary wall 0.3µm), P1 - P2 is the partial pressure gradient for diffusion
D is the diffusion co-efficient descibed by: D = solubility/sqroot MW
For gases of physiological interest MW is roughly equivalent thus solubility is the principal determinant of the diffusion co-efficient. Most notably CO2 has a solubilty in plasma 20x that of O2 and thus diffuses 20x faster for the same driving pressure.
Combination with Haemoglobin
In addition rate of diffusion A to a is determined by extent and rate of binding to proteins. Binding of these gases to Hb effectively maintains the partial pressue gradient for diffusion (by preventing partial pressure equilibration between A and a). The rate of this combination limits the rate at which partial pressure is decreased in plasma and thus limits the rate of diffusion as described by Fick's Law above.
Diffusion Limited Gas Transfer
Figure 3-2 page 28 of West goes here.
CO : strictly diffusion limited, equilbration of the partial pressure A-a is incomplete at end of the pulmonary capillary transit time (PCTT). CO binds avidly and rapidly with Hb and thus the partial pressure gradient for diffusion is maintained throughout the PCTT (see fig 3-2). Thus gas transfer is effectively limited only by the rate of diffusion. Therefore used to estimate diffusion capacity of the lung as determined by the equation:
DL =VCO/PACO2
Perfusion Limited Gas Transfer
N2O is perfusion limited. It doesn't bind at all with Hb and thus partial pressure rapidly equilibrates between blood and alveolus limiting the rate of diffusion. In this case the amount of gas transfer is entirely dependant on blood flow (see fig 3-4).
Transport of Oxygen and Carbon Dioxide
normal physiological: transport of O2 is perfusion limited,
* exercise at high altitude- PCTT is markedly decreased due to increased pulmonary blood flow, and due to the markedly decreased barometric pressure the partial pressure gradient for diffusion is decreased.
* lung disease any lung disease that decreases the area for diffusion (e.g. CAL) or incresaes the thickness of the diffusion barrier (e.g interstital lung disease) will decrease the rate of diffusion. These effects will also be exacerbated by exercise (decreased PCTT). See West fig 3-3.
As mentioned carbon dioxide is 20x more soluble than oxygen and thus it's rate of diffusion is 20x faster. As such its transfer is normally perfusion limited i.e partial pressure A-a is rapid and complete with PCTT).
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Physiol-02A1 Explain how oxygen supply of organs is maintained during isovolaemic haemodilution. 45%
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O2 flux = arterial O2 content x cardiac output
Oxygen bound to Hb PLUS dissolved O2 (which is negligible under normobaric conditions)
CaO2= 1.34 x Hb (gm/dL) x SaO2 + (PaO2 x 0.003)
According to Poiseuille's law:
Flow = P.π.r4/8.η.L
Where P = driving pressure, r4 = radius to the fourth power, η = viscosity, L = length
Oxygen delivery
Anaemia = decreased Hb, therefore decreased CaO2
However, anaemia leads t o decreased η. This increases venous return, which increases diastolic filling and hence stroke volume (Frank-Starling reflex) and initiates Bainbridge reflex (atrial stretch receptors send a vagal afferent to the medulla, = efferant vagal & sympathetic signals to increase rate of contraction)
Another bonus of the decrease in η is the decreased total peripheral resistance, and hence less afterload.
Combining increased SV, Rate, and decreased TPR, = higher cardiac output. So, even with lower CaO2, the increased perfusion makes up for it.
Capillary bed flow
Local tissue effects mean that the hypoxia causes tissue vasodilation. This is a form of Autoregulation: The arterioles dilate in response to local hypoxia.
For each 1mmHg increase in PaCO2, the brain's perfusion increases by 1ml per 100mg tissue per minute, to a maximum of 80mmHg PaCO2
O2 extraction
* The Hb-oxygen dissociation curve is altered, due to acidosis and CO2. A right shift ensures the HbO2 dissociates more easily at a given PO2, thus increasing O2 delivery to tissues, which maintains the O2 concentration gradient from blood to mitochondria.
* The decreased tisue PO2 also means a greater concentration gradient.
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Physiol-00A2 Briefly describe the factors that influence the partial pressure of oxygen in mixed venous blood 56%
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Mixed venous blood: True mixed venous blood must be obtained from a pulmonary artery catheter where blood from SVC, IVC and coronary sinus have fully mixed. Systemic blood, returning from the all tissues, is collected and mixed in the right ventricle and pulmonary artery. Thus, mixed venous pO2 and pCO2 reflect O2 extraction and CO2 addition from the entire body.
Typical values for a mixed venous blood gas on a person breathing room air are:
PvO2 of 40mmHg
PvC02 of 45mmHg
Sa02 of 75%.
These values typically correspond to a Venous 02 content of 15mls/decilitre for normal ranges of Hb in the blood.
Arterial values are:
PaO2 of 100mmHg
PaC02 of 40mmHg
Sa02 of 97.5%
Relationship between PO2 and O2 content in mixed venous blood:
P02s relationship with O2 content dependent on shape of Hb02 dissociation curve.
2 important characteristics of the curve are the flat upper part and steep lower part. The former tends to buffer Haemoglobin saturation against a substantial drop in P02 which is useful in the lungs to maintain arterial Hb saturation. The latter helps with large 02 unloading and a maintained 02 diffusion gradient from the blood to the tissues.
Right shifted Hb02 decreases Hb’s affinity for 02 and increases the amount dissolved i.e. P02 – factors which right shift are decrease in pH, increase in C02, and increase in temperature and increase in 2,3 DPG levels.
FICK equation:
Modification of the FICK equation:
VO2 = (CaO2 - CvO2).Q
gives
Cv02 = Ca02 – V02/Q
which demonstrates the inverse relationship between oxygen extraction by tissues and the cardiac output. If cardiac output decreases, oxygen extraction by the tissues increases, causing mixed venous 02 concentration to fall. This fall in concentration causes a decrease in mixed venous Pv02.
Cv02 is directly proportional to Ca02. However, clinically, this factor is not as important as the level of cardiac output. This is because relatively large increases in partial pressure of oxygen (eg hyperbaric) are required to substantially increase the 02 content of arterial blood above 20ml/dl as Hb is near fully saturated at a Pa02 of 100mmHg and any additional increase in partial pressure contributes a relatively miniscule 0.003mls of 02/mmHg/ml of blood.
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Physiol-99A3 Describe the factors that affect the transport of oxygen and carbon dioxide form the alveolus to the blood. 44%
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Factors affecting gas transport from alveolus to blood
Fick's Law of diffusion
Applied to the lung
Solubility of gases and molecular weights
CO
-recruitment
-maintains gradient
Perfusion vs diffusion limitation
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Physiol-96B8 Briefly explain how an oxygen debt arises and how the body deals with it 75%
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Oxygen Debt is the extra oxygen required to restore the body to a resting state after strenuous exercise. These include: replenishment of fuel stores, cellular repair, innervation, and anabolism.
-effect is greatest soon after the exercise
-decays to a lesser level over time
-may last 16 hours
Exercise causes
1. Increased muscle blood flow via metabolic autoregulation (increasing supply to meet demands) increased O2 extraction (ODC to right) and increased O2 delivery (increased CO and local flow)
2. depletion of ATP and phosphcreatinine stores: only enough for a couple of sprints, therefore more ATP needs to be produced
3. Glycolysis, glycogenolysis and aerobic metabolism (oxidative phosporylation) produced more ATP
4. Rapid depletion of gylcogen stores (400g in muscle, 100g liver)
5. If aerobic threshold is passed, then anaerobic metabolism will supplement (less efficient, only 2 ATP per glucose, cf 36 ATP of aerobic), glycolysis :glucose to pyruvate to lactate (to replenish NAD+), no O2 for further oxidative phosporylation. Lactic load.
6. If exercise is strenuous enough can result in muscle damage
Ultimately, after exercise has stopped : extra oxygen required to
1. restore ATP and phosphocreatinine in muscles 2-5 minutes
2. restore oxygen-myoglobin stores
3. restore oxygen haemoglobin stores, dissolved stores
4. restore glycogen stores 2-3 hours
5. lactic acid metabolized by liver : anabolism back to glucose or glycogen or catabolised to HCO3-, or to CO2 and water
6. repair any damaged tissue, hours to days
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Physiol-96A1 List the normal values for mixed venous blood gases and briefly explain the factors determining mixed venous oxygen tension.
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Mixed venous blood: True mixed venous blood must be obtained from a pulmonary artery catheter where blood from SVC, IVC and coronary sinus have fully mixed. Systemic blood, returning from the all tissues, is collected and mixed in the right ventricle and pulmonary artery. Thus, mixed venous pO2 and pCO2 reflect O2 extraction and CO2 addition from the entire body.
Typical values for a mixed venous blood gas on a person breathing room air are:
PvO2 of 40mmHg
PvC02 of 45mmHg
Sa02 of 75%.
These values typically correspond to a Venous 02 content of 15mls/decilitre for normal ranges of Hb in the blood.
Arterial values are:
PaO2 of 100mmHg
PaC02 of 40mmHg
Sa02 of 97.5%
Relationship between PO2 and O2 content in mixed venous blood:
P02s relationship with O2 content dependent on shape of Hb02 dissociation curve.
2 important characteristics of the curve are the flat upper part and steep lower part. The former tends to buffer Haemoglobin saturation against a substantial drop in P02 which is useful in the lungs to maintain arterial Hb saturation. The latter helps with large 02 unloading and a maintained 02 diffusion gradient from the blood to the tissues.
Right shifted Hb02 decreases Hb’s affinity for 02 and increases the amount dissolved i.e. P02 – factors which right shift are decrease in pH, increase in C02, and increase in temperature and increase in 2,3 DPG levels.
FICK equation:
Modification of the FICK equation:
VO2 = (CaO2 - CvO2).Q
gives
Cv02 = Ca02 – V02/Q
which demonstrates the inverse relationship between oxygen extraction by tissues and the cardiac output. If cardiac output decreases, oxygen extraction by the tissues increases, causing mixed venous 02 concentration to fall. This fall in concentration causes a decrease in mixed venous Pv02.
Cv02 is directly proportional to Ca02. However, clinically, this factor is not as important as the level of cardiac output. This is because relatively large increases in partial pressure of oxygen (eg hyperbaric) are required to substantially increase the 02 content of arterial blood above 20ml/dl as Hb is near fully saturated at a Pa02 of 100mmHg and any additional increase in partial pressure contributes a relatively miniscule 0.003mls of 02/mmHg/ml of blood.
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Physiol-07B11 Explain the principles of ultrasound used in medical imaging.
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Definitions
Ultrasound is sound waves of frequency 2.5 to 7.5 MHz, and ultrasonography is an ultrasound-based medical diagnostic imaging technique. The best example of ultrasound imaging in Anaesthesia is Echocardiography, as it demonstrates all the useful modalities of ultrasound imaging. Choice of frequencies is not arbitrary; rather it is a trade-off between resolution (improved with higher frequencies) and depth of tissue penetration (improved at lower frequencies). The range of 2.5-7.5 MHz allows about 25cm penetration and resolution of objects 1mm in size.
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Physics Sound waves
1. Sound waves are made of high pressure and low pressure pulses traveling through a medium. The high pressure areas (compression) are where the particles have been squeezed together; the low pressure areas (rarefaction) are where the particles have been spread apart. [1] (http://www.physics247.com/physics-tutorial/ultrasound-physics.shtml). Ultrasound is sound higher than is audible by humans (20 KHz) although in practice it refers to frequency greater than 1 MHz. As all waves, it follows the relationship v=f λ (velocity is the product of frequency and wavelength).
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Principles of Ultrasound generation
1. The piezoelectric effect is a form of electromechanical coupling that can be elicited from some material (ceramics, crystals). The direct effect is the production of electricity when a stress is applied to a material and the converse effect is the production of stress when an electrical potential is applied. The converse piezoelectric effect is the source of sound waves from the ultrasound probe. The probe contains an array of piezoelectric crystals (to allow 2D imaging).
2. The pulsed sound wave propagates through the body in the direction of orientation of the probe, and will encounter tissues of different densities, which will have different acoustic impedance. When a sound wave encounters a material of different acoustic impedence, there will the reflection (and refraction). It is the reflected wave that is used to contruct the image. Energy is lost when there is reflection and refraction, but most of the attenuation of the sound wave is due to acoustic impedance. (Acoustic Impedance, the ratio of Acoustic Pressure to Acoustic Flow, is analogous to electrical impedance - the resistance to flow of an alternating current, and is proportional to tissue density). (A definition if asked : "Attenuation is loss of energy, expressed as change in intensity, as the energy travels through a medium. Rate of attenuation is called attenuation coefficient. For soft tissue, the attenuation coefficient is half the frequency per cm.")
3. The reflected wave is used to construct an image. However, there will be a latency; a time taken for the wave to travel to the tissue interface to be reflected and travel back. Additionally, there is the assumption made that the wave velocity is constant (1500m/s)(which is of course incorrect, the velocity of sound is different in different tissues).
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Modes
1. A Mode: a single transducer emits a wave and the reflection is displayed as a function of depth. Not used diagnostically, but maybe therapeutically.
2. B Mode: ultrasound from a linear array transducer allows construction of a 2-D image.
3. M-mode: M for "motion". Used to view rapidly moving structures as a linear array transducer can produce 30 images per second allowing assessment of, for example, valve movement in real time.
4. Pulsed-wave doppler: Used to measure blood flow velocity. A small area is defined on the 2D scan and the velocities of the blood in that area is displayed. It uses the Doppler effect, that the reflected wave from a moving object will have a different wavelength (hence frequency) to the incident wave, and the change in frequency (doppler shift) will be proportional to the velocity of the object. The Doppler Eqn is : V=(Fd * C) / (2 * F0 * cos θ) where V is the velocity to be measured, Fd is the measured change in frequency, C is the speed of sound in the tissue (assumed 1500 m/s), and F0 is the frequency of the transducer (ref Miller). θ is the angle between the beam and the direction of movement of the blood, if the same direction the cosine (0) will be one, and so give and accurate result. If θ is greater than 20 degrees there will be significant error. If combined with a measure of aortic root area as well as aortic root flow velocity, could be used to calculate cardiac output I guess.
5. Continuous-Wave Doppler: an extention of PW Doppler; two crystals, one to emit and one to receive continuously. See Miller for explanation.
6. Color Doppler: application of color to the image to indicate whether the flow is towards (red) or away "blue" from the transducer - is only a qualitative technique, but can show direction of blood flow across a valve or VSD. (Confusing terminology, considering "red-shift" usually refers to an object, like a quasar, moving away from you).
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Physiol-08B9 what is humidity and how can it be measured?
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Absolute humidity
The absolute amount of water vapour in a gas expressed in either mg/L of gas mixture or mmHg (partial pressure).
Relative humidity
Amount of water vapour in a gas expressed as a percentage of that which could be held by the gas if it were fully saturated at the same temperature, i.e.
R.H. = Actual Water Content / Water Content Fully Saturated %, or
R.H. = Actual Vapour Pressure / Saturated Vapour Pressure %
MEASUREMENT OF HUMIDITY
Wet and dry bulb hygrometer
A system using two thermometers, one with a wet and the other a dry bulb. Air movement over the wet bulb causes evaporative cooling, generating a difference in temperature readings. This difference relates to the rate of airflow over the wet bulb and the relative humidity. Tables are used to look up the relative humidity from the two temperatures.
Regnault’s (dewpoint) hygrometer
Using a precisely cooled shiny plate, the user observes the temperature at which condensation first occurs. At this temperature, the gas is fully saturated with water, hence both the water content and the relative humidity at any other temperature can be ascertained from a vapour pressure table.
Mass spectroscopy
Mass spectroscopy can be very accurate but only if condensation does not occur in the sample line. This is the best technique for assessing "in-circuit" humidity, as it can assess breath by breath changes.
Humidity transducers
Transducers are available in which the electrical conductivity of a membrane changes with water vapour pressure.
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Physiol-07B16 Draw the ECG depicting one cardiac cycle for lead II. Label diagram and give normal values. What is the PR interval and what factors can affect this?
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The answer to this question should include:
1. A diagram of a typical lead 2 ECG trace, with axes, and labels on P, QRS, and T waves, PR and QT intervals, and ST segments.
2. Quantification of the normal values of duration of PR, QRS and QT interval.
3. Definition and explanation of the significance of the PR interval – in particular the importance of the AV node.
4. A list of factors that increased or decreased the PR interval – autonomic system, cardiac abnormalities/disease (WPW, ischaemia), drugs, other physiological derangements (hypothermia, hypokalemia)
Additional marks were given for detailed description of cellular mechanisms of changes in the PR interval and an outline of the allowable normal deviation from isoelectric values of the ST segment, and size of the Q wave.
Common mistakes made by the candidates included:
1. Inability to quantify the time intervals. These values are essential to the clinical interpretation of the ECG for the rest of an anaesthetist’s career.
2. Confusion of milliseconds with seconds was very common.
3. The PR interval was not accurately described – it is from the start of the P wave to the start of the QRS complex (which is usually the Q wave, not the R wave).
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Physiol-07A15 Describe the effects of resonance and damping on an invasive arterial blood pressure tracing. 21%
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* Some attempt at a definition of the concepts
* Evidence of understanding that the system’s f0 needs to be several fold the frequency of the pulse and the consequences for the pressure waveform of not being so
* Means whereby the f0 of the system can be maximised
* Effects of under, over and optimal damping on the arterial pressure waveform
* Causes of damping in the system
Marks were awarded for other information, including that the measured MAP tends not to be affected by resonance and inappropriate damping; clear diagrams explaining the waveform changes; correct explanation of damping co-efficients and the meaning of the term, especially if a correct diagram of the response to a step change in pressure was included; that the transducers used today have high natural resonant frequency but the other components of the measuring system are the main cause of low f0 in the system; correct use of an equation relating f0 to mass, elasticity and area and especially if this could then be related to practical means of increasing f0 in the measuring system; difference between optimal and critical damping.
Common problems in the answers were:
* Very few answers included a good attempt at defining the concepts especially damping (delay in response due to frictional resistance, or similar)
* Discussion of resonance and damping without any attempt at describing the effects on an arterial waveform (at least half the candidates)
* Wasting time with long descriptions of the components of the measuring system or of zeroing or of indications for arterial line placement. Zeroing is irrelevant to the question;
* Quoting figures for damping coefficients with no evidence of any understanding of the meaning of the term
* Using vague terms like “interfere with the trace” with no mention of in what way;
* Stating that damping is used or added to the transducer in order to combat resonance-damping and resonance are features of any oscillating system and the measuring systems used must in some way optimise these inherent features;
* Those candidates who attempted a diagram demonstrating response to a step change in pressure in various damping situations were often wrong
* Several dozen answers compared the radial and aortic pressure traces and described the differences in terms of resonance and damping in the arterial tree. When this information was correct, marks were given but it was not possible to get a pass mark for this information only.
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Physiol-06B12 Explain the difference between viscosity and density. Outline the effects of changes in viscosity and density on the flow of gases and liquids. 47%
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Viscosity is a measure of the resistance of a fluid which is being deformed by either shear stress or extensional stress. The study of viscosity is known as rheology.
Water has a lower viscocity than honey. SI unit is pascal.second (equal to kg/m/s)
Gases
* Viscosity is independent of pressure and
* Viscosity increases as temperature increases.
Liquids
* Viscosity is independent of pressure (except at very high pressure); and
* Viscosity tends to fall as temperature increases
The density of a material is defined as its mass per unit volume. SI unit is kg/m^3 (1 kg/L = 1 kg/dm³ = 1 g/cm³ = 1 g/mL). In general density can be changed by changing either the pressure or the temperature. Increasing the pressure will always increase the density of a material. Increasing the temperature generally decreases the density
Helium and Oxygen has same viscocity but helium is less dense.
Effect of laminar flow
Hagen Pousille Equation
Flow= dP.pi.r^4/8nl
ie : flow is inversely proportion to viscocity
Laminar verus turbulent flow
Re=pVD/n
p is density
V velocity
D diameter
n viscocity
Re>3000 turbulent
Re<2000 laminar
The second part of this question should have included discussion on how both viscosity and density effect laminar and turbulent flow. The effects of viscosity on laminar flow, the Hagen- Poiseuille equation and the Reynold’s number were well described by most candidates. Common omissions were; comment on the effect of density on laminar flow, and comment on the effect of changing viscosity on turbulent flow. A common mistake was to state that turbulent flow was directly (rather than inversely) related to density. Many candidates gave detailed descriptions of the characteristics of laminar and turbulent flow that did not pertain to either viscosity or density and therefore did not attract any marks.
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Physiol-06A15 Briefly describe the measurement of pH in a blood sample using a pH electrode. 49%
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For a pass, the answer needed to include a description of the apparatus used, including the presence of pH sensitive glass, two reference electrodes Ag/AgCl and the same, or calomel (Hg/HgCl;) although more modem machines do not use the calomel electrode, a salt bridge to complete the circuit, connecting the calomel or 2'ld Ag/AgCl electrode to the test solution., a buffer solution separated from the sample by pH sensitive glass. The only variable in the circuit, given constant temperature, is the difference in pH between the buffer and sample. The electrode potential depends on the Hydrogen ion activity, so the voltage measured m the circuit is proportional to pH. There is a need to calibrate against two known pH Phosphate solutions, and the system must be temperature controlled to 37C. The device is an example of an ion-sensitive electrode.
A clearly-labeled diagram was a great help, and although not required for a pass, most of the better answers did include one. In the absence of a diagram, a very clear description was required. Some answers unfortunately had a diagram at odds with the text, making it very difficult to assess understanding.
Better answers included detail about how the glass is pH-sensitive, why saturated KCl is used as the salt bridge, a correct definition of pH, and additional information about minimization of error. Lengthy discussion of CO; control in hypothermia gained little and usually left minimal information that actually answered the question.
Answers which described the Clarke or Severinghaus electrodes gained no marks. Many answers included a reasonable diagram but text that inferred a very poor understanding of what was drawn. The concept of an electrical circuit was absent in most answers that failed. Several dozen answers defined pH incorrectly, as a variable in the Henderson-Hasselbalch equation. No candidate mentioned solid-state ion-sensitive field-effect transistors which have been used in pH measurement for 10 or more years.
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Physiol-05A16 Briefly explain the principles of Doppler ultrasound used to measure cardiac output.
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Ultrasound-Based Methods for Cardiac Output Monitoring
The popularity and safety of diagnostic Doppler echocardiography in clinical medicine have driven the application of these techniques for measurement of cardiac output. All of the ultrasound-based methods for cardiac output monitoring use the Doppler principle. When ultrasound waves strike moving objects, these waves are reflected back to their source at a different frequency, termed the Doppler shift frequency, that is directly related to the velocity of the moving objects and the angle at which the ultrasound beam strikes these objects. For blood flow measurements, the red blood cells flowing through a major artery serve as the moving objects targeted by the ultrasound beam. The Doppler equation describes these relationships (Equation 10). To measure blood flow velocity, this equation is rearranged to solve for velocity (Equation 11).
10
F_d = \frac{2 F_t V \cos\theta}{C}
where
Fd = frequency shift
Ft = transimitted freqeuncy
V = velocity of flow
cosθ = cosine of the angle of transmitted freqeuncy to flow (normally assumed to be 1)
C = velocity of sound through medium (normally assumed to be approx 1560 metres/s)
11
v=f.c/2.f0.cosQ
where f = Doppler shift frequency
v = velocity of red blood cell targets
f0 = transmitted ultrasound beam frequency
theta = angle between the ultrasound beam and the vector of red blood cell flow
c = velocity of ultrasound in blood (approximately 1570 m/sec)
In general, measurement of blood flow velocity requires just a single measurement, the Doppler shift frequency, because the velocity of ultrasound in blood and the transmitted ultrasound frequency are known, and cosine theta is assumed to equal 1 as long as the angle of insonation is small. This assumption requires that the ultrasound beam be oriented as much as possible in a direction that is parallel to blood flow. For example, for angles less than 20 degrees, cosine theta will be greater than 0.94, thereby introducing an error of less than 6% in the cardiac output calculation. Once the Doppler shift frequency is measured and blood flow velocity is calculated, stroke volume can be determined from Equation 12.
SV = v · ET · CSA (12)
where SV = stroke volume (mL)
v = spatial average velocity of blood flow (cm/sec)
ET = systolic ejection time (sec)
CSA = cross-sectional area of the vessel (cm2 )
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Physiol-04B11 Briefly explain how oximetry can be used to estimate the partial pressure of oxygen in a blood sample. 31%
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Comments
- Oximetry utilises spectrophotometry to calculate haemoglobin saturation (not oxygen partial pressure).
- calculates haemoglobin saturation by transmitting radiation of a particular frequency through a sample of substance. Amt of substance is calculated from amt of absorption of radiation.
- Beer’s Law- absorption of radiation by a given thickness of solution of given concentration, is the same as that of a solution of twice the thickness but half the concentration.
- Lambert’s Law- a layer of equal thickness absorbs an equal fraction of radiation which passes through it.
- oximetry for haemoglobin saturation generally uses at least two frequencies- red light (wavelength 660nm) and infrared light (940nm)- absorptions for oxy and deoxyhaemoglobin are different at both these frequencies (oxy absorbs less red light hence looks redder; deoxy absorbs more infrared).
- although at other frequencies, the absorption for oxy and deoxyhaemoglobin is the same (eg at around 800nm and 600nm- these are isobestic points).
- other forms of haemoglobin include carboxyhaemoglobin and methaemoglobin- these have different patterns of absorption of radiation.
- oximetry which is limited to red and infrared wavelengths will not take these other forms of Hb into account, and may give false readings, eg methaemoglobinaemia typically reads around 85%, and carboxyhaemoglobin is read as oxyhaemoglobin so falsely high reading.
- partial pressure of oxygen in blood is related to haemoglobin saturation as described by the oxygen-haemoglobin dissociation curve.
- standard values are: 0% saturation at 0mmHg, 10% saturation at 10mmHg, 50% saturation at 27mmHg (P50), 75% saturation at 40mmHg (mixed venous blood), 91% saturation at 60mmHg (the ICU point), 97% saturation at 100mmHg (normal arterial value), 99% saturation at 150mmHg.
- the position of the dissociation curve changes with certain variables however- eg it shifts to the right with increased temperature, increased pCO2, increased H+, and increased red cell 2,3 DPG. It shifts left with the opposite changes.
- the oxygen dissociation curve is also different for different types of haemoglobin, eg foetal haemoglobin has a dissociation curve shifted up to the left of that of adult haemoglobin (because of decreased affinity for 2,3 DPG).
- while it is possible to estimate partial pressure of oxygen in a blood sample from haemoglobin saturation, it is inaccurate for the above reasons, and particularly inaccurate when haemoglobin is fully saturated, because the partial pressure could be anything equal to or greater than the minimum partial pressure required for full haemoglobin saturation.
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Physiol-03A13 Briefly describe the principles and sources of error in the measurement of systemic arterial blood pressure using an automated oscillometric non-invasive monitor. 81%
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This question was passed by 81% of candidates.
Most candidates demonstrated a good understanding of the principles of the device and the strengths and weaknesses in detection of systolic, diastolic and mean pressures.
Some candidates presented their answer as if this device was synonymous with a particular brand. It is very reasonable to present the specifications of a particular brand as an example of such a device but not to imply that there is only one type.
Some descriptions of the equipment were problematic.
The concept of the bladder within the cuff was often not clear and lead to confusion about describing the positioning and size of the bladder. Descriptions of the recommended dimensions of the cuff (and bladder) often did not specify whether length or width were being presented.
There were some instances of confusion between historical two tube and two cuff equipment (particularly oscillotonometry cf oscillometry) and current single cuff and tube equipment. Occasional candidates also confused detection of oscillations with detection of Korotkoff sounds. Modern oscillometry devices have the transducer in the control box not in the cuff.
Formulas presented for calculating the diastolic pressure were often presented as variations of Mean Arterial Pressure = Diastolic Arterial Pressure + 1/3 pulse pressure. These were usually technically correct but would be better presented as Diastolic Arterial Pressure = a formula related to directly measured parameters (or other algorithm related to change in percentage size of oscillations detected).
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Physiol-04A14 Briefly describe the differences between laminar and turbulent flow. List the factors that increase the probability of turbulent flow. 70%
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70% of candidates passed this question.
The question most naturally fell into three areas:
* A description (and diagrams) of the nature of laminar and turbulent flow and the significance this might have for passage of fluid through a tube.
* A description of the different ways that laminar and turbulent flow are related to pressure, radius and length of tubing, viscosity and density. These were usually summarized by equations (+/- graphs) with interpretation.
* A description of how diameter, velocity, density and viscosity can be used to predict the likelihood of turbulent flow, as summarized by the Reynold's number. This section should also include mention of the geometry of the tube potentially affecting the nature of the flow as the Reynold's number is for parallel-sided cylindrical tubing. Concepts of critical velocity, entrance length and transitional or mixed flow types could also reasonably be included.
There were two main areas which created problems with understanding.
* The relationship of turbulent flow to driving pressure, tube length and density was often poorly described even when an acceptable equation was quoted. The "meaning" of the equation was often not understood and commonly misrepresented in graphical form. Most of the confusion arose from difficulties dealing with the flow tending to vary with the square root of pressure and radius to a power of 2 to 2.5 (i.e. the square root of the power 4 or 5) depending on which source was quoted. If these equations are written as "driving pressure is proportional to": then flow will be squared and radius to the 4th or 5th power. The fact that turbulent flow can not be described by a simple equation and will vary with the degree of turbulence means that the study sources will have slightly differing summaries of the relationships. These were all acceptable.
* Although the Reynold's number can be incorporated into complex equations for predicting rate of flow, for the purposes of this question the relevant property of the Reynold's number was its ability to predict the likelihood of turbulence. This needed to be distinguished from equations for estimating flow rates such as the Hagen Poiseuille for laminar flow or the Fanning for turbulent flow. Some candidates tried to apply the Reynold's number equation to describe factors affecting rate of turbulent flow rather than likelihood of turbulent flow. This resulted in major errors in describing the factors affecting rate of turbulent flow.
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Physiol-02A7 Outline the principles of a pneumotachograph. What factors affect the accuracy of this device? 44%
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* pneumotachographs are used to measure gas flow and sometimes volume in lung ventilation.
* Poiseuille's Law states that, under capillary conditions, in a straight rigid tube, delivery is proportional to pressure loss per unit of length.
* Q = pi r4 (P1-P2) / 8 eta l
where Q is gas flow, r is radius, eta is viscosity, and l is length.
A pneumotachograph consists of a gauze screen with a diameter large enough to ensure laminar flow through the gauze. The gauze acts as a resistance to flow, so respiratory airflow from the patient causes a small pressure drop (1-2cmH2O) across the gauze. The pressure change is measured by a transducer which converts the pressure change into an electrical signal which can be displayed and recorded.
Factors which affect accuracy include temperature, type of gas (different viscosities), turbulence (because Poiseuille's Law relates to laminar rather than turbulent flow), condensation onto the gauze of the pneumotachograph.
Laminar flow depends on fluid viscosity; turbulent flow depends on density.
Because of effect of chg of temp and humidity, some pneumotachograph heads are maintained at a constant temperature by a heating element- prevents changes in temp affecting accuracy, and also prevents water vapour condensation on gauze.
Because high flows (higher than the device is designed for) lead to turbulence, a variety of sizes are available for different flow rates (eg different sizes for adults and kids)
If flow is too low, the pressure drop across the gauze will be too small for the transducer to detect.
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Physiol-00A1 Explain how cardiac output is measured using a thermodilution technique 50%
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Thermodilution
1. An Indicator Dilution method using Fick's Law, where the indicator is "cold".
2. Cold water injected down Pulmonary Artery Catheter.
3. Thermistor on the end measures temperature change.
4. Flow rate (CO) is the Amount of Indicator injected divided by the AUC.
5. Sterwart-Hamilton Equation provides approximation, but makes assumptions.
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Limits
1. Assumes constant flow.
2. Assumes structurally normal heart (eg. normal valves)
3. Measures global function; no information on regional abnormalities.
4. When measuring preload it cannot differentiate between a change in LV Compliance and a change in LVEDV.
5. Risk of injury on insertion / flotation of PAC.
6. Minimal evidence of improved mortality with use of PAC to guide therapy.
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Alternative Techniques
1. MRI with velocity encoded phase contrast
2. Dye Dilution (indiocyanine)
3. Doppler
4. PICCO
Ref: http://www.manbit.com/PAC/chapters/PAC.cfm http://www.frca.co.uk/article.aspx?articleid=251
Fick Principle:
\dot{Q} = \frac{\dot{V_{O2}}}{Ca_{O2}-Cv_{O2}}
Simple version of Stewart Hamilton Equation:
\dot{Q} = \frac{Mass \ added}{\int_0^{\infty} C(t)dt}
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Physiol-99B7 Describe how the partial pressure of oxygen in a blood sample is measured using a Clark electrode. 28%
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Comments
* Partial pressure: pressure a gas would exert if it alone occupied a space.
* blood gas analysers allow measurement of the O2 tension in blood using the clark electrode (also called polarographic electrode).
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Principle
* draw diagram from Davis & Kenny 5th edition, p 204
* uses platinum wire as a cathode, kept in glass rod.
* silver wire is the anode, kept in AgCl gel.
* the 2 electrodes are held in a KCl electrolyte solution
* whole cell is wrapped in a plastic membrane, permeable to gases but not liquids or solids.
* a 0.6V polarising voltage is supplied to the electrodes-
AT ANODE: Ag reacts with KCl creating AgCl and free electrons,
AT CATHODE: O2 combines with electrons and water (O2 + 4e +2H2O makes 4(OH)-
* A CURRENT FLOWS WHICH IS DEPENDENT ON OXYGEN TENSION
* electrode is kept at 37 degrees.
* has accuracy of +/- 2 mmHg
* calibration occurs via use of standardised gas mixtures.
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Equipment
* draw diagram from Davis & Kenny 5th edition, p205
* membrane is required because if electrode contacts blood, protein deposits form and affect function.
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Problems & limitations
* O2 electrode must be clean/ uncontaminated.
* plastic membrane must be intact.
* blood sample must be taken anaerobically and heparinised.
* analysis must be prompt as O2 falls with time, especially at room temp due to O2 consumption by cells, ice storage of samle helps to slow this).
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Physiol-99A5 Differentiate between the terms ‘heat’ and ‘temperature’. Explain briefly the principles of a mercury thermometer, indicating its advantages and disadvantages. 82%
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Heat is a unit of energy, therefore measured in joules, it is the kinetic energy of the molecules in the a substance "vibration". It may be transferred from one body to another down a temperature gradient. And converted to other forms of energy : mechanical (movement), chemical (glucose).
Temperature is the thermal state of a substance which determines direction of transfer of heat. From hotter to colder. If no flow occurs, they are the same temperature. Measured in Kelvin, 1/273.16 is the thermodynamic temperature of the triple point of water (it exists as a sold, liquid and gas in equilibruim)
K=degC+273.15, triple point of water occurs a 0.01degC
The two are related in specific heat capacity. Measure of the heat energy required to increase the temperature of a kg of substance by one degree from 15degC to 16degC. Joules/kg/degree
Mercury thermometer is a non electric temperature measurement techinique.
Utilised change in volume with change in temperature.
Bulb filled with mercury
Long collumn, height is calibated using know tempertures
0degC melting pure ice
100degC boiling water
divide into 100 equal parts
Advantages
-easy to use
-portable
-reusable
-accurate and reproducable
Disadvantages
-slow 2-3 minutes to equilibrate
-injury :
inserted into orifices eg. rectum : perforation; breaking glass : lacerations; mercury spillage : poisoning
-hygiene
-
Other methods of temperature
1. alcohol thermometer
2. Bourdon gauge (bimetalic strip)
3. Electrical : resistance thermoemeter, thermistor, thermocouple
82% of candidates passed this question. Most passed well and there were a number of very good answers. There was a reasonable amount of confusion about the difference between Heat and Temperature. Mentioning S.I. units and relating the entities via Specific Heat Capacity enhanced definitions and gained extra marks. Most candidates gave a reasonable explanation of the physical principles of the mercury thermometer, although many omitted calibration principles and did not mention the importance of the relative volumes of the Mercury Reservoir in the bulb and the capillary column. It is also critical that the capillary tube is evacuated.
The concept of a time constant was often mentioned but also often misunderstood. In general, advantages and disadvantages were well done with a number of candidates having prepared exemplary lists.
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Physiol-99B1 How does a fall in temperature influence blood gas solubility and acid base values? 28%
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1999
28% of candidates passed this question. This question was asked in the March/April examination in 1998, and most of the Examiner's comments from that time apply to this 1999 exam. When temperature is lowered, the solubility of a gas in a liquid increases, since the decreased kinetic energy of the gas particles reduces the partial pressure exerted by a given amount of the gas in the solution. When in equilibrium with a liquid/gas interface, a larger amount of gas will be dissolved at a lower temperature, hence the solubility is greater. Henry's Law defines the proportional relationship of amount of gas in solution, to its partial pressure. The solubility coefficient is inversely proportional to temperature (Ostwald) or defined at a fixed temperature (Bunsen). There was considerable confusion about the basic physical principles involved, in particular concerning Henry's Law. Effects of temperature on haemoglobin/oxygen affinity were also mentioned, and were generally well understood by candidates.
pH increases as temperature falls, due to decreased ionic disassociation. The increase in pH in blood follows closely the change seen in neutral water. Decreased temperature also affects pH, which was generally overlooked by candidates when attempting to apply the Henderson-Hasselbach equation to explain this effect. Alpha-stat and pH-stat strategies of blood gas interpretation were again often misunderstood.
Candidates need to remember that this is primarily an examination of physical and physiological principles, often in the context of patient management, rather than of pathophysiology.
Refer to Nunn, Blitt & Hines, and Scurr & Feldman.
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1998
Overall the question was poorly answered, with only 21% passing. There were few good answers. A lowering of temperature decreases kinetic energy of molecules in a liquid. This will decrease the movement of gas molecules from a solvent and thus increase solubility. Partial pressures will decrease as stated by Henry’s Law.
Ionic dissociation will be decreased, with less formation of hydrogen ions and relative anions. pH will increase. pH and pK are temperature dependent. These physical principles were understood by less than a quarter of candidates.
The wording of the question allowed a number of approaches. Most candidates described the effects of hypothermia on values of arterial blood gases and acid base values. Clinical experience of blood gas results obtained from hypothermic patients obviously influenced many of these answers. The effects of anaesthesia and the patients pathology may have more significant effects on these results than hypothermia. This makes deducing the basic principles from these results difficult. Knowledge of the basic principles is necessary to interpret results in a clinical context.
The common errors included:
* Lack of knowledge or misunderstanding of the physical principles
* Confusing content/partial pressure/solubility
* Misuse of the Henderson-Hasselbach equation. CO2 and H2CO3 are not identical in this equation
* Misquoting Henry’s Law
* Confusing solution of a gas in a solvent, and its escape from solution, with change of a substance from its gaseous to liquid form, and the reverse
* When mentioned, pH-stat and alpha-stat strategies of interpreting blood gas results were usually wrongly described and misunderstood.
* Irrelevant descriptions of the general physiological effects of hypothermia without correctly relating them to the question.
* The information required is in the relevant chapters of Nunn, Miller and Blitt and Hines.
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Physiol-07B13 What are the physiological reasons making it safe to give O negative blood to patients.
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The aim of blood transfusion is usually to increase the oxygen carrying capacity of the blood. It achieves this through increasing the amount of haemoglobin by increasing the number of red blood cells (RBCs). Before the discovery of blood groups, recipient's of blood transfusions would often have a "transfusion reaction" where there would be distruction of the donor RBCs and haemolysis. This would most often occur over several days but would occasionally occur over a few hours.
There are many genetically coded antigens displayed on the surface of RBCs. The most important groups that potentially cause transfusion reactions are the ABO and the Rhesus groups of antigens.
ABO
Antigenetic carbohydrate chains which are displayed on the surface of the RBC.
A and B antigens are derived from a parent "H" carbohydrate chain that is not antigenetic.
Antigen expression is associated with tolerance and antibodies are formed to the antigens that are not displayed. This occurs in the first decade of life (probable exposure to the antigen in food and/or bacteria).
People fall into four ABO blood types...
O - (most common) - neither A nor B antigen displayed, Antibodies to both A and B develop during first decade of life (universal donor)
A - (next most common) - A antigen dislpayed, antibodies to B develop in first decade
B - (uncommon) B antigen displayed, antibodies to A develop in first decade
AB - (rare) Both A and B antigens displayed, no antibodies to A or B develop (universal recipient)
Therefore donor blood must not contain antigens for which the recipient has antibodies. ie Blood group B can recieve blood that is B or O but not A nor AB. If antibodies to the donor blood are present, they will cause the donor RBCs to clump together (agglutination) and eventually burst (haemolysis).
Note that the donor blood could contain antibodies for the recipient's blood (eg O blood to B recipient - O blood will have B antibodies). This has the potential to cause a reaction against the recipient's blood. This "graft vs host" reaction is avoided by giving a transfusion of packed red blood cells rather than whole blood.
Rhesus (Rh)
A different group of antigens displayed on the RBC surface.
C, D, E, c, d or e "rhesus factors"
Rhesus Positive blood is blood which displays the "D" antigen, this is the most antigenic.
Patients with Rhesus negative blood do not spontaneously form antibodies to the D antigen unless they are exposed to Rhesus positive blood.
A reaction to Rh positive blood is usually a delayed reaction taking days - initially an IgM response
There are other antigens which are displayed on the RBC surface which can cause possible reactions (approx 30 identified). However, the ones apart from ABO and Rh tend to be minor and cause mild reactions only.
O negative blood is the universal donor and can usually be safely transfused to patients of any blood type because it does not display the A, B, or Rh (D) antigens. Therefore there is no immune response by the host to the donor blood.
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Physiol-07A10 Explain the mechanisms that prevent blood clotting in intact blood vessels (do not draw the clotting cascade). 57%
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Haemostasis: physiological mechanisms which prevent blood loss from damaged vessels, yet allow blood to remain fluid in the circulation.
Haemostasis is a fine balance between the procoagulant systems and anticoagulant systems present in the body.
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Four main features that prevent blood clotting in intact vessels:
1. endothelial factors: no collagen or tissue thromboplastin exposure, glycocalyx, prostacyclin, nitric oxide, thrombomodulin, heparin sulphate, smooth surface.
2. blood flow
3. coagulation factors inactive state
4. inhibitory systems: antithrombin III, thrombomodulin system (protein C, protein S), extrinsic pathway inhibitor, fibrinolytic system.
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Endothelial factors
* Without vessel damage there is no collagen exposure and no binding of vWF, hence platelet adhesion is not stimulated.
* Without vessel damage there is no exposure of tissue thromboplastin exposure and therefore no activation of the extrinsic clotting cascade.
* Vessels has a mucopolysaccharide coating called the glycocalyx which repels platelets and clotting factors.
* Nitric oxide causes platelet inhibition and local vasodilation.
* Thrombomodulin production by the endothelial cells causes activation of the protein C system, which leads to fibrin lysis.
* Heparin sulphate is a natural heparin present in endothelial cells and enhances the activity of antithrombin III up to a thousand fold.
* Smooth surface of the endothelium minimises contact activation of the intrinsic system and encourages smooth blood flow to prevent stasis.
* Endothelial cells produce
1. prostacyclin, which causes vasodilation and inhibits platelet aggregation
2. antithrombin and protein C activator (thrombomodulin), both of which inhibit coagulation
3. tissue plasminogen activator which activates fibrinolysis
[edit]
Blood flow
* Flow dilutes and removes activated clotting factors which are later inactivated by the RAS.
* Laminar flow causes axial streaming of platelets and minimises endothelial contact and hence platelet activation and intrinsic system activation.
[edit]
Inactive coagulation factors
Coagulation factors circulate in an inactive state and conversion to the active form is unusual in intact vessels.
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Intrinsic inhibitory systems
In general there is a higher concentration of natural anticoagulants compared to procoagulants. These include
1. Antithrombin III: a circulating protease inhibitor that binds to proteases in the coagulation system blocking their activity as clotting factors. This binding is facilitated by heparin. The clotting factors inhibited are; IIa, IXa, Xa, XIa, XIIa. The antithrombin and heparin combination is responsible for 70% of plasma capacity to limit coagulation.
2. Thrombomodulin system: All endothelial cells other than the cerebral microcirculation produce thrombomodulin which is a thrombin binding protein. When thrombin binds to thrombomodulin it becomes an anticoagulant by activating Protein C. Protein S enhances the activity of protein C which inactivates factors Va and VIIIa and inactivates an inhibitor of tissue plasminogen activator, which increases formation of plasmin.
3. Extrinsic pathway inhibitor: Inhibits the activity of the VIIa-tissue factor complex.
4. Fibrinolytic system: Plasmin is the active component of the plasminogen fibrinolytic system. Plasminogen activator is released from local endothelium in response to thrombin production. The activator converts plasminogen to plasmin Plasmin lyses fibrinogen and fibrin which works to break down the clot. Plasmin must be bound because free plasmin is neutralised by alpha2 antiplasmin.
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Physiol-06A11 Briefly outline the role of platelets in haemostasis. 60%
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Haemostasis: physiological mechanisms which prevent blood loss from damaged vessels and allow blood to remain fluid in the vasculature.
Platelets: small cellular fragments in the circulation formed by budding off from megakaryocytes.
The three main stages of haemostasis are:
1. vasoconstriction
2. formation of a platelet plug
3. formation of a blood clot
Haemostasis is achieved by an interaction between responses by blood vessels, platelets and plasma proteins (both procoagulant and anticoagulant).
Platelets form a platelet plug through:
1. platelet adhesion
2. platelet activation and release reactions
3. platelet aggregation
4. procoagulant activity
Platelet adhesion
Damage to the endothelium exposes subendothelial collagen to which von Willenbrands Factor (vWF) binds. Adhesion to collagen is facilitated by glycoprotin Ia. Multiple binding sites on vWF molecule are exposed for platelet glycoprotein Ib and further platelets adhere to the site of injury. Platelets have a large surface area onto which coagulation factors are absorbed. Platelet glycoprotein IIb-IIIa complex is exposed and binds vWF and fibronectin.
Platelet activation
Platelet activation leads to mediator release, and is stimulated by adhesion to proteins (eg.collagen), soluble agonists (adrenaline, ADP, serotonin, thrombin) and cell contact during platelet aggregation. Mediators of platelet release reactions include fibrinogen, beta-thromboglobulin, PAF-4, factor V, vWF, PDGF and thrombospondin -all realeased from the alpha granules in platelets. Activation of platelets leads to; procoagulant mediator release, other ligand release, exposure of membrane binding sites (eg. GP IIa-IIIb complex). Activation promotes coagulation, as they have exposed phospholipid binding sites (the prothrombinase complex) which is involved in activation of factor X and of prothrombin to thrombin.
Platelet aggregation
Platelet release reactions promote platelet aggregation in several ways:
* ADP: increased number of fibrinogen receptors on platelet surface
* fibrinogen & vWF: enhanced platelet aggregation and adhesion via binding to GPIIa-IIIb complex.
* thrombospondin: stabilises platelet aggregate
* Platelet prostaglandin synthesis is activated to form thomboxane A2 which potentiates the platelet release reaction, promotes platelet aggregation and also has vasoconstrictor activity.
There is formation of a temporary platelet plug and its strength is increased by platelet contraction and formation of a fibrin mesh.
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Platelet procoagulant activity
There is increased procoagulant activity after platelet activation. Procoagulant action requires Ca++ influx accross the plasma membrane and reorientation of phosphatidyl serine in the platelet membrane. Platelet factor 3 is exposed on the platelet membrane to become vailable for coagulation protein complex formation.
Additional Comments
As described above, Haemostasis involves:-
* vasoconstriction to avoid blood loss from damaged vessel
* platelet plug - via adherence, activation/release, aggregation
* Clot formation & retraction
The "plug" part has been well covered above.
Vasoconstriction
* partly neural reflexes
* vasoactive mediators - especially thromboxane A2 from platelets, which are also involved with platelet aggregation
Clot formation
* platelets important due to release of many coagulation factors from their granules (such as factor V, fibrinogen)
* also release vWF (not only important in adherence/aggregation of platelets, but also bind VIII - protecting it from degradation in the circulation and bringing it to the site of clot formation)
* platelet factor 3 / phospholipid is part of the "prothrombinase complex" (also involving V, Xa and calcium) - this vitally converts prothrombin to thrombin
* clot retraction requires platelets - probably via the contractile mechanism of actin/myosin contained in platelets
Platelets also release Platelet-Derived Growth Factor which stimulates new endothelial cell growth for wound healing
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Physiol-05B11 Outline the principles of compatibility testing of blood for transfusion. 75%
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Blood transfusion: infusion of safe and compatible blood (or blood components) from a donor to a recipient.
Blood testing is required prior to transfusion to avoid serious reactions due to blood group incompatibility or presence of antibodies in the recipient.
Transfusion reactions include:
1. Haemolytic transfusion reactions
2. Nonhemolytic febrile reactions
3. Anaphylactic reactions
4. Acquired infectious diseases
5. Graft versus host disease
6. Transfusion-related acute lung injury
7. Massive transfusion complications
Compatibility testing involves three steps:
1. blood type (safety: 99.4%
2. antibody screen (safety 99.8%
3. cross match (safety 99.85%
Blood typing
* ABO and Rh groups for donor and recipient groups must be determined
* Principle of ABO grouping involves exposure of the persons red cells to anti-sera containing IgM anti-A, anti-B and anti-AB antibodies andIgG anti D sufficiently potent to agglutinate Rh(D)-positive cells in saline.
Table for ABO and Rh antigens and antibodies
ABO antibodies form within first 10 years
Rh D antibodies form with previous exposure (transfusion or fetal blood)
Antibody screen
* Antibody screening for unexpected anti-RBC antibodies is routinely done on pretransfusion specimens from elective recipients and prenatally on maternal specimens. eg Rh0(D), Kell (K), or Duffy (Fya).
Cross match
* The donor's red cells are suspended in saline and tested against recieptant’s serum.
The Indirect Coomb's Test
screen for unexpected anti-RBC antibodies.
Reagent RBCs are mixed with the patient's serum, incubated, washed, tested with antihuman globulin, and observed for agglutination.
Direct antiglobulin testing (the direct Coombs' test) detects antibodies that have coated the patient's RBCs in vivo.
1. Hemolytic transfusion reactions: the result of antibodies in the recipient's plasma directed against antigens on the donor's erythrocytes→ rapid intravascular hemolysis of the donor RBC →haemoglobinemia, haemoglobinuria, DIC, renal failure.
2. Nonhemolytic febrile reactions: thought to be due to recipient antibodies formed against donor WBCs or platelets OR formation of cytokines during storage.
3. Anaphylactic reactions: a hereditary IgA deficiency. complement-binding anti-IgA antibodies to donor IgA. Proteins leading to anaphylaxis This is an anaphylactoid reaction and is observed more frequently with components containing large amounts of plasma, such as whole blood, pooled platelets, and fresh frozen plasma.
4. Acquired diseases: Infectious diseases also may be transmitted through transfusion.
5. Graft versus host disease: (GVH) disease occurs in recipients when donor lymphocytes mount an immune response against the recipient's lymphoid tissue.
6. Transfusion-related acute lung injury: transfusing any plasma-containing blood product. It is caused by the interaction between the recipient's leukocytes and preexisting donor antileukocyte antibodies. This results in complement activation and increased pulmonary vascular permeability. In addition, mediators of inflammation that form while the blood is in storage are also felt to be contributory.
7. Massive transfusion is defined as the replacement of the entire blood volume within a 24-hour period or the replacement of 10 units of blood over the course of a few hours. Complications of massive transfusion include the following:
* Coagulopathy is caused by a dilutional effect on the host's clotting factors and platelets, as well as the lack of platelets and clotting factors in packed red blood cells.
* Volume overload
* Hypothermia
* Hyperkalemia may be caused by lysis of stored red cells and is increased in irradiated red blood cells.
* Metabolic acidosis and hypokalemia may be caused by the transfusion of a large amount of citrated cells.
* Hypocalcemia due to citrate toxicity may occur in those with hepatic failure, congestive heart failure (CHF), or other low-output states. It is increasingly uncommon with the use of component therapy.
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Physiol-02B12 Briefly explain the changes that occur in stored whole blood 58%
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Blood can be stored for up to 35 days. The length of storage time is determined by assessing survival rate of transfused cells at 24 hours post transfusion, with the minimal acceptable survival rate at 24 hours 75% of RBC's. Storage of blood is possible due to presevative methods. These include preservative solution (CPDA), aseptic technique and temperature of 4 degrees.
Changes include:
1. Red cells:
* become spherical and experience membrane destabilisation leading to increased haemolysis especially after rapid transfusion. This haemolysis causes a small increase in plasma Hb. 75% RBC's survive to 28 days.
2. 2,3 DPG:
* Levels fall greatly causing left shift of the Hbo2 dissociation curve and theorectical decreased O2 unloading at tissues.
* The P50 of stored blood may fall to 15mmHg.
* 2,3 DPG levels are less effected with use of the CPDA preservative currently used, compared to ACD preservative used in the past. Despite this levels still effectively nil at 2 weeks.
* Up to 48 hours post-transfusion before normal levels return.
* Despite theoretical effect on P50 esp. in massive transfusion, little clinical relevance has been proven in vivo ("Nunn's Applied Respiratory Physiology" A. B. Lumb and J. F. Nunn, 6th ed, Elsevier-Butterworth Heinemann, 2005. page 180.)).
3. White cells:
* Granulocytes loose their phagosytic and bactericidal properties within 6 hours of blood collection, but maintain their antigenic properties.
4. Platelets:
* There is loss of most functional platelets by 36 hours stored at 4 degrees.
5. Coagulation Factors:
* labile factors V & VIII -
o Factor V decreases to 50% by 14 days. (Normal haemostasis requires factor V level > 20% normal).
o Factor VIII decreases to 50% by 24 hours and 6% by 21 days. (Abnormal haemostasis when Factor VIII <35% of normal). Other coagulation factors not significantly affected until 21 days.
6. Biochemical Changes:
* Altered RBC membrane permeability and RBC haemolysis contribute to some of the changes seen.
* ↑ K+ (28mmol?l at 28 days).
* ↑ lactate.
* ↑ free Hb.
* ↓ Na+ (154 mmol/L at 28 days) from 165mmol/L due to addition of NaCitrate
* ↓ Ca+ (effectively zero due to citrate).
* ↓ glucose (12 mmol/L at 28 days) from 19mmol/L
* ↓pH (6.7 at 28 days). This pH causes great impairment in protein behaviour and cellular processes.
* 7. Immunity: Formation of microaggregates(fibrin residues, degenerate leucocytes, platelets) all bind fibronectin causing decreased serum fibronectin and therefore insufficient macrophage activity and altered antigen presenting cell activity. Immunosuppression is possible.
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Physiol-01B7 Explain the main difference between the intrinsic and extrinsic pathways of coagulation. 41%
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General: Coagulation is a bio-amplification system by activating a cascade of circulating precursor enzymes
-> Ultimate aim is the conversion of soluble fibrinogen to stable fibrin which combined with platelets forms a firm and stable haemostatic plug.
There are 2 'historical' pathways described by which the coagulation cascade can be activated: Intrinsic & Extrinsic pathways. Both end up activating the common pathway which begins with the activation of factor X leading to the activation of II (thrombin) and fibrin formation
Intrinsic pathway
* Activated by: Contact with negatively charged surfaces in vivo (collagen, subendothelial connective tissue) and in vitro (glass)
* Factors Involved: XII, XI (deficient in haemophilia B), IX (deficient in Haemophilia A)[+Ca + VIIIa + PF3]
* Time to Activation: 1 - 6 min (slow)
Extrinsic pathway - more important role in vivo
* Activated by: Factor VII activation by tissue factor (TF) on the surface of subendothelium
* Factors Involved: VII
* Time to Activation: 15s (fast)
Common Pathway
* Activated by: Intrinsic (via IXa in the presence of Factor VIII, Ca2+ & PF3) & Extrinsic pathways (via VIIa in the presence of Ca2+, PF3)
* Factors Involved: X (in presence of Va), II
Drugs
* Warfarin: Descreases production of factors II, VII, IX, X. Main effect: Descreased activity of extrinsic and common pathways
* Heparin: Facilitates activity of antithrombin III (ATIII) in inhibiting activity of Xa and IIa of common pathway (LMWH only inhibits Xa activity)
Investigations
APTT: Measures activity of intrinsic pathway via contact activation (glass), PF3, Ca2+ (↑w heparin)
PTT/INR: Measures activity of thromboplastin, PF3, Ca2+ (↑w warfarin)
Sepsis/inflammation results in ↑factor VIII production → enhanced intrinsic pathway activation
Recent evidence suggests an alternate pathway for activation of intrinsic pathway:
Factor VIIa → activates Factor IX
Contact phase involving prekillakrein and HMWK appears only to occur in vitro
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Physiol-00A8 Briefly describe the breakdown of haemoglobin after red cell lysis 17%
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Intravascular Lysis
Hb from red cells destroyed within the vascular compartment escape into plasma and is subsequently bound by haptoglobin. Haptoglobin is a dimeric glycoprotein which is capable of binding 2 Hb dimers. The complex is cleared from the plasma with a half life of 10-30 minutes by the liver. In the liver the hemoglobin is broken down into Fe, globin and biliverdin (heme oxygenase). Biliverdin is further broken down into blilirubin which is conjugated and excreted via bile. CO is released in the course of cleavage of heme by heme oxygenase.
Red cell lysis may be accelerated in individuals such as those with sickle cell disease, have accelerated red cell destruction occurring primarily within macrophages and theoretically the haptoglobin level is expected not to drop below the usual level. However, there is either enough intravascular hemolysis in such hemolytic disorders to depress the plasma haptoglobin level or sufficient leakage from the phagocytic cells into the plasma to bind to haptoglobin.
Extravascular Lysis
Red cells that are engulfed by phagocytic cells of the reticculo endothelial system are degraded within lysosomes into lipids, protein, and heme. The proteins and lipids are reprocessed in their respective catabolic pathways and the heme is cleaved by a microsomal heme oxygenase into iron and biliverdin which is subsequently catabolized to bilirubin by bilverdin reductase.
Bilirubin Excretion
Bilirubin, is excreted through the bile into the gastrointestinal tract where it is converted to urobilinogen by bacterial reduction. Urobilinogen is a colourless product of bilirubin reduction. It is formed in the intestines by bacterial action. Some urobilinogen is reabsorbed, taken up by the hepatocytes into the circulation and excreted by the kidney. This constitutes the normal "intrahepatic urobilinogen cycle".
Increased amounts of bilirubin are formed in haemolysis which generate increased urobilinogen in the gut. In liver disease (such as hepatitis) the intrahepatic urobilinogen cycle is inhibited also increasing urobilinogen levels. Urobilinogen is converted to the yellow pigmented urobilin apparent in urine.
The urobilinogen remaining in the intestine (stercobilinogen) is oxidized to brown stercobilin which gives the faeces their characteristic color.
Only relatively small quantities are lost from the body because approximately 95% of the bile acids delivered to the duodenum are absorbed back into blood within the ileum (enterohepatic circulation).
[Fate of Globulin in liver...] - re-enters amino acid pool for use as with any other amino acid...not necessarily for Hb formation (see examiners note).
[Iron regulation...] - tranferrin...to iron pool
[lewildbeast - I found this question surprisingly hard to answer, please feel free to modify/edit]
Additional Comments
The average lifespan of a red cell is 120 days. This represents the degradation of about 6g/day of Hb.
In intravascular haemolysis, the Hb released is bound by haptoglobin (and haem by haemopexin) to ensure no iron loss.
Lysis of red cells by the reticuloendothelial system is more important however.
Haemoglobin is degraded into 3 component parts - haem, iron, and globin chains.
Globin chains
* degraded by macrophages of RES into constituent amino acids
* amino acids can then be reused for protein synthesis
Haem & Iron
* Haem can not be reutilised, and is broken down to iron (for reuse) and bilirubin
* Haem oxygenase metabolises haem into - Biliverdin (splitting of porphyrin ring), Fe2+, CO
* Fe2+ is converted to Fe3+ (?involving caeruloplasmin). This is the form in which Fe is stored or transported by ferritin or transferrin
* Fe is either stored in RES, or transported back to liver / bone marrow, for storage or use in further synthesis (mainly Hb)
* Biliverdin is reduced to bilirubin (biliverdin reductase)
* Bilirubin is transported to hepatocytes (bound to albumin in plasma due to low solubility)
* Conjugated in liver which increases water solubility
* is then excreted in bile - as part of the enterohepatic circulation, or excreted in bowel
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Physiol-97B5 Briefly describe the complement system 21%
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Complement System: a series of proteolytic reactions generated by plasma proteins to form part of the body's innate immunity.
Complement reactions involve more than 25 plasma proteins which are mainly produced in the liver, although there may also be production locally at sites of inflammation. The major plasma proteins involved are named C1q, C1r, C1s, C2-C9. Complement proteins are activated in a sequential manner and there is amplification of the effect with time. Activation can be via the classical or alternative pathway. The classical and alternative pathways converge at the breakdown of C3 and form a final common pathway.
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The classical pathway
* Can be activated by antigen-antibody complexes, CRP or aggregated immunoglobulins.
* Can be activated by IgM or some classes of IgG, but not by IgA, IgD, or IgE.
* Consists of 11 enzymes (C1q, C1r, C1s, C2-C9).
* Starts when antigen-antibody complexes bind to C1q.
* Reactions involving C4 and C2 lead to the C4b-2a complex known as C3 convertase.
* C3 convertase cleaves C3 into C3a and C3b which is the first step on the final common pathway.
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The alternative pathway
* Is continuously active.
* There is spontaneous coversion of C3 to hydrolysed C3, leading to reactions that split small amounts of C3 to C3a and C3b.
* Does not require antibodies to be activated.
F2.gif
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The common membrane attack pathway
* Both the above pathways produce C3 which cleaves C5 into C5a and C5b.
* The formed C5b combines with C6,C7,C8 and C9 to produce the membrane attack that damages cell membranes by punching holes in the cell membrane and causing cell lysis.
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Functions of complement activation
1. Cell lysis of bacteria (due to the membrane attack complex)
2. Release of inflammatory mediators such as histamine from mast cells (via C3a and C5a).
3. Local vasodilation (via C3a and C5a).
4. Neutrophil aggregation (via C3a and C5a).
5. Chemotaxis to attract phagocytes (via C3a and C5a).
6. Opsonisation of bacteria (via C3b).
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Anaphylatoxins
This is a term given to the proteins C3a and C5a, which bind to receptors on mast cells (C3a and C5a) and basophils (C3a) resulting in degranulation and release of vasoactive mediators which causes: local vasodilation, neutrophil aggregation, and chemotaxis.
An answer to a complement SAQ should include a diagram of the cascade and explanation. eg. [1] (http://images.google.com/imgres?imgurl=http://www.socgenmicrobiol.org.uk/jgvdirect/18709/Figs/F2.gif&imgrefurl=http://www.socgenmicrobiol.org.uk/jgvdirect/18709/Figs/F2_pg.htm&h=599&w=454&sz=187&tbnid=kx8iVx3ejLwjKM:&tbnh=135&tbnw=102&prev=/images%3Fq%3Dcomplement%2Bcascade&start=3&sa=X&oi=images&ct=image&cd=3) A simpler diagram than this would be appropriate.
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Physiol-02B15 Give a brief account of the mechanisms which regulate gastric secretion.
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Gastric secretions : 2L per day
Slightly hyperosmolar 325mOsm/L
K+ 10mmol/L
H+ 150mmol/L pH 1-2
Na+ 4mmol/L
Also intrinsic factor (atral cells)
pepsinogens
mucus
Cells
-neck cells : mucus
-chief cells : pepsinogen
-parietal : acid + intrinsic factor
-enterochromaffin like cells : somatastatin and histamine
-G cells : gastrin
3 Phases to gastric secretion
Gastric secretions include HCl, pepsinogen and gastrin as well as mucous and intrinsic factor. It is high in potassium and low in sodium.
1. Cephalic phase - responsible for 50% of secretions in response to smell, sight, taste or thought of food. This is via vagal stimulation of ACh release and inhibition of somatostatin.
2. Gastric phase - responsible for almost 50% of secretions via vago-vagal and local reflexes in response to gastric distension and then in response to the resulting acidic pH. Amino acids and peptides in the stomach also stimulate gastric secretion
3. Intestinal phase - only a small amount of secretion in response of movement of chyme into the duodenum. Peptides in the duodenum and amino acids in the blood stimulate secretion. Gastric secretion is inhibited by GIP and Secretin (via production of somatostatin) in response to a high fat load delivered to the intestine.
Chemical mediators
-increased secretion : histamine (H2), ACh, gastrin
-decreased secretion : somatastatin, epidermal growth factor, Beta-adrenergic, enteroglucagon
Other
-protein+peptides directly stimulate paritetal cells to secrete acid
-high gastric acid inhibits acids release (negative feedback)
Mechanism of HCl secretion
Basolateral membrane
-NaKATPase
-HCO3/Cl antiporter
Apical
-Cl- channel
-K+ channel
-H+/K+ antiporter
CO2 diffuses into cell
combines with H2O usually slow, but parietal cell is rich in Carbonic Anhydrase which catalyses this reaction
Dissociation into H+ and HCO3-
H+ moves out into lumen due to H+/K+ antiporter
HCO3- moves back into blood via HCO3-/Cl- antiporter
Cl- moves down concentration gradient into lumen
K+ is moved into cell via NaKATPase (which drives the whole process) and moves into the lumen via K+ channel resulting in lumenal high K+ which drives the H+/K+ antiporter
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Physiol-97A4 What factors oppose gastro oesophageal reflux? 35%
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Physiological factors
1. Tonic contraction of the oesophageal musculature in the distal portion acts as a lower oesophageal sphincter. This keeps the intraluminal pressure at 30mmHg. Relaxation occurs as a peristaltic wave approaches from above and allows food to enter the stomach.
2. Once a food bolus has passed, the sphincter increases the intra-luminal pressure by 1-15mmHg above the normal pressure for 10-15 seconds.
3. A vagal reflex causes an increase in LOS tone whenever intra-gastric pressure increases.
Anatomical factors
1. Approximately one eighth of the oesophagus lies within the abdominal cavity and is therefore susceptible to the same increases in intra-abdominal pressure as the stomach. As intra-abdominal pressure increases, the abdominal portion of the oesophagus caves inward and prevents the rise in intra-gastric pressure pushing stomach contents into the oesophagus.
2. The gastro-oesophageal angle is oblique and this forms a flap-like valve mechanism.
3. The oesophagus passes into the abdomen flanked by the diaphragmatic crura which prevent reflux of gastric contents by acting as a pinch cock.
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Physio-93** Describe the mechanism of swallowing
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Definition of Swallowing
A complex reflex that is responsble for the movement of a food bolus from the mouth to the stomach. The afferent limb is glossopharyngeal and vagus nerve afferents; the controller is the swallowing centre of the medulla and the efferent limb is via vagal efferents to the pharynx and oesophagus. The mechanism can be divided into 3 phases (as per Power and Kam):
Oral phase
The food bolus is formed by the tongue and the associated stimulation of glossopharyngeal afferents initiates the involuntary reflex.
Pharyngeal phase
1. Pause in respiration
2. Nasopharynx closed by soft palate
3. Vocal cords adducted
4. Larynx elevated and epiglottis swings down
5. Contraction of the pharynx and opening of the upper oesophageal sphincter
Oesophageal phase
When the food bolus enters the oesophagus there is closure of the UOS and opening/relaxation of the LOS and peristaltic contractions move the food down. There are slow primary peristaltic contractions that are coordinated by the swallowing centre via vagal efferents, and there is a local reflex secondary peristalsis mediated by the enteric nervous system (stretch receptors in the wall of the oesophagus activate the intrinsic nerves of the oesophagus).
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Describe how the kidney establishes the medullary concentrating gradient
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Medullary concentration gradient describes the increasing osmolarity of kidney interstitium from cortex to medullar.
Osmolarity is the number of osmoles per L of solution. ei, the dilution of water but solutes.
The term countercurrent multiplication refers to the process underlying the process of urine concentration, that is, the production of hyperosmolar urine by the mammalian kidney.
Components
1. Properties of Loop of Henle : Counter Current Multipler
2. Role of Urea
3. Properties of Vasa Recta : Counter Current Exchange
Loop of Henle
- two parallel limbs of renal tubules running in opposite directions, separated by the interstital space of the renal medulla
-DLOH : impermeable to NaCl, but permeable to water (via osmosis)
-TALOH : impermeable to water, but Na is actively secreted into interstitium
Countercurrent multiplication is a hypothesis describing the mechanism whereby urine is concentrated in the nephron : Pump, Equilibration, and Shift steps.
Pump: The Na+/K+/2Cl- transporter in the TALOH helps to create a gradient by shifting Na+ into the medullary interstitum. Since the ascending limb of the loop of Henle consists of epithelium containing many tight junctions impermeable to water, this creates a hypoosmolar solution in the tubular fluid and a hyperosmolar fluid in the interstitium.
Equilibration: Since the descending limb of the loop of henle consists of very leaky epithelium, the fluid inside the descending limb becomes hyperosmolar as well.
Shift: The movement of fluid through the tubules causes the hyperosmotic fluid to move further down the loop. Repeating many cycles causes fluid to be near isosmolar at the top of Henle's loop and very concentrated at the bottom of the loop. Interestingly, animals with a need for very concentrated urine (such as desert animals) have very long loops of Henle to create a very large osmotic gradient. Animals that have abundant water on the other hand (such as beavers) have very short loops. The vasa recta have a similar loop shape so that the gradient does not dissipate into the plasma.
Renal urea handling is the part of renal physiology that deals with the reabsorption and secretion of urea.
Urea allows the body to create hyperosmotic urine (urine that has more ions in it--is "more concentrated"--than that same person's blood plasma). Preventing the loss of water in this manner is important if the person's body needs to save water in order to maintain a suitable blood pressure or (more likely,) in order to maintain a suitable concentration of sodium ions in the blood plasma.
About half of the urea filtered (40%[1]) is normally found in the final urine, since there is more reabsorption than secretion along the nephron.
It is regulated by antidiuretic hormone, which controls the amount reabsorbed in the collecting duct system and secreted into the loop of Henle.
Vasa recta
-supplies nutrients to the interstitium
-counter current exchange
-movement of water out is return in as blood flows down vasa recta then back up
-maintains the medullary concentration gradient.
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Physiol-07B12 Discuss the role of the kidney in regulating potassium homeostasis.
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Potassium
The major intracellular univalent cation, principle determinant of the Resting Membrane Potential of many cells, eg. cardiac muscle, due to its Nerst Potential due to the unequal distribution across the plasma membrane and slight permeability of the plasma membrane.
Renal control of potassium balance
Filtration
* is freely filtered at the glomerulus at a relatively constant rate (5 mmol/l x 180 l/day = 900 mmol/day).
Proximal Tubule
* Reabsorption.
* occurs at relatively fixed rate, but depends on dietary intake of K. Between 55% - 80%
* reabsorption occurs mostly by paracellular diffusion (concentration gradient created by the reabsorption of water)
Loop of Henle
* Mainly ascending limb 5-35% reabsorbed
* reabsorption by Na/K/2Cl symporter (energy provided by Na/K pump) & some paracellular diffusion
Distal Tubule
* reabsorption or secretion depending on dietary intake
Collecting Duct
* relatively constant K load delivered here, most important region as K is regulated here
* reabsorption by Type A intercalated cells via H/K pump
* secretion via principal cells (via action of Na/K pump BLM, and K channels (ROMK) in apical membrane
*the principal cells are under the control of aldosterone
Control of potassium secretion
1. Tubular flow: Increased Urine Volume "washes away" more K in the DCT and CD.
2. Plasma Potassium levels: can stimulate the basolateral Na-K=ATPase in the Principal cells, and stimulates the production and release of Aldosterone from the Adrenal Cortex zona glomerulosa.
3. Aldosterone: acts on Principal cells to cause K secretion by direct action on Potassium Channels on the apical membrane and Na-K-ATPase on the basolateral membrane. (Also causing Na retention).
4. Acid-Base Balance: Alkalaemia causes relative K loss, Acidaemia causes relative K retention (see below**)
5. Plasma Sodium levels: overall effect is relatively little change in K secretion
* Increased Na will cause a decrease in aldosterone secretion (decreased K secretion)
* Increased Na will cause a higher urine flow (increased K secretion)
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Physiol-06B11 List the hormones that regulate tubular reabsorption and describe their action and site of action. 81%
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Hormones are chemical messengers secreted into the blood in small amounts from ductless glands, and exert specific effects at receptors. Tubular reabsorption refers to the uptake of certain molecules from the tubular lumen in the nephron, through the interstitium and into the renal peri-tubular capillaries. Reabsorption can be a passive process, or can take place through primary or secondary active transport mechanisms with other molecules.
Several hormones exert an effect on the kidney:
1) Renin: this proteolytic enzyme is secreted from the granular cells of the juxtaglomerular apparatus in response to: - Adrenergic stimulation of beta 1 receptors (SNS nerves or circulating adrenaline - Reduced tubular flow of Na – tubulo-glomerular feedback - Intrarenal baroreceptor mechanisms in afferent arteriole. It is inhibited by - angiotensin 2 - ANP It catalyses cleavage of angiotensinogen to angiotensin
2) Angiotensin II: this polypeptide has many systemic effects. In the kidney it constricts afferent and efferent renal arterioles, favouring increased GFR which is offset by reduced renal blood flow, conserving salt and water. It has a direct effect on the proximal tubule resulting in increased Na reabsorption, and subsequent water reabsorption. It also catalyses the formation of aldosterone
3) Aldosterone: peptide hormone formed in the zona glomerulosa of the adrenal cortex, in response to hyperkalaemia, ACTH and angiotensin II. It functions to increase Na reabsorption in exchange for K in the DCT and collecting duct
4) ADH – formed in the hypothalamus and released from the posterior pituitary. Causes vesicles containing aquaporins to fuse with the luminal membrane of the collecting duct and increase water reabsorption
5) Adrenaline: direct effect on Na reabsorption in the proximal convoluted tubule and increases renin release
6) Parathyroid hormone: released from the parathyroid gland, causing reabsorption of Ca in the late distal tubules and early collecting ducts, and reduced phosphate reabsorption in the proximal tubules
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Physiol-06A14 Explain the physiological processes which cause oliguria in response to hypovolaemic shock 38%
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Shock is a medical emergency in which the organs and tissues of the body are not receiving an adequate flow of blood. This deprives the organs and tissues of oxygen (carried in the blood) and allows the buildup of waste products. Hypovolaemic shock is a result of decreased circulating blood volume. This may be due to haemorrhage or other acute fluid losses (such as GI).Oliguria refurs to the subsequent reduction in urine volume as a compensatory mechanism by the kidney.
The physiological processes which cause oliguria in response to hypovolaemic shock are multifactorial:
A sudden decrease in blood volume will be detected as a drop in pressure by the Baroreceptors. The baroreceptors fire less often as a result. This sensory feed back is via the vasomotor centre in the medulla oblongata which results in a increased production of antidiuretic hormone from the posterior pituitary. This results in increased production of aquaporin receptors in the collecting ducts which leads to increased water reabsorption and thus an increased total body water with restoration of the Extracellular fluid compartment.
If there is a very large decrease in plasma volume (as there is in shock), very high concentrations of ADH exert a direct vasoconstrictor effect on arteriolar smooth muscle. This results in increased total peripheral resistance, which helps to restore blood volume faster than the restoration of fluid volumes, also increase urea absorption in the med collecting tubule more ability to concentrate urine.
Renal arterioles and mesangial cells also participate in this constrictor response, contributing to the reduction in GFR (promoting sodium and water retention).
Osmoreceptors in the hypothalamus detect changes in osmolality ( ratio of solute to water). An increase in osmolality stimulates production of ADH and thus tends to preserve normal osmolality.
Decreased pressure in the renal artery leads to decreased afferent arteriolar pressure which is detected by the granular cells of the Juxtaglomerular apparatus. These granular cells contain the hormone Renin which is released as a result of this stimulus. Renin causes the production of Angiotensin II from Angiotensin I in the liver and lungs. This has a direct vasoconstrictive effect in the systemic circulation and via Angiotensin receptors in the afferent arterioles tending to increase peripheral vascular resistance restoring circulatory pressure. ***EDIT - I thought angiotensin II effects were on the efferent arterioles, and possibly at high concentrations on the afferent (but not confirmed)? That's info from the Short Course notes***
Angiotensin II causes the release of Aldosterone from the Adrenals. Aldosterone acts on the Principal cells of the cortical connecting tubule and collecting ducts to increase Sodium uptake.
Sympathetic stimulation causes increased constriction of renal arterioles tending to decrease blood flow and GFR. Increases the activity of the Granule cell via beta1 Adrenoceptors, and therefore Renin.
GFR is affected by a reduction in renal blood flow as a result of reduced arterial BP. Decreased afferent arteriolar pressure causes a reduction in Glomerular capillary hydraulic pressure resulting in decreased GFR. Decreased peritubular capillary pressure and decreased interstitial pressure lead to an increase in the fluid reabsorbtion by the proximal nephron.
Decreased pressure is detected by intrarenal baroreceptor and reduction in delivery of NaCl to the macula densa. This causes increased activity of Granular cells to produce Renin. Decreased excretion of salt and water (pressure natriuresis/ diuresis) and therefore an increase in Plasma vol and ECF vol (and BP).
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Physiol-05B10 Describe the forces acting across the glomerular capillar membrane. Explain how afferent and effferent arteriolar tone affect glomerular filtration rate. 62%
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Glomerus: specialized structure of the kidney, consists of efferent, afferent arterioles (in series), capillary (endothelium) and bowman's capsule.
Forces acting across the glomerular membrane are known as Starling forces which are dependent the hydrostatic and osmotic pressure gradients across the capillary wall
NFP: (HPGC+OPT) - (HPT+OPGC)
where:
* Kf = glomerular coefficient related to hydralic permeability and surface area of the glomerulus.
* HP = hydrostatic pressure.
* OP = oncotic pressure.
* GC= glomerular capillary.
* T = Bowman's capsule.
Unlike other capillary beds NFP at the glomerulus is always outward.
* HP in the glomerular capillaries is high as they are short straight branches from interlobular arteries and because the efferent arterioles have high resistance (60mmHg on afferent side and 58mmHg on efferent)
* The HP in the bowmans capsule is normally small (exception: urinary obstruction).
* The main force opposing filtration is the OP in the glomerular capillary, which is due to the plasma proteins - due to the fact they are unable to be filtered. As such under normal circumstances the oncotic pressure in the bowmans capsule effectively zero. (afferent 25mmHg to efferent 35mmHg)
* The approximate NFP at the start of the glomerular capillary is 24 mmHg, which drops to 10 mmHg at the efferent end of the glomerular capillary - due to fluid leaving the glomeruli and causing the capillary oncotic pressure to rise, balancing the HP.
* Unlike the systemic capillary the HP remains relatively constant along the glomerular capillary length.
Effect of afferent and effferent arteriolar tone on GFR
GFR=kf x NFR
kf is filtration coefficient
which is surface area x permeability
GFR=180L/day
* ↑ afferent arteriolar tone (AAT) will always ↓ HPGC and thus ↓ GFR.
* ↑ of both AAT and efferrent arteriolar tone (EAT) will decrease renal blood flow (RBF) according to Ohm's Law.
* ↑ efferent arteriolar tone will initially tend to icrease or maintain HPGC and thus GFR, but if great enough will also decrease GFR due to ↓ RBF (again Ohm's Law - pressure - flow x resistance).
* GFR is normal autoregulated over the normal physiological range by glomerulotubular feedback and the myogenic autoregulation of renal arteriolar pressure, however sympathetic nervous system input, ADH, and renin angiotensin system input can override this autoregulation to cause profound changes in GFR.
* Differential effects on AAT and EAT are important physiologically - eg. angiotensin II selectively increases EAT, thus tending to maintain GFR in the face of ↓ RBF. Similarly PGI2 and PGE2 selectively cause a decrease in AAT.
The Starling equation is an equation that illustrates the role of hydrostatic and oncotic forces (the so-called Starling forces) in the movement of fluid across capillary membranes.
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Physiol-04A16 Explain how the kidney handles glucose. Describe the physiological consequences of glycosuria. 57%
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Glucose Transport
* Glucose is freely filtered in the glomerulus:
Normal plasma glucose ~ 5 mmol/L
GFR = 125 ml/min
→ 0.625 mmol/min → 900 mmol/day.
* Normally completely reabsorbed in the proximal tubule.
* Thus the amount reaborbed is directly ∝ to the amount filtered up to the transport maximum (Tm) for glucose.
Tm ~ 2 mmol/min
* The renal threshold (RT) is the plasma glucose concentration at which glucose appears in the urine.
* From the Tm above we would predict that glucose would begin to appear in urine at around:
Tm ~ 2 mmol/min
GFR = 125 ml/min
→ RT ~ 2 mmol/min ÷ 0.125 L/min → 16 mmol/L
* However in reality glucose appears in the urine at a significantly lower value: ~ 11mmol/L
* This is due to the pheomenon of splay.
* Splay is due to the fact that:
o not all glomeruli have the same Tm
o all glucose is not removed from the tubule at Tm.
* Transport of glucose from tubular lumen across the apical membrane of tubular epithelial cells of the proximal convoluted tubule is via the sodium-glucose symporter SGLT1.
* SGLT is an example of secondary active transport, energy for which is provided by the Na+ concentration gradient created by the Na-K-ATPase located at the basement membrane.
* Active transport at SGLT1 is saturable and is the rate limiting step that dictates Tm.
* Transport across the basolateral membrane of the tubular epitheilium is via facillitated diffusion using the GLUT2 uniporter.
[edit]
Consequences of Glycosuria
* Glycosuria leads to an osmotic diuresis: glucose in the tubular lumen increases the osmolality of the filtrate, this decreases the osmotic gradient over which water can move out of the renal tubules.
* The presence of glucose in the distal portion of the nephron also causes dilution of the medullary osmotic gradient with a subsequent decrese in urinary concentrating ability.
* This leads to significant water and electrolyte loss.
* The physiological consequences of water and electrolyte loss will depend on the severity of the loss (on the degree and duration of glycosuria).
* Water and electrolyte loss will be sensed by the volume and osmoreceptors initiating an attempt to conserve water and electrolytes (e.g via ADH release and the renin-angiotensin-aldosterone system).
* Note however that the kidney cannot alter Tm and thus cannot combat the osmotic diuresis cause by glycosuria - as such normal renal water and electrolytes homeostatic control is significantly impaired.
* The thirst mechanism will attempt to replace water losses - polydipsia is a typical symptom of a patient presenting with untreated diabets mellitus.
* Glycosuria also ↑ the probability of urinary tract infection, and represents a loss of nutrient and energy substrate.
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Physiol-04A13 Describe the concept of renal clearance and its use to estimate glomerular filtration rate 69%
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Definition
* Renal clearance is the volume of plasma from which a substance is completely removed via the kidneys per unit of time .
(Note specifically the unit is volume per unit time rather than amount per unit time.)
* Inulin
GFR can be calculated experimentally using inulin. This is a substance which is freely filtered and neither excreted nor reabsorbed. The amount of inulin in the urine per unit time have been provided by filtering exactly at the glomerulus.
Also : non toxic, not metabolized, does not influence RBF or GFR.
Its renal clearance equals GFR.
Inulin is infused intravenously to a test subject to achieve a steady state plasma concentration (equilibrated with all fluid compartments) and urine samples are collected.
Clearance (mls/min) = UV/P
where
*U = Concentration in urine
*V= Urine volume (in mls/min)
*P= Plasma concentration
*NB: Units for U & P have to be the same, then cancel out.
Typical numbers
Urine conc = 35mg/mL
Urine Rate = 0.9mL/min
Plasma conc = 0.25mg/mL
Clearance = UV/P = 35x0.9/.025 = 126ml/min
* Creatinine
More practically in healthcare settings creatinine is utlised. This is a metabolic product of creatine metabolism, predominantly in muscles. This is highly variable due to variability in muscle mass between individuals. Renal clearance of creatinine is somewhat higher than GFR due to the fact that is secreted in the tubules. A 10-20% secretory fraction corresponds to the likely overestimation in GFR for which a compensation is made. This secretory fraction increases as GFR decreases (secretion likely stays relatively constant whilst GFR decreases) resulting in greater overestimation of GFR using creatinine clearance in low GFR states.
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Physiol-03B14 Outline the role of the kidney in the regulation of body water. 34%
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Kidney
-major regulator of body water
-recieved 20% of total cardiac output, 1L/min
-produces 180L of solute per day (GFR) or 130ml/min
Therefore filters 180L of water per day!
Key role in water balance as it has a huge capacity to reabsorb H2O or excrete H2O
In state of
-water excess, produces large volume hypo-osmolar (dilute) urine of 100mOsm/L
-water deficit, produces small volume of hyper-osmolar (concentrated) urine of 1200mOsm/L
Control of body water
-feedback mechanism involving sensor, integrator and effector
Sensors
-low and high pressure baroreceptors of atria and pulmonary artery; and aortic and carotid bodies
-osmoreceptors in the hypothalamus
Integrator
-hypothalamus
Effector
usual reabsorption of water : PCT 60%, LOH 15%
role ADH and DCT and CD in fine tuning urine osmolality and water reabsorption
role of medullary concentration gradient
small mention of aldosterone
2003
Important concepts expected were:
* The identification and separation of discussion about sodium chloride and associated water (i.e. saline) and "pure" water regulation.
* Description of the ability and associated mechanisms for production of either hypo- or hyper tonic urine relative to plasma.
* Identification and discussion of the role of ADH within this process.
Common errors or omissions included:
* Many answers failed to address the question as asked.
* Terms such as water, volume and fluid depletion were used in ambiguous ways.
* Directionless relationships e.g. a change in X causes a change in Y.
* Failure to discuss how dilute urine is produced.
Better answers:
* Discussed the threshold and gain for hypo-osmolarity vs. hypo volemia.
* Set the role of the kidney within the broader scope of water homeostasis.
[edit]
1999
The difficulty in presenting the wide range of pertinent material that could be discussed meant that high marks were difficult to achieve.
The key concept was that the kidney is usually the major effector of body water regulation based on the large renal blood flow and glomerular filtration and its capacity to excrete either dilute or concentrated urine in response to the requirements of maintenance of body water volume and osmolality. Most candidates focussed on either the details of renal tubular handling of water, or on how the kidneys function in relation to the body's sensors of intravascular volume and osmolality and how the hypothalamus has a key role in integrating this process. Either approach done well, with reference to the importance of regulation of urine volume and osmolality achieved a pass.
Discussion on other sites of water loss and their potential for regulation compared with the kidneys and the effect of various situations which may disturb the kidney's ability to perform its role in regulation of body water were included by some candidates.
If integrated with discussion of the kidney's role in body water regulation, these were also considered pertinent material.
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Physiol-03A16 Describe the functions of the loop of Henle, including the physiological mechanisms involved. 64%
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The main function of the loop of Henle is to establish a concentration gradient in the renal medulla, which allows the collecting duct to regulate water excretion. The loop of Henle is made up of the thin descending limb, thin ascending limb (juxtamedullary nephrons- longer nephron, not in cortical nephron) and thick ascending limb.
The concentration gradient is:
* produced by counter current multipliers (loops of Henle), and
* maintained by counter current exchangers (vasa recta).
The ability of the loops of Henle to produce this gradient is dependent on the thin descending loop being permeable to water and the active transport of Na, K and 2Cl out of the tubule into the renal tubule cell (Na pumped in exchange for K into interstitium by NaKATPase, Cl and K diffuses into interstitium via channels).
Counter current multiplication: In the thick ascending limb Na and Cl is pumped out. Water will flow out of the descending loop of Henle to equilib with the interstitium making it hypertonic. As more fluid flows into the descending limb, the hyper osmolar fluid moves into the ascending loop where more Na and Cl pumped out decreasing its tonicity and making interstitium more hypertonic leading to more water flowing out of descending limb. The process repeats itself so that the gradient between the turn of the loop (hypertonic) and the distal end of the ascending limb (hypotonic) grows.
The osmolality of the tubular fluid entering the loop of Henle is about 300mosm/kg (hypotonic) and the osmolality of the tips of the papillae in the medulla is about 1200mosm/kg (4x plasma). Nephrons in the cortex have a short loop of Henle whereas nephrons in the juxtamedullary region of the cortex have long loops extending into the medullary pyramids (15%) , these have a thin ascending limb also. The thin ascending limb is permeable to Na and Cl but impermeable to water, therefore Na and Cl move out into the interstitium adding passive countercurrent multiplication.
Role of urea:
* Important in determining maximal osmolality of urine. (Half of medullary osmolality consists of urea).
The cortical collecting ducts and the outer medullary collecting ducts are IMpermeable to urea (as water resorbed incr conc urea).
Inner medullary collecting ducts highly permeable to urea (incr by ADH). Therefore diffusion urea (and water) out of these ducts. Therefore urea concentration in interstitium equals urea concentration in tubules (therefore Na and Cl in the interstitium need only balance the solutes OTHER than urea in the tubular fluid).
Amount of urea in interstitium dependant on amount filtered dependant on protein in diet therefore concentrating ability of kidney dependant on amount of protein in diet.
Countercurrent exchange in the vasa recta:
* Maintains osmotic gradient in the medulla
* Solutes (NaCl and urea) diffuse out of the ascending vessel into the descending vessel and therefore recirculate.
* Water diffuses out of the descending vessels into the ascending vessel and therefore bypass the medulla.
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Physiol-00B8 Describe the factors governing glomerular filtration rate 52%
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* Glomerular filtration rate (GFR) is the flow rate of filtered fluid through the kidney.
* The rate of filtration in any of the body's capillaries including the glomeruli is determined by the hydraulic permeability of the capilaries, their surface area, and the net filtration pressure (NFP) acting across them.
GFR = hydraulic permeability x surface area x NFP
= Kf x NFP
* Kf (the filtration coefficient) represents the product of the hydraulic permeability of the glomerular capillaries and the surface area (SA) for filtration.
* SA (and thus Kf) may be increased physiologically by mesangial cell relaxation (e.g. in response to ↓ ADH and angiotensin levels) → ↑GFR.
NFP is the algebraic sum of the hydrostatic and osmotic pressures across the glomerular capillary membrane:
NFP= (PGC-PT) - σ(πGC - πT)
where
PGC = capillary hydrostatic pressure (arterial end ~60 mmHg, venous end ~58 mmHg)
PT = tubular hydrostatic pressure (a. & v. end ~15 mmHg)
πGC = plasma osmotic pressure (a. end ~21 mmHg, v. end ~33 mmHg)
πT = tubular osmotic pressure (a. & v. end = 0)
σ = reflection coefficient
* The reflection co-efficient represents the 'leak' of plasma proteins across the capillary membrane, where 1 equals no leak (i.e complete protein 'reflection').
* σ at the glomeruls is normally 1 - i.e no protein is filtered.
* σ may decrease in disease states e.g. nephritis → proteinuria.
* As no protein is normally filtered
o πT is zero and can be ignored.
o σ is effectively 1 and thus can also be ignored.
Thus the formula simplifies to:
GFR= Kf(PGC - PT - πGC)
* Hydraulic pressure changes very little along the glomeruli as a result of the large surface area collectively providing a small resistance to flow (cf. systemic capillaries where capillary hydrostatic pressure falls significantly along the length of the capillary).
* Oncotic pressure does change substantially as water is moving out of the vascular space thereby raising the protein concentration left behind (cf. systemic capillaries where capillary π remains almost unchanged along the length of the capillary)
* Because of large increase in oncotic pressure, the net filtration pressure is reduced towards the end of the glomerular capillaries - however it remains outward along the length of the GC (cf. systemic capillaries where at the distal end the NFP becomes inward).
Changes in the PGC may be caused by:
1. Changes in renal blood flow (RBF): ↓RBF → ↓GFR
* renal blood pressure and thus flow is normally autoregulated over the physiological range (80-180 mmHg) by the myogenic mechanism and to a lesser degree by tubuloglomerular feedbcak.
* this autoregulation may be overridden by symapthetic nervous system (SNS) input or the renin-angiotensin system (RAS)
2. Changes in afferent-arteriolar resistance (AAR) and efferent-arteriolar resistance(EAR):
* ↑ AAR → ↓PGC → ↓GFR
* moderate ↑ EAR → ↑PGC → ↑ GFR
* major ↑ EAR → ↓PGC (due to decreased RBF) → ↓ GFR
The significance of 2. is that the kidney can regulate HP GC independently of RBF by differential effects on AAR and EAR for example:
* angiotensin selectively increases EAR
* prostaglandins selectively decrease AAR.
* An ↑ in PT may be caused by obstruction of the tubule or extrarenal urinary system → ↓ GFR.
* A decrease in plasma oncotic pressure will tend to increase GFR (eg hypoalbuminaemia of chronic liver disease).
* If renal perfusion is low, then there will be a steeper rise along the capillary from begginning to end in plasma oncotic pressure due to the initial reduction in plasma volume. This will tend to cause a greater impact on the the NFP, thereby reducing GFR.
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Physiol-98B3 Describe the process of tubuloglomerular feedback. 70%
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* Tubuloglomerular feedback describes the ability of any particulaur nephron in the kidney to deliver ultrafiltrate at a relatively constant rate to the distal convoluted tubule (DCT) in the face of changing glomerular filtation rate.
* The juxtaglomerular apparatus (JGA) is the unit responsible for sensing and effecting any changes and is comprised of:
o specialised cells at the junction of the ascending limb of the Loop of Henle and of the DCT called macula densa cells
o renin-secreting cells of the afferent arterioles called juxtaglomerular cells.
* Tubuloglomerular feedback:
o occurs within a nephron unit, separate to extra-renal influences, giving each of the million nephrons per kidney the ability to set its glomerular filtration rate (GFR) - ie is an example of autoregulation.
o is a negative feedback loop, so if GFR increases, the sensing and effecting mechanism will bring about changes to decrease GFR.
Mechanism:
* ↑GFR →NaCl delivery to the distal tubule.
* macula densa cells sense increase NaCl delivery (probably sense the increase rate of Cl- absorption across their membrane rather than Na+).
* This causes the release of an unknown paracrine vasoconstrictor substance (?adenosine/?thromboxane A2) in the direction of the afferent arteriole to cause increased resistance and decreased flow in that particular vessel → ↓ filtration in that nephron.
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Briefly discuss the physiological roles of plasma proteins
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Plasma: the fluid medium of the intravascular compartment which transports substances between body tissues.
Plasma proteins: globular molecules from simple unconjugated proteins(eg. albumin) to complex proteins (eg. glycoproteins, lipoproteins) which are mostly synthesised in the liver and circulate in the plasma. Typically 70g/L.
Major classes of plasma proteins
1. Albumin (45g/L)
2. Globulins (25g/L) Four subgroups are; alpha-1, alpha-2, beta, gamma
3. Fibrinogen (3g/L)
* Plasma proteins exist in equilibrium with the tissue proteins as an exchangeable pool.
Major functions of plasma proteins
1. Oncotic pressure
Maintenance of body water compartments is assisted by plasma proteins because capillary walls are relatively impermeable to plasma proteins (cf. all other solutes), causing the proteins to exert a force of 25mmHg accross the capillary wall which prevents extravasation of the intravascular volume into the interstitial fluid. This force is opposed by the hydrostatic pressure gradient across the capillary wall according to Starling's forces:
NFP = \left [ (P_C - P_I) - \sigma (\pi_C - \pi_I) \right ]
where:
NFP = net filtration pressure
P = hydrostatic pressure
π = oncotic pressure
C = capillary
I = interstitium
σ = reflection co-efficient.
Interestingly, while albumin exists in the highest concentration in plasma, quantatatively more albumin exists outside the circulation at any given time (but is distributed in a much larger volume thus is at a low concentration).
2. Transport Functions
* Plasma proteins bind to many substances (eg. hormones and drugs) and transport them around the body.
* Many ligands can bind to albumin including; free fatty acids, bilirubin, Ca++, cortisol, thyroxine, copper, drugs.
* Also minor contribution to transport of CO2 from tissues to lungs as carbamino compounds. (NB: haemoglobin is much more important than plasma proteins for forming carbamino compounds).
3. Acid-base Balance
* Plasma proteins are responsible for 15% of the buffering capacity of blood due to weak ionisation of the imidazole groups (average pKa about 6.8) in the histidine residues.
* CO2 can combine chemically with the terminal amine groups in blood proteins, forming carbamino compounds.
4. Proteolytic Systems
* Complement: involves >25 plasma proteins,
* Kinins: circulating vasodilator hormones eg. bradykinin.
* Coagulation system: antithrombin III, protein C (clot inhibition), fibrinogen (haemostasis), clotting factors II, VII, IX, X,
* Fibrinolytic system: protein C, Protein S, Plasminogen.
5. Role in Immunity
Cytokines, antibodies, complement.
[edit]
6. Enzyme Activity
Pseudocholinesterase, alpha-1 antiprotease, alpha-1 antitrypsin.
[edit]
7. Metabolism
Provides amino acids to tissues for synthesis or catabolism. It is a circulating protein store (as opposed to muscle which is the largest, but distant)
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Physiol-01A7 Describe how the body detects and responds to a water deficit 50%
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* Water deficit causes contraction of total body water, including intracellular and extracellular compartments.
* A water deficit causes a relative increase in serum Na+.
* Na+ (and it's obligatory associated anions) account for 92 % of ECF tonicity.
* Total body water is 600mls/kg, or 42L for a 70kg man.
* TBW is 2/3 intracellular and 1/3 extracellular.
* A large water deficit of 4 litres will cause a moderate drop in intravascular volume by around 10%.
Water balance in the body can be considered as a feedback system.
Sensors: osmoreceptors, baroreceptors (low pressure and high pressure), macula densa.
Central controller: hypothalamus
Effectors: thirst, ADH, ANP, renin angiotensin system.
Effectors feed back to the sensors to change the output.
[edit]
Osmoreceptors
* specialised cells in the hypothalamus which respond to changes in CSF tonicity.
* very sensitive to changes in tonicity, essentially monitors of ECF Na.
[edit]
Low pressure baroreceptors / Volume receptors
* stretch receptors located in the walls of the large veins and right atrium.
* monitor effective intravascular volume by assessing central venous presure.
[edit]
High pressure baroreceptors
* found in the carotid sinus and aortic arch.
* monitor arterial BP, so detect BP changes that occur with very large changes in total body water.
* less sensitive than osmoreceptors but more potent.
* hypovolaemia is a more potent stimulus for ADH than is hyperosmolarity or hypertonicity.
* rate of ADH secretion is inversely proportoinally to baroreceptor firing.
* 10-25% decrease in blood volume causes ADH release.
[edit]
Hypothalamus
* Thirst centre
* osmoreceptors located in hypothalamus
* OVLT (organum vasculosum of the lamina terminalis), The organum vasculosum of the lamina terminalis regulates noradrenaline release in the anterior hypothalamic nucleus. Changes in either plasma sodium concentration or arterial pressure can differentially affect hypothalamic neurons.
* SFO (subfornical organ), responds to angiotensin II
* Contains supraoptic and paraventricular nuclei for ADH systhesis.
[edit]
Thirst
* physiological urge to drink
* thirst centre in hypothalamus responds to hypertonicity, hypotension, hypovolaemia, AGII.
* also behavioural aspects of water intake.
[edit]
ADH
* adjusts water output through effect on the kidney.
* hormone produced in the supraoptic and paraventricular nuclei in the hypothalamus.
* a nonapeptide
* secreted from the hypothalamus and moves down via axonal transport to the posterior pituitary where it is secreted into the circulation.
* secretion is stimulated by: incr plasma tonicity, hypotension, stress, hypovolaemia, AG II, drugs (eg.barbiturates, chlorpropamide).
* acts on renal cortical and medullry collecting ducts via two cell types: principal cells (water reabsorption, Na/K excretion) and intercalated cells (H+ secretion).
* combines with V2 receptors on basolateral membrane of principal cells, adenyl cyclase activated, cyclic AMP formed, cytoplasm vessicles fuse with luminal mambrane, water channels "aquaporin 2" in vesicles allow water reabsorption down osmotic gradient.
* half life of 15 minutes
* inactivated in liver and kidney
* in absence of ADH the cortical and medullary collecting ducts have low permeability to water
ANP and the renin angiotensin system
* hormone isolated from the right atrium
* increases GFR
* increases urinary sodium and water excretion
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Outline the determinants and regulation of extracellular fluid volume.
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* ECF: that portion of total body water outside body cells, including intravascular, interstitial, and transcellular fluid volumes.
* ECF is 35% of total body water, or 15L in a 70kg male.
* Na+ (and its associated anions - mainly Cl-) is responsible for ~90% of extracellular tonicity.
* Cl- usually passively follows Na+ and as such regulation of Na+ balance is the major factor in determination of ECF volume.
* Na+ balance:
o Input: 100-300mmol/day in average western dietary intake.
o Output: Kidney (most), also sweat, faeces (small amount)
[edit]
Regulation
Control of Na+ balance is a negative feedback control system.
[edit]
Sensors
* Major role:
o Osmoreceptors: Organum vasculosum of the Lamina Terminalis (OVLT) and Subfornical Organ (SFO) - both circumventricular organs associated with the hypothalamus. Sensitive to a 1% change in ECF osmolarity.
o Low pressure (stretch) baroreceptors in the atria and great vessels. Senistive to ~10% change in intravascular volume, however once stimulated dominate over osmoreceptor input.
o Intrarenal mechanisms: intra-renal baroreceptors at juxtaglomerular cells, macula densa cells.
* Minor role:
o High pressure baroreceptors in carotis sinus and aortic arch which respond to arterial pressure - very large changes in ECF volume will be reflected in blood pressure. Travel via vagal nerves to brain.
[edit]
Effectors
1. Renin-angiotensin-aldosterone system
2. Intrarenal mechanisms
3. ADH
4. ANP
[edit]
1. Renin-angiotensin-aldosterone system
Renin:
* acid protease secreted by juxtaglomerular cells - specialised cells in the media of the afferent arteriole.
* released primarily in response to
1. intrarenal baroreceptors: ↑ arteriolar pressure at JG cells.
2. decreased chloride sensed at macular densa due to decreased GFR.
3. ↑ symapthetic tone.
* Angiotensin II and ADH inhibit renin secretion.
* stimulates the conversion of angiotensinogen to angiotensin I
* angiotensin I then converted to active angiotensin II by agiotensin conerting enzyme - principally (70%) in the lungs.
Angiotensin II:
* 8 amino acid peptide hormone.
* T½ 1-1½ minutes.
* direct effect on Na+ (and biacarb)reabsorbtion in the proximal tubule.
* indirect effect on Na+ reabsorbtion through ↑ aldosterone release, and through ↑ ADH and ACTH release.
* stimulates thirst centre.
Aldosterone:
* a corticosteroid produced by zona glomerulosa cells of adrenal cortex.
* most important regulator of Na+ excretion/reabsorbtion.
* acts on intracellular receptors to produce changes in protein expression (30-60 minute latency).
* stimulated principally by ATII (also minor stimulation by ACTH, Na, K).
* promotes reabsorption of Na+ (& K+ secretion) in a variety of tight epithelia - principally in the distal portion of the nephron but also in sweat/ salivary glands, colon and rectum.
* in DCT and CD acts by insertion of Na+ channels in luminal epithlial membrane, and up regulation of sodium potassium ATPase on basolateral membrane.
[edit]
2. Intra-renal mechanisms
Glomerulotubular balance (GTB):
* Overall renal Na+ excretion = filtered load - tubular reabsorption.
* Filtered load ∝ GFR.
* GTB is a form of intrarenal autoregulation.
* Works by an unknown mechanism.
* Causes a constant proportion (~65%) of Na+ is reabsorbed in the PCT in the face of changes in GFR.
* Mitigates the effect of changes in GFR on Na+ (and thus water) reabsorbtion.
Tubuloglomerular Feedback (TGF):
* autoregulates GFR and to a lesser extent renal blood flow (RBF) within a single nephron.
* if GFR ↑ macula densa cells somehow detect an ↑ NaCl delivery to DCT (probable mediator is Cl-.
* this causes release of an unknown mediator or mediators (possibly adenosine) which causes
o afferrent arteriolar constriction → ↓ GFR & RBF.
o ↓ prostagladin release which normally cause arteriolar dilatation ↓ GFR & RBF.
o ↓ renin release.
* sensitivity of TGF is increased when ECF volume is decreased.
Renal Sympathetic Nerves:
* direct effect on Na+ reabsorbtion by action of α1 and β1 receptors on renal tubular cells.
* indirect effect on Na+ reabsorbtion by:
o renal vasoconstriction → ↓ GFR
o ↑ renin secretion by action of JG cells, and ↑ gain for renin release to non-sympathetic stimuli for renin release.
[edit]
3. ADH
* hormone produced in the supraoptic and paraventricular nuclei in the hypothalamus.
* moves down via axonal transport to the posterior pituitary where it is secreted into the circulation.
* secretion is stimulated by:
o ↑ plasma tonicity.
o hypotension.
o stress, pain, emotion.
o Nausea & vomiting.
o exercise.
o change in posture.
o hypovolaemia.
o ATII.
o drugs (eg.barbiturates, chlorpropamide).
* half life of 15 minutes.
* inactivated in liver and kidney.
Direct effect on Na+ reabsorbtion by:
* synergistic action with aldosterone - Na+ channels inserted into luminal membrane of principal cells of cortical CD.
Indirect effect on Na+ balance by:
* combination with V2 receptors on basolateral membrane of principal cells → adenyl cyclase activated → cyclic AMP formed → cytoplasmic vesicles fuse with luminal membrane → water channels "aquaporin 2" in vesicles allow water reabsorption down osmotic gradient. In absence of ADH the cortical and medullary collecting ducts are impermeable to water.
* stimulates thirst centre.
* ↓GFR by mesangial cell contraction and renal vasocontriction (V1 receptors).
* inhibits renin release.
[edit]
4. Atrial Naturetic Peptide
* released from the cardiac atria in response to stretch (↑ volume).
* also found in hypothalamus and other brain regions.
* increases excretion of Na by:
1. increasing GFR: relaxation of mesangial cells and afferent arteriolar vasodilation.
2. Probable direct inhibition of Na+ reabsorption in medullary CD.
3. reduction of renin (and thus ATII), aldosterone, and ADH release.
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Physiol-07A11 Discuss how the body handles a metabolic acidosis. 57%
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Acidosis : a process which left unchecked has a potential to cause acidemia (pH<7.35)
Increased anion gap
Causes include:
* lactic acidosis
* ketoacidosis
* chronic renal failure (accumulation of sulfates, phosphates, uric acid)
* intoxication:
o organic acids (salicylates, ethanol, methanol, formaldehyde, ethylene glycol, paraldehyde, INH, toluene)
o sulfates, metformin (Glucophage)
* massive rhabdomyolysis
Normal anion gap
Causes include:
* longstanding diarrhea (bicarbonate loss)
* pancreatic fistula
* uretero-sigmoidostomy
* Renal tubular acidosis (RTA)
* intoxication:
o ammonium chloride
o acetazolamide (Diamox)
o bile acid sequestrants
o isopropyl alcohol
* renal failure (occasionally)
* Glue sniffing
How body handles metabolic acidosis
1. Buffering
Buffer is a solution containing a weak acid and its conjugate base which resists changed in pH
a) intracellular : bicarbonate pKa=6.1, most abdundant system and is open at both ends H+ HCO3 = CO2+ H2O.
b) intracellular :
Hb : pKa=6.8, second most abdunant buffer, deoxyHb more powerful buffer due to increased carriage of CO2 (Haldane effect), contains 3xhistadine residues than average plasma protein
carbaminocompounds
histadine residues
c) interstitual - phosphate system,
2. Compensation
-excretion of 'volatile acid' ie CO2, this does not excrete the 'fixed acid' load (the metabolic cause)
-therefore considered a buffering system
-excretion of CO2 is rapid, high capacity, 20,000mmol/day
System involves
-Peripheral and central chemoreceptors; central : medulla, respond to [H+] in brain ECF; peripheral : aortic and carotid bodies, send pO2, pCO2 and pH.
-Process : ventilation centre in midbrain/pons
-Muscles of respiration : increased minute ventilation (increased tidal volume and resp rate : Kaussmal's breathing)
PaCO2= k. VCO2/VA
(ie, increasing VA decreases the arterial PCO2)
pH defined by Henderson Haesselbalch equation
pH=pKa + log [HCO3]/0.03pCO2)
3. Correction
-excretion of fixed, non volatile acids
-slow (days)
-smaller capacity than lungs : 70mmol/day
a) reabsorb HCO3
b) excrete H+
c) excrete tritratable acids
d) excrete NH4+
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Explain how a metabolic acidosis develops in hypovolaemic shock.
Describe the consequences of this metabolic acidosis for the body.
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Shock occurs when delivery of nutrients to organs is inadequate to meet organ demands.
Hypovolaemic shock can be due to reduced cardiac output or hypovolaemia.
-Resulting in inadequate perfusion of organs (reduced oxygen delivery; oxygen flux equation)
-and switch from aerobic metabolism to anaerobic metabolism
-lactatic acid produced (replenish NAD+/NADH for glycolytic pathway, very inefficient, only 2 ATP for glucose, versus 33 ATP from aerobic metabolism)
-Anion Gap metabolic acidosis
Acidosis : a process which left unchecked has the potential to cause acidemia (pH 7.35)
Consequences for the body
CVS : arryhthmias, reduced inotropy, SNS overacitivity (tachycardia, vasoconstriction), peripheral arteriolar vasodilation, venoconstriction
Resp : hyperventilatin : Kussmauls breathing, acid shift of ODC to right, decreased 2,3DPG shift to the left
Kidney : excrete acid, retain HCO3 etc
ANS : increased SNS, tachycardia, sweating,
CNS : confusion, agitation, coma
Electrolytes : hyperkalemia (shift of K out of cells), total body K deficient
overall dysfunction of NaKATPase, resulting in death.
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Physiol-03A9 Explain the role of haemoglobin as a buffer. 38%
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Only 38% of candidates passed this question.
A definition of a buffer was required, and also that buffering capacity or effectiveness depends on the concentration of the buffer relative to the ambient pH of the solution.
Haemoglobin, although intracellular (within the erythrocyte), functions mainly as an "extracellular" buffer for CO2 (volatile acid) formed from aerobic metabolism.
The solubility of CO2, the presence of carbonic anhydrase within the erythrocyte and the buffering capacity of haemoglobin all contribute to make the haemoglobin buffering system extremely efficient.
Haemoglobin is a quantitatively important buffer because there is a large amount present in blood - 150gm/L.
Also the imidazole groups of the histidine residues of the globin chains are an effective buffer as their pKa of 6.8 is close to the pH within the erythrocyte.
The buffering capacity of haemoglobin is greatest when it is needed most, that is when haemoglobin is deoxygenated in venous blood with a higher CO2 content.
Deoxygenated haemoglobin is a better buffer than oxyhaemoglobin as it is a weaker acid, and the pKa of its imidazole groups are higher at 7.9.
This information was deficient in most answers.
The increased buffering capacity of deoxygenated haemoglobin contributes approximately 30% of the Haldane effect.
Many candidates incorrectly stated that haemoglobin functioned as a buffer by the formation of carbamino compounds.
The dissociation of carbamino compounds within the erythrocyte actually adds hydrogen ions that need to be buffered by haemoglobin and other buffers.
Better answers mentioned the fact that the bicarbonate buffer system cannot buffer carbonic acid (CO2) as they form part of the same weak acid - conjugate base pair.
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Description :
univalent cation,
total 40-45mmols/kg,
found mainly intracellularly 90%, 150mmol/L
Also extracellularly 2%, 4mmol/L
Also bone 8%
Physiological function
1. major component of intracellular tonicity
2. involved in Na K ATPase of all cells
3. membrane potentials (resting and AP) Nernst Potential
4. critical for some enzyme activities : cell growth and metabolism
5. neuromuscular excitability
6. acid base regulation : maintaining electroneurality in acid/base disturbances
Cellular K buffering
When K is added to the ECF, most of the added K is taken up by the cells, reducing the ECF K+ increase. Similarly, if K is lost from the ECF, some K+ leaves the cells, reducing the ECF K decline.
Buffering of ECF K through cell K uptake is impaired in the absence of aldosterone or of insulin or of catecholamines.
Renal regulation of Potassium
In normal function, renal K excretion balances most of the K intake (about 1.5 mmol/Kg per day). The kidneys excrete about 15 % of the filtered K load of 10 mmol/Kg per day.
Along the proximal tubule the K concentration remains nearly equal to that in plasma. Since the PCT reabsorbs about 2/3 of the filtrate water, it also reabsorbs about 2/3 (66%) of the filtered K. This reabsorption is mostly passive and is driven by the positive tubule electrical potential present along the S2 and S3 segments and by paracellular solvent drag.
Along the descending limb of the loop of Henle, K is secreted into the tubule lumen from the interstitium. Along the thick ascending limb, K is reabsorbed via Na-K-2 Cl cotransport. In the loop, there is net K reabsorption of 25% of the filtered K.
Along the distal tubule and collecting ducts, there is net secretion of K which is stimulated by aldosterone and when there is dietary K excess. Secretion decreases and becomes net reabsorption in K deficiency. Regulation of renal K excretion is in the CD and is mostly by changes in the rate of K secretion.
In the CD, K secretion is by the principal cells (via luminal K channels and basolateral Na-K ATPase) and K reabsorption is by the alpha intercalated cells via a luminal H-K ATPase.
K secretion from principal cells into the CD lumen is enhanced by luminal and cellular determinants:
Luminal determinants that stimulate K secretion are increases in tubule urine flow (which reduces the intratubular K concentration), the delivery of sodium to the CD, and the delivery of poorly reabsorbed anions (other than Cl) to the CD. Na delivery followed by its reabsorption increases K secretion by increasing the lumen negative electrical potential and by stimulating the activity of the Na-K ATPase which results in enhanced accumulation of K in the cells. The presence in the CD of poorly reabsorbed anions (SO42-, excess of HCO3, beta hydroxybutyrate, or HPO42-)enhances the negativity of the CD lumen, favoring K secretion.
Cellular determinants of K secretion are the activity and abundance of K channels at the luminal cell membrane and of Na-K ATPase at the basolateral membrane. Both of these are enhanced primarily by aldosterone, and also by ADH (by decreasing urine flow, ADH reduces K secretion, but by increasing luminal permeability, ADH promotes it) and by dietary K excess. K deficiency is associated with increased activity and expression of luminal H-K ATPase in the alpha intercalated cells of the CD, which act to promote reabsorption of K from the lumen.
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Desciption :
Bivalent cation
Total body 10mmol
Distributed : 1% extracellularly : 1.0mmol/L
Intracellularly 10mmol/L bound to ATP
Functions
1) intracellular catalyst or cofactor, over 300 enzymes, eg oxidative phophorylation, sodium pump, anything involved ATPase
2) Ca++ antagonist, reduces nerve and muscle excitability, inihibits transmitter release and excitation contraction coupling
3) blocking of NMDA receptor
4) vasodilator
Derrangement
1.0 :referance range
2.0-3.5 : therapeutic range - anticonvulant, vasodilator
>4.0 : ECG changes, increase QT, wide QRS
5.0 : Loss of patella reflex
6.0 : respiratory paralysis, complete heart block
12.0 : asystole
Regulation of Magnesium
Orphan ion, no hormonal regulation
Glomerulus : 80% filtered only
Reabsorption : different to the rest
PCT : 15% due to concentration gradient produced by movement of Na and H2O
Ascending LOH : 60% due to electrical gradient produced by Na K Cl movement and H2O
DCT : 10% unknown, likely electrical gradient
Other
-secreted in the gut
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Description : univalent cation
Total : 60mmol/kg (4000mmol in reg males)
Distribution
Extracellular : 50%; 140mmol/L
Intracellular : 5%; normal 12mmol/L, but RBC 20mmol/L
Bone : 45%
Requirements : 1mmol/kg/day
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Physiol-08A9 The skin, the kidneys, and the carotid bodies are examples of where specific organ blood flow is far in excess of that organ's metabolic requirements. For each example, explain what the physiological role of the high organ blood flow is, why this high flow is an advantage to the person and a brief description of the mechanisms involved.
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Examiners report 11% passed
Skin : Thermoregulation role with heat conversation / loss. Normothermia allows normal enzyme function. High flow via superficial arteriole network and arterio-venous anastomosis with sympathetic nervous system control. Addidtional marks for role as blood reservior, correct value for blood flow and importance of sweating.
Kidneys : Role is to excrete waste products and sodium/water balance. Advantage is the maintenance of constant internal environment. High flow via short large renal arteries, parraell interlobular arteries and parallel afferent arteriole branches. Additional marks for renal blood flow value.
Carotid bnodies : high flow mean organ oxygen requirements do not interfere with measuring PaO2. The advantage is early detection of hypoxia. High organ flow occurs due to the small size of the organ and the flow directly from the carotid artery. Additional marks for the organ blood flow rate and lack of effect from anaemia or carbon monoxide poisoning.
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Physiol-03B9 Describe the effects of tachycardia on myocardial oxygen supply and demand in a normal heart. 40%
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Myocardial oxygen demand is determined by:
* myocardial wall tension
* contractility
* heart rate
Oxygen (or blood) supply is determined by
1. Coronary vessel resistance
* autoregulation - both myogenic and metabolic
* autonomic input
* physical factors such as wall tension causing compression of cardiac vessels
1. Mean arterial pressure
In the normal adult, coronary blood flow at rest is 250 ml/min; oxygen consumption by cardiac mm of 8-10 ml/min/100g of tissue
At rest, cardiac mm has high O2 extraction ratio- 65% vs 20% body average. Leaves pO2 in coronary sinus 20 mmHg.
AS heart rate increases, oxygen demand increases. As O2 extraction ratio is so high, in order to meet increased demand FLOW of blood must increase.
Flow can increase by 4-5 x in coronary vessels up to 1250 ml/min. This is due to metabolic autoregulation. When metabolism increases, (ie increased O2 demand) there is an increase in tissue concentrations of vasodilating metabolites eg adenosine, K+ ions, increased CO2 and Decreased O2. This results in vasodilation and therefore increased flow.
If increased heart rate is related to sympathetic stimulation (as in exercise) there is also Beta 2 mediated coronary vasodilatation, which also helps to increase flow.
These mechanisms help to maintain flow and tend to compensate for decreased coronary perfusion time in LV in tachycardia.
* At rest (HR 70 bpm) systole 0.3s, diastole 0.55s
* During systole braches of LCA which supply subendocardium of LV are strongly compressed secondary to high ventricular pressure, virtually abolishing blood flow.
* Majority of LV flow occurs during diastole (approx 85%)
* Right coronary flow is reasonably constant throughout cardiac cycle due to much lower pressurs in R ventricle.
* See graphs of coronary blood flow (as in Brandis)
* With tachycardia, time for diastole is shortened. Eg HR 200 bpm, systole and diastole both 0.15s. Much decreased time for perfusion of LV.
* In the normal heart, autoregulation and sympathetic stimulation tend to increase blood flow enough to compensate for decreased perfusion time.
* However as flow to subendocardium of LV ceases altogether during systole, it is most vulnerable to rate related ischaemia.
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Physiol-00A2 Briefly describe the factors that influence the partial pressure of oxygen in mixed venous blood 56%
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Mixed venous blood: True mixed venous blood must be obtained from a pulmonary artery catheter where blood from SVC, IVC and coronary sinus have fully mixed. Systemic blood, returning from the all tissues, is collected and mixed in the right ventricle and pulmonary artery. Thus, mixed venous pO2 and pCO2 reflect O2 extraction and CO2 addition from the entire body.
Typical values for a mixed venous blood gas on a person breathing room air are:
PvO2 of 40mmHg
PvC02 of 45mmHg
Sa02 of 75%.
These values typically correspond to a Venous 02 content of 15mls/decilitre for normal ranges of Hb in the blood.
Arterial values are:
PaO2 of 100mmHg
PaC02 of 40mmHg
Sa02 of 97.5%
Relationship between PO2 and O2 content in mixed venous blood:
P02s relationship with O2 content dependent on shape of Hb02 dissociation curve.
2 important characteristics of the curve are the flat upper part and steep lower part. The former tends to buffer Haemoglobin saturation against a substantial drop in P02 which is useful in the lungs to maintain arterial Hb saturation. The latter helps with large 02 unloading and a maintained 02 diffusion gradient from the blood to the tissues.
Right shifted Hb02 decreases Hb’s affinity for 02 and increases the amount dissolved i.e. P02 – factors which right shift are decrease in pH, increase in C02, and increase in temperature and increase in 2,3 DPG levels.
FICK equation:
Modification of the FICK equation:
VO2 = (CaO2 - CvO2).Q
gives
Cv02 = Ca02 – V02/Q
which demonstrates the inverse relationship between oxygen extraction by tissues and the cardiac output. If cardiac output decreases, oxygen extraction by the tissues increases, causing mixed venous 02 concentration to fall. This fall in concentration causes a decrease in mixed venous Pv02.
Cv02 is directly proportional to Ca02. However, clinically, this factor is not as important as the level of cardiac output. This is because relatively large increases in partial pressure of oxygen (eg hyperbaric) are required to substantially increase the 02 content of arterial blood above 20ml/dl as Hb is near fully saturated at a Pa02 of 100mmHg and any additional increase in partial pressure contributes a relatively miniscule 0.003mls of 02/mmHg/ml of blood.
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Physiol-99B5 Describe the ways in which CO2 is carried in the blood 55%
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CO2 is carried in blood in three different ways. (The exact percentages vary depending whether it is arterial or venous blood).
Most of it (about 70% – 80%) is converted to bicarbonate ions HCO3− by the enzyme carbonic anhydrase in the red blood cells,[38] by the reaction CO2 + H2O → H2CO3 → H+ + HCO3−. 5% – 10% is dissolved in the plasma[38] 5% – 10% is bound to hemoglobin as carbamino compounds[38] Haemoglobin, the main oxygen-carrying molecule in red blood cells, carries both oxygen and carbon dioxide. However, the CO2 bound to hemoglobin does not bind to the same site as oxygen. Instead, it combines with the N-terminal groups on the four globin chains. However, because of allosteric effects on the hemoglobin molecule, the binding of CO2 decreases the amount of oxygen that is bound for a given partial pressure of oxygen. The decreased binding to carbon dioxide in the blood due to increased oxygen levels is known as the Haldane Effect, and is important in the transport of carbon dioxide from the tissues to the lungs. Conversely, a rise in the partial pressure of CO2 or a lower pH will cause offloading of oxygen from hemoglobin, which is known as the Bohr Effect.
Carbon dioxide is one of the mediators of local autoregulation of blood supply. If its levels are high, the capillaries expand to allow a greater blood flow to that tissue.
Bicarbonate ions are crucial for regulating blood pH. A person's breathing rate influences the level of CO2 in their blood. Breathing that is too slow or shallow causes respiratory acidosis, while breathing that is too rapid leads to hyperventilation, which may cause respiratory alkalosis.
Although the body requires oxygen for metabolism, low oxygen levels do not stimulate breathing. Rather, breathing is stimulated by higher carbon dioxide levels. As a result, breathing low-pressure air or a gas mixture with no oxygen at all (such as pure nitrogen) can lead to loss of consciousness without ever experiencing air hunger. This is especially perilous for high-altitude fighter pilots. It is also why flight attendants instruct passengers, in case of loss of cabin pressure, to apply the oxygen mask to themselves first before helping others — otherwise one risks going unconscious.[38]
Typically the gas we exhale is about 4% to 5% carbon dioxide and 4% to 5% less oxygen than was inhaled.
According to a study by the United States Department of Agriculture, an average person's respiration generates approximately 450 liters (roughly 900 grams) of carbon dioxide per day
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Physiol-99A3 Describe the factors that affect the transport of oxygen and carbon dioxide form the alveolus to the blood. 44%
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Overall this question was well answered with 44% of candidates achieving a pass.
The factors that affect transport of oxygen and carbon dioxide between alveolus and blood can be described by Fick's Law of simple diffusion ie. Diffusion constant, surface area, membrane thickness, and concentration gradient (or more correctly partial pressure gradient).
Marks were awarded for relating these factors to the alveolus and lung.
The influence of solubility and molecular weight on the diffusion constant for individual gases should have been described, with comparisons for oxygen and carbon dioxide.
Additional marks were awarded for describing the influence of cardiac output and the rate of combination of oxygen with haemoglobin.
Oxygen diffusion is normally perfusion limited.
Increases in cardiac output (eg. with exercise) normally result in recruitment of alveoli thereby increasing the surface area for diffusion.
However, in the presence of disease or a low partial pressure gradient (eg. at high altitudes), an increased cardiac output may reduce red blood cell transit time resulting in insufficient time for equilibration of oxygen, making oxygen, unlike carbon dioxide, diffusion limited.
The combination of oxygen with haemoglobin is important because it ensures a low capillary partial pressure of oxygen and maintains a gradient for oxygen diffusion despite a higher oxygen concentration in the blood.
In this way haemoglobin concentration, the affinity of haemoglobin for oxygen, and capillary blood volume influence the rate of oxygen diffusion.
Many candidates wasted time providing detailed descriptions of oxygen and carbon dioxide transport in the blood, the haemoglobin-oxygen dissociation curve, alveolar ventilation, or ventilation-perfusion mismatch.
Failure to address the question led to a reduction in scores.
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Physiol-97A3 Describe the role of haemoglobin in the carriage of carbon dioxide in the blood 59%
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An adequate answer included:
1. Most CO2 is carried as bicarbonate: buffering of H+ by Hb permits far more CO2 to be carried than if this buffering was absent. Hb has far more histidine resude than plasma protein, thus higher buffering capacity.
2. Carbamino haemoglobin (not carboxyhaemoglobin as stated by some candidates): what it is, where the binding occurs, importance in CO2 transport. Some candidates felt because of the small amount of carbamino Hb formed is small compared with HCO3- concentration, its role must be small. In fact, it has a major role because of its importance in the Haldane effect.
3. The Haldane effect: mainly effects carbamino formation with a lesser effect on buffering. This may be illustrated on CO2 dissocation curve, which should be drawn (including axis labels and representative points on both axes) and explained.
Extra points were awarded for noting proportion of CO2 that is carried (and the A-V difference) as HCO3- and as carbamino Hb, for mentioning the amount of CO2 carriage for which the Haldane effect is responsible and for noting (correctly) the binding sites for H+ and those for CO2. Candidates were expected to show understanding of the mechanism by which is CO2 is carried, rather than just reproduce verbatim what the standard textbooks say on the subject. This implies some understanding of the effect of H+ buffering and of carbamino formation on the partial pressure gradients down which CO2 diffuses in the tissues and in the lungs, and the influence of the Haldane effect on these diffusion gradients.
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Physiol-96B8 Briefly explain how an oxygen debt arises and how the body deals with it 75%
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Oxygen Debt During muscular exercise, blood vessels in muscles dilate and blood flow is increased in order to increase the available oxygen supply. Up to a point, the available oxygen is sufficient to meet the energy needs of the body. However, when muscular exertion is very great, oxygen cannot be supplied to muscle fibers fast enough, and the aerobic breakdown of pyruvic acid cannot produce all the ATP required for further muscle contraction.
Lactic Acid During such periods, additional ATP is generated by anaerobic glycolysis. In the process, most of the pyruvic acid produced is converted to lactic acid. Although about 80% of the lactic acid diffuses from the skeletal muscles and is transported to the liver for conversion back to glucose or glycogen.
Oxygen Ultimately, once adequate oxygen is available, lactic acid must be catabolized completely into carbon dioxide and water. After exercise has stopped, extra oxygen is required to metabolize lactic acid; to replenish ATP, phosphocreatine, and glycogen; and to pay back any oxygen that has been borrowed from hemoglobin, myoglobin (an iron-containing substance similar to hemoglobin that is found in muscle fibers), air in the lungs, and body fluids.
The additional oxygen that must be taken into the body after vigorous exercise to restore all systems to their normal states is called oxygen debt (A.V. Hill 1886-1977).
Eventually, muscle glycogen must also be restored. This is accomplished through diet and may take several days, depending on the intensity of exercise. The maximum rate of oxygen consumption during the aerobic catabolism of pyruvic acid is called "maximal oxygen uptake". It is determined by sex (higher in males), age (highest at about age 20) and size (increases with body size).
Highly trained athletes can have maximal oxygen uptakes that are twice that of average people, probably owing to a combination of genetics and training. As a result, they are capable of greater muscular activity without increasing their lactic acid production, and their oxygen debts are less. It is for these reasons that they do not become short of breath as readily as untrained individuals.
Oxygen consumption following exercise After a strenuous exercise there are four tasks that need to be completed:
Replenishment of ATP Removal of lactic acid Replenishment of myoglobin with oxygen Replenishment of glycogen The need for oxygen to replenish ATP and remove lactic acid is referred to as the "Oxygen Debit" or "Excess Post-exercise Oxygen Consumption" (EPOC) - the total oxygen consumed after exercise in excess of a pre-exercise baseline level.
In low intensity, primarily aerobic exercise, about one half of the total EPOC takes place within 30 seconds of stopping the exercise and complete recovery can be achieved within several minutes (oxygen uptake returns to the pre-exercise level).
Recovery from more strenuous exercise, which is often accompanied by increase in blood lactate and body temperature, may require 24 hours or more before re-establishing the pre-exercise oxygen uptake. The amount of time will depend on the exercise intensity and duration.
The two major components of oxygen recovery are:
Alactacid oxygen debit (fast component) the portion of oxygen required to synthesise and restore muscle phosphagen stores (ATP and PC) Lactacid oxygen debit (slow component) the portion of oxygen required to remove lactic acid from the muscle cells and blood
Recovery following maximal exercise
The replenishment of muscle myoglobin with oxygen is normally completed within the time required to recover the Alactacid oxygen debit component.
The replenishment of muscle and liver glycogen stores depends on the type of exercise: short distance, high intensity exercise (e.g. 800 metres) may take up to 2 or 3 hours and long endurance activities (e.g. marathon) may take several days. Replenishment of glycogen stores is most rapid during the first few hours following training and then can take several days to complete. Complete restoration of glycogen stores is accelerated with a high carbohydrate diet.
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Physiol-05B9 Describe the gravity dependent processes which affect pulmonary blood flow. What changes take place when the pressure increases in the pulmonary vessels? 82%
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Gravity results in a hydrostatic pressure gradient dependant on vertical proportions of the lung. 2/3 lung below and 1/3 lung above the RV. (dependant on posture ie supine/upright)
Postural changes: when supine, distribution of flow from base to apex becomes uniform, blood flow in posterior lung exceeds anterior lung. There is an increase in apical flow and basal flow remains virtually unchanged.
Pressure in the pulmonary artery just exceeds hydrostatic pressure in the lung apex to ensure blood reaches there > provides max surface for gas exchange.
West’s 4 zones:
* Zone 1:
PA>Pa>Pv Apex, pathological Alveolar pressure exceeds a & v pressures Eg hypotension, emboli, incr alv pressures (PPV)
* Zone 2:
Pa> PA> Pv Increase in arterial pressure due to increase in hydrostatic pressure. Venous pressure still very low. Blood flow is reliant on difference between arterial and alveolar pressure> Starlig resistor (where flow depends on pressure from outside lumen)
* Zone 3:
Pa>Pv>PA Base of lung, normally Hydrostatic pressure inc Pa and Pv, therefore flow dependant on Pa-Pv pressure difference
* Zone 4:
Base of lung at low volumes Region reduced blood flow Due to narrowing (loss of traction) of extra alveolar vessels (larger vessels in lung parenchyma where calibre depends on lung volume vs capillaries whose calibre depends on alveolar pressure NB very large vessels near hilum exposed to intrapleural pressure) at low lung volumes there is an increase in PVR> decr perfusion
When there is an increase in pulmonary arterial or venous pressures there is a decrease in PVR due to 2 processes:
1. Recruitment is when pulmonary arterial pressure increases from low levels, closed vessels begin to conduct blood.
2. Distension occurs at higher vascular pressure. In zone 3 vessels increase in caliber.
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Physiol-04A9 Briefly outline the differences between the pulmonary circulation and the systemic circulation 26%
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1: Systemic
2: Pulmonary
Vessels
1 : Relatively thick walled with abundant smooth muscle - esp arterioles.
*aorta long, thick walled and minimally distensible.
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2: Thin walled, minimal smooth muscle, thus very distensible vs. systemic vessels.
*Pulmonary a. short, thinwalled and distensible.
Innervation
1: Abundant autonomic (esp symathetic) innervation which in conjunction with abundant smooth muscle means PVR highly regulated by automonic nervous system.
2: Extensive autonomic innervation still present aslthough effect less pround due to less vascular smooth muscle as above.
Function
1: Regulating flow to various organs in face of peturbations in demand, volume and pressure.
*Regulating flow in the face of markedly variable hydrostatic pressures (e.g. upstretched arm vs. foot)
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2: accepting entire CO with minimal requirement for regulation/redirection of flow (exception local redistribution of flow in response to area of low {{PAO2}}).
* maintaining maximally efficient flow to gas exchanging surface of the lung in the face of alterations in CO, alveolar and transmural pressure (see regulation of PVR).
Pressure and Flow'
Pressures (mmHg)
1: 120/80 MAP 100
2: 25/8 MAP 15
Atrial pressure (mmHg)
1: Left 5
2: Right 2
P. drop inlet-outlet (mmHg)
1 : 100 (i.e resistance high)
2 :10 (i.e resistance 10x less)
Major point of resistance
1: Arterioles
2 :Evenly spread across pulmonary circulation.
Nature of Flow
1: Dampened, relatively linear.
2: Undampened, highly pulsitile (up until capillary bed).
Role as filter of blood
1: No
2 :Yes
Regulation of Flow & Resistance
Increased CO or Arterial P
1 :Response principally regulated via autonomic nervous system (baroreceptor reflex).
2: Prinicipal factor intrinsic qualities of the pulmonary vessels themselves:
*Resistance inversely proportional to flow & pressure due to ''capillary recruitment'' and ''vascular distention'' (see West fig 4-4).
Change in Lung Volume
1: Nil
2: PVR increases at low and high lung volumes (see West fig 4-6):
*at low lung volumes extra-alveolar vessels collapse as smooth muscle tone tone exceeds traction from surrounding parenchyma.
*at high lung volumes capillaries are stretched and thus diameter decreases → ↑ R.
Autonomic Regulation
1: Principal determinant of systemic vascular resistance - particularly sympathetic tone at arterioles (major point of resistance in systemic circulation).
2: Sympathetic stimulation of the cervical ganglia reduces pulmonary blood flow by up to 30% (i.e less effect than in systemic circulation but still significant).
Hypoxia
1: Hypoxia causes NO mediated decrease vascular tone thus decrease vascular resistance.
decrease {{PAO2}} esp below 70% of normal causes increase pulmonary vascular tone.
* Probably an as yet unidentified messenger released from alveolar epithlial cells and acting on pulm. arteriolar smooth muscle (Guyton 11ed page 485).
* can increase vascular resistance by 5x
* OPPOSITE to effect on systemic circ where hypoxia causes NO induced vasodilation.
* main role in localised redistribution of pulmonary blood flow to better ventilated areas of lung (decrease physiological shunt).
Hypercarbia increase{{pco2}} decrease pH
1 : Vasodilation (esp cerebral circulation).
2: Vasoconstriction - thus like hypoxia helps divert blood flow away from poorly ventilated areas of lung (although effect of hypoxia much more dramatic).
Posture (Hydorstatic forces)
1: hydrostatic pressures though larger than those exerted on the pulmonary circulation (e.g head to toe =170cm{{H20}}, lung apex to lung base = 30 to 40 cm{{h20}}) relative to the systemic MAP they are smaller.
2: while hydrostatic forces on pulmonary vaculature are less than in systemic circulation lower pressures mean that flow is dramatically affected (forces are relatively larger vs. pulmonary MAP):
* see West's zones of the lung (see West fig 4-8):
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Physiol-02A4 Outline the physiological factors that influence pulmonary vascular resistance 57%
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Definitions & Normal Values
The resistance of a system of blood vessels may be defined as:
vascular \ resistance = (input pressure - output) /{blood flow}
Pulmonary mean arterial pressure ≈ 15mmHg (normal range (NR) 10-20)
Left Atrial Pressure ≈ 5mmHg (NR 0-10)
Cardiac output at rest ≈ 6 L.min- (NR 4-8)
thus pulmonary vascular resistance (PVR):
PVR = {15 - 5}/{6} = 1.7 mmHg.L/min
with a range of roughly 1-2 mmHg/L.min
* units known as the Wood's unit.
* may also be expressed as dyne/sec/cm5
* Notably this approximately 10x less than the systemic vascular resistance.
* As there is far less damping of pulsatile flow due to the thin walls in the pulmonary vessels, vascular impedence is a better term than resistance (resistance an adequate term for constant flow but impedance a better measure for pulsitile flow as it takes into account factors that oppose change in flow e.g viscosity, rate of change).
It is also useful to consider the determinants of resistance to laminar flow in a tube:
Flow = pressure difference x resistance (Ohm's law)
where
Resistance = 8ηL/πr4
and where
r = radius of tube through which fluid is flowing
L = length of tube
η = fluid viscosity
PVR will be altered by any factor that influences the above variables, as will be seen below.
Potential Answer Structure
* defintions & normal values as above
* pressure and CO (vol) relationship (West 4-4)
* lung vol relationship (West 4-6)
* smooth musc tone
o hypoxia (West 4-10)
o others
+ NO
+ histamine/serotonin
+ drugs
+ autonomic tone
* posture
* viscosity
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Physiol-05A13 Describe the non-respiratory functions of the lung. 56%
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The non-respiratory functions of the lung may be grouped under the following headings:
1. Blood reservoir
2. Blood filtration
3. Defense against particulates
4. Heat & H2O exchange
5. Metabolism
[edit]
1. Blood Reservoir
The pulmonary circulation acts as a reservoir for blood:
* holding about 20% of the blood volume, or ≈ 1000 ml
* of which < 100 ml is in pulmonary capillaries.
[edit]
2. Blood Filtration
The capillaries act as a particulate filter for blood-borne particles:
* particles <10 µm filtered as the the capillary diameter is 7 µm.
* however, some particles as large as 500 µm may traverse the lung presumably via shunt pathways.
* also acts as a 'imunological filter' helping prevent microbial spread form venous to arterial system.
* pathological anatomical shunts may bypass this filtering (e.g paradoxical embolus via patent foramen ovale).
[edit]
3. Defense Against Particulates
Note examiner makes distinction upper airways cf. lung, so discussion of mucocillary escalator, cough and sneeze etc. probably not appropriate for this question? Gray 18:42, 18 Feb 2007 (EST).
* only the tiniest suspended particles make it as far as the alveoli, the vast majority being filtered in the upper airways by impaction (large airways) and sedimentation (teminal and resp. bronchioles).
* particles <0.1μm can deposit on alveolar walls by diffusion (as air flow at the level of the alveoli is effectively nil).
* particles that settle in the alveoli are engulfed by macrophages and leave via the blood or lymphatics.
* in this same way the alveolar macrophages act as a defence against any inhaled microbes that make it as far as the alveoli, or in clearing infection due to multiplication of microbes in the alveoli (e.g in pneumonia).
[edit]
4. Heat & Water Exchange
* acts as a source for considerable heat exchange and results in the insensible loss of water especially for neonates and small children.
* that said majority of heat & H2O exchange occurs in the conducting airways.
* role of the lung may increase in very dry or cold climates or with markedly increased rate of ventilation.
[edit]
5. Metabolism
The lung contributes to 1-2% of the basal O2 consumption; however this may be dramatically increased in ARDS/IRDS.
Below is modification of Ganong 22nd ed. Table 34-6
[edit]
Synthesized and Used in Lung
* Dipalmitoylphosphatidylcholine (DPPC) (http://en.wikipedia.org/wiki/Dipalmitoylphosphatidylcholine) - a component of surfactant.
* mucopolysaccarides for mucus coating of airways.
* collagen and elastin for structural framework of lung.
[edit]
Synthesized or Stored and Released into Blood
May act locally or systemically e.g. histamine → bronchoconstriction.
* Prostaglandins*.
* Leukotrienes* (incl. SRS-A).
* Histamine (lung rich in mast cells).
* Kallikrein.
*Arachidonic acid metabolites.
[edit]
Substrate Activation
Angiotensin I to Angiotensin II:
* by ACE located in small pits in the surface of capillary endotheilial cells.
* the only known biological activation by passage of a substance thru the pulmonary circulation (West).
[edit]
Substrate Inactivation or Uptake
* bradykinin ~ 80% (by ACE).
* serotonin ~ 98% (uptake and storage rather than enzymatic).
* PGE1, PGE2, PGF2α (not PGA2 or PGI2 (prostacyclin)).
* leukotrienes ~ 98%.
* noradrenaline ~ 30% uptake .
* fibrinolysis.
* acetylcholine.
* adenonucleotides
* drugs: tricyclic antidepressants, fentanyl, propofol, propranolol, lignocaine, imipramine, nortryptyline.
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Physiol-08B15 Describe the changes that occur with ageing that can affect oxygen delivery to the tissue during moderate exercise.
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Physiol-08B15 Describe the changes that occur with ageing that can affect oxygen delivery to the tissue during moderate exercise.
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Physiol-08A16 Discuss the physiological causes of early post-operative hypoxaemia. 13%
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Physiol-08A16 Discuss the physiological causes of early post-operative hypoxaemia. 13%
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Physiol-04A12 What are the physiological consequences of decreasing functional residual capacity by one litre in an adult? 50%
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Definition & values
FRC = RV + ERV
Normal is 30ml/kg (giving 2.1 litres in a 70kg adult male)
It is the balance of the outward elastic recoil of the chest wall and the inward elasctic recoil of the lung
[edit]
Consequences of reducing FRC by 1L in an adult
* significant, as it is a decrease of nearly 50%
Decreased O2 store: most noticable with a RSI of an obese woman at term
Decreased O2 buffering capacity, with increased variation of breath-to-breath paO2
Decreased lung volume, with the following effects:
* Increased work of breathing
- increased elastic work (due to decreased compliance)
- increased resistance work (due to increased AWR - less radial traction on walls of airways)
- increased small airways closure and increased pressure required to open airways ("critical pressure")
* Increased pulmonary vascular resistance (and increased RV resistance work)
* FRC will fall below closing capacity
- Closing capacity = FRC in a 44yo in supine position, so anyone this age and above will be affected
- Atelectasis/small airway closure during normal tidal breathing
- Increased V/Q mismatch and shunt due to above, causing hypoxaemia
[edit]
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Physiol-01B1 Explain the effects of intermittent positive pressure ventilation on left ventricular output. 55%
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IPPV uses positive intrathoracic pressure as a means of ventilating the lungs, in contrast to the negative pressures which occur in normal breathing. This impacts on left ventricular output in the following sequence;
1. As inspiration begins, intrathoracic pressure rises, ‘squeezing’ the blood from the lungs and great vessels into the left heart. This increases left heart preload and therefore results in increased LV output.
2. Further positive intrathoracic pressure now impairs venous return to the right heart and increases right heart afterload, reducing the output from the right heart and therefore decreasing left ventricular preload. LV output then falls gradually.
3. As expiration begins, the removal of positive intrathoracic pressure allows the great vessels and lungs to expand, reducing return to the left heart, and causing a further transient reduction in LV preload.
4. Removal of the increased RV afterload and increased venous return then ‘normalises’ the left heart preload and therefore LV output increases back to preinspiratory levels.
Important points:
* Ventricular interdependance: Increased RV afterload and endsystolic volumes increase the RV chamber and push the interventricular septum to the left. This, coupled with external splinting due to positive thoracic pressure decreases ventricular compliance, further adding to the reduction in LV preload.
* LV Afterload: is decreased (increased intrathoracic pressure reduces the transmural gradient and therefore reduces tension in the LV wall - Law of LaPlace tension proportional to transmural pressure), therefore IPPV is beneficial in CCF by both reduction in LV preload and afterload.
* Effect of PEEP: The presence of higher inspiratory pressures or positive end expiratory pressure (PEEP- which prevents 3 and 4 from occurring back to basal levels) exaggerates the decrease in LV output seen.
* Effect of hypovolaemia: The presence of hypovolaemia reduces central venous pressures, reducing the ability to offset the reduction in venous return caused by PEEP, also exaggerating the reduction in LV output seen with IPPV.
* Overall CVS effects: are unpredictable but in young people with normal LV function IPPV tends to cause a reduction in cardiac output and BP, and in the elderly or those with impaired LV function cardiac output and BP tend to be unchaged or improved.
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Physiol-02A2 Draw a labelled diagram of a cardiac action potential highlighting the sequence of changes in ionic conductances. Explain the terms 'threshold', 'excitability', and 'irritability' with the aid of a diagram. 56%
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* An action potential is a wave of electrical discharge that travels along the membrane of an excitable cell.
* The cardiac action potential differs between different types of cardiac cell. That is, the action potential observed in the SA node area (slow response) is different to that seen in the ventrcles (fast response).
* Ventricular cardiac action potentials are primarily controlled by INa (SCN5A), IKr (HERG+miRP), and IKs (KvLQT1+minK), and can be divided into phases 0-4:
myocardactionpotential.gif
Phase 0 - Depolarisation.
* Fast sodium channels (INa) open when the membrane potential reaches threshold to allow rapid entry of sodium into the cell (increased gNa).
* Potassium conductance is reduced because the potassium inward rectifier channel becomes non-conducting at positive potentials.
* The peak of the action potential may reach +40mV.
Phase 1 - Spike/Partial repolarisation
* closing of fast sodium channels (and decreased gNa)
* opening of the "transient outward" potassium channel (Ito).
Phase 2 - Plateau.
* Due to rising permeability of the cell to calcium (and therefore increased Ca influx), maintaining depolarisation.
* The Ca influx (mainly through Ca L-type channels) is balanced by a K efflux (through Ito & IKr - the rapid delayed rectifier).
Phase 3 - Repolarisation.
* Continued K efflux with at least 4 K currents (the rapid and slow delayed rectifiers, the inward rectifier (with an OUTWARD K current - don't believe everything you read about rectifiers!), and the transient outward K current).
* gCa/ICa decreases as Ca channels close.
* Na channels remain in the "inactive" state until about halfway through phase 3 (Absolute refractory period), then as more H gates open in the Na channels the permeability increases, and with an appropriate stimulus, another action potential can result (Relative Refractory period).
Phase 4 - Resting Membrane potential (-90mV).
* mainly determined by [K], as there is a much larger permaebility to K than other ions (the reason why the RMP is slow close to the Nernst potential for K) - can be determined by the Goldmann equation
* the inward rectifier K channel is responsible for the stability of the RMP (as it tends to oppose the effect of a change in membrane potential, until it is blocked at much less negative/or positive values
* there is only a very small contribution from other ions due to their low permeability (and also from the electrogenic Na/K pump)
Differences in a "Slow Response" cell (as the question did not state what type of cell)
* No Fast sodium channels (therefore no Fast response)
* No K inward rectifiers (so less stable RMP - in fact, this allows diastolic depolarisation)
* HCN channels responsible for the pre-potential (the "funny" current)
* less negative RMP (-60mV), and therefore slower conduction, and less negative threshold (-40mV)
* RMP not stable during phase 4
* There is less of a plateau in phase 2
Threshold
* is the electrical point at which an action potential is self-propogated.
* This value is approx. -65-70mV for a "fast response" cell, and about 40mV for a "slow response" cell. It causes opening of Na channels in fast cells, and Ca channels in slow cells.
* This is determined by the sensitivity of the ion channel responsible for depolarisation, and also the relative concentrations of the ion being transported. For example the threshold of ventricular muscle cells is governed by the voltage sensitivity of the SCN5A fast sodium ion channel, and the concentration of Na+ oudside the cell. In the SA node threshold is reached by steady depolarisation of the resting membrane, rather than by a sudden change in electrical potential (as is the case for ventricular myocytes). This allows the SA node to make its own beat (automaticity) and allows regular pacemaker activity (rhytmicity).
(I am uncertain as to whether the [Na] gradient does actually effect the threshold level - it affects the amplitude of the action potential though)
Excitability: cardiac excitability depends on activation, inactivation and recovery of various ion channels. In ventricular muscle (fast response action potential) inactivation of INa channels results in an absolute refractory period, where a second action potential is impossible. About halfway through repolarisation (phase 3), at approximately -50mV, enough INa channels have recovered from their inactive state to allow the possibility of another action potential, but only in the presence of a greater than normal stimulus. This is called the relative refractory period and is important in the long QT syndrome and early after depolarisation (EAD). In slow response tissue (SA node and AV node) refractoriness is much longer and extends well into the resting potential phase (phase 4).
* the excitability refers to the slope of the upstroke in phase 0
* the excitability is reduced (compared to normal) during the relative refractory period, and progressively increases as phase 3 progresses
* the excitability is related to the conduction velocity, as the steeper the upstroke, the higher the conduction velocity
Irritability: one of 2 things,
1. The ease of stimulating an arrythmia. Immediately after the action potential, the membrane is transiently hyper-excitable and is said to be in its vulnerable period. During this time relatively weak stimuli in the form of delayed after depolarisations (DAD) can propogate action potentials, leading to extra beats or sustained arrhythmias.
2. a diminished potential between RMP and threshold (as the examiner notes state above)
* this means the action potential is easier to stimulate, as potential change to threshold is less
* however it causes a flatter upstroke than usual (less excitable), causing a decrease in conduction velocity
-note the relationship between irritability and excitability (irritability affects excitability, but not the other way around)
-therefore they both affect conduction velocity
A small word on Conduction Velocity
* [Na] gradient affects AP amplitude - therefore conduction velocity
* gNa is a determinant of the rate of depolarisation (the slope of the upstroke)= excitability, and therefore conduction velocity
* [K] gradient determines the level of the RMP, which affects the irratibility, and also the rate of depolarisation (excitability), and therefore the conduction velocity
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Physiol-09A13 What is the Frank-Starling mechanism and describe its relationship to excitation contraction coupling.
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Frank Starling mechanism
-describes the effect of preload on cardiac muscle function
-greater volume of blood entering the ventricule (LV EDP) greater volume of blood ejected to a point
Draw graph
Axis : SV (ml) vs LVEDP (mmHg)
main points
0,0
10,60
20, 100 then decreases
label 20,100 as optimial sarcomere length reached
Mechanism
-stretching of muscle fibres
-increased affinity of troponin C for Ca++
-increases the rate of cross-bridge attachment and detachment, and the amount of tension developed by the muscle fiber
-maximal forced generated at initial sarcomere length of 2.2 um
-rarely exceed this is normal individual due to fibrous pericardium
Excitation Contraction Coupling
-the process whereby an action potential triggers a myocyte to contract
-depolarized by AP, Ca++ enter the cell during phase 2 through L-type calcium channels located on the sarcolemma
-This Ca++ triggers a subsequent release of calcium that is stored in the sarcoplasmic reticulum (SR) through calcium-release channels ("ryanodine receptors")
-increased intracellular calcium concentration from about 10-7 to 10-5 M
-The free calcium binds to troponin-C (TN-C) that is part of the regulatory complex attached to the thin filaments inducing a conformational change in the regulatory complex such that troponin-I (TN-I) exposes a site on the actin molecule that is able to bind to the myosin ATPase located on the myosin head. This binding results in ATP hydrolysis that supplies energy for a conformational change to occur in the actin-myosin complex. The result of these changes is a movement ("ratcheting") between the myosin heads and the actin, such that the actin and myosin filaments slide past each other thereby shortening the sarcomere length. Ratcheting cycles occur as long as the cytosolic calcium remains elevated. At the end of phase 2, calcium entry into the cell slows and calcium is sequestered by the SR by an ATP-dependent calcium pump (SERCA, sarco-endoplasmic reticulum calcium-ATPase), thus lowering the cytosolic calcium concentration and removing calcium from the TN-C. To a quantitatively smaller extent, cytosolic calcium is transported out of the cell by the sodium-calcium-exchange pump. The reduced intracellular calcium induces a conformational change in the troponin complex leading, once again, to TN-I inhibition of the actin binding site. At the end of the cycle, a new ATP binds to the myosin head, displacing the ADP, and the initial sarcomere length is restored.
Mechanisms that enhance the concentration of cytosolic calcium increase the amount of ATP hydrolyzed and the force generated by the actin and myosin interactions, as well as the velocity of shortening. Physiologically, cytosolic calcium concentrations are influenced primarily by beta-adrenoceptor-coupled mechanisms. Beta-adrenergic stimulation, as occurs when sympathetic nerves are activated, increases cAMP which in turn activates protein kinase to increase in calcium entry into the cell through L-type calcium channels. Activation of the IP3 signal transduction pathway also can stimulate the release of calcium by the SR through IP3 receptors located on the SR. Furthermore, activation of the cAMP-dependent protein kinase phosphorylates a protein (phospholamban) on the SR that normally inhibits calcium uptake. This disinhibition of phospholamban leads to an increased rate of calcium uptake by the SR. Therefore, beta-adrenergic stimulation increases the force and shortening velocity of contraction (i.e., positive inotropy), and increases the rate of relaxation (i.e., positive lusitropy).
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Physiol-07A13 Describe the determinants of Venous Return and the effect general anaesthesia would have on these. 60%
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Venous return is the volume of blood returning to the right heart from the systemic venous circulation
Normal values
5L/min
70ml/kg/min
Under steady state conditions VR=CO, although there is beat to beat variation. However, since right and left heart in series in a closed loop system, both must be equal.
When CO does not equal VR results in cardiac failure.
VR=(MSFP-RAP)/MVR
MSFP is pressure in the systemic vascular system (venous+arterial) if the the heart stopped. It is determined by vascular volume and the vessel compliance.
RAP is the right atrial pressure
MVR is the mean venous resistence
Changes with anaesthesia
MSFP
-fasting, haemorrhage, 3rd space losses => hypovolaemia
-vasodilation due to opoids, induction agents, spinal
RAP
-reduced contractility
-frank starling mechanism
MVR
-reduced, venodilation
Other
1. Loss of muscle contraction : Rhythmical contraction of limb muscles as occurs during normal locomotory activity. Squeezing of veins, antegrade flow produced by valves. Venous pooling
2. increased venous compliance. Direct due to opoids, inhalation agents, also loss of sympathetic activation (alpha adrenergic)
3. IPPV. Decreased venous return and decreased afterload. Transmission of intrathoracic positive pressure (loss of thoracic pump)
4. Vena cava compression. An increase in the resistance of the vena cava, as occurs when the thoracic vena cava becomes compressed during a Valsalva maneuver or during late pregnancy, decreases return.
5. Gravity. Trandelenberg vs head up. Lithotomy.
6. Valves
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Physiol-06B9 Describe the factors that oppose left ventricular ejection. 14%
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Describe Factors Opposing Left Ventricular Ejection:
Afterload is the sum of all factors opposing the ejection of blood by the left ventricle (LV).
Afterload is also defined as the myocardial wall tension that must be generated by the LV to eject blood into the aorta.
[edit]
T α PR/h (Similar to Law of Laplace)
T: wall tension P: LV pressure R: LV cavity radius h: LV wall thickness
Therefore if:
Increase LV pressure (hypertension) increase afterload.
Increase LV cavity radius (LV dilation, overfilled, cardiomypothy) increase afterload
Increase LV thickness (hypertrophy) decrease afterload because greater number of sarcomeres are sharing the load.
Systemic Vascular Resistance: (SVR)
The sum of of resistances to flow of blood through all of the parallel vascular beds of the systemic circulation. 900 – 1200 dynes.sec/cm5
SVR is a MAJOR part of afterload.
Bit of background: Flow = Pressure drop/resistance
Therefore CO = (MAP – CVP)/SVR CO: cardiac output L/min MAP: mean arterial pressure mmHg CVP: central venous pressure (or RAP) mmHg
Often disregard CVP as so low and MAP high so CO = MAP/SVR Can make SVR = MAP/CO (Remind you of pulmonary vascular resistance equation?)
SVR 18 mmHg/L/min or x80 = 1440 dynes.sec/cm5
[edit]
R = 8nl/πr4
R: resistance to laminar flow through tube (blood vessel) ie. SVR
n: viscosity of fluid (blood)
l: length of tube (vessel)
π: 3.14
r: radius of tube (vessel)
Therefore: Increase viscosity of blood (increase erthrocythaemia, thrombocythaemia, leukocythaemia, decrease temperature) will increase afterload
Increase length of vessel will increase afterload (shunt may reduce afterload)
Radius of arterioles is major factor in determining SVR and afterload. Raised to power -4 so small increase radius will decrease afterload significantly and vice versa (vasoconstriction or vasodilation)
Aortic Outflow Tract Obstruction: impedes the ejection of blood from LV into aorta and increases afterload (aortic stenosis, LV hypertrophy)
IPPV: Intermittent Positive Pressure Ventilation Applying positive pressure to thorax squeezes heart so greater pressure difference between heart and extra-thoracic vascular tree – aids ejection of blood and reduces afterload.
Decreased aortic compliance with age increases afterload.
Atheromatous disease of aorta and arterial tree increases afterload.
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Physiol-1990-a Discuss the relationship between cardiac output and venous return. Include factors that determine the magnitude of both.
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Relationship
- Cardiac output and venous return must be the same as the heart and blood vessels form a complete circuit
- Circular reasoning to say that one is the result of the other
- Differences may exist transiently only
- The relationship is best illustrated with
o Cardiac function curves – cardiac output (dependent variable) as function of right atrial pressure (independent variable)
o Vascular function curves – right atrial pressure (dependent) as a function of cardiac output
Graphs
Some Revision Points
- When plotted on the same graph the convention of placing the independent variable on the x-axis is broken for the vascular function curve
- Relationship between the curves is known as ‘coupling of heart and peripheral circulation’
- Equilibrium point defines the cardiac output and RAP where the CVS operates
- Mean systemic filling pressure is the pressure that would exist in the vasculature if the cardiac output were momentarily reduced to zero
- The flat portion of the VFC occurs when the pressure in the RA drops below zero causing the thoracic veins to collapse and venous return to cease
- Isolated changes as described below rarely happen in real life
Factors Determining Magnitude
1. Blood Volume and Venous Tone
- Changes in blood volume in the absence of other influences cause a parallel shift in the vascular function curve equivalent to changes in the MSFP
- The collapse pressure remains unchanged
- Illustrates importance of increases in venomotor tone to maintain CO in hypovolaemic states
2. Peripheral Resistance
- Resistance to venous return is effectively the total peripheral resistance governed by arteriolar tone
- The curve pivots around the unchanged MSFP if vascular compliance remains constant
- MSFP unchanged because the arterioles contain only 3% of blood volume
- Cardiac output varies inversely with arteriolar tone
- Cardiac function curve shifts slightly down with the increasing afterload (not shown)
3. Sympathetic Tone (Contractility)
- Increased sympathetic activity increases myocardial contractility in addition to combined effects on vascular function curve.
- Result is a shift in the equilibrium point up and to the left i.e. more cardiac output even with a reduced filling pressure
4. Additional Influences
Gravity
- Venous pooling due to the greater distensibility of the large veins
- Effect resembles that of hypovolaemia with reduced venous return and cardiac output
- Reflex mechanisms restore tone
Muscular Activity and Venous Valves
- Increases venous return and decreases tendency for blood to pool in the upright posture
Respiratory Activity
- Causes fluctuations in vena caval flow
- Has a pump-like function
- Effects of PEEP and IPPV discussed elsewhere
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Physiol-96A3 Draw a pressure volume loop for a left ventricle in a healthy adult and state the normal pressures and volumes. Outline the information which can be obtained from a pressure volume loop and how such a loop can be constructed.
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Normal Pressures and Volumes
A Mitral valve opens - 70 mls and 0 – 5 mmHg
A → B Diastolic Filling along diastolic elastance curve of LV (gradient of this curve gives the elastance or distensibility, the inverse of compliance). Also known as end diastolic pressure volume line
B Mitral valve closure. LVEDV – the best indicator of preload 140 mls
B → C Isovolumetric contraction
C Aortic valve opens Occurs at arterial diastolic pressure: 80 mmHg
C →D Ventricular systole & ejection of blood. Peak pressure = arterial systolic BP = 120 mmHg. Early phase is rapid ejection followed by reduced ejection
D Aortic valve closure. End Systolic point
D → A Isovolumetric relaxation
Information Obtainable
Stroke Volume
LVEDV – LVESV = 70mmHg
LVEDV
- Left ventricular end diastolic volume is the best indicator of preload of the heart
- LVEDP used clinically can be misleading because of variable compliance of the LV
Ejection Fraction
- Normally around 50%
Work
- Pressure x Volume = Work (in Joules)
- External work performed by the LV during that cardiac cycle is represented by the area contained within the loop (also called stroke work)
- Increased contractility is assoc with increased area and therefore work
- Diastolic work is done in the process of relaxation of the ventricle as ATP is consumed for reuptake of Ca ions into the SR. Diastolic filling is reduced when relaxation is impaired e.g. ischaemia, hypertrophic cardiomyopathies
- Potential Energy is generated during isovolumetric contraction when there is pressure change without volume change. This energy is released as heat during diastole. The amount is represented by the triangle formed by the end systolic pressure volume line, the end diastolic pressure volume line and the line of isovolumetric relaxation.
- The mechanical work plus the heat generated correlate well with myocardial oxygen consumption
Diastolic Compliance
- The curve of pressure change with left ventricular filling is the elastance curve for the LV
- Mathematically, the inverse of this is the compliance curve and is a measure of the ‘stiffness’ of the LV
- The important feature is that the heart is easy to fill to a point and is then difficult to overfill
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- Diastolic function curve is altered with a) reduced compliance b) increased chamber volume c) pericardial restriction d) abnormal relaxation (see Fig 4.25 Kam)
Contractility
- “Is defined as the intrinsic ability of the muscle fibre to shorten independent of preload and afterload” – Power and Kam
- Serial points of the end-systolic pressure (D) form the ‘end-systolic pressure line’ (‘Ees’ for end systolic elastance’ )
- The slope of this line is an index of contractility: Steeper slope = greater contractility
- With increasing contractility the loop shifts upwards and to the left
- Note: contractility is load dependent. Even the slope of Ees is partly dependent on afterload (Refer to Colin Royse’s research)
Afterload
- The best index of afterload is the slope of a straight line connecting the LVEDV (on the x-axis) with the end systolic point for the loop (D) or the angle this line makes with the x-axis
- The steeper the line (the greater the angle) the greater the after load
Disease States
- Displacement of the curve and distortion of its shape are typical in certain pathological conditions
o Ischaemia – curve is leaning to the right due to lengthening of ventricular muscle during isovolaemic contraction (systolic lengthening) and shortening during isovolaemic relaxation (post-systolic shortening). Systolic lengthening is caused by ischaemic muscle ‘bulging’ during contraction
o CCF is seen as reduced EF, LVEDV increases, poor compliance and poor contractility
Constructing a LV Pressure Volume Loop
- Pressure can be obtained by
o Using invasive methods and placement of a transducer in the LV
o Indirectly via echo or Pulm capillary wedge pressures
- Volume estimates can be obtained using
o echocardiography and extrapolation from 2D images
o nuclear med scans (e.g. gated blood pool)
o conductance catheter
o ventriculography
o implanted ultrasonic micro crystals
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Physiol-04B10 List the physiological factors which affect left atrial pressure and explain their effects (19% pass rate)
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Venous return:
1. Blood volume - increase VT
2. Posture
3. Venous tone - increase VT increase VR increase LA volume
4. Intrathoracic pressure (increase ITP - decrease VT)
5. Intrapericardia pressure
6. Muscle pump.
VR = (MAP – RAP) / TPR
MAP = mean arterial pressure, RAP = right atrial pressure, TPR= total peripheral resistance.
Notes:
* Muscle pump – muscular compression that compress veins (eg legs) leading to VR.
* Decreased ITP - Decrease RAP this pressure gradient favouring venous return.
* Intrapericardial pressure can increase RAP thus decreasing tendency for VR.
* Venous tone – venoconstriction - VR
-venodilatation (eg post spinal) - decrease VR
* Posture – suddenly standing from supine position cause venous pooling of blood thus decreased VR. This initiates reflex effects to cause venoconstriction and increase HR (slower in elderly so will faint).
* Blood volume- (see 3.17- Brandis p 99- Guyton vascular and cardiac fxn curve)
volume (hypervolaemia) – vascualr fxn curve shifts right - RAP + VR ( CO)
2) Left Ventricular Emptying - Contractility - Afterload.
Contractility – the performance of the heart at a given preload and afterload (physiol defn- change in peak isometric force at a given initial fiber length). Hyodynamic heart- increase EDV - slow rising ventricular pressure reduced ejection phase - LA pressure (decreased SV).
increased contractility - decreased LAP
Afterload – Physiol defn- the tension at which isotonic contraction of the muscle fiber begins.
Clinical defn- the impedance to the ejection of blood from LV to aorta.
afterload = MAP = VR = LAP.
Tachycardia - Tachycardia caused by direct pharmacological action (atropine) will also cause a decrease in LAP as venous return is not also increased as in sympathetically driven tachycardia.
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Physiol-05B13 Explain how cardiac output is measured using a thermodilution technique (53% Pass)
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Structure
* definition CO & normal values
* Fick principle
* Indicator dilution and relationship to Fick Principle
* Thermodilution: theory
* Thermodilution: method
* Thermodilution: Advantages, limitations, and means of minimising limitations.
[edit]
Answer
Cardiac output (CO) is the volume of blood being pumped by the heart per minute and is equal to the heart rate multiplied by the stroke volume. The normal value at rest for a 70 kg male is around 5 L/min. CO is a measure of the fundamental ability of the heart to deliver blood to and from the tissues and thus clinically is a very useful physiological parameter. However, clinical estimation of CO obviously relies on indirect methods, each of which have benefits and limitations.
CO has traditionally been estimated using the ‘Fick Principle’ which is an expression of the law of conservation of mass. It states that the amount of an indicator substance taken up or added by an organ (or the whole body) per unit time is equal to the arterio-venous difference of the substance times the blood flow.
Traditionally this was done by measuring the uptake of oxygen (the indicator) by the lungs and measuring the arterio-venous O2 difference. CO is then estimated using the expression:
\dot{Q} \ (l.min^-) = \frac{\dot{V}_{A}O_{2} \ (ml.min^-)}{C_{a}O_{2}-C_{v}O_{2} \ (ml.L^-)}
where \dot{Q} is cardiac output
\dot{V}_{A}O_{2} is alveolar oxygen consumption
C_{a}O_{2} is arterial O2 content
C_{v}O_{2} is venous O2 content.
Thermodilution is currently the most commonly used technique to estimate CO. It is a variation on the ‘’indicator dilution’’ technique of CO estimation. Like the Fick method it uses the principal of conservation of mass and an indicator substance (in this case the indicator is a thermal mass).
Indicator dilution works on the principal that if a known quantity of an indicator substance is introduced to an unknown flow, assuming no indicator is lost and mixing is thorough the flow will be equal to the amount of indicator injected divided by the average downstream concentration of the indicator.
In practice this is done by measuring the downstream concentration of the indicator over time, and then integrating the area under the measured concentration-time curve to obtain the average indicator concentration.
This is expressed by the relationship:
\dot{Q} = \frac{q}{\int\limits^{t2}_{t1} {cdt}
where q is the quantity of indicator injected
c is indicator concentration
dt is change in time.
The standard set up for estimation of CO by thermo dilution involves the use of a Swan-Ganz catheter with its tip place in the pulmonary artery. A proximal port of the catheter is used for injecting a known volume of saline or dextrose at a known temperature. Passage of the injectate through the right heart ensures adequate mixing, and a thermistor at the tip of the catheter measures the change in temperature over time. Software then integrates the recorded temperature-time curve and computes CO. Often CO is normalised to body surface area to give the cardiac index (CI).
Advantages of the thermodilution method of CO estimation are:
* crystalloid is a innocuous non-toxic indicator, and the small volume required for measurement allows repeated measurements to be made.
* The thermal mass of the indicator is minimal vs that of the whole circulation, and thus the ‘indcator’ rapidly disappears and the measurement is not contaminated by recirculation.
* Arterial puncture is not necessary.
Limitations include:
* insertion of Swan-Ganz catheter is invasive and carries risks (e.g pneumothorax, haemorrhage, arrhythmia).
* accuracy is limited to roughly ± 10%. This can be minimised by doing repeated measurements (generally three), discarding any obviously spurious measurements, smooth rapid injection, and injecting at the same phase of the respiratory cycle.
* inaccuracies may be introduce by R-L shunts, tricuspid regurgitation, high positive ventilatory pressures, or equipment malfunction (e.g misplaced catheter).
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Physiol-08B14 Explain in physiologic terms the effect of severe aortic stenosis on myocardial oxygen supply and demand.
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* first part of the answer was a description of aortic stenosis with extra marks for giving the measure of severity
* the main part of the answer interrelated the effects of inc myocardial work (Laplace Law) and dec myocardial perfusion
* additional marks were awarded for discussing the varying effects of LV hypertrophy on both supply and demand
* marks are also awarded for mentioning how inc heart rate inc demand and dec supply
Errors
* confusing the effects of altered pressure with altered flow
* failing to indicate that severe aortic stenosis is a chronic condition
* including the effects of anaesthesia and signs and symptoms of aortic stenosis
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Physiol-04B16 Explain the physiological processes involved in the development of interstitial oedema 76%
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The physiological processes involved in development of interstitial oedema
- The development of interstitial oedema is related to problems with the tissue microcirculation
- The amount of fluid in the interstitium is governed by fluid input and output of the interstitial space
- Input
* The microcirculation is governed by the factors according to Starling
* Hydrostatic pressure in the capillaries and the interstitium
* Oncotic pressures in the capillaries and the interstitium
* The filtration and reflection coefficients (measures of endothelial cell / basement membrane permeability to fluid and protein)
* Derangements in any of these factors can aid the development of interstitial oedema in the tissues.
* In most tissues, there is net filtration of fluid into the interstitium
Eg. Fluid filtered/absorbed = fc(Pc – Pi) – rc(Oc – Oi)
= 1.0 (25 - -6) – (25 – 5)
= net filtration 10-11mmhg (will be less, and favour absorption at venous end).
(where fc = filtration coefficient, P = hydrostatic pressure, O = oncotic pressure, rc = reflection coefficient)
- Output
* This fluid is returned to the circulation via the lymphatics
* Therefore, problems with the lymphatic system can also aid the development of interstitial oedema
[edit]
Microcirculation factors / Starling’s factors
- Hydrostatic pressure
* Greater hydrostatic pressure in the capillaries (or less in the interstitium – less common, but such as negative pressure pulmonary oedema), causes a pressure gradient for fluid to enter the interstitium
* Usually this pressure is greater in the arterial end of the capillary bed, and less in the venous end
* When the oncotic pressures are taken into account, this means that there is usually net filtration at the arterial end, and net absorption at the venous end
* Therefore, either an increase in hydrostatic pressure in the arterial side of the capillary bed (eg, due to decreased arteriolar tone), or increased venous pressure (such as R-heart failure causing increased systemic venous pressure, or portal venous flow obstruction due to liver cirrhosis) will increase the amount of fluid in the interstitium
- Oncotic pressure
* A decreased capillary oncotic pressure will decrease net absorption forces (such as in hypoalbuminaemia in malnutrition / or chronic illness)
* An increased interstitial oncotic pressure (caused by increased capillary permeability to proteins – eg, caused by inflammation / sepsis) will exert osmotic pressure to keep fluid in the interstitium despite other opposing factors
- Filtration/reflection coefficients
* Most tissues have capillary beds which are very permeable to water, but not very permeable to protein
* If permeability increases (such as in inflammatory response), and protein leaks into the interstitium – it exerts an oncotic pressure to keep fluid there, as above
* This is more likely to lead to development of interstitial oedema
[edit]
The Lymphatic system
* Usually, net fluid filtered into the tissue interstitial space, is usually cleared or drained by the lymphatic system
* These start as small lymphatic capillaries with one way valves, which allow fluid to flow into them, but not backwards
* Lymphatic drainage is aided by:
1. The lymphatics travel with blood vessels, and the pulsation of blood vessels aids the movement of lymph back to the thorax
2. Muscle movement – as in veins, muscle “pumps” can squeeze the lymphatic vessels which causes lymph flow in one direction due to one-way valves
3. Negative pleural / intrathoracic pressure (especially aids lymph drainage in the lungs, and is greater with greater negative pressures as in inspiration)
4. Posture/gravity – ie, lymph drainage from the legs is assisted if feet are “up”
* Any decrease to lymphatic drainage will tend to assist the development of interstitial oedema
* Ie, no limb movement due to bed rest, or damage to lymph vessels by surgery (ie, breast/axillary surgery can lead to lymphoedema in the arm)
* The lymph eventually drains into the venous circulation via the thoracic duct
[edit]
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Physiol-99B8 Draw both aortic root and a radial artery pressure wave forms on the same axes. Explain the differences between them. 50%
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Draw diagram from Brandis page 101
The radial curve, as compared to the aortic curve has:
Delayed onset (slightly)
because of the time taken to travel distally
Steeper upstroke
Due to decreased compliance of peripheral arterial tree compared to aortic compliance
Higher systolic pressure (20-40 mm Hg higher)
Due to
Conversion of kinetic to potential energy in less compliant distal arteries
Backward deflection of pressure wave from branch points
Decreased elasticity of smaller vessels
Transmission of high pressure more rapidly than low pressure portion of pulse wave with “crowding together” and peripheral peaking
Narrower at its peak
Due to higher velocity of the higher pressure peak
Precise mechanism of the peaking of the pressure wave is controversial
Several mechanisms contribute:
Reflection
Tapering
Resonance
Changes in transmission velocity with pressure level
Incisura (anacrotic notch) occurs later or none at all
Due to damping of high pressure components
Damping of the high-frequency components of the arterial pulse caused by viscoelastic properties of the arterial walls
Diastolic hump (Dicrotic notch) usually occurs
Due to reflection and resonance
Lower diastolic pressure (10-20 mm Hg lower) and hence larger pulse pressure
Pulse wave loses energy due to alternating transfer between potential and kinetic energy
Similar mean pressure
Changes that occur with ageing
Aortic atherosclerosis and loss of elastic fibres result in decreased aortic compliance
Decreased myocardial performance
The aortic curve in the elderly tends to have a
Slower upstroke
Due to decreased myocardial contractility
Higher systolic peak
Due to low aortic compliance
If this systolic peak is particularly elevated then it is referred to as systolic hypertension
Radial artery curve would be similar to aortic curve because
Low aortic compliance causes pressure wave to travel faster and be less distorted
In summary:
Difference between aortic and radial curves in the elderly are less than between these two curves in younger subjects
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Describe the vasoactive substances released by the endothelium.
Explain the role they play in regulating blood flow through the peripheral circulation.
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Endothelial cells line the whole of the CVS, forming the surface in contact with circulating blood, and as such the endothelium may be considered an important organ in its own right.
[edit]
Substances Released by the Endothelium
Endothelium plays major roles in:
* autoregulation of blood flow
* coagulation and fibrinolysis
* angiogenesis
Endothelial cells release/produce multiple substances to facilitate these processes:
1. Vasoactive substances
* prostacyclin
* nitric oxide (endothelium-derived relaxing factor)
* endothelins
2. Factors involved in coagulation and fibrinolysis
* thrombomodulin (expressed on cell surface)
* tissue plasminogen activator (tPA)
* heparan sulphate
3. Angiogenesis
* growth factors such as VEGF (vascular endothelial growth factor)
[edit]
Role in Regulating Blood Flow in Peripheral Circulation
Substances released by the endothlium play a pivotal role in localisd regulation of peripheral blood flow.
1. Prostacyclin
* Produced from arachadonic acid by prostacyclin synthase in the COX pathway.
* Inhibits platelet aggregation (main role) and promotes vasodilation.
* In balance with thromboxane A2 released from platelets (fosters localised platelet aggregation and clot formation) thus preventing excessive extension of clot and allowing continued blood flow around clot in vessels with an intact endothelium.
* aspirin irreversibly inhibits COX, inhibiting production of both prostacyclin and TXA-2, but unlike platlets the endothlium is able to produce more COX and thus the balance is tipped toward prostacyclin and anti-coagulation.
* is also released by shear stress (lesser role) and thus may have a direct vasodilatory effect.
2. Nitric oxide (EDRF)
* Synthesised in endothelial cells from Arginine + O2 + NADPH by NOS-3 (nitric oxide synthase 3).
* Production stimulated by increased Ca2+ concentration in endothelial cell.
* Increased Ca2+ promoted by ACh, substance P, VIP, bradykinin, H1 receptors (not H2), and shear stress (flow).
* Released from endothelial cell and diffused accross to vascular smooth muscle cell, where it activates soluble guanyl cyclase, producing cGMP.
* cGMP causes smooth muscle relaxation by activating myosin phosphatase that reduces the concentration of phosphorylated myosin.
3. Endothelins
* Endothelin-1 is an extremely potent vasoconstrictor (also less important are endothelins -2 and -3)
* Local paracrine (http://en.wikipedia.org/wiki/Paracrine) regulator of vascular tone.
* Not stored in cells, but synthesized from DNA stimulated by endothelial damage, angiotensin 2, catecholamines, hypoxia, insulin and thrombin.
* Synthesis is inhibited by NO, ANP and prostacyclin.
* Endothelin-1 acts on ETA rceptor - a specialised G protein coupled receptor on vascular smooth muscle which produces phospholipase C to cause vasoconstriction.
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Physiol-01B8 Explain the physiological processes involved in the development of interstitial oedema 46%
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The physiological processes involved in development of interstitial oedema
- The development of interstitial oedema is related to problems with the tissue microcirculation
- The amount of fluid in the interstitium is governed by fluid input and output of the interstitial space
- Input
* The microcirculation is governed by the factors according to Starling
* Hydrostatic pressure in the capillaries and the interstitium
* Oncotic pressures in the capillaries and the interstitium
* The filtration and reflection coefficients (measures of endothelial cell / basement membrane permeability to fluid and protein)
* Derangements in any of these factors can aid the development of interstitial oedema in the tissues.
* In most tissues, there is net filtration of fluid into the interstitium
Eg. Fluid filtered/absorbed = fc(Pc – Pi) – rc(Oc – Oi)
= 1.0 (25 - -6) – (25 – 5)
= net filtration 10-11mmhg (will be less, and favour absorption at venous end).
(where fc = filtration coefficient, P = hydrostatic pressure, O = oncotic pressure, rc = reflection coefficient)
- Output
* This fluid is returned to the circulation via the lymphatics
* Therefore, problems with the lymphatic system can also aid the development of interstitial oedema
[edit]
Microcirculation factors / Starling’s factors
- Hydrostatic pressure
* Greater hydrostatic pressure in the capillaries (or less in the interstitium – less common, but such as negative pressure pulmonary oedema), causes a pressure gradient for fluid to enter the interstitium
* Usually this pressure is greater in the arterial end of the capillary bed, and less in the venous end
* When the oncotic pressures are taken into account, this means that there is usually net filtration at the arterial end, and net absorption at the venous end
* Therefore, either an increase in hydrostatic pressure in the arterial side of the capillary bed (eg, due to decreased arteriolar tone), or increased venous pressure (such as R-heart failure causing increased systemic venous pressure, or portal venous flow obstruction due to liver cirrhosis) will increase the amount of fluid in the interstitium
- Oncotic pressure
* A decreased capillary oncotic pressure will decrease net absorption forces (such as in hypoalbuminaemia in malnutrition / or chronic illness)
* An increased interstitial oncotic pressure (caused by increased capillary permeability to proteins – eg, caused by inflammation / sepsis) will exert osmotic pressure to keep fluid in the interstitium despite other opposing factors
- Filtration/reflection coefficients
* Most tissues have capillary beds which are very permeable to water, but not very permeable to protein
* If permeability increases (such as in inflammatory response), and protein leaks into the interstitium – it exerts an oncotic pressure to keep fluid there, as above
* This is more likely to lead to development of interstitial oedema
[edit]
The Lymphatic system
* Usually, net fluid filtered into the tissue interstitial space, is usually cleared or drained by the lymphatic system
* These start as small lymphatic capillaries with one way valves, which allow fluid to flow into them, but not backwards
* Lymphatic drainage is aided by:
1. The lymphatics travel with blood vessels, and the pulsation of blood vessels aids the movement of lymph back to the thorax
2. Muscle movement – as in veins, muscle “pumps” can squeeze the lymphatic vessels which causes lymph flow in one direction due to one-way valves
3. Negative pleural / intrathoracic pressure (especially aids lymph drainage in the lungs, and is greater with greater negative pressures as in inspiration)
4. Posture/gravity – ie, lymph drainage from the legs is assisted if feet are “up”
* Any decrease to lymphatic drainage will tend to assist the development of interstitial oedema
* Ie, no limb movement due to bed rest, or damage to lymph vessels by surgery (ie, breast/axillary surgery can lead to lymphoedema in the arm)
* The lymph eventually drains into the venous circulation via the thoracic duct
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Physiol-97B1 Explain the local effects of a decrease on plasma colloid osmotic pressure in the skeletal muscle capillary bed 64%
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Definition of plasma oncotic pressure
Plasma oncotic pressure or “colloid osmotic pressure” is the component of the total osmolality of the plasma due to the colloids
Colloids are large molecular weight particles (MW > 30,000). In plasma, proteins (albumin, globulins, fibrinogens) are the major colloid present and are responsible for the majority of the oncotic pressure of plasma
Albumin is the major contributor to plasma oncotic pressure
Accounts for 65-75% of total value
Typical value of plasma oncotic pressure: 25-28 mm Hg
Total osmotic pressure of plasma: about 6000 mm Hg
Significance of plasma oncotic pressure
Oncotic pressure is the key factor that restrains fluid loss from the capillaries
Plasma proteins are essentially confined to the intravascular space, exerting an osmotic force to draw fluid into the capillaries.
However, the electrolytes that are responsible for the major fraction of plasma osmotic pressure are equal in concentration on both sides of the capillary endothelium
Starling’s Hypothesis for explaining fluid exchanges in the capillary
The Starling Hypothesis states that the fluid movement due to filtration across the wall of a capillary is dependent on the balance between the hydrostatic pressure gradient and the oncotic pressure gradient across the capillary.
The Starling forces are:
Hydrostatic pressure in the capillary (Pc)
Hydrostatic pressure in the interstitium (Pi)
Oncotic pressure in the capillary (πc)
Oncotic pressure in the interstitium (πi)
So net fluid flux across the capillary wall (Qf) is represented by Starling’s equation:
Qf = k { (Pc – Pi) – σ (πc - πI) }
k = filtration coefficient
σ = reflection coefficient
Nb. Capillary hydrostatic pressure falls along the length of the capillary from the arteriolar end to the venous end and hence driving pressure will decrease (and become negative) along the length of the capillary. The other Starling’s forces remain constant along the capillary
Typical values for Starling forces
Arteriolar end (mm Hg) Venous end (mm Hg)
Pc 32 15
Pi 0 to - 6 0 to -6
πc 25 25
πI 0 to 5 0 to 5
Net Filtration pressure 7 mm Hg - 10 mm Hg or (10 mm Hg reabsorption)
In an ideal capillary, the net driving pressure is outward at the arteriolar end and inward at the venous end of the capillary
This change in net driving pressure is due to the decrease in the capillary hydrostatic pressure along the length of the capillary
This assumes the reflection coefficient is high
Filtration
32 mm Hg Interstitial fluid
Capillary wall
Arteriolar end Oncotic pressure 25 mm Hg Venous end
Absorption 15 mm hg
When there is decreased oncotic pressure eg if oncotic pressure is 10 mm Hg
Arteriolar end (mm Hg) Venous end (mm Hg)
Pc 32 15
Pi 0 0
πc 10 10
πI 0 0
Net Filtration pressure 22 mm Hg 5 mm Hg
Hence, get net efflux of fluid from capillary resulting in an increase in interstitial fluid volume
Increased interstitial fluid volume may impair diffusion of oxygen and nutrients from the capillaries to the cells leading to hypoxia and reduced aerobic metabolism
Safety factors that protect against development of oedema when albumin levels are low:
Increased interstitial fluid hydrostatic pressure causes an increase in lymph flow which can remove much of the excess interstitial fluid and return it to the circulation
Increased interstitial fluid volume causes an increase in interstitial hydrostatic pressure (Pi) which tends to oppose further excess filtration
Decreased interstitial protein concentration (due to decreased amounts of albumin leaking out of the capillary) which decreases interstitial oncotic pressure
Clinically, oedema does not occur until albumin levels are less than 20g/L
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Physiol-07B9 Describe the cardiovascular response to central neural blockade.
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Neuraxial blocks typically produce variable decreases in blood pressure that may be accompanied by a decrease in heart rate and cardiac contractility. These effects are generally proportional to the degree (level) of the sympathectomy. Vasomotor tone is primarily determined by sympathetic fibers arising from T5 to L1, innervating arterial and venous smooth muscle. Blocking these nerves causes vasodilation of the venous capacitance vessels, pooling of blood, and decreased venous return to the heart; in some instances, arterial vasodilation may also decrease systemic vascular resistance. The effects of arterial vasodilation may be minimized by compensatory vasoconstriction above the level of the block. A high sympathetic block not only prevents compensatory vasoconstriction but also blocks the sympathetic cardiac accelerator fibers that arise at T1–T4 . Profound hypotension may result from vasodilation combined with bradycardia and decreased contractility. These effects are exaggerated if venous return is further compromised by a head-up position or by the weight of a gravid uterus. Unopposed vagal tone may explain the sudden cardiac arrest sometimes seen with spinal anesthesia
Deleterious cardiovascular effects should be anticipated and steps undertaken to minimize the degree of hypotension. Volume loading with 10–20 mL/kg of intravenous fluid for a healthy patient will partially compensate for the venous pooling. Left uterine displacement in the third trimester of pregnancy helps minimize physical obstruction to venous return. Despite these efforts, hypotension may still occur and should be treated promptly. Fluid administration can be increased, and autotransfusion may be accomplished by placing the patient in a head-down position. Excessive or symptomatic bradycardia should be treated with atropine, and hypotension should be treated with vasopressors. Direct -adrenergic agonists (such as phenylephrine) increase venous tone and produce arteriolar constriction, increasing both venous return and systemic vascular resistance. Ephedrine has direct -adrenergic effects that increase heart rate and contractility and indirect effects that also produce some vasoconstriction. If profound hypotension and/or bradycardia persist despite these interventions, epinephrine (5–10 g intravenously) should be administered promptly
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Physiol-06A9 Outline the systemic cardiovascular response to exercise. 71%
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The response to exercise depends on the degree and type of exercise.
Can be divided into Neural, Humoral and local factors.
The main effect is to increase blood flow to the working skeletal muscles, and heart. This is via an increased cardiac output and oxygen delivery, and decreased resistance to flow of the working tissues – also involves a redistribution of blood flow from non-working tissues.
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Overall
* CO increases (up to 3-5 fold)
1. Increased HR (3 fold)
2. Increased SV (10-30%)
* Decreased TPR (due to vasodilation in skeletal muscle capillary beds, except in isometric exercise, where there is increased resistance to blood flow due to prolonged compression of intra-muscular capillaries)
* Overall, increased MAP (due to greater increase in CO than decrease in TPR)
1. Systolic pressure rises most
2. MAP only slightly
3. This minimises the "pressure work" of the heart, as it pumps a greater cardiac ouput into a dilated TPR
* Oxygen consumption can increase 60-fold
* Increased CO, and increased oxygen extraction
* Increased muscle blood flow (15-30 fold)
* Cerebral blood flow stays constant (but decreases as a proportion of CO)
Neural factors - Central
* Anticipation of physical activity inhibits vagal impulses to heart and increases sympathetic outflow to heart
* This can increase HR and contractility (and therefore cardiac output and BP) before exercise even really starts.
- Reflexes
* Muscle
1. Mechanoreceptors (responding to stretch and changes in muscle length, joint position)
2. Chemoreceptors (probable)
3. Travels centrally (unknown where central controller is )
4. Sympathetic efferents to heart and blood vessels are effected
* Baroreceptor reflex
1. Aims to maintain MAP where there is conflicting factors from the heart and blood vessels (increased CO, but decreased SVR)
- Heart
* Sympathetic stimulation directly causes increased HR and contractility
- Blood vessels
* Vasoconstriction
1. Skin, splanchnic vessels, kidneys, inactive muscles
2. Blood flow to skin then increases as body temperature rises
3. This increased resistance offsets the lower resistance in working muscles (a local factor effect)
* Venoconstriction
1. Enhances venous return
2. Increases effective circulating volume to increase cardiac output
Hormonal factors
* release of NA facilitates and increases above sympathetic effects
* adrenaline can cause some vasodilation in skeletal muscle beds via beta 2 receptors
Local factors
- overrides neural stimulation of skeletal muscle vascular resistance (which would increase)
- metabolic autoregulation
* K
* Adenosine
* K-ATP channels
* NO
- All cause vasodilation, to increase the flow to working muscles.
- The local capillary bed recruits extra blood vessels, and surface area for diffusion of nutrients/wastes increases markedly (and diffusion distance decreases)
* Hb-O2 curve
- in the muscle capillary bed, there is increased CO2 formed, decreased pH and increased temperature, which all shift the curve to the R (which aids in unloading oxygen to the tissues)
- Oxygen extraction increases, and AV difference increases.
Other circulation factors
* increased muscle blood flow results in increased venous return from muscles to the heart
* Venous return is enhanced by the increased actions of the “muscle pumps”
* Venous return is enhanced by the increased actions of the thoracic pump
* There is little role for the Frank-Starling law of the heart in pumping an increased stroke volume in mild-moderate exercise (as per Levy & Pappano, p. 244)
The differences between Isometric and Isotonic muscle contraction
* The start of exercise is similar, with an increased HR (probably mediated centrally)
* Isometric contraction
1. Muscle blood flow is reduced due to an increased vascular resistance
2. increased BP
3. relatively little change in SV
* Isotonic contraction
1. an increase in SV
2. a decrease in TPR
3. sl increase in systolic pressure, with same or lower diastolic pressure
4. much greater flow to contracting muscle (during relaxation phase)
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Physiol-05B15 Describe the autonomic innervation of the heart and the direct effect of autonomic stimulation on the heart. 43%
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Autonomic NS: The portion of the nervous system that regulates involuntary body function including those of the heart and intestines. It comprises of the sympathetic and parasympathetic NS.
The heart has dual and opposing nerve supplies.
1. Sympathetic - catecholamine transmitters --> inc. HR and contractility
2. Parasympathetic - Acetylcholine --> dec. HR
Changes between symapthetic and parasympathetic tone are usually reciprocal. Parasympathetic tone usually predominates in the resting heart. When both division of the ANS are abolished the HR of a young adult averages about 100BPM (the intrinsic HR).
[edit]
Parasympathetic
Beat to beat effect on the heart (low latency).
* nerve fibres originate in the medulla oblangata within the
o Nucleus ambiguus (associated with the NTS) and dorsal motor nucleus of vagus
o Travel via the L&R vagus(X) nerves to the mediastinum where they
o Synapse with the postganglionic cells on the epicardial surface mostly near the SA & AV nodes
* R vagus → SA node (slow firing of SA node)
* L vagus → AV node (slow conduction of AV node) but there is some overlap...
Rapid onset and offset of action due to
1. Acetycholine release activates K channels via a GS protein → hyperpolarising membrane (no secondary messenger)
2. Abundant acetylcholinesterase in the SA & AV nodes, therefore rapid breakdown of ACh
3. Inc. in PSNS activity → inhibition of SNS activity by suppressing norad. release (i.e PSNS overrides SNS)
[edit]
Sympathetic
* Fibres from the vasomotor centre in the rostral ventrolateral medulla project to preganglionic sympathetic fibres in the intermediolateral grey columns of the upper spinal cord (C7- T5/6). Excitatory transmitter is glutamate.
* Pre-ganglionic neurons emerge from the spinal column and synapse in the stellate and middle cervical ganglia & then form a complex nerve plexus (with PSNS fibres) to the heart.
* Post ganglionic fibres run with the great vessels to the epicardial surface. They then penetrate they myocardium usually along the coronary vessels
* R fibres → inc. HR
* L fibres → inc. contractility
* neurotransmitter released - NA (act mainly on β1 receptors in the heart) → longer duration and slower onset of action compared with ACh (secondary messenger and only a small amount of NA released)
* also much slower offset cf. PSNS as NA either reuptake into nerve terminals or carried away in blood stream.
* also can inhibit effects of vagal stimulation - probably via neuropeptide Y - co-transmitter in sympathetic nerve endings.
Effect due to NA → G protein receptor → activate G protein → inc. Ca channel activity → inc in Cyclic AMP by adenyl cyclase. Therefore contraction increased by
* inc ca influx
* inc Trop C affinity for calcium.
and increased relaxation by
* inc Trop I affinity for Ca
* inc Ca reuptake into sarcoplasmic reticulum
Some innervation of coronary vasculature by the SNS fibres which in vitro cause vasocontriction, however this effect is amply offset by the local autoregulation of coronary vascular tone - thus despite this innervation, when HR and contratctility ↑ due to ↑ SNS stimulation, coronary vasodilation actually occurs in response to the increase in cardiac work.
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Summary
Therefore effects of autonomic stimulation Symp
* inc HR
* inc conduction velocity through AV node
* inc contractility and automaticity of atria
* inc contractility of ventricle
* indirectly stimulate cornary vasodilation (due to ↑ in cardiac work).
Para
* dec HR
* dec CV through AV node
* dec contractility of atria and ventricles
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Physiol-05A14 Describe the compensatory mechanisms in a fit person moving from the supine to the standing position. 52%
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Haemodynamic Alterations
- Assuming the upright position alters the hydrostatic pressures in the blood vessels as a result of gravitational forces.
- Effects of gravity on the circulation depend in part on blood volume – effects are exaggerated in low volume states
- Compensatory mechanisms are designed to maintain blood flow to the brain to prevent cerebral ischaemia and loss of consciousness
- MAP
• Feet 180 – 200mmHg
• Head 60 – 75mmHg
- Venous pressure
• Feet 85 - 90mmHg
• Head 0mmHg
- When a patient is supine the pressures throughout the circulation are equal to MAP (approx 100mmHg)
- If the individual does not move approx 300 – 500mLs of blood pools in the venous capacitance vessels of the lower extremities
- With prolonged standing further fluid accumulates in the interstitial spaces due to increased hydrostatic pressure in the capillaries
Compensatory mechanisms
Autonomic
- Most important of compensatory mechanisms. Highly developed in bipeds
- Reduced MAP is detected by high pressure baroreceptors in carotids and aortic arch causing a decrease in their firing rate
- Reduced signal via CN IX and CNX to nucleus tractus solitarius reduces the inhibition on the vasomotor centre and reduces the excitatory signal to the vagal centre
- Sympathetic discharge causes
• Venoconstriction of capacitance vessels increasing venous return to the heart
• Vasoconstriction of resistance vessels in skeletal muscle, skin, kidneys and gut leading to increased TPR
• Increase in cardiac contractility and heart rate restoring cardiac output
• Release of Adrenaline from adrenal medulla (erect levels are 50 – 100% greater than when supine)
- Low pressure receptors in the atria, SVC, IVC and pulmonary veins are less important in this immediate response
Cerebral Autoregulation
- Cerebral circulation is tightly auto regulated by metabolic and myogenic mechanisms over range MAP 50-150mmHg
- With change to upright position the arterial MAP decreases by 20 – 40mmHg but the venous pressure also decreases by 5 – 8mmHg so the fall in perfusion pressure is not as great
- Intracranial pressure also falls reducing the external compression on the cerebral vessels and decreasing vascular resistance
- Reduced blood flow causes a rise in PaCO2 and decrease in pH that actively dilates the cerebral vessels
- O2 extraction is increased so that O2 consumption is ultimately the same in the supine or erect position
Mechanical
1. Thoracic Pump
- Inspiratory effort increases the negative intrathoracic pressure increasing the venous return and increasing CO
- Descent of the diaphragm further increases abdo:thorax pressure gradient and encourages venous return
2. Muscle Pump
- Valves in the venous column of blood prevent transmission of full column of pressure to the feet, keeping venous pressure under 30mmHg
- Continuous movement causes calf muscle pump to return blood to heart
Humoral
- Release of Adrenaline from adrenal medulla has sympathetic effects
- Erect posture triggers low pressure atrial receptors and release of ADH and ANP
- Reduced renal blood flow due to SNS stimulation also increases the release of renin
- Renin increases the circulating concentrations of angiotensin II and aldosterone augmenting the vasoconstriction and enhancing water retention
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Physiol-03B10 Describe the role of baroreceptors in the control of systemic arterial pressure. 57%
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The control of blood pressure is a closed loop negative feedback system. Like all negative feedback systems it contains:
* sensor → the baroreceptors
* input pathway → afferent ANS pathways
* central controller → the vaso motor centre
* output pathway → the efferrent ANS pathways
* effector → cardiovascular changes e.g HR, contractility, vasoconstriction etc.
* effect → change in blood pressure.
Baroreceptors are sensory nerve ending that are sensitive to stretching and play a critical role in the vascular reflexes to changes in BP and volume
There are 2 types of baroreceptors:
* High pressure stretch receptors located in carotid sinus and aortic arch.
* Low pressure volume receptors located in the atria and pulmonary veins (aka cadiopulmonary receptors).
They respond to stretching, increased stretch → increased firing.
[edit]
Common Pathways
1. Afferents:
* Vagus (CN X) - cardiopulmonary (low pressure barorecptors) and aortc arch baroreceptors.
* Sinus nerve → Glossopharengeal (CN IX) - carotid sinus baroreceptors.
* terminate in Nucleus of the Tractus Solitarius (NTS) in the medulla.
2. Central Integration:
* Sympathetic
o Excititatory glutaminergic neurons from NTS stimulate GABA inhibitory neurons in caudal and intermediate ventrolateral medulla (CVLM & IVLM).
o These project onto and inhibit discharge of excitatory glutaminergic sympathetic neurons in rostral ventrolateral medulla (RVLM) - thus decreasing sympathetic tone.
* Parasympathetic
o Excitatory neurons from NTS project onto vagal motor neurons in vagal dorsal motor nucleus and in nulclues ambiguus (NA) - thus increasing parasympathetic tone.
3. Efferents:
* Sympathetic
o Glutaminergic neurons from RVLM project onto sympathetic pre-ganglionic neurons in the intermediolateral grey columns of the spinal cord (IML).
o Preganglionic fibres from IML (again probably glutaminergic) synapse with postganglionic sympathetic neurons in the sympathetic chain (stellate and middle cervical ganglia for the heart - see also Physiol-05B15) and on the adrenal medulla (adrenaline and noradrenaline release).
o Post ganglionic fibres innervate the heart, resistance vessels and venous capacitance vessels causing vaso and venoconstriction, ↑ HR and contracility (note also some ACh sympathetic fibres that casue vasodilation in certain tissues e.g muscle - the sympathetic vasodilator system).
* Parasympathetic
o Vagal motor fibres from the vagal dorsal motor nucleus and NA innervate the SA node (right) and AV node (left) causing a decrease in heart rate (see also Physiol-05B15).
[edit]
High Pressure
* carotid sinus and aortic arch.
* tonically active at normal BP thus inhibit tonic medullary sympathetic output and stimulate vagal activity.
* respond to both sustained presuure and pulse pressure.
* increase in BP → increased firing.
* rate of firing ∝ pressure in range 70-110mmHg (i.e linear).
* > 150 mmHg no further increase in firing.
* < 30 mmHg no further decrease in firing.
* Baroreceptor baseline function can be reset in hypertensive patients:
o reset in 1-2 days.
o rapidly reversible if BP returned to normal.
* baroreceptor function can be tested by the valsalva manoeuvre. If functioning normally the R-R ratio should be greater than 1.5.
[edit]
Low pressure
These are more involved in the control of body water/blood volume as opposed to beat by beat control.
2 types (assess CVP and cardiac distension)
* A - Fire during atrial systole (correspond with A wave)
* B - Fire during atrial filling (correspond with V wave)
* increased BP → increased firing of A and B receptors → travels via vagus (X) nerve to the medulla → decrease in vasomotor activity resulting in
o increase in HR (via selective increase in SNS to SA node)
o dec SNS activity to kidneys → inc RBF → inc urine output
o inhibits AGII, aldosterone & ADH release
o also stimulation can lower BP reflexively by inhibiting vasoconstrictor centre in the medulla
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Physiol-94B2 Explain the cardiovascular responses to a Valsalva manoeuvre maintained for 30 seconds. What can be learnt about cardiovascular function from observing these responses?
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Definition
- Forced expiration against a closed glottis
- Clinically may be performed by blowing into a mercury column maintaining 40mmHg of pressure
- Described in 1704 by Valsalva
- Causes a rise in intrathoracic, intraabdominal and CSF pressures
- CVP increases approximately 7mmHg for a 10mmHg increase in mouth pressure
- Can be described in four distinct Phases
Phase 1
- Transient rise in BP
- Transient decrease in HR
o Caused by the direct transmission of increased intrathoracic pressure to the thoracic aorta and compression of intrapulmonary vessels leading to increase in return of blood to left side of the heart.
Phase 2
- Reduced venous return
- Reduced cardiac output
- Reduced BP ⇒ stimulates baroreceptors ⇒ sympathetic stimulation causes…
- Increase in HR
- Peripheral vasoconstriction leading to restoration of BP by depending on duration of manoeuvre and autonomic response
- In healthy subjects the BP usually rises above the baseline level reflecting the strength of the compensatory mechanism
Phase 3
- Immediately following release of positive pressure
- Transient fall in BP
- Minimal change in HR
o Caused by release of transmitted pressure on aorta and intrapulmonary vessels.
Phase 4
- Intra thoracic pressure returns to baseline
- Venous pressure returns to normal
- Cardiac output is restored
Restored cardiac output into constricted peripheral vasculature causes
- Overshoot of BP ⇒ detected by baroreceptors
- Reflex bradycardia (via vagal activity) and peripheral vascular relaxation
Abnormal Responses
- Can occur with diminished baroreceptor reflexes e.g. quadriplegia, diabetic autonomic neuropathy
o Excessive fall in BP in Phase 2
o Absence of overshoot during phase 4
Left ventricular dysfunction
o Square wave response is seen
o Elevated BP throughout Phase 2
o No overshoot in 4 (β blocked patients also lack this overshoot)
o Little change in heart rate
o Elevated central venous pressures maintain blood flow to the heart. Pressure change is primarily due to transmission on thoracic aorta
Valsalva Ratio
- Ratio between longest RR interval in phase 4 and the shortest RR interval during phase 2. (or max HR divided by min HR)
- HR responses are secondary events that reflect reflex function.
- Normal value is greater than 1.5
Clinical Uses of the Valsalva
- Reversion of supraventricular tachycardia
- Testing autonomic function
- Aid in the assessment of some heart murmurs (louder in HOCM)
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Physiol-08A14 Describe the pathways whereby myocardial ischaemia may be experienced as pain in the throat or arm regions.
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Pain is the unpleasant emotional and sensory experience associated with potential or actual tissue damage or described as such damage.
Referred pain describe the phenomenon of pain perceived at a site adjacent to or at a distance from the site of an injury's origin
Myocardial ischaemia results when metabolic demands of cardiac tissue exceeds supply. resulting in tissue damage and the release of inflammatory mediators (K+, adenosine, cytokines, prostancoids , Lactate, Serotonin, Bradykinin, Histamine, Reactive oxygen species , Adenosine)
Angina Pectoris Resultant pain from myocardial ischaemia
Vague, Diffuse discomfort felt in:
* Chest
* Neck
* Lower jaw
* Down either arm but especially Left
Pain Pathways
-innervation of cardiac tissue is visceral
-no noiceptors
-chemo/mechanoreceptors, that sense the inflammatory soup
-in myocardial muscle and around blood vessels
Afferents
-Travel via C-fibres
-Via parasympathetic : vagus to C10
-Via sympathetic : T1-4
Convergent-projection
-visceral C-fibres afferents synapse onto second order neurons in laminar II and share ascending somatic pathways (spinothalmic projections)
-parasympathetic C10 : neck and arms
-sympathetic T1-4 : upper chest
Process by brain
-Cerebral cortex (conscious sensation of pain, emotional response, behavioural response)
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Physiol-08A9 The skin, the kidneys, and the carotid bodies are examples of where specific organ blood flow is far in excess of that organ's metabolic requirements. For each example, explain what the physiological role of the high organ blood flow is, why this high flow is an advantage to the person and a brief description of the mechanisms involved.
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Skin : Thermoregulation role with heat conversation / loss. Normothermia allows normal enzyme function. High flow via superficial arteriole network and arterio-venous anastomosis with sympathetic nervous system control. Addidtional marks for role as blood reservior, correct value for blood flow and importance of sweating.
Kidneys : Role is to excrete waste products and sodium/water balance. Advantage is the maintenance of constant internal environment. High flow via short large renal arteries, parraell interlobular arteries and parallel afferent arteriole branches. Additional marks for renal blood flow value.
Carotid bnodies : high flow mean organ oxygen requirements do not interfere with measuring PaO2. The advantage is early detection of hypoxia. High organ flow occurs due to the small size of the organ and the flow directly from the carotid artery. Additional marks for the organ blood flow rate and lack of effect from anaemia or carbon monoxide poisoning.
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Physiol-03B9 Describe the effects of tachycardia on myocardial oxygen supply and demand in a normal heart. 40%
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Myocardial oxygen demand is determined by:
* myocardial wall tension
* contractility
* heart rate
Oxygen (or blood) supply is determined by
1. Coronary vessel resistance
* autoregulation - both myogenic and metabolic
* autonomic input
* physical factors such as wall tension causing compression of cardiac vessels
1. Mean arterial pressure
In the normal adult, coronary blood flow at rest is 250 ml/min; oxygen consumption by cardiac mm of 8-10 ml/min/100g of tissue
At rest, cardiac mm has high O2 extraction ratio- 65% vs 20% body average. Leaves pO2 in coronary sinus 20 mmHg.
AS heart rate increases, oxygen demand increases. As O2 extraction ratio is so high, in order to meet increased demand FLOW of blood must increase.
Flow can increase by 4-5 x in coronary vessels up to 1250 ml/min. This is due to metabolic autoregulation. When metabolism increases, (ie increased O2 demand) there is an increase in tissue concentrations of vasodilating metabolites eg adenosine, K+ ions, increased CO2 and Decreased O2. This results in vasodilation and therefore increased flow.
If increased heart rate is related to sympathetic stimulation (as in exercise) there is also Beta 2 mediated coronary vasodilatation, which also helps to increase flow.
These mechanisms help to maintain flow and tend to compensate for decreased coronary perfusion time in LV in tachycardia.
* At rest (HR 70 bpm) systole 0.3s, diastole 0.55s
* During systole braches of LCA which supply subendocardium of LV are strongly compressed secondary to high ventricular pressure, virtually abolishing blood flow.
* Majority of LV flow occurs during diastole (approx 85%)
* Right coronary flow is reasonably constant throughout cardiac cycle due to much lower pressurs in R ventricle.
* See graphs of coronary blood flow (as in Brandis)
* With tachycardia, time for diastole is shortened. Eg HR 200 bpm, systole and diastole both 0.15s. Much decreased time for perfusion of LV.
* In the normal heart, autoregulation and sympathetic stimulation tend to increase blood flow enough to compensate for decreased perfusion time.
* However as flow to subendocardium of LV ceases altogether during systole, it is most vulnerable to rate related ischaemia.
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Physiol-03A12 Explain the mechanisms that maintain cerebral blood flow on moving from a supine to a standing position. 60%
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Haemodynamic Alterations
- Assuming the upright position alters the hydrostatic pressures in the blood vessels as a result of gravitational forces.
- Effects of gravity on the circulation depend in part on blood volume – effects are exaggerated in low volume states
- Compensatory mechanisms are designed to maintain blood flow to the brain to prevent cerebral ischaemia and loss of consciousness
- MAP
• Feet 180 – 200mmHg
• Head 60 – 75mmHg
- Venous pressure
• Feet 85 - 90mmHg
• Head 0mmHg
- When a patient is supine the pressures throughout the circulation are equal to MAP (approx 100mmHg)
- If an upright individual does not move approx 300 – 500mLs of blood pools in the venous capacitance vessels of the lower extremities
- With prolonged standing further fluid accumulates in the interstitial spaces due to increased hydrostatic pressure in the capillaries
Features of Cerebral Blood Flow
- CBF is typically 50ml/min/100g or approx 750ml/min or 15% of CO at rest
- 20% of total body oxygen consumption for 2-3% of body mass
- Lack of stored metabolic substrate and high O2 requirements make the brain sensitive to hypoxia
- CBF is directly coupled with metabolic requirements (metabolic autoregulation)
- CBF is also subject to myogenic autoregulation
- CVR is not influenced by humoral or autonomic factors despite being well innervated with serotonergic, cholinergic and adrenergic nerves
- Autonomic nerves are, however, very important in determining CPP (i.e. MAP)
- CBF = CPP/ CVR and
- CPP = MAP – ICP (CVP)
- Munroe – Kellie doctrine states that because the cranium is rigid and its contents incompressible the volume of its contents (blood, CSF and brain) must be relatively constant.
- Any increase in volume (e.g. increased CBF) causes a rapid increase in ICP reduction of CPP
Compensatory mechanisms - Global
Mechanical
1. Thoracic Pump
- Inspiratory effort increases the negative intrathoracic pressure increasing the venous return and increasing CO
- Descent of the diaphragm further increases abdo:thorax pressure gradient and encourages venous return
2. Muscle Pump
- Valves in the venous column of blood prevent transmission of full column of pressure to the feet
- Continuous movement prevents rise of venous pressure over 30mmHg
Autonomic
- Most important of compensatory mechanisms. Highly developed in bipeds
- Reduced MAP is detected by high pressure baroreceptors in carotids and aortic arch causing a decrease in their firing rate
- Reduced signal via CN IX and CNX to nucleus tractus solitarius reduces the inhibition on the vasomotor centre and reduces the excitatory signal to the vagal centre
- Sympathetic discharge causes
• Venoconstriction of capacitance vessels increasing venous return to the heart
• Vasoconstriction of resistance vessels in skeletal muscle, skin, kidneys and gut leading to increased TPR
• Increase in cardiac contractility and heart rate restoring cardiac output
• Release of Noradrenaline from adrenal medulla (erect levels are 50 – 100% greater than when supine)
- Low pressure receptors in the atria, SVC, IVC and pulmonary veins are less important in this immediate response
Humoral
- Release of Noradrenaline from adrenal medulla has sympathetic effects
- Erect posture triggers low pressure atrial receptors and release of ADH and ANP
- Reduced renal blood flow due to SNS stimulation also increases the release of renin
- Renin increases the circulating concentrations of angiotensin II and aldosterone augmenting the vasoconstriction and enhancing water retention
Compensatory Mechanisms – Local
Autoregulatory
- Cerebral circulation is tightly auto regulated by metabolic and myogenic mechanisms
- With change to upright position the arterial MAP decreases by 20 – 40mmHg but the venous pressure also decreases by 5 – 8mmHg so the fall in perfusion pressure is not as great
- Intracranial pressure also falls reducing the external compression on the cerebral vessels and decreasing vascular resistance
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Metabolic
- Reduced blood flow causes a rise in PaCO2 and decrease in extracellular pH that actively dilates the cerebral arterioles
- Local metabolites with vasodilator functions include H+, K+, adenosine, phospholipid and glycolytic metabolites and NO
- O2 extraction is increased so that O2 consumption is ultimately the same in the supine or erect position despite the 20% reduction in CBF
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Physiol-03A10 Describe the factors influencing hepatic blood flow. 55%
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Normal
- derived from both hepatic artery and portal vein
- Total liver flow is 1500mL/min or 30% of CO.
- Total oxygen consumption in 50ml O2/min (20% total; same as brain)
1. Hepatic Artery
- High pressure (mean 90-100mm Hg), high resistance, and high velocity system
- Delivers 25-30% of flow
- Contributes 50% of O2 supply
- Hepatic arteriole pressure is 35 mmHg due to high resistance
- Hepatic sinusoidal pressure is low at 2 mmHg (pre-post capillary)
2. Portal Vein
- Low pressure (mean 10 mmHg), low resistance and low velocity
- Valveless vein draining intestines, spleen, stomach, pancreas and gall bladder
- 70% of total flow with 50% of O2 supply
- Fasting venous saturation is 85% which decreases with increased gut activity
- High saturation due to mesenteric shunting
- Portal venous pressure depends on
o Tone of mesenteric arterioles
o Intrahepatic resistance
3. Hepatic Veins
- Venous blood from the liver returns to the IVC via L and R hepatic veins
- Separate set drains caudate lobe
- Vasoconstricts in response to Noradrenaline, Histamine, Angiotensin, Hepatic nerve stimulation
- Hepatic venous pressure also influenced by external factors such as intra-abdominal pressure, Gravity, Gut wall activity
4. Hepatic Microvasculature
- Small vessels of portal vein and Hepatic artery run parallel with bile canaliculi
- The ‘hepatic triad’ eventually anastomoses to form sinusoids
- Mixed blood flows from edge of acinus to central veins
- Increasing O2 extraction maintains supply in low blood flow
5. Capacitance Function
- Reservoir of approx 450ml of blood
- 250ml may be mobilised in hypovolaemia
- Can also buffer against increased volumes
Regulation of Hepatic Blood Flow
1. Intrinsic mechanisms
Autoregulation
- Hepatic artery displays some autoregulation
- Flow maintained until systolic pressure <80 mmHg
- Portal venous system has NO autoregulation and flow is linearly related to pressure
- Therefore, reduced cardiac output (and reduced BP) will reduce flow.
Semi -Reciprocal Flow
- Reduction in portal blood flow causes decrease in hepatic arterial resistance thus increasing flow, up to 50% of total liver blood flow
- Known as ‘hepatic arterial buffer response’ – adenosine implicated
- Alterations in hepatic artery flow do not alter portal venous flow
2. Extrinsic Mechanisms
Neural and Blood-borne Factors
- Hep. Artery has α, β and dopamine receptors
- Portal veins only has α and dopamine
- Adrenaline – Portal venous constriction and vasoconstriction (α) then vasodilation (β) of hep. Artery
- Dopamine has limited effect at normal concentrations
- Glucagon – increases flow by vasodilation
- VIP and Secretin – vasodilate the hepatic artery. No venous effect
- Angiotensin II – constricts vein and artery
- Vasopressin – Vasoconstricts hepatic vasculature thus reducing portal flow
Gases
- Hypocapnia - reduces hepatic flow by 30% due to increased portal resistance
- Hypercapnia - increases flow by decreased portal resistance
- Hypoxia – initially decreased hepatic artery flow 20% then returns to baseline
Anaesthesia
- Spinal and epidurals reduce total hepatic flow due to ↓portal flow and ↓MAP
- Inhalational agents reduce total flow. Halothane worst via increased hepatic artery resistance
- Iso/ Des/ Sevo produce minimal total change and maintain hepatic oxygenation
- Intravenous agents cause dose dependent reduction in flow due to ↓CO and loss of hepatic buffer
Miscellaneous
- Post prandial – ↑↑ hepatic flow
- Respiration - ↑ hepatic outflow during inspiration, ↓ outflow during expiration
- IPPV – reduces flow by ↓ CO
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Physiol-02B11 Outline the factors that determine coronary vascular resistance 65%
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Physiol-02B11 Outline the factors that determine coronary vascular resistance 65%
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Physiol-97A8 List the determinants of coronary artery blood flow. Briefly compare phasic coronary blood flow in the left and right coronary arteries. 51%
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Review of Coronary Circulation
- The left and right coronary arteries derive from the aortic root above the aortic valve
- Left coronary artery
• Left anterior descending and circumflex branches supply the left ventricle and left atrium. Dominant in approx 20% of subjects
- Right coronary artery
• Supplies right ventricle and atrium. Dominant in approx 50% of subjects
- Dominance is determined by the supply to the AV node and PDA.
- They are large epicardial arteries that supply intramyocardial arterioles and a rich subendocardial plexus
- Coronary artery flow:
• 250ml/min
• 85ml/100g/min
• 5% of cardiac output at rest
- High Oxygen consumption
• 10mlO2/100g/min
Determinants of Coronary Artery Blood Flow
- Influences on flow in a vessel are described by the variables in Poiseuille’s Equation:
- Q = π.r4.ΔP
8η.L
- Flow is inversely proportional to the viscosity of the fluid and the length of the tube
- Flow is proportional to the driving pressure and the fourth power of the radius
- In the coronary vessels the a key determinant of coronary vascular resistance is vessel calibre - this changes primarily in response to metabolic demands
Coronary Perfusion Pressure
- Used to describe the driving pressure in the heart as it incorporates the external pressure on the vessels not just the difference between the arterial and venous circulations
- Coronary Perfusion Pressure = Aortic root P – ventricular intracavitary P
- Flow = Driving pressure / Resistance where driving pressure is aortic root pressure minus the left ventricular end diastolic pressure (hydraulic analogue of Ohm’s law)
Myocardial Contractility / Intramural Pressure
- Left ventricular intra-mural pressure – greatest near endocardial surface
- Compressive effect on arteries esp. during systole regulates flow
Metabolic Autoregulation
- Principal mechanism in determining flow rates in coronary vessels
- Strong parallel between metabolic demands of the heart, coronary vascular resistance and hence coronary blood flow. This effect is present even in the denervated heart
- Adenosine is the principal metabolite released and is a potent coronary vasodilator
- Other metabolites may include H+, lactate, CO2, prostaglandins, NO and K+. The actions and interactions have not been delineated
Myogenic Autoregulation
- Smooth muscle in coronary arteries contracts in response to increasing wall tension
- Coronary blood flow is relatively constant in the pressure range of 60 – 180mmHg
Autonomic Nervous System
- Coronary arteries contain alpha and beta receptors as shown by effects of antagonist drugs
- Epicardial arteries have a preponderance of α1 receptors (vasoconstrictor)
- Coronary resistance vessels participate in baroreceptor and chemoreceptor reflexes in altering vascular tone
- Despite this the effects are negligible relative to metabolic controls
Heart Rate
- Approximately 75% of the coronary artery flow occurs during diastole when then coronary perfusion pressure is greatest
- Tachycardia reduces the time of diastole relative to that of systole therefore reducing coronary blood flow
- This may lead to inadequate oxygen supply particularly in diseased arteries.
Phasic Coronary Blood Flow
- Refers to the variations in flow between systole and diastole compared to the continuous flow pattern seen in peripheral arteries
- Effect is greatest in the left coronary artery as intramural pressure may equal driving pressure thus reducing PP to zero.
- Consequently the bulk of LCA flow occurs during diastole
- The RCA is less effected as the driving pressure greatly exceeds intramural pressure in both systole and diastole.
- Balloon pumps aim to increase the coronary vessel flow by increasing the driving pressure during diastole when most perfusion occurs
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Physiol-07B15 Discuss how liver function can be assessed by clinical laboratory testing.
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Standard Liver Function Test
Transaminases
ALT : Alanine Transaminase, 5-40 IU/L, found in heptaocyte, ↑in liver cell damage eg viral hepatitis
AST : Asparate Tranaminase, 10-40 IU/L, found in liver parenchymal cells, indicator of acute liver damage, also in RBC, cardiac and skeletal muscle (ie not sensitive)
Biliary Enzymes
ALP : Alkaline phosphatise, 30-170 IU/L, found in endothelium of bile ducts, also in bone and placenta, increased in bile duct obstruction and intraheptaic cholestasis
GGT : Gamma Glutanyl Transpeptidase, found in bile duct endothelium, sensitive for cholestatic damage, also increases with ETOH
Total Bili : breakdown of heme→bilivirdin→bilirubin→enterohepatic circulation
-includes unconjugated + conjugated with glucuronide
3 causes
1. prehepatic : increased heme via hemoloysis
2. intra hepatic : decreased uptake/metabolism/secretion : liver injury
3. post hepatic : obstruction of ducts
Direct Bilirubin : Conjugated
Normal : like pre-intrahepatic
Raised : suggest post hepatic
Tests of synthesis
INR : coagulation products, short ½ life, insensitive, acute liver dysfunction
Albumin : ½ 13 days, chronic dysfunction
Urea : metabolism of protein and ammonia, mild to severe dysfunction
Glucose : decreased gluconeogenesis, fulminate end stage failure
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Physiol-08B12 Detail the protective and regulatory roles of the liver.
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Immune Function and Inflammation
The liver is the largest of the reticuloendothelial organs and has a prominent role in host defense. Kupffer cells account for nearly 10% of the hepatic mass. These cells filter splanchnic venous blood before it reaches the central circulation, phagocytizing and processing antigens and other substances absorbed from the gastrointestinal tract. In sepsis, Kupffer cells are responsible for scavenging bacteria, inactivating bacterial products, and clearing inflammatory mediators.
Kupffer cell activation (e.g., by inflammatory stimuli) produces or triggers the release of proinflammatory substances (reduced oxygen species, nitro-radicals, leukotrienes, proteases), including cytokines and chemokines, which recruit neutrophils to the liver and heighten the inflammatory response.
Although Kupffer cells are essential for defending the body against foreign intrusions, their activation can also harm the liver when they induce, or exacerbate, hepatocellular injury in diseases involving the liver. During oxidative stress, endothelial cells of the hepatic sinusoids or terminal hepatic veins are vulnerable to toxic injury because of their low glutathione content. These cells may be a pathogenic focus of drug-induced vascular injury. Hepatic stellate cells are the principal liver cell type involved in matrix deposition and hepatic fibrosis. Activated stellate cells (as occurs in methotrexate-induced hepatic fibrosis) may be transformable by certain drugs into collagen-synthesizing myofibroblasts.
Endocrine Function
The liver plays a central role in the metabolism of hormones and hormone-binding proteins. It synthesizes (angiotensinogen, thrombopoietin, insulin-like growth factor 1 ) and inactivates (aldosterone, estrogens, androgens, antidiuretic hormone) a wide variety of hormones. Nearly half the insulin produced by the pancreas never reaches the systemic circulation because it is degraded during a single passage through the liver. Thyroxine (T4 ), the major secretory product of the thyroid gland, is actively taken up by the liver and converted to triiodothyronine (T3 ) or inactivated.
store of glycogen , glucose control
contribute to body heat ,more at rest
defence against toxic substance ( medication ,drugs)
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Physiol-05A9 Describe the control of gastric emptying.
Physiol-09A14 Describe the physiological processes that influence the rate of gastric emptying.
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Gastric Emptying
Gastric emptying is a coordinated movement of chyme from the stomach to the duodenum, the flow of which is driven by the Gastric Antral Pressure and hindered by the resistance of the Pylorus. The Antral pressure is under positive and negative neurohumoral control and is influenced by Gastric factors (which generally provide positive effects), and duodenal factors (generally negative feedback to decrease gastric emptying).
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Gastric factors
1. Vago-vagal excitatory reflex to increase Antral Pump activity is stimulated by gastric distension.
2. Gastrin secretion is stimulated by gastric distension and by protein intake and this further stimulates Antral Pump activity.
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Duodenal factors
The composition of the fluid entering the duodenum influences the rate of gastric emptying via hormonal feedback and also by reflex vagal inhibition. Stimulation of the duodenum causes inhibition of Antral Pump activity. the duodenum responds to the following stimuli:
* High acidity : via increased secretin
* Fat/protein breakdown products : via increased cholecystekinin
* Carbohydrates : via GastroIntestinal Peptide
* Hyperosmolarity : the duodenum possesses osmoreceptors
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Physiol-04B13 Describe the functions of the gastric secretions 45%
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2500 ml gastric secretion per day.
Surface mucus cells - throughout stomach:
* viscous mucus
* HCO3-
Alkaline mucus coats stomach and protects from acidic gastric secretions.
Gastric (aka oxyntic) glands - body and fundus:
1. Chief (aka peptic) cells
* pepsinogen - cleaved into pepsin by HCl, powerful proteolytic enzyme with optimum pH 1.8 - 3.5. In response to ACh via vagal and enteric nervous plexus, and in reposne to HCl. Protein digestion, bacteriocidal - important role in innate immunity.
2. Parietal Cells
* HCl - 160mmol/L, pH 0.8, 3 x106 [H+] cf. plasma. Bacteriocidal/bacteriostatic - important in innate immunity. Stimulates pepsinogen release and provides optimum pH for it's activity. Converts Ferric iron to more soluble and thus absorbable ferrous form, stimulates duodenal secretions for digestion and duodenal negative feedback on gastric motility/emptying. Indirect stimulaton of bilary and pancreatic secretion via duodenum.
* intrinsic factor - essential for vitamin B12 absorbtion in ileum. Lack → pernicious anaemia.
3. Enterochromaffin like cells (ECLs)
* Histamine - HCl secretion by parietal cells directly ∝ to histamine release by ECLs. Stimulated mainly by gastrin, less so by vagal ACh and othe endocrine/paracrine factors released by enteric nervous system.
4. Mucus neck cells
* Watery mucus - food lubrication and gastric protection.
Pyloric glands - antrum:
1. G Cells
* Gastrin (G34 & G17) - stimulate parietal cell HCl production via ECL histamine release (plus ↑ gastric emptying/motility). Secreted in response to protein in stomach.
2. Mucus neck cells
* Watery mucus - food lubrication and gastric protection.
Others
* gastric lipase - small role in fat digestion (majority in small intensine).
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Describe the physiological changes that occur in respiratory function during pregnancy.
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O2 Consumption
-Increases 25% at term : due to metabllic requirements of placenta, uterus and growing feotus) + increased WOB and cardiac work (minor addition)
Increased 100% during labor
Control of Ventilation
1. Ventilation increases by 50% (early in term, maybe by 8-10 weeks gestation) due to stimulatory effects of progesterone
2. This is due to an increase in TV by 40% and RR by 10%
3. Stimulation of the Medullary Respiratory Centre by progesterone causes a left shift of the Ventilation:C02 response curve.
**will return to normal approx 7 days post partum
Anatomy
1. Diaphragm displaced upwards by 4cm
2. AP and transverse diameters of thoracic cage increase by 2-3cm
3. Circumference of Chest Wall increases by 5-7 cm (due to relaxin produced by the corpus luteum)
4. Oedematous upper airway (1:300 failed intubation rate)
5. Dilated upper airways = decreased AWR by 35% (bronchodilation due progesterone)
Lung Volumes
1. Most lung volume changes occur (or are most prominent) after 20 weeks gestation
2. ERV and RV (hence FRC) reduced by 20% standing and 30% supine (significant increase in propensity to hypoxaemia upon induction of anaesthesia)
3. Tidal Volume increases by 30%
4. Hence TLC only decreases minimally (5%) and VC stays the same
5. Chest Wall Compliance decreases by 20%
6. Anatomical Dead Space increases 45% but the VD:VT ratio is unchanged
** will return to normal in 48hours post partum
Blood Gases
1. PaCO2 28 - 32 mmHg
2. HCO3- 18 - 21 mmol/L
3. Base Deficit -2 to -3
Airway Closure and V/Q matching
ERECT : No effect on dynamic airways compression, lung volume loops or closing capacity
SUPINE : FRC decreases 70%
Other
* Lung compliance unchanged
* Chest wall compliance decreases (uterus mass effect and breast weight on chest)
* Labour: hyperventilation during contractions causing hypocapnia, then hypoventilation between contractions. Epidural obliterated these changes.
OVERALL
50% loss of respiratory reserve
Due to
1. increased BMR
2. decreased FRC
3. dcreased CVS reserve
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Physiol-07B14 Describe the cardiovascular changes that occur in the fetus at birth.
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Physiol-07B14 Describe the cardiovascular changes that occur in the fetus at birth.
Immediately following birth the fetal circulation changes from 2 circulations in series into 2 circulations in parallel.
This is achieved through
1. loss of placenta
2. first breath
3. closure of shunts
1. loss of placenta
-clamping of the umbilical vessels
-loss of low pressure placental circulation
-large increase in SVR
-increased afterload
-subsequent increase in SV + CO to compensate
-increased LV+LA pressure
-obliterated umbilical vien forms ligamentum teres
2. first breath
-large negative intrapleural pressures
-collapse lungs begin to inflate
-PVR reduces as lung volume increases
-further reduction in PVR following inspiration of air , loss of HPV
-consequently reduced RV afterload
-reduced RV+RA pressures
3. closure of shunts
i) Foramen ovale : immediate physical closure as LAP>RAP, but anatomical closure by 4-6 weeks, in 20% of population remains anatomically open, but physically closed
ii) Ductus arteriosum (shunt from pul artery to descending aorta) spasm immediate triggered by normoxic blood (reduced PGE2 synthesis), complete closure by 2 weeks
iii) Ductus venosum (shunt from left portal vein to IVC) spasm immediate, unknown mechanism, but complete closure by 2 weeks.
-obliterated DV forms ligmentum venosum
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Physiol-07A14 Explain the mechanisms whereby oxygen transfer is facilitated at the placenta. 59%
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Placenta : interface between materal and fetal circulation
Oxygen passes from the mother to the fetus at the placenta by diffusion.
Fick's Law of diffusion
Flow=(DAP)/T
D=diffusion coeffecient =solubility/sq root of MW
A=surface area
P=pressure gradient
T=thickness
Comparision to lungs
Thickness : placenta 3.5um, lung0.5um
SA: placenta 16m2, lung 50-60m2
Placenta is inefficient at gas exchange but this is overcome by
1. counter current flow : always a gradient for oxygen flow into fetal circulation
2. fetal vs adult Hb
3. double bohr
4. higher oxygen carrying capacity (high Hb concentration)
Maternal Uterine blood gas results
PaO2 100mmHg, SatO2 98%, CaO2 16ml/dl, PaCO2 40mmHg
PvO2 40mmHg, SatO2 75%, CvO2 12ml/dl, PvO2 50mmHg
Fetal : Umilical blood gas results
PaO2 20mmHg, SatO2 45%, CaO2 12 ml/dl
PvO2 30mmHg, SatO2 70%, CaO2 16ml/dl
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Physiol-02B16 Explain the Bohr and Haldale effects in trans-placental gas exchange (pass:77%)
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Definitions:
Bohr Effect- is the process where there is a shift to the right of the ODC associated with a rise in blood pCO2 and/or fall in pH. This rise in CO2 results in a lower affinity of Hb for O2 favoring delivery of O2 to the tissues --> leads to a conformational shape change --> decreases the accesibility of the O2 to the heam groups --> unloading
Haldane Effect- is the process where there is an increased capacity for Hb to carry CO2 when it is in the deoxygenated state and results from
* Increased buffering ability of deoxyhb --> more CO2 carried as HCO3-
Comment: The buffering of H+ ions is by imidazole moieties on histidine residues of globin molecules. DeoxyHb is more basic in nature and therefore is able to buffer in this way (30% of Haldande Effect).
* Increased formation of carbamino groups
* Both due to the conformational change in the Hb molecule when O2 is not present
Trans-placental gas exchange
* Placenta is an organ designed for efficient transfer of substances from mother to baby and baby to mother
* Maternal blood supply and foetal blood supply in close contact separated by membrane 3.5μm thick
* Majority of transfer is by simple passive diffusion, esp when referring to gasses
* Exchange of any substance across the placental membrane is determined by Ficks diffusion equation
* Rate of diffusion = (conc.grad. x area x permeability) / membrane thickness
Double Bohr effect
* CO2 released from the foetus and taken up by the maternal blood lowers the maternal pH from 7.42 to 7.3
* This leads to conformational change in the maternal Hb --> release of more O2 to the foetus
* When the foetus released the CO2 its pH moved in the opposite direction from 7.21 -> 7.32
* This causes the reverse conformational change in the foetal hb leading to an increased affinity for O2 facilitating O2 uptake by the foetus
* This accounts for 2-8% of transplacental O2 transfer.
Double Haldane effect
* Haldane effect in the mother --> when there is O2 unloading from the maternal blood the Hb is more able to carry the CO2 given up by the fetus
* because the Hb molecules increased buffering ability and increased ability to form carbamino compounds.
* Conversely the uptake of O2 by the foetus will decrease the ability to carry CO2 in the forms of HCO3- and carbamino compounds
* This leads to an increase in CO2 delivery from the fetus to the mother
* This accounts for 46% of the transplacental CO2 transfer
If you have time you could add in: Uterine artery
* pO2 100 mmHg (SO2 ~98%)
* pCO2 32mmHg
* pH 7.42
* blood flow 700ml/min
* O2 available for the foetus and placenta = 42 ml/min
* Uterine requirement O2 = 15 ml/min
* Placental requirement O2 = 1-2 ml/min
* Therefore O2 available for foetus = 25 ml/min
Uterine vein
* pO2 33 mmHg (SaO2 ~?60%)
* pCO2 46 mmHg
* pH 7.3
Umbulical artery
* pO2 18 mmHg (SO2 ~?50%)
* pCO2 55 mmHg
* pH 7.21
* umbulical blood flow 300 mls/min
* foetal O2 uptake = 18-27 ml/min
Umbulical vein
* pO2 28 mmHg (SO2 ~???%)
* pCO2 40 mmHg
* pH 7.32
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Physiol-05A12 Describe the physiological factors influencing the carbon dioxide tension in arterial blood. 38%
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The partial pressure of carbon dioxide in mixed venous blood depends on the carbon dioxide content of the blood and represents a balance between CO2 production in the tissues and content in the arterial blood.
Production
Carbon dioxide is an end product metabolism of sugars (RQ 1.0) , fats (RQ 0.68) and amino acids (RQ 0.8) with oxygen ,in a process known as aerobic metabolism. CO2 production is related to metabolic rate. Increased metabolic rate : exercise, hyperthryoidism, sepsis. Decreased metabolic rate : hypothermia, rest, hypothyroidism (big list but no time)
-glycolysis no CO2 produced
-pyruvate is converted to acetyl-CoA and CO2 (glucose : 2 pyruvate, a-a: pyruvates)
-fatty acids catabolised to produce acetyl-CoA
-acetyl CoA enters KREB cycle produces 2 CO2
Total amount of CO2, 10000mmol per day
Excretion
Major determinant of PCO2 in blood, tightly controlled by respiratory centre.
Normal Values : PaCO2 35, PvCO2 45
Determined by Alveolar ventilation
PaCO2=VCO2/VA
Sensor : central and peripheral chemoreceptors (aortic and carotid, afferents via vagus and glossopharyngeal), sensitive to PCO2 and H+
Integrator : medullary respiratory centre
Effector : respiratory muscles (diaphragm, intercoastal, sternoclidomastoids) to increase RR and Vt = increase in Va
Partial pressure in blood
CO2 carriage : dissolved, bicarb, carbaminocompounds
AV CO2 different and relative contributions
CO2 dissociation curve
And factors that push left: deoxyHb (Haldane effect)
CO2 is very lipid soluable, therefore crosses alv-cap membrane easily, therefore perfusion limited.
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Physiol-08B11 Write brief notes on the physiological changes association with sleep.
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Sleep
A state of unconsciousness from which an individual can be aroused by sensory stimulation, and which is under a degree of circadian control.
CNS
Sleep associated with characteristic EEG changes which form the basis of the classification of sleep stages:
NREM sleep: slow wave, 70-80min
* Stage I: low amplitude high frequency EEG activity, beta waves
* Stage II: appearance of sleep spindles: alpha like 10-14Hz waves, and large biphasic K complexes.
* Stage III: lower frequency higher amplitude waves, δ waves.
* Stage IV: further slowing of frequency and increase of amplitude.
* NREM sleep is restful and dreamless.
REM sleep:
* high frequency 'desynchronised' low amplitude EEG activity resembling EEG of wakefulness.
* threshold for arousal is elevated
* occurs for 5-20min each 90 min of sleep.
* average of 4-5 REM periods per night.
* selective deprivation of REM causes 'REM rebound' but significance is unclear.
* associated with active dreaming.
Sleep cycle:
* Sleep is enetered in stage one and generaly progress through to stage III or IV.
* Periods of REM alternate with NREM.
* Periods of REM generally become longer and more frequent later in the night.
* Sleep doesn't strictly pass from stage to consequtive stage.
* general dominace of ↑ PNS activity during sleep - less so during REM.
CVS
NREM: → 10 to 30% ↓ in HR, BP.
REM:
* irregular heart rate, variable effect on BP
* ↑ cerebral blood flow and O2 consumption.
Respiratory System
* Respiratory rate generally unchanged during sleep.
* Tidal volume decreases, and minute ventilation in paralell with it.
* Small increase in PaCO2 (~3 mmHg).
* Small decrease in PaO2 (~3 mmHg).
* Slope of both the hypercapnic & hypoxic ventilatory response curves are markedly reduced (~33% NREM, more in REM).
* Loss of activity and tone in upper airway muscles with ∝ ↑ in upper airway resistance.
* diaphragmatic function relatively preserved.
* consequently, negative airway pressure generated by diaphragm may → occlusion of airway → sleep apnoea.
NREM:
* Decreased TV and minute ventilation with each deepening stage.
* Decreased upper airway muscle tone with each deepening stage.
REM:
* irregular respiartory rate.
* Tidal volume smallest in REM, reduced ~25%.
* Upper airway tone at minimum - 20-30% normal.
Skeletal muscle
NREM * generalised decrease in tone, more so with each successive stage.
REM: * marked inhibition of neck and airway muscle tone
* tone elsewhere preserved
* locus-ceruleus dependant relative paralysis of volunatry skeletal muscle activity
* locus-cereleus lesioned cats thrash around in REM sleep as if they are acting out their dreams so presumably this paralysis is a protective mechanism.
Endocrine
* Melatonin, prolactin, testosterone, and growth hormone are all maximally secreted at night.
* Cortisol trough occurs just before morning.
* ↑ ADH → concentrated low volume urine.
Metabolic
* 10-30% reduction in MR
* slight ↓ in core temperature (0.5°C)
* ↑ in shivering threshold.
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Physiol-08A13 Describe the production of cerebrospinal fluid, its role and its fate.
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Defn: "The cerebrospinal fluid (CSF) is located within the ventricles, spinal canal, and subarachnoid spaces.
Numbers
Vol : total 150ml, 75ml in ventricles, 75ml around spine
-500ml/days or 21ml/hour
-ICP 5-15mmHg
-biochemistry
Na 147 active transport NaKATPase
K 2.9
Mg 2.2
Ca 2.3
Cl 113
HCO3 25.1
PCO2 50
pH 7.3
Osmo 290
Little protein (20g/L)
60% of plasma glucose facilitated transport, saturated above 15mmol/L
Function:
1. cushions the brain and reduces effective weight (boeyancy)
2. regulates brain extracellular fluid
3. allows for distribution of neuroactive substances
4. "sink" that collects the waste products produced by the brain, no lymph system
5. protective role as buffering for any rise in ICP by CSF translocation
Production:
500ml/day constant!
70% choroid plexi of lat, 3rd and 4th Ventricles
30% endothelial cells lining capillaries of brain
Circulation:
foramens of Magendie and of Luschka into the subaracoid space of the brain and spinal cord
Absorption
varies depending on ICP
90% arachnoid villi
10% directly into cerebral venules.
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List the physiological factors that determine intracranial pressure.
Explain briefly how intracranial pressure is regulated.
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Intracranial Pressure (ICP)
According to the Monro-Kellie doctrine, ICP is the pressure exerted by three compartments (brain, CSF and cerebral blood volume) within the intracranial vault, which is rigid (except in very young children) with a fixed volume. The pressure exerted by each compartment is determined by the amount of space each takes up. An increase in size in any of the three components will lead to a corresponding increase in ICP unless there is a compensatory decrease in another component.
A normal ICP in adults is 0-15 mmHg, up to 10mmHg in children, and 5mmHg in infants. Sustained ICPs of 25-30mmHg are generally fatal.
Increased ICP may crush brain tissue, cause midline shift, cause ischaemia by limiting cerebral blood flow, (ischaemia then causing cerebral oedema and further swelling), and cause brain herniation and death.
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Determinants of ICP
Brain: intracerebral oedema, tumours and other space occupying lesions may cause increased pressure.
CSF: rate of production is not determined by ICP, but by blood flow to the choroid plexus, which is determined by cerebral blood flow. Absorption (via the arachnoid villi or directly into cerebral venules) increases as CSF pressure rises above around 7cm of H2O. Normal amt of CSF is around 150mL, and around 500mL CSF is formed (2/3 by the choroid plexus and 1/3 by the ependyma of the walls of the ventricles) daily. CSF acts as a buffer for increased ICP by translocation to the extracranial subarachnoid space.
Cerebral blood volume: as with CSF production, cerebral blood volume is affected by cerebral blood flow. Normally, cerebral autoregulation couples CMRO2 to cerebral blood flow, so that metabolic demands are met (flow-metabolism coupling). Other things which affect cerebral blood volume include drainage (eg blockage of venous drainage leads to increased cerebral blood volume).
Cerebral blood flow (CBF) = cerebral perfusion pressure (CPP) / cerebrovascular resistance (CVR)
CPP is the pressure driving blood supply to the brain. It is MAP – venous pressure or ICP, whichever is greater. Positioning head up decreases CPP by effects of gravity, thereby decreasing cerebral blood flow. CVR is affected by metabolic autoregulation, pressure autoregulation, chemical factors, and the nervous system. Metabolic autoregulation refers to the fact that as CMRO2 increases in an area of the brain, resistance in that area decreases (?2 to rls of vasodilator) and flow increases. Pressure autoregulation refers to the ability of vessels (via myogenic mechanism) to maintain the same blood flow over a wide range of MAPs (50-100mmHg). Chemical factors include paCO2 and paO2. increased paCO2 causes vasodilation. Decreased paO2 (below around 50mmHg) causes vasodilation. SNS chgs CVR very little. BUT it has an enormous influence on CPP.
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Physiol-03B15 Briefly describe the NMDA (N-methyl d-aspartate) receptor and its physiological role in the central nervous system. 55%
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NMDA receptor:
* Distributed throughout brain and spinal cord.
* Contributes to excitatory neurotransmission
* Located on secondary afferent neurons (ie, post synaptic to primary afferent neuron)
* Transmembrane 5 subunit structure with a central (nonselective) cation ionophore.
* Both ligand gated and voltage dependent receptor
* Ligand is glutamate. Glycine is a co-agonist; the binding sites are separate.
* At rest, ionophore is blocked with Mg2+ - this is voltage dependent.
* Associated with AMPA receptor and neurokinin-1 receptor (which lead to partial membrane depolarisation).
* Partial depolarisation of the cell membrane (required for displacement of Mg plug), AND binding of glutamate AND binding of glycine are required for efficient opening of NMDA receptor channel, at which point Mg2+ plug leaves ionopore, allowing flow of cations (Na and Ca into cell, K out of cell)
NMDA receptor role:
* there is no activity at NMDA receptors in normal nociceptive transmission processes (membrane not depolarised long enough for displacement of Mg).
* In presence of persistent pain from abnormal conditions, frequency of pain signal transmission increases glutamate in synaptic cleft, which causes secondary afferent neurons to be depolarized long enough for Mg ions to be dislodged from ionophore.
* NMDA receptor activation leads to central sensitization via 2nd messengers and generation of substances eg NO, which causes increased excitability of secondary afferent neurons and increased transmission of pain signals, even in response to benign stimuli
* neuronal plasticity (learning and memory)
* ‘windup’ likely due to increased spinal cord expression of c-fos protooncogene
* Implicated in cerebral ischaemic damage
Antagonists:
* Ketamine (binds to phencyclidine binding site on NMDA receptor; inhibits activation by glutamate; decreases presynaptic rls of glutamate; potentiates effects of GABA).
* Phencyclidine
* Xenon
* Nitrous oxide
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Physiol-02A5 Outline the factors contributing to the generation and maintenance of the resting membrane potential 77%
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Definition -
The potential difference (units volts) that exists across the cell membrane at an unexcited state
Resting Membrane Potential (RMP) produced as:
* the cell membrane is semi-permeable, with variable permeability to different solutes.
* potential is created by different concentration across th cell
* produced and maintained by Na+-K+-ATPase (which pumps 3Na out for 2K in)
Intracellular Extracellular mV
Na 10 145 +70
K 135 4 -94
Cl 9 125 -70
The Nernst Equation
-ionic movement via Fick's Law of diffusion (equation)
-as ions are charged, movement ions produces a potential across the membrane
-Nerst Equation quantifies the potential produced by different ion concentrations across a membrane at electrochemical equilibrium (ie no flow of ions) at 37deg
eg for potassium Vk+ = RT/zF ln[K+i]/[K+o]
* VK+ is the equilibrium potential for potassium, measured in volts
* R is the universal gas constant.
* T is the absolute temperature, measured in kelvin.
* z is the number of elementary charges of the ion in question involved in the reaction
* F is the Faraday constant.
* [K+]o is the extracellular concentration of potassium, measured in mmol·l-1
* [K+]i is likewise the intracellular concentration of potassium.
The equilibrium potential for an ion would be equal to the RMP should the membrane be permeable only to that ion.
The Goldman Equation
RMP = - RT/F ln blah blah
Basically combination of several Nerst equations which factors in conductances of various ions acting across the membrane.
Determinants of Resting Membrane Potential
1. K+ Diffusion Potential
At resting state, K+ is most permeable with little conductance of other ions (especially Na), therefore RMP approaches Nernst for K+= -95mV
2. Na+ Influx
While the resting membrane is very impermeable to Na+ the electrochemical gradient for its movemnet into the cell is so large that there is a small 'leak current' of Na+ into the cell. This Na+ leak is the single factor responsible for most of the deviation of the RMP from the equalibrium potential for K+
3. Na+-K+-ATPase
As noted there is a constant slow leak of Na+ into the cell. Therefore, Na+-K+-ATPase is essential to maintain the relative concentration gradients of these ions and thus the RMP. By transferring 3 Na+ out for every 2 K+ pumped in, leaving a net negative charge balance on the inside of the cell membrane. This contributes roughly -4mV to the RMP.
4. Gibbs-Donnan Effect
The Gibbs-Donnan effect accounts for the effect of non-diffusible ions on the RMP. In vivo the high concentration of negatively charged intracellular proteins has a small but significant effect on RMP. The presence of this net fixed negative charge on the inside of the cell effects the distribution of permeable ions across the membrane.
Resting Membrane Potential in Differing Tissues
Typical values of RMPs:
* Ventricular Myocyte: -90mV
* Cardiac Pacemaker cell: -60mV
* Skeletal Muscle cell: -80mV
* Myelinated Axon: -70mV
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Physiol-00B6 Briefly discuss the physiological control of intraocular pressure 30%
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Intraocular pressure (IOP) is the fluid pressure inside the globe of the eye. Normal IOP is between 10 and 20mmHg.
Components influencing intraocular pressure:
* The globe of the eye is relatively noncompliant. There are two main components within the globe which can change in volume- aqueous humour and blood (especially in the choroidal vessels). Small changes in volume of either component can lead to large changes in pressure, given the globe’s low compliance (much like the Monro-Kellie doctrine of intracranial pressure).
Aqueous humour:
* Normal production: by the eye’s ciliary body. Aqueous humor circulates through the anterior segment of the eye (comprising the anterior and posterior chambers) and also through the vitreous humor of the posterior segment. It is produced by filtration from capillaries in the ciliary process in the posterior chamber, and circulates into the anterior chamber.
* Normal drainage: In the anterior chamber, aqueous humor is reabsorbed into venous blood by a network of trabeculae that drain into the canal of Schlemm (a venous canal which encircles the iris, around the scleral-corneal junction).
* Normally production is matched by drainage.
* Factors which ↑ IOP: Increased production of aqueous humor, or decreased drainage, eg due to blockage of the canal of Schlemm, eg 2° to mydriasis, inflammation, thrombosis in venous system.
Blood volume:
factors which change volume
* Increased blood flow, eg 2° increased MAP
* vasodilation
* obstruction to venous drainage
Other factors: reduced compliance of the globe, or reduced volume- eg 2° to ↑ extraocular muscle tension
Consquences of increased intraocular pressure:
* Ischaemic injury.
* Corneal opacification.
* Optic nerve damage.
* note that ↑ IOP does not cause glaucoma (significant proportion of cases have normal pressure) but ↑ IOP exacerbates it. Therapy is thus aimed at lowering IOP.
Drugs which can increase intraocular pressure:
* suxamethonium
* corticosteroids (any route of admin)
* antidepressants (TCAs, SSRIs)
* mydriatics (closed angle → obstructed drainage of canal of Schlemm)
Drugs which can lower IOP:
* β-blockers and carbonic anhydrase inhibitors - ↓ aqueous humour production.
* cholinergic agents - ↑ aqueous humour drainage.
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What is saltatory conduction and what are the advantages of this type of conduction? 80%
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Saltatory- derived from saltare (‘to jump’), refers to jumping conduction, ie conduction along a myelinated nerve fibre, in which conduction jumps from one node of Ravier to the next.
* The axons of many nerve fibres in the CNS and PNS are myelinated.
* Myelin is a protein lipid complex that is wrapped around the nerve axon.
* Myelin is laid down when Schwann cells in the PNS or oligodendrocytes in the CNS wrap their cell membranes around the axon up to 100 times.
* Schwann cells wrap a single axon, wheras oligodendrocytes send out processes which may wrap the axons of multiple neurons.
* Myelin serves as an insulator, and ionic movements across the membrane do not occur in myelinated regions.
* The myelin sheath is interupted by 1µm spaces which are known as the Nodes of Ranvier (NOR).
* Ionophores (ion channels) are concentrated at the NOR.
* In an unmyelinated neuron the action potential 'flows' forward along the axon as the current sink of the action potenital propogates as it progressively depolarises the section of membrane ahead of itself.
* The high resistance of the myelin sheath allows the AP to jump passively from NOR to NOR - the deploarisation at one NOR during the action potential providing sufficient current to depolarise the membrane to threshold at the adjacent NOR.
* This makes conduction of the action potential much faster (up to 50x) than in unmyelinated fibres of similar size.
* It is also more energy efficient, as there is less net movement of ions thus requiring less energy expenditure by the sodium potassium ATPase to restore the normal ion balance.
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Explain briefly the physiological mechanisms whereby an action potential arriving at a synapse might not be conducted. 22%
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Question regarding normal normal synaptic transmission, and thus possible disturbances of this.
1. Post synaptic refractoriness : absolute and relative
2. summation
3. inhibitory post synaptic potentials
4. hyperpolarization
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Physiol-06B13 Briefly describe the structure of a mammalian skeletal muscle fibre and explain how its structure is related to its contractile function. DO NOT describe excitation-contraction coupling. 35%
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Structure & Function
* Muscle fibre is a specialised cell in the body
* Arranged in parallel between tendinous ends
* This enables contraction to occur in the same direction (longitudinal), and also to be additive
* Each fibre consists of a single, multi-nucleated, cylindrical cell, surrounded by membrane
* The fibre contains myofibrils, which consist of individual filaments (the contractile proteins)
Contractile Proteins
* Myosin (thick) filament is surrounded by thin filament (actin, tropomyosin, troponin)
* These filaments are attached at Z lines (anchor points)
* When activated, the myosin fibres pull on surrounding actin filaments to slide past each other, which shortens the muscle fibre (and the whole muscle)
* The troponin-tropomyosin complex has a role in the inhibition and activation of the attachement between myosin and actin, and is also regulated by Calcium influx
Sarcotubular system
* Cell membrane = sarcolemma
* Continuous with T-Tubule system, basically extensions of external cell membrane which invaginates and traverses deep within cell and surrounding myofibrils to ensure action potential / electrical stimulus spreads to most parts of cell. In close contact with Sarcoplasmic reticulum (modified ER) which is a source of Ca.
* This Sarcotubular system is involved in excitation-contraction coupling – allows fast spread/transmission of action potential to inner/outer parts of cell, around all myofibrils - which will result in coordinated and synchronised contraction of myofibrils due to Na/Ca influx and Ca release from Sarcoplasmic reticulum.
* The cell membrane also contains the motor end plate (where the NMJ lies)
* Contains all important nicotinic Ach receptors which transduce the impulse from the supplying nerve fibres into contraction of the muscle
* NMJ cleft also contains Achase, important in stopping muscle contraction
Electrical features
* Like any cell, there is a negative RMP
* This is produced by having varying conductance to certain ions, and by the action of a membrane Na-K-pump
* These electrical features are very important, because it is the ability to depolarize which allows Ca efflux from the SR which causes muscle contraction
Energy / metabolism
* Muscles are very active organs, so therefore need a high metabolic capacity and energy supply
* Need energy for
- Na-K-Pump to maintain RMP
- SR-Ca pump to cease contraction, and relax
- Contractile function of myofibrils
* High ability to produce phosphate energy compounds
- Phosphorylcreatine
- ATP
Fibre Type
* Some muscle are known as “slow-twitch / red fibre muscles”
- They have a high oxidative capacity
- Many mitochondria
- Increased capillary concentration
- High concentration of myoglobin (to facilitate oxygen transfer)
- High ability to generate ATP
- Ability to generate contraction over a long period of time
- Ie, axial muscles involved in posture
* Some are fast twitch / white fibres
- Higher anaerobic capacity (increased amounts of glycolytic enzymes)
- High Ca-pump capacity
- faster, more explosive contraction, but fatigues easily
- Ie, quadriceps
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Physiol-05B14 Describe the processes of excitation and contraction within smooth muscle cells. 53%
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Excitation-Contraction Coupling
the means by which the signal to initiate muscle contraction is transduced to initiate the physical process of contraction within the myocyte.
Excitation
* Vm is unstable and has no true resting value, continuous drift
* shows continuous irregular contractions independant of nerve supply - i.e. has tone.
* change in tone correlate with less negative Vm, no real APs
* when action potential like spikes to occur contraction occurs after ~200 ms, with peak tension up to 500 ms later indicating excitation contraction coupling is much slower than in striated muscle (10 ms).
* smooth muscle unique in that it may contract or relax when stretched in the absence of extrinsic stimulation.
* may also be stimulated by autonomic nerves or circulating neurotransmitters or drugs.
* ACh or NA may be excitatory or inhibitory depending on the tissue concerned.
* nerves that synapse on smooth muscle (SM) serve to modify its activity rather than 'initiate it as it does in skeletal muscle.
Contraction
* as in striated muscle ↑ in intracellular Ca2+ concentration is the initiator of contraction.
* unlike straited muscle SM has poorly developed sarcoplasmic reticulum, and most Ca2+ is from extracellular influx via v-gated and ligand gated Ca2+ channels.
* SM contains actin and myosin filaments that as in striated muscle form the 'machinery' of contraction.
* SM lacks troponin (which is intimately involved in EC-coupling in striated muscle).
* actin and mysosin lack the ordered arrangement that gives striated muscle it's characteristic appearance. Rather actin filaments are anchored at dense bodies.
* sidepolar arrangement of filaments allows SM to shorten up to 80% (cf. 30% for striated).
* SM is plastic - has no true resting length.
* SM cells contain large amounts of regulatory protein calmodulin.
* Calmodulin binds Ca2+.
* Ca2+-calmodulin complex activates myosin light chain kinase (MLK).
* MLK phsophorylates the myosin regulatory light chain.
* phosphorylation is required for myosin crossbridge cycling (cf. striated muscle).
* myosin regulatory light chain is dephosphorylated by myosin phosphatase to cease contraction.
* phosphorylated mysosin binds ATP.
* power stroke hinging of mysosin head occurs with ATP → ADP.
* ADP is released and new ATP binds causing release of myosin from actin and resetting of mysosin to 'cocked' position.
* this cycling is very much slower than in striated msucle (up to 300x), possibly due to reduced ATPase activity of the myosin head.
* fraction of time during cycle which crossbridge is attached is much larger - this is the main determinent of force of contraction.
* this slow cycling means energy required to sustain prolonged contraction is very low cf. straiated muscle. Important in light of smooth muscle function.
* latch-bridge mechanism:
-sustained crossbridge attachment allowing sustained force of contraction without further ATP use.
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Physiol-04B14 Briefly describe the difference between a single twitch and a tetanic contraction in a skeletal muscle fibre. Include in your answer the physiological basis for the development of a tetanic contraction. 54%
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Single Twitch
supra maximal stimulus 0.6V
* Stimulated by a single nerve stimulus
* A brief contraction of skeletal muscle follows, followed by relaxation
* There is only one nerve stimulus, therefore only one contraction
* The following single twitch contraction will be approximately the same force and duration.
* The twitch may last between 10 – 200ms depending on how “fast” the fibre type is
Tetanic contraction
-50-100Hz for 3 seconds
* Stimulated by repetitive nerve firing, at an increasing rate (above a critical frequency)
* The muscle fibre contracts not long after the AP, but due to the repetitive signaling, does not have time to relax
* Continues to be stimulated to contract
* When the “tetanic” firing rate is reached, muscle exhibits a continuous contraction, with no relaxation (and summation of contraction)
* The force of muscle contraction is about 4 x greater than that of a single twitch contraction
Physiological Basis for Tetanic contraction
* Nerve firing produces an action potential in the muscle
* The action potential is brief, and exhibits a period of refractoriness
* The muscle contaction however, is slightly slower, and occurs after the action potential (only just beginning to contract as the membrane is repolarising)
* The muscle contractile mechanism does not exhibit a refractory period
* The next action potential occurs before the contractile proteins have “relaxed”, they are therefore continually stimulated, as long as the AP firing rate is rapid enough, to not allow a period of relaxation in the muscle
* This causes “summation” of contractions
* As the muscle has no time to relax, the Ca concentration (intracellularly) gets higher, which causes a higher force of contraction (and ongoing actin-myosin cross-bridge cycling)
* Due to the ongoing depolarization, and opposing action of Ca pump in SR – this process utilizes a great deal of energy
* Firing rate required for tetanic contraction is related to the duration of muscle twitch for that fibre, if the next AP stimulus occurs before the end of the contraction, it will exhibit tetany (this is the critical frequency for that fibre)
- ie, if twitch duration is 10ms, frequency of stimulation will have to be > 100/sec
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Physiol-01A2 Briefly describe the effect of resting muscle length and load conditions on the tension generated by a skeletal muscle. How do these factors affect the velocity of shortening? 19%
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The main points expected for a pass were the relationship of resting muscle length to tension development, and the components of active and passive tension which contribute to total tension as length is increased. The inverse relationship of load to velocity of shortening was also expected. High scoring candidates made effective use of correctly labelled graphs to illustrate points, and explained that developed tension was maximal at resting length. Most candidates were able to illustrate the role of actin/myosin cross-bridge formation in the development of tension, but there was often confusion with cardiac muscle, and a Frank-Starling mechanism was often invoked for skeletal muscle. Diagrams frequently referred to left ventricular haemodynamics rather than skeletal muscle. Muscle spindle control and Golgi tendon organ involvement were not required in the answer and did not attract marks
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Physiol-09A15 Describe the formation, fate and role of lactate in energy production
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Physiol-09A15 Describe the formation, fate and role of lactate in energy production
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Physiol-09A10 Describe the physiological effects of the glucocorticoids
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Definition
Glucocorticoids are steriod hormones produced by the adrenal cortex which regulates metabolism of CHO, fats and proteins and is involved in reactions to stress and inflammation.
Normal Values
-plasma=14 ng/ml = 305 nmol/L, diurnal variation
-PPB 96%
-T1/2 60min
-onset of effect quick
Production
-produced in Zona Fasiculata of Adrenal Cortex
-pre-cursor : cholesterol
-LDL in circulation moved into cytoplasm
-cholersterol is esterfied by cholesterol mutase to free cholesterol
-shuttles to mito by sterols
-metabolised by P450 enzymes in mito and SER to cortisol and corticosterone
-immedately secreted
Metabolism
-by liver, slow, 3 pathways
1. P450 enzymes to androgens
2. cortisterone to cortisol
3. conjugated to glucornides and excreted by kidney
Regulation
-pituitary axis
-CRH from hypothalamus : stimulated by stress and emotions from limbic system, diurnal stimulation, inhibtion by coritsol
-ACTH from anterior pituitary, stim by CRH+R (Gs linked), inihibited by cortisol
-ACTH R is Gs linked
Actions
-only free cortisol is able to exert effects
Mechanism
-cytoplasmic glucocortiod receptor
-complex diffuses into nucleus to alter gene transcription, mRNA and protein production
-may well be membrane receptors as well
Substrate metabolism
-anti insulin effects: increased gluconeogenesis, lipolysis, protein catabolism
-increased serum glucose, fatty acid and amino acids
Permissive activity
-physiological amounts needed for normal function
-SM of blood vessels unresponsive to circulating catecholamines: hypotensive
-cognition : confused, irritable, poor attention
-mineralocorticoid action : Na and water retention
Stress
-increased CRH, ACTH and cortisol in stress : infections, trauma, surgery
-unknown mechanism
-but adrenectomised patients high mortality with stress
Inflammation
-decrease circulating eosinophils
-increase neutrophils, lymphcytes and basophils
Disease
-Cushing disease : hypothalmic or pituitary over production
-Cushing syndrome : adrenal over production
-Addisions disease : adrenal insuffiency
-Adrenal insuffiency related to exogenous long term steriod use.
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Physiol-08B10 Describe sepsis and describe the metabolic consequences of sepsis.
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48% of candidates passed this question.
A basic definition of sepsis was expected. Recognition of the spectrum of severity encompassed by the term sepsis gained additional marks, as did a brief description of the mechanisms and mediators of sepsis. Given the wording of this question equal marks were given for the general (non-metabolic) and metabolic features of sepsis. The general features were best organised by a system s approach namely cardiovascular, respiratory, haematological, endocrine and CNS. Of these the cardiovascular features required the most detail.
Important information to be included in the metabolic part of the answer included the general catabolic state, hypermetabolism , fever, tissue hypoxia, metabolic acidosis, insulin resistance and the effect of sepsis on the metabolism of carbohydrates, proteins and lipids. Clear writing and simple organisation involving underlined headings and common abbreviations allowed candidates to cover this broad question well. Those who failed this question simply did not provide enough content and detail. The most common mistake was to write at length about metabolic acidosis to the exclusion of a wider ranging answer.
Detailed metabolic pathways were not expected.
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Physiol-08A11 Outline the physiological consequences of diabetic keto acidosis.
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Massive topic, definitions, outline of mechanisms and outline effects.
Definition of DKA
Include metabolic aspects, fluid and electrolyte abnormalities, and severe metabolic acidosis
Mechanism
lack of insulin, gluconeogenesis, lipolysis, fat breakdown = ketoacid overproduction, hyperglycemia and osmotic diruiesis
Effects
Acidemia on all body systems
Electrolyte derrangements : mainly K+
Water deficit, hypovolemia
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Physiol-07A16 Briefly outline the components of parenteral nutrition, explaining the rationale for the use of each component. 42%
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Parenteral nutrition : provision of nutrient intravenously bypassing the enteric system.
Sterile bag of nutrient solution (500ml-4L) infused into large vein via CVC or PICC line.
GIT is non-functional because of interruption in its continuity or because it absorptive capacity is impaired.
Indications
1. non functioning gut : ileus
2. malnourished patients in whom enteric usage anticipated for > 7days
3. severe mucositis : chemotheraphy
4. major resections of small bowel
5. intestinal atresias, radiation enteritis
May be used as the sole nutritional technique or supplement enteral nutrition. Usually short term, but there are long term TPN patients : longest known being 35 years.
Components
Energy : CHO/Lipid
-attempt to match metabolic energy requirements, usually in catabolic state but may be in a hypometabolic state.
-25kCal/kg/day, increase with burns, sepsis
-Harris-Benedict equation : unreliable, but tries to estimate metabolic energy requirements
-can use O2 consumption/CO2 production
-glucose to lipid usually 60:40 or 50:50
Nitrogen/protein
-1-1.5g/kg/day
-provide amino acids for protein anabolism + energy source
-glutamine
Volume
-match
-baseline requirement 1ml/kg/hour
-add losses from wounds, drains, stomas and fistulae
Electrolytes
-match losses
-Na, Cl, K, Mg, PO4, Ca, Frequent monitoring is needed
-Vitamin C, thiamine, zinc
Complications
• Co-morbidity (mechanical ventilation, severe associated disease, abdominal surgery..);
• Line sepsis;
• Infective agents gaining access to TPN solutions;
• Hyperglycaemia.
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Physiol-06B16 Describe the physiological consequences of acute hypoglycaemia. 57%
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Hypoglycaemia is a plasma glucose level below 3 mmol/L which results in neurological and endocrine changes.
Glucose concentrations is maintained between 4-8mmol/L despite eating, digestion and fasting. Ultimately is a balance between input and output.
Input : orally ingested, gluconeogenesis and glycogenolysis by the liver
Output : uptake into muscle + fat, glycolysis, glycogenesis, lipogensis.
Insulin is the main regulator.
Increased insulin
-stimulates uptake from plasma to muscle and fat, glycolysis, glycogenesis, lipogenesis
-inhibits gluconeogensis, glycogenolysis
Opposing insulin is glucagon
Causes
fasting (inadequate input)
exogenous insulin
insulin secreting pancreatic tumor
alcohol or betablockers
Endocrine response
Attempt to increase serum glucose by gluconeogenesis, glycolysis, protein catabolism, liposis
Cortisol, glucagon, growth factor
Cortisol
-released by adrenal cortex from beta adrenergic stimulation
-Shakiness, anxiety, nervousness, tremor, Palpitations, tachycardia. Sweating,
-effects of cortisol
Glucagon
Hunger, Nausea, vomiting, abdominal discomfort, Headache
-effects of glucagon
Growth hormone
-
Neuroglycopenic manifestations
Brain reliant on glucose as metabolic substrate
No glucose stores in the brain
Manifestations include agitation, impaired judgement/concentration, fatigue/lethargy, confusion, ataxia, coma, generalised serizures
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Physiol-06A13 Describe the factors which influence metabolic rate 48%
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Metabolic rate
the rate of energy production by the body per unit time. The sum of external work, energy storage, and heat production.
* Metabolic rate should be distinguished from basal metabolic rate which is metabolic rate under a standard set of conditions (at rest, thermoneutral zone temperature, 12 hours post meal).
* Metabolic rate is measured by calorimetry (direct via measuring heat energy produced, or indirectly via measuring O2 consumption).
The determinants of metabolic rate are:
Muscular activity: this is the largest source of energy expenditure – skeletal muscle can have the biggest effect on metabolic rate due to its potentially high consumption. Metabolic rate can be increased to 10 times (or 20 times in traqined athletes) basal rate for short periods of time (minutes). In addition, metabolic rate remains elevated after exercise to repay oxygen debt.
Food:there is an increase in metabolic rate after food consumption. This is termed the Specific Dynamic Action which is the energy expenditure required to consume and process food (to increase the metabolic rate by 100kcal, 30kcal is expended in processing protein, 6kcal for CHO and 4 kcal for fat). Metabolic rate falls with starvation (up to 40% with prolonged starvation).
Temperature:(environmental and core temperature). The relationship of metabolic rate to temperature is “U-shaped”. When environmental temperature is lower than body temperature, heat conserving mechanisms are activated and metabolic rate rises. However, as environmental temperature drops and there is more severe hypothermia, metabolic rate lowers. In addition, as core temperature rises, there is an increase in metabolic rate (for every 0.5 °ree;C, MR rises by 8%). Ganong says 14% increase in MR for every degree rise in body temperature. Nosek says 10% per degree change in bodsy temperature in either direct - I suppose after the intial increase in MR with hypothermia.
Hormones: circulating levels of thyroid hormones and catecholamines can effect metabolic rate. Thyroid hormones increase the rates of activity of most cells in the body. Stimulating the sympathetic nervous system increases the metabolic rates of many of the body’s tissues, including increased glycogenolysis in liver and muscle and mobilisation of FFAs. Catecholamines cause a fairly rapid change in MR, whereas thyroid hormone cause a more prolonged and slower change in MR.
Note other factors:
* Height/weight/body surface area: metabolic rate increases with all these factors. Correlates best with body surface area.
* Sex: metabolic rates of females are 10% less than males.
* Gestation & lactation ↑MR.
* Emotional state: anxiety and tension elevate metabolic rate, related to increased SNS activity and muscle tensing.
* Growth ↑MR.
* Age: MR (corrected for body weight) ↓ with increasing age.
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Physiol-04B12 Briefly describe the secretion and functions of renin and angiotensin 48%
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Renin
A glycoprotein polypeptide ENZYME produced in the kidney (JGA) and involved in the regulation of water and electrolyte balance and blood pressure control.
Plasma 2-24 ng/L in upright
Synthesised as prorenin by JGA cells of the kidney and other tissues eg ovary
Processed by kidney only to Renin : stored and released by juxtaglomerular cells
Release stimulated by:
• afferent arteriolar hypotension sensed by intrarenal baroreceptors
• tubuloglomerular feedback sensing a increased in solute presentation to JGA.
• sympathetic nerve activity, neural and circulating on β1 receptors
• PGE2 & I2
Inhibited by:
• ANP
• A-II (neg feedback)
• opposite to above
Catalyzes conversion of angiotensinogen to A-I.
No other effects
Angiotensin II
An octapeptide hormone involved in the Renin Angiotensin system which regulates electrolyte and water balance and arteriolar tone.
Plasma = 25 pg/ml
Production
Liver
-Angiotensinogen : 32 aa
-increased by glucocortiods, thyroid hormones, estrogens, cytokines and ATII
Renin
-Angiotensinogen to ATI in circulation
-inactive, decapeptide, only a substrate for ATII production
-rate limiting factor
Lungs
-ACE : ATI to ATII , also inactivates bradykinin
V. Short (1-2 mins)
Minimal
Rapid, various peptidases
-inactivated by cleaving of further aa’s to ATIII to ATIV
AT1 R Gq (PLC) + Gi (AC, cAMP)
-increase intracellular Ca : vasocontraction
-also activates various tyrosine kinases
Actions include:
Kidney
• increased Na / HCO3 reabsorption in PCT,
• increased afferent arteriole & efferent vasoconstriction , reduce RBF and GFR
• increased mesangial cell contraction, reduce GFR
• increased aldosterone from adrenal cortex
Arteriolar
• increased SNS response (direct action to increase NA release from postganglionic nerves)
• potent systemic vasoconstriction (4-8 x NA)
CNS
• increased ADH release
• ↑ ACTH release
• increased thirst acts on Organum Vasculosum
Negative feedback actions:
• decreased renin
• decreased PG E2 & I2 meaning don’t get unopposed vasoconstriction.
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Physiol-03A15 Describe the physiological actions of thyroid hormones. 38%
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Definition : steriod hormones produced by the thyroid which act on nearly every cell in the body.
They act to increase the basal metabolic rate, affect protein synthesis, help regulate long bone growth (synergy with growth hormone), neuronal maturation and increase the body's sensitivity to catecholamines (such as adrenaline) by permissiveness
Mechanism of Action
* There are two forms of thyroid hormone - Tetraiodothyronine (Thyroxine/T4) and Triiodothyronine (T3).
* Circulating thyroid hormones (T3 and T4) enter cells and bind to thyroid hormone receptors in the nucleus.
* The hormone-receptor complex then binds to DNA via zinc fingers and can alter gene expression (usually of enzymes).
* This process takes time therefore the actions of thyroid hormone are not immediate.
* The half life of T3 is 1.5 days, T4 7 days.
* Plasma T4 roughly 50 x higher than plasma T3 level (~100 vs ~2 nmol/L).
* Both are highly protein bound, and it is the free hormone which is physiologically active.
* T3 is 3-5 x as potent as T4, as it is less tightly protein-bound, binds more avidly to the receptor and acts rapidly.
* Free thyroid hormone in plasma provides negative feedback and inhibits pituitary secretion of TSH.
Cardiovascular effects
* increased expression of alpha-MHC (myosin heavy chain) over beta-MHC. alpha-MHC has more ATPase activity therefore increases speed of contractions.
* increases number and affinity of beta receptors thereby increasing myocardial sensitivity to catecholamines.
* increased cardiac output: increased pulse pressure and heart rate, shortened circulation time.
Metabolic effects
* increased oxygen consumption by most cells (except brain, uterus, testes, spleen).
* increased NA/K ATPase activity.
* increased metabolism of fatty acids.
* increased heat production, therefore stimulates initiation of heat-loss mechanisms such as cutaneous vasodilatation and decreased peripheral vascular resistance.
* increased absorption of carbohydrate from the gut (increased post-prandial BSL).
* increased nitrogen excretion - if not matched by increased intake this leads to catabolism of endogenous protein and fat, and weight loss.
* can unmask vitamin deficiencies as the demand for these is increased.
* increased milk secretion.
* decreased plasma cholesterol due to increased LDL receptors in the liver.
Skeletal muscle effects
* weakness
* also changes myosin heavy chain gene expression but ? effect
Growth and development
* essential for normal growth.
* essential for normal bone development.
* potentiates effects of Growth Hormone.
* GH not secreted in the absence of thyroid hormone.
Nervous system effects
* affects cortex, basal ganglia and cochlea - deficiency during development leads to mental retardation, motor rigidity and deafness.
* affects deep tendon reflexes - reaction time increases in hypothyroidism and decreases in hyperthyroidism.
Catecholamines:
* levels stay normal but effects of hyperthyroidism (CVS, tremor, sweating) can be abolished by sympathectomy and to a large degree by beta blockers.
Calcitonin
* Secretion regulated by calcium content of plasma supplying thyroid
* Secretion proporitonal to calcium concentration above 9.5mg/dL
Actions:
* lowers circulating calcium and phosphate
* inhibits bone reasorbtion by supressing osteoclastic activity
* increases calcium excretion in urine
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Physiol-01B3 Describe the fuel sources used during early and sustained fasting in man. 51%
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51% of candidates passed this question.
A large number of the candidates who did not achieve a pass were borderline fails.
The main points expected for a pass included:
* a definition of early and sustained fasting. A wide range of definitions was accepted so long as early fasting was considered less than 24h.
* A brief description of the conversion of liver glycogen stores to glucose during early fasting was required as was the importance of glucose as a source of energy.
* Similarly, a brief description of the role of gluconeogenesis, lipolysis, and the production of ketone bodies during sustained fasting was expected.
* The fuel sources could be considered as either the substrates (ie glycogen, protein and fat), or their breakdown products (ie glucose, amino acids, free fatty acids, glycerol, and ketone bodies).
* The reliance of the brain on glucose or ketone bodies was considered core knowledge.
Additional marks were awarded for
* providing quantitative information,
* a description of the Cori and alanine cycles,
* the fuel sources used by individual organs (eg brain, heart, muscle etc),
* the initial sparing of protein during sustained fasting (due to preferential breakdown of triglycerides), and
* the time course of changes in fuel utilisation.
* Candidates who mentioned the continued absorption of food remaining in the gut during early fasting received credit.
Common mistakes were:
* to consider ATP or creatine phosphate as 'fuel' sources, to discuss the effects of water deprivation (while the question asked for a description of fuel sources)
* to consider other aspects of starvation.
Common omissions were to overlook the importance of glucose, especially in early fasting, and free fatty acids in sustained fasting.
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Physiol-00B7 Outline the actions of insulin that affect fat metabolism 28%
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Insulin is a polypeptide hormone secreted by b cells of the pancreas which has a key role in the metabolism of carbohydrates, proteins and lipids.
Mechanism of action
-insulin has short half life 15minutes
-attaches to insulin receptor :
-alpha domain : extracellular, binds to insulin
-beta domain : transmembrane protein, tyrosine kinase activity, autophophorylates and phosphorylates other enzyme systems.
Outline of effects
1. Decreased fat utilisation due to increased intracellular availability of glucose
2. Increased production of fat which occurs mostly in the liver
3. Increased uptake of free fatty acids by fat cells
4. Increased storage of fat
5. Decreased breakdown of fat.
Liver
-insulin increases GLUT4
-increased glucose into cell (facilitated diffusion)
-trapped by increased activity of glucokinase (G6P)
-2 paths
1. increased glycogenolysis, total of 100mg produced
-once saturated glucose moves down glycolytic pathway
-promotes glycogenesis, and inhibits glycogenoloysis (phosphorylase)
2. increased glycolysis results in increase pyruvate (and thus Acetyl CoA)
-enter Kreb cycle for aerobic metabolism
-limits fatty acid breakdown, as glucose is now prefered substrate
-excess AcetylCoA produces fatty acids
Fat
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Physiol-08A10 Define "thermoneutral zone". Briefly explain how the body regulates temperature when the ambient temperature exceeds the thermoneutral zone.
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The Thermoneutral zone is the range of ambient temperatures where a person can maintain their body temperature with no increase in metabolic rate (or oxygen consumption) above basal levels (also, body temperature being able to be maintained with changes in cutaneous blood flow alone).
For an Adult = 27-31 degrees Celsius naked
For a neonate = 32-34 degrees
Aim to maintain core temperature between 36-38 deg C
Regulation of temperature is typical of any feedback system
1. Detectors : peripheral and central receptors
Peripheral sense ambient temperature :
Hot receptors : skin, static discharge btn 30-40degC, increase to max 46degC
Cold receptors : skin, face is sensitive, increase discharge below 25degC, A delta fibres
Central sensors : spinal cord, visceral organs
2. Central Contoller : Hypothalamus
Optimal set temperature
Integrates afferent thermal inputs
Anterior : regulates responses to hot : sweating and vasodilation
Posterior : regulated responses to cold : vasoconstriction, shivering, establishes reference temperature
3. Effectors : autonomic, hormonal and behavioral
Ambient temp 1. Skin blood flow 1-150ml/100g/min, large variation, regulating convection, radiation, conduction, increased alpha adrenergic vasoconstriction, AV shunts, skin BF decreased, shunt away from peripheral compartment, first response, extremely energy efficient
2. Shivering : involuntary contraction of muscles, 250Hz, increased MR 100% + non shivering thermogenesis beta 3 adrengeric, brown fat, uncoupled oxidative phosphorylation
3. Behavioral : increased clothing, fetal position, movement
Ambient temp>TNZ
Skin blood flow : high variation, 150ml/100mg/min, vasodilation, increased heat loss through peripheral compartment through radiation and evaporation
Sweating : latent heat of water 4.2kj/kg per deg, highly efficient form of heat loss, 3L per day for unclimitised, 12L for climitised.
Behavioral : reduced clothing, reduced activity
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Physiol-01A5 Explain briefly the role of the skin in maintaining a normal body temperature 71%
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The skin is vital in maintaining normal body temperature (36.7 to 37.1 deg C).
The thermoneutral zone is the range of ambient temperatures in which the naked organism can maintain normal body temperature with minimal energy expenditure (and therefore minimal O2 consumption). In adult humans this is 25 to 30 deg C, in neonates 32 to 34 deg C.
Both within and outside the thermoneutral zone, the skin plays a vital role in the mechanisms for thermoregulation. The skin has specialised subepithelial receptors for warmth (incl. VR1 and VRL-1, via C fibres, fire maximally at 45-50 deg C) and cold (incl. CMR-1, via A delta and C fibres, fire maximally at skin temp 25-30 deg C), which provide afferents to the hypothalamus. The hypothalamus integrates peripheral and central afferents and coordinates effector responses to balance heat production and heat loss to maintain normal body temperature.
The skin is thus both a receptor and effector in the thermoregulatory control loop.
Heat is gained or lost from the body via:
* convection - heat transfer through a fluid medium such as air or water
* conduction - heat transfer through a solid medium
* radiation (proportional to the 4th power of the temp difference between patient and ambient) - due to emission of infrared waves
These mechanisms may cause heat loss or gain from the environment, depending on the temperature gradient that exists. Together account for 70% heat loss. These take place via the skin surface.
* evaporation
This mechanism can facilitate heat loss only. Accounts for 27% heat loss - mostly via respiratory system when in thermoneutral zone (obligatory heat loss). Increased secretion of sweat by the skin is the major effector of evaporative heat loss (can increase heat loss by up to 500%). Notably evaporation is the only available means of heat loss when the amibient tempoerature is greater than body temperature.
Mechanisms to maintain body temperature include behavioural (the most important in the conscious person, but abolished under anaesthesia) and autonomic mechanisms.
Behavioural mechanisms
Behavioural mechanisms (eg varying clothing, seeking shelter) work by making more or less of the skin surface available for convection/conduction/radiation.
Skin vasoactivity
Thermoregulatory autonomic responses are primarily effected via the skin. Skin blood flow can be markedly changed by autonomically (alpha receptor) mediated vasodilation or vasoconstriction.
In the absence of heat stress, normal skin blood flow is 300ml per min. In extreme cold, can decrease to 50ml/min; in extreme heat can increase to 3,000 ml/min. This enables increased or decreased radiant, conductive and convective heat gain or loss, by increasing or decreasing the thermal gradient between the skin and ambient temperatures.
Sweating
Sweating is sympathetically (cholinergic) mediated. 0.58 kcal/g water evaporated can be lost (due to specific latent heat of vaporization). Becomes more important as ambient temperature increases, but effectiveness decreases with increasing humidity. The ability to sweat is not fully developed in neonates therefore they are more easily heat stressed.
Piloerection
Piloerection occurs in humans but is of little importance in retaining heat, in comparison to other mammals covered with fur.
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Physiol-97B4 Briefly describe the influence of general anaesthesia on intraoperative temperature regulation. 46%
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General anaesthesia is a state of total unconsciousness resulting from the administration of appropriate amount of anaesthetic drugs.
Regulation of temperature is typical of any feedback system
1. Detectors : peripheral and central receptors
Peripheral sense ambient temperature :
Hot receptors : skin, static discharge btn 30-40degC, increase to max 46degC
Cold receptors : skin, face is sensitive, increase discharge below 25degC, A delta fibres
Central sensors : spinal cord, visceral organs
2. Central Contoller : Hypothalamus
Interthreshold range
normally 0.5°C of 37degC core body temperatures in which none of the thermoregulatory responses are activated by the hypothalamus.
↑ to 4°C by anaesthesia
Integrates afferent thermal inputs
Anterior : regulates responses to hot : sweating and vasodilation
Posterior : regulated responses to cold : vasoconstriction, shivering, establishes reference temperature
3. Effectors : autonomic, hormonal and behavioral
* obliterates behavioural response as part of regulatory control (they’re asleep!)
* dose-dependent reduction in regulatory control, and affects vasoconstriction/shivering 3x > sweating
* Can be a 20-fold increase (4 degrees) in interthreshold range (normally 0.2-0.4 degrees)
* ie, heat-response (vasodilation / sweating) increased by 1 degree
* cold-response (vasconstriction / shivering) decreased by 3 degrees
* GA’s linearly affect warm-response thresholds
* Opioids / propofol decrease cold-response(vasoconstriction / shivering) linearly
* Volatile anaesthetics decrease cold-response non-linearly
* Volatiles may decrease maximum response to sweating, shivering, and also effect gain of response
* Muscle relaxants block shivering response
* Spinal / Regional anaesthesia block local neurally-mediated response (may be a significant area of body)
Due to the changes in the interthreshold range - usually hypothermia more common
Other factors affecting body temperature intraoperatively
* greater SA exposed for heat loss from skin by evaporation / radiation / convection
* evaporation/heat loss from fluid inside body cavities
* heat energy transferred from body in humidifying dry inspired gases (latent heat of vaporisation needed for evaporation of water from the trachea)
* The initial (rapid) drop in core body temperature under GA is due to redistribution of heat from the core to the peripheries, due to loss of tonic vasoconstriction - rather than any heat exchange with the surrounding environment.
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Physiol-93A3 Give a brief account of the physiological consequences of hypothermia
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The physiological changes of hypothermia are classified according to the severity of the drop in body temperature:
* mild hypothermia is defined as a temperature between 35 and 32.2 degrees,
* moderate between 28 and 32.2 and
* severe below 28 degrees celcius.
Respiratory changes include: tachypnea and a progressive decrease in respiratory minute volume and declining oxygen consumption, bronchorrhea and bronchospasm in mild hypothermia. In moderate hypothermia, there is hypoventilation, a loss of protective airway reflexes and a decrease in oxygen consumption by 50%. In severe cases, there is pulmonary congestion and edema, a further drop in oxygen consumption and finally apnea.
Cardiovascular changes in mild hypothermia include tachycardia, followed by progressive bradycardia as more heat is loss. There is associated vasoconstriction and an increase in cardiac output (SVxHR) and blood pressure. At moderate hypothermia, there is a decrease in heart rate and cardiac output, increased incedence of atrial and ventricular arrythmias, ECG changes and prolonged systole. In severe cases, there is a decrease in BP, heart rate and cardiac output. Reentrant dysrythmias are more common. The ventricular arrythmia threshold is lowered and eventually there is asystole.
Neuromuscular changes include increased preshivering muscle tone, followed by shivering induced thermogenesis and ataxia in mild hypothermia. This is followed by hyporeflexia, diminished shivering induced thermogenesis and rigidity. In severe hypothermia, there is decreased nerve conduction velocity and peripheral areflexia.
CNS changes include a linear depression in cerebral metabolism, amnesia, apathy, impaired judgement and maladaptive behaviour. In moderate hypothermia, EEG abnormalities can be noticed, conscious state is further depressed, pupillary dilation and hallucinations and interestingly paradoxical undressing. In its most severe state, there is loss of cerebrovascular autoregulation, blood flow, loss of occular reflexes and a decrease in EEG activity.
Renal and endocrine changes: In mild hypothermia, there is increased diuresis and an increase in circulating catecholamines and steroids. T3 and T4 are increased. In moderate hypothermia, there is an increase in renal blood flow. Renal autoregulation remains intact. The action of insulin becomes impaired. Finally in severe hypothermia, the renal blood flow mirrors the decrease in cardiac output. Oliguria sets in and poikiothermia ensues. There is an 80 percent decrease in basal metabolism.
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Physiol-93A3 Give a brief account of the physiological consequences of hypothermia
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Hypothermia is a condition in which an organism's temperature drops below that required for normal metabolism and bodily functions.
Core body temperature is maintained near a constant level through biologic homeostasis. 37 +/- 0.4degC
The physiological changes of hypothermia are classified according to the severity of the drop in body temperature:
1. mild hypothermia is defined as a temperature between 35 and 32.2 degrees,
2. moderate between 28 and 32.2 and
3. severe below 28 degrees celcius.
Cardiovascular System
-Initial tachycardia and vasocontriction with mild hypothermia - increased CO (via rate, contractility and stroke volume).
-Sympathetically driven.
-Progressive decrease in CO thereafter (halved at 28°C).
Arrhythmias
-Progressive bradycardia and increasing degrees of heart block with increasing degrees of hypothermia.
-1st degree heart block common <33°C, CHB <20°C.
-Atrial fibrillation common <34°C, asystole (about 20°C)
-Increased ventricular irritability makes ventricular fibrillation a risk from about 28°C if the heart is stimulated (physically, rewarming, alkalosis, or hypocapnia.
ECG Changes
-J wave (pathognomonic deflection at the junction of the QRS complex and ST segment segment) and T inversion <33°C. J waves
-ST elevation or depression also possible.
Haematological System
-Impaired oxygen unloading - Haemoglobin has an increased affinity for oxygen leading to decreased oxygen availability, however oxygen solubility is increased (Henry's Law) though this effect is not clinically relevant.
-This is balanced to some degree by the resultant lactic acidosis.
-In severe hypothermia, the acidosis is frequently profound, so that there is an overall right-shift to the ODC.
-Increase in blood viscosity - Changes in vascular permeability result in the loss of plasma to extravascular compartments.
-Inhibition of coagulation factor activity and platelet function (clinically significant at <34°C)
Respiratory System
-Initial tachypnoea in mild hypothermia, followed by a reduction in minute volume and reduced oxygen consumption.
-bronchospasm and bronchorrhoea.
-Protective airway reflexes are reduced predisposeing to aspiration pneumonia.
-Sensitivity to pCO2 stimulation below 34°C; hypoxic drive is maintained to deeper levels of hypothermia.
-Respiratory drive ceases at about 24°C
Neurological System
-Initial confusion, amnesia. Progressive deterioration until coma at 30°C.
-Progressive hyporeflexia
-shivering is replaced by muscular rigidity at about 33°C. Rigor mortis-like appearance at 24°C
+/- involuntary flapping tremor
-CBF <6-7% with CMRO2
-Loss of autoregulation at ~25°C
-Flat EEG at ~20°C
Renal and Metabolic
-Initial cold induced diuresis (shunting of blood from peripheries to centre)
-Followed by decreased RBF and GFR due to decreased cardiac output
-ARF is seen in over 40% of patients with accidental hypothermia who require admission to an intensive care unit.
-Impaired renal function
-Hyperglycaemia due to multiple causes (decreased insulin release due to corticosteroids and direct cooling on islet of Langerhan cells, increased insulin resistance of peripheral tissues, and increased GNG)
-Decreased metabolic rate ~50% by 28°C
Gastrointestinal system
-Decreased GI motility <34°C, Ileus <28°C.
-Spontaneous gastric ulceration
-Acute pancreatitis
-Impaired liver function
Prevention of inadvertent hypothermia intraoperatively
Limit phase 1 distribution
-0.5-1.5 degree fall in core temperature from redistribution from central to peripheral compartment
-preheating : heats peripheral compartment to reduce phase 1, 30 minutes via forced air warmer
Ambient temperature
decreasing the gradient for heat loss via radiation and convection from exposed surfaces.
airway heating/humidification
Latent heat of evaporation to humidify alveolar gases
Bypassing nasal humification
hme [=artificial noses]
retain good amt of heat/moisture in resp tract
heating effic ~1/2 of active methods
much cheaper than “ “
iv fluids
1 litre crystalloid at room temp } dec core T 0.25deg
“should warm if using large volumes”
passive insul
aim is to trap a layer of still air around pt
all diff materials eg space blanket, cotton, surg drapes ~effic
idea with reflective ones is that u will dec radiative losses better
prewarmed materials make little diff
SA is most impt consideration, not specific site
minimise exposure of viscera/wound to air
cutaneous warming
nearly ineffective at rewarming
mainly used to minimise heat loss via redistribution+radiation
risk of burns
infrared systems
only a little more effic than passive insul
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Discuss the physiological effects of pneumoperitonium during a laparoscopy surgical procedure.
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A pneumoperitonium the introduction of gases into the peritoneal space.
It requires a insufflant system and access to the peritoneal cavity via closed (Veress needle) or open technique. 15mmHg at 1L/min to 500ml then increased to 20-25mmHg at 2L/min.
CO2 is used because it is colourless, does not support combustion, inexpensive, available and very soluable in blood. Otherwise helium can be used (but is less soluable, but avoid problems associated with hypercarbia). Used to use room air, oxygen and nitrious oxide.
Physiological effects divided into
1. pressure effects
2. effects of hypercarbia
3. other
Pressure effects
CVS : reduced VR secondary to compression of vena cava, increased vascular resistence
RESP : splinting of diaphragm, dead space unchanged, but FRC decreased
Effects of reduced FRC : VQ mismatch, increase PVR, atelectasis, WOB
Worse with lithotomy or trendelberg
Better with PEEP
GU : direct compression of vessels in renal cortex (not artery or vein), medullarly vessels uneffected, however there is reduced RBF and GFR resulting in oligura/anuria
GI : direct compression of viscera and vessels, reduced mesenteric blood flow and intestinal motility.
Effects of hypercarbia/acidosis
META : transperitoneal absorption of CO2 (Fick)
hypercarbia and respiratory acidosis
RESP : Increased ETCO2
ODC curve to the right
CVS : tachycardia and ventricular extra systoles, reduced contractility and CO (countered by increased sympathetic response)
CNS : increased CBF, reduced MRO2
ANS : sympathetic response, increased coritsol
GU : activated RAS + aldsterone = > Na and fluid retention
All this can be corrected by increasing the minute ventilation to enhance CO2 elimination, aim for ETCO2 of 40, check with ABG
Other
Peritoneal irritation : bradycardia
Venous stasis secondary to vena cava compression : DVT
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Discuss the physiological effects of a pneumothorax
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Discuss the physiological effects of a pneumothorax
Pneumothorax is a life threatening condition where gas is present in the pleural cavity resulting in collapsed lung
Causes
1. spontaneous (tall, young males)
2. lung disease (emphysema)
3. traumatic (barotrauma, puncture to chest wall, CVC placement)
4. for thoracic surgery
Discussion of awake spont vent PTX
RESP
-collapse of one lung : no ventilation but perfusion = right to left shunt,
-pulmonary circulation accomadates entire CO due to 2 circulations in series
-equal distribution to 2 lungs, therefore potential 50% shunt
-however, shunt decreases to 20-30% due to increased PVR of collapsed lung as a result of 1. HPV, 2. reduced lung volume
-effects of shunt : mixture of deoxy blood with oxy blood, hypoxemia
-ODC
-isoshunt diagram
-stimulation of irritant receptors to hyperventilate
-reduced in alveolar CO2
-increased alveolar PO2
-stimulation of peripheral chemoreceptors to hypoxemia
CVS
-sympathetic response to pain, irritant receptors, chemoreceptors
-increased HR and SV (CO)
-compressive effects of PTX
-compress IVC and SVC
-reduced VR/CO
-vasoconstriction
-hypertension/hypotension
CNS
-hypoxia : agitation, coma, seizures
Metabolic
-sympathetic stimulation : cortisol
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