surgical phsyiology

Surgical PhysiologyFor MRCS part 3

By Dr. MMM

Surgical Physiology 2

C.N.S.


Membranes

What is the main function of the cell membrane?To control the entry and exit of molecules from the cell and so regulate the interacellular environment.

Describe the basic structures of a cell membrane?The cell membrane consists of a continous lipid bilayer studded with protein molecules.

How does this structure allow control of the movement of molecules into and out of the cell?The lipid bilayer has hydrophilic groups facing outwards while hydrophobic groups face each other across the middle. Most large water soluble molecules, charged molecules and ions cannot cross the lipid barrier. Size, charge and water solubility all decrease the ability of a molecule crossing the fatty membrane. These substances depend on the membrane proteins for their entry and exit from the cell. These patients can act as channels sensitive to voltage or ligand binding or as energy-dependent pumps. Fat soluble substances like oxygen and carbon dioxide can cross easily as can water.

What is the overall charge of the outer surface of the cell membrane?Negative.

What part of the membrane structure is responsible for this negative charge?The cell has a "glycocalyx" formed by membrane carbohydrates, which are negatively charged. These carbohydrates also act as receptor substrates and can bind to carbohydrates on other cells.

Ion channels

What is the basic structures of an ion channel?They are proteins, which form tubular structures with a central pore which transverse the cell membrane and can allow communication between the extracellular fliud and the intracellular compartment.

Are they simple pores?No, they are selectively permeable to specific ions and can be opened and closed.

What would be the consequences for nerve conduction if they were simple pores?If they were open all the time there could be no electrical potential across the cell membrane and cells would be isoelectric with the extracellular environment. The lack of ion gradient would remove the power source for the action potential to be generated when ion channels open and so nerve conduction would not be possible.


What features of an ion channels make it selective for sodium or potassium ions?This is determined by the pore diameter and the charge within the channels. A sodium selective channel is highly charged and narrow. In a charged environment ions dehydrate and the dehydrated Na+ ion is smaller than dehydrated K+ and so can selectively pass through. The potassium selective channel is less charged so the ions are hydrated, a hydrated K+ ion is smaller than hydrated Na+ and the pore is the right size to let the hydrated K+ through.

How can mechanism of channel gating be classified? Please give examples.Channels can be voltage or ligand gating. An example of a voltage-gated channel is the Na+ channel in the membrane of a nerve fibre where the gate is strongly shut when the intracellular charge is negative. If the cell becomes less negative the gate opens allowing Na+ ions to flood in and generate the action potential. An example of a ligand-gated channel is the acetylcholine receptor at the neuromuscular junction. Acetylcholine interacts with the channel leading to a conformational change which opens the central pore to allow Na+ ion to flood into the cell.


Receptors

What is a receptor?The specific molecular site to which a pharmacological agent binds and mediates its effect.

Explain how binding to a receptor can lead to a cellular response?A receptor has two components:

The binding part which protrudes from the cell membrane. An ionophore component which passes through the membrane to the

intracellular compartment. The ionophore can be an enzyme or an ion channel. In the case of an ion channel , binding of a ligand leads to the opening of a

gate and influx or efflux of ions as is the case at the neuromuscular junction when acetylcholine binds.

Enzyme-linked receptors alter the metabolic activity of the cell often via second messengers.

Cyclic adenosine monophosphate (AMP) production by adenyl cyclase is mediated by ligand-binding followed by G-protein activation. Protein kinase can lead to altered gene expression in the nucleus. In general, enzyme-linked receptors lead to slow, prolonged changes in cell activity and ion channels to rapid, short-lived response-binding.

What is a neurotransmitter?A chemical which binds to a receptor and leads to an effect on a synapse function in nerve conduction.

Give an example of an excitatory neurotransmitter and inhibitory neurotransmitter?Acetylcholine is an excitory neurotransmitter at muscarinic receptors.Gamma-amino-butyric acid (GABA) is the main inhibitory neurotransmitter in the brain.When is manipulation of the acetylcholine receptor of interest to the surgeon?Blocking transmission at the neuro-muscular junction by blocking the acetylcholine receptor with a muscle relaxant paralyses the patient.

How do patients with myasthenia gravis behave differentially to muscle relaxants?They are resistant to depolarizing agents like suxamethonium but more senstives to non-depolarizing agents such as atracurium.


Action potentials

What is an action potential? It is a rapid change in the membrane potential followed by rapid return to the resting membrane potential. It is due to voltage-dependent ion channel proteins.In the plasma membrane; the size and shape of action potential differ considerably from one tissue to another.

What tissue have an action potential?The tissues which have an action potential include neurons and all types of muscle cell.

Draw and describe a neuronal action potential ?There are three phases

1. Resting phase: negative charge maintained by Na+/K+/ ATPase.2. Depolarization phase: after a threshold is reached Na+ channels open and the

cell becomes more positively charged and actually overshoots beyond neutral.3. Repolarisation phase: Na+ channels close and K+ channels open leading to the

cell returning to a negative state. A gain there is overshoot and the cell become hyperpolarized.

What determines the conduction velocity of an action potential?Two factors determine action potential velocity:

1. Diameter of the axon, large cells a faster conduction velocity 2. Mylination increases velocity because the action potential is propagated from

one node of Ranvier to the next because the intervening membrane is non-excitable and cannot fire an action potential. This jumping of potential from node to node is termed salutatory conduction. (A node of Ranvier is the gap between two adjacent schwann cells).

What affects the magnitude of the action potential along the length of a neuron?The action potential is an all or nothing phenomenon. It has the same magnitude along the entire length of the neuron. Information is therefore coded in terms of frequency of impulses.


What do the terms "threshold", all or none and summation mean with reference to the action potential ?The cell membrane has a resting potential across it, with the inside usually -70 mV negative compared to the outside. Application of a current will decrease this difference-depolarization up to a point known as the "threshold" after which an action potential is generated by reversing the membrane polarity, i.e. the inside now becomes positive with regard to the outside. This generates an action potential which is then propagated, without decrement, down the entire length of the fibre. Depolarization occurs because opening of Na+ into the cell changing its polarity. Almost as soon as the sodium gate is opened, it begins to close and a potassium gate opens to allow repolarization.The all or none phenomenon indicates that a larger depolarizing current does not create a larger action potential; similarly, once initiated an action potential will spread across the whole membrane. If the current is big enough to create an action potential in one small corner of the membrane, it will depolarize the whole membrane. If the current is big enough to create an action potential in one small corner of the membrane, it will depolarize the whole membrane, if it is not sufficient, none of the membrane depolarizes, i.e. all or none.Summation refers to a phenomenon of muscle fibres whereby the addition of individual muscle twitches creates a stronger and more concerted twitch. It occurs by firstly, increasing the number of motor units contracting stimultaneously and secondly by increasing the frequency with which they contract.

What is the difference between the action potential of a neuron and cardiac muscle?Cardiac muscle cells have an additional voltage channel which creates the characteristic cardiac action potential. This is the slow Ca +2 channel. This channel opens and the muscle is depolarized. It maintains the depolarized state so creating a plateau phase. During this phase, contacting is stimulated by release of more Ca++ from the sacroplasmic reticulum. The cell is also refractory to further stimulus during this phase and therefore tetany is not possible.


Cardiac action potential

Can you describe the phases of the cardiac action potential ?1. The resting potential of ventricular muscle cells is -90 mV.2. The action potential commences when the membrane of the ventricular muscle

is brought to a threshold of a round -75 mV by excitation from adjacent muscle cells.

3. Once the threshold has been reached, the action potential proceeds in three phases: Phase1 (rapid depolarization): at the threshold,

Voltage-regulated fast sodium channels open and. The membrane rapidly becomes permeable to sodium resulting in a rapid depolarization of the sarcolemma (duration 3-5 ms).

Phase2 (plateau phase): as the membrane potential approaches +30 mV, The voltage-regulated sodium channels close. At the same time, The slow voltage-regulated calcium channels open.

Because calcium channels are slow channels, they remain open for lomger (175 ms) and, as result, the membrane potential remains near 0 mV for an extended period of time known as the "plateu phase".

Phase3 (repolarization): as the plateau continues, The slow calcium channels begins to close and The slow potassium channels begin to open.

The result is a period of rapid repolarization that restores the resting potential

4. Refractory period: following an action potential, the muscle will not respond to a second stimulus. During the absolute refractory period the muscle cannot respond at all to any stimulus (duration 200 ms). This is followed by a relative refractory period, during which the muscle will only respond to a stimulus that is stronger than normal (duration 50 ms).

What is the main difference between the cardiac action potential and the skeletal muscle action potential? Cardiac muscle demonstrates a plateau phase but skeletal muscle does notIn skeletal muscle cell, rapid depolarization is immediately followed by a period of rapid repolrization.

Draw and describe a typical cardiac action potential?A typical cardiac action potential is known in figure . there are four phases to the cardiac action potential:1. depolarization and overshoot due to Na+ channels opening 2. repolarization as Na+ channels shut.3. plateau phase as Ca+2 enter.4. repolarization as K+2 effluxes5. slow upwards drift due to Na+ entry. Cell is refractory during this period.


Draw and describe the action potential in the sino-atrial node.There are three phases to the nodal action potential:

1. Upwards drift due to leak of Na+ ions into the cell.2. When threshold of -40 mV reached rapid entry of Ca++ ions occurs.3. Repolarization due to K+ efflux.

Do you know of any drugs that act on the cardiac action potential?Anti-arrythmic drugs act by altering the flux of ions across the membranes of excitable cells in the heart. The primary mechanisms of action correspond to the mechanisms used in the "Vaughan Williams" classification system:

Class I drugs act via inhibition of sodium channels: IA: quinnidine and procainamide (prolong repolarization). IB: lidocine and phenytoin (shorten repolarization). IC: flecainide and propafenone (little effect on repolirization).

Class II drugs block B-adrenergic receptors in the heart: Propanol and esmolol.

Class III drugs inhibit potassium channels: sotalol, amiodarone and bretylium. Class IV drugs inhibit calcium channels:

Verapamil and diltiazem.

o Adrenaline : this increases the rate of sodium leak, decrease the time between action potentials and hence increases heart rate.

o Acetylcholine : this decreases the rate of sodium leak which has the opposite effect to adrenaline, and hence slows down the heart rate.

o Calcium channel blockers : these shorten the plateau phase and hence decrease the force of contraction of cardiac muscle.


Nerve action potential

Can you draw and label a nerve action potential?

Can you describe the sequence of events that occur during a nerve action Potential?

The resting membrane potential in a neurone is approximately -70 mV (due to the different concentrations of sodium, potassium is mostly intracellular and potassium is mostly extracellular).

A stimulus activates the fast sodium channels, causing rapid influx of sodium ions into the cell and subsequent depolarization of the membrane potential.

Depolarization overshoots the zero to +30mV, which inactivates the sodium channels and therefore stops further influx of sodium ions.

Voltage dependent potassium channels open, causing influx of potassium ions and repolarization back to the resting membrane potential of -70 mV.

When sodium channels are inactivated, the cell is refractory to any further stimulius

The Na+/K+- ATPase pump plays an important role in maintaining intra- and extracellular concentrations of sodium and potassium ions.

What influences the speed of neural conduction? Diameter of the nerve: speed increases with increasing diameter. Myelination:

Propagation of the action potential between the nodes of Ranvier (salutatory conduction)

The node of Ranvier is an unmyelinated gap between adjacent Schwann cells.


Muscle

What are the different types of muscle found in the body? Skeletal (striated):

Long, cylindrical, non-branching fibres. Parallel or oblique.

Smooth (non-striated): Narrow, parallel, spindle-shaped cells. Slow but sustained contraction. Autonomic nerves; gap junctions.

Cardiac (striated): Less powerful than skeletal muscle but more prone to fatigue.

What is the structure of skeletal muscle and how does it contact? Epimysium (around muscle bundles). Perimysium (around muscle fascicles). Endomysium ( around individuals myofibrils). Sarcomeres contain actin(I) and mysosin (H); actin is attached to Z lines and

myosin is attached to M lines.Acetylcholine is released at the synapse when the depolarization impulse arrives at the neuromuscular junction. This leads to a cascade of events which results in depolarization of the sarcoplasmic reticulum and release of calcium. The calcium binds to troponin on the thin filaments, changing the position of tropomysin on the thin filaments. This expose actin and leads to the formation of cross-bridge.

What is the difference between the muscles of marathon runners and the muscles of sprinters?Marathon runners have predominately slow-twitch fibres (red):

Aerobic- more mitochondria, enzymes and triglyceride. Low concentration of glycolytic enzymes (ATPase) and glycogen. Best remembered by the expression "slow red ox".

Sprinters have predomintaley fast-twitch fibres (white): Larger, stronger motor units. ATP-creatine phosphate system.

Peripheral nerves


What are the different layers within a peripheral nerve?External epineurium surrounding internal epineurium, surrounding fascicular groups (consisting of endoneuruium), surrounding nerve fibres (consisting of schwann cell/myelin sheath) surrounding the axon.

What physiological changes occur in the nerve following injury? Proximal stump undergoes wallerian degeneration to the proximal node of

Ranvier. Cell body increases RNA synthesis. Multiple axonal sprouts-growth cones with filipodia. Distal pump undergoes Wallerian degeneration (leaving empty neural tubes,

schwann cells and basal lamina). Axonal sprouts reaching distal schwann cells continue to grow (1 mm/day),

others degenerate.

How do you classify nerve injuries? Neurapraxia:

Reversible conduction block. Local ischaemia and selective demyelination of axon sheath. Good prognosis.

Axontmesis: Disruption of axon and myelin sheath, leaving epineurium intact. Fair prognosis.

Neuronotmesis: Complete nerve division with disruption of the endoneurium. Poor prognosis.

Muscle contraction


What is the motor unit?The motor unit is the basic element of motor control. It contains of an α-motor neuron, its motor axon, and all the skeletal muscle fibres that it innervates. The number of muscle fibres supplied by a single α-motor neuron is determined by the type of movement that the muscle performs, so muscles performing coarse movements (such as quadriceps femoris) will have a large number, and muscles performing fine movement such as extraocular muscles) will have a small number.

What is the structure and function of muscle stretch receptors?Muscle stretch receptors (muscle spindles and golgi tendon organs) are specified sensory receptors that discharge when the muscle is stretched. They are vital for motor control and proprioception. The most complex is the muscle spindle, which is composed of two types of fibres:

Intra-fusal muscle fibres : are richly innervated and enclosed within a connective tissue capsule. They contain two types of fibre: nuclear bag and nuclear chain fibres.

A. The nuclear bag fibres are innervated by large, myelinated groupIa fibre. B. The nuclear chain fibres are innervated by medium sized, myelinated

group II fibres. Gamma motor neurons innervated the intra-fusal muscle fibres to regulate the sensitivity of the muscle spindles to stretch.

Extra-fusal fibres : lie between the regular muscle fibres. The contractile unit of a striated muscle cell is the sarcomere. Within one striated muscle cell are large numbers of sarcomers linked end to

end by Z disks There are two types of sliding muscle filaments, thick and thin.

Thick filaments are composed of myosin, consisting of a head projecting from a tail. The head forms the crossbridge to the thin filaments.

The thin filaments are composed of actin, tropomyosin and troponin.

What is the structure of striated muscle? The contractile unit of a striated muscle is the sarcomere. Within one striated muscle cell are large numbers of sacromers linked end to

end by Z disks. There are two types of sliding muscle filaments, thick and thin.

What is the mechanism of excitation-contraction coupling?Muscle cells contract by the sliding filamenrt cross bridge mechanism. There are four steps to this cross bridge mechanism:

1. The ATP bound to myosin is hydrolyzed to form a myosin-ADP-phosphate complex with high energy enabling binding to the actin of thin filament.

2. The ADP and phosphate are released after myosin binds to actin. This causes a conformational change in the myosin head that results in sliding of the thin fibres towards the centre of the sacromer (i.e. contraction).

3. The actin- myosin complex binds ATP to release the cross bridge.4. The myosin ADP-P complex is formed to complete the cycle.

What is the important difference between skeletal and cardiac excitation-contraction coupling?The important difference is that is that no tetany in cardiac muscle because the action potential is longer than the contractile response.


Neuromuscular junction

What do you understand about the neuromuscular junction?


The neuromuscular junction is the synapse between the presynaptic motor neurone and the postsynaptic muscle membrane.

The axon divides into terminal buttons that invaginate into the muscle fibre. The synaptic cleft is 50-70 nm wide and filled with extracellular fluid. The orifices (synaptic cleft) lie opposite the release points for acetylcholine

and contain high concentrations of acetylcholinestrase. The action potential concluded along the motor nerve causes depolarization

and an influx of calcium. The influx of calcium stimulates the release of acetylcholine from storage

vesicles into the synapse; acetylcholine binds to nicotinic receptors on the motor end plate.

Stimulation of the acetylcholine receptors results in opening of sodium channels (and some potassium channels), and influx of sodium and potassium into the cell results in depolarization.

Depolarization is called the end plate potential- if the end plate potential is sufficiently large, an action potential is produced and muscle contraction occurs.

Acetylcholine is hydrolyzed by acetylcholinesterase and the product choline is taken back up through the presynaptic membrane to re-produce acetylcholine.

Do you know any toxins that block neuromuscular transmission?Botulinum toxin:

Botulinum toxin is an exotoxin produced by clostridium botulinum, a Gram-positive spore-forming bacillus.

The toxin is internalized in the presynaptic membrane and binds to the veicle membrane.

This prevents the release of the vesicle and therefore acetylcholine at the neuromuscular- junction.

Do you know any anaesthetic agents that block neuromuscular transmission?Depolarizing muscle relaxant:

Produce what appears to be a presistant depolarization of the neuromuscular junction.

Cause depolarization by mimicking the effect of acetylcholine but without being rapidly hydrolysed by acetylcholineesterase.

Examples include suxamethonium and decamethonium.Non-deplolarizing muscle relaxant:

Complete with acetylcholine for nicotine receptor binding sites. The blockade is competitive, so muscle paralysis occurs gradually. Examples include tubocurium and vecuronium.

What is the molecular basis of myasthenia gravis and how is it diagnosed?Anti body-mediated destructions of acetylcholine receptors.This results in weakness and faiguability of skeletal muscle (e.g. fatigueable ptosis of eyelid clinically on prolonged upward gaze).


Edrophonium (Tensilon) is a short-acting acetylcholinestrase inhibitor, and its adminstration briefly reverses the weakness, by increasing the amount of available acetylcholine in the neuromuscular junction. Thiss is used as a diagnostic tool.Tjymectomy can be curative.

Spinal cord and reflexes

Describe in general terms the internal organization of the spinal cordThe internal architecture of the spinal cord consists of grey and white matter:


A. The grey matter forming proportionally more of the content at cervical and lumbar enlargements. It is arranged in a butterfly shape centrally and is organized as ten numbered laminate each side:

Lamina I lying posteriorly. The posterior laminaea I-VI, receive the cutanous and visceral primary

affrent fibres. Laminae VII, VIII and X lie centrally and not receive peripheral fibres. Lamina IX occipies the anterior horn and contains the α and γ motor

neurons.

B. The white matter contains the ascending and descending long tract. The descending, corticospinal, vestibulospinal and reticulospinal tracts lie in the lateral white fibres.

The corticpspinal tract is the principal descending motor tract and is also known as the pyramidal tract, thus

The other two ascending tracts constitute the extrapyramidal network and are responsible for controlling posterior columns, and the anteriorly situated spinoreticular and spinothalmic tracts.

Where do motor and sensory pathways decussate?The descending motor pathways of the corticospinal tract decussate as they exit the medulla and so travel down the cord on the " the opposite side".


Ascending spinothalamic and spinoreticular tracts cross obliquely in the cord before ascending. The obliquity increases the more cranial the segment.

What would happen if you hemisected the cord?Hemisection of the cord gives rise to the well-described entity of Brown-Sequard syndrome:

Ipsilateral spastic weakness due to division of corticospinal tracts, and dorsal column division gives loss of point position sense and vibration sensation.

There is a contralateral loss of pain and temperature sensation due to division of the crossed spinothalamic tract, this loss is noted between 2 and 6 dermatomes lower than the level of the lesion owing to the obliquity of the crossing fibres.

What is a reflex?It is defined as a stereotypical response to a sensory input. It must involve as a minimum, a sensor, an afferent neuron and an efferent neuron. All reflexes except the stretch reflex also include interneurons.

Describe the pathway of the simple reflex?The simplest reflex of all is the stretch reflex, which is monosynaptic. Striking the patellar tendon with a tendon hammer activates muscle spindle endings that are "stretched". The stimulus travels by 1α afferent fibres into the posterior horn of the spinal cord, where they synapse with γ motor neurons anteriorly that travel to the neuromuscular junction in the quadriceps which contracts.

What is a crossed reflex?Before describing the crossed extensor reflex, it is necessary to describe the flexor or withdrawal reflex. Standing on a drawing pin with an unshod right foot sends pain stimuli into the dorsal horn via nociceptive pathways. Here, the stimulus passes into the interneurons, which eventually sends the stimulus to the motor neurons of both the hip, causing iliopsoas flexion, and knee, resulting in hamstring flexion to withdraw the foot. At the same time, inhibitory motor stimuli are sent to the opposing muscle group to allow the flexion to occur unhindred. This is the withdrawal reflex. In addition, interneurons pass to the collateral cord at the same segmental levels to stimulate the motor neurons of the left leg to cause extension, thus allowing the right foot to come off the ground, and the drawing pin, whilst the left leg supports the body weight.

Thermoregulation

How are changes in body temperature detected?


The hypothalamus and spinal cord have thermoreceptors for core temperature. Skin has receptors for peripheral temperature. All signal are sent to the hypothalamus.

How do we regulate our body temperature?Core body temperature is normally maintained fairly rigidly within fine limits. The central control of thermoregulation is the hypothalamic thermostat, which not only contains its own thermosensory cells that are exquisitely sensitive to temperature change, but also receives the input from skin temperature receptors. There are many more cold receptors than warm ones, hence we recognize cooling of our environment much more easily. There are 3 principal mechanisms for heat loss as follows:

1. Vasodilatation of the cutaneous venous plexuses , which are tonically constricted under sympathetic control. Full vasodilatation compared with full constriction has an eightfold increase in heat conductance.

2. Sweating allows a significant increase in the amount of evaporative losses. Initially, in a hot environment, this is maximal at about 700 ml of sweat per day with a heavy salt loss but, after 4 weeks of acclimatization, this system will produce up to 2000 ml of low sodium sweat, increasing the efficiency of the evaporative loss system by tenfold. Sweating is under the control of sympathetic cholinergic receptors, although circulating catecholamines can also influence sweating.

3. The final mechanism of heat production and mechanisms such as shivering and chemical thermogenesis are inhibited

There are 3 mechanisms of heat production:1. Skin vasoconstriction : reduces radiant heat loss from the skin.

Pilorection: although somewhat rudimentary in humans, is an attempt to create a larger air pocket around the body, and decrease conductive and convective losses. Shivering: under direct hypothalamic control, which increases muscle production of heat.

2. Chemical thermogenesis results in uncoupling of oxidative phosphorylation in the cells regulated by catecholamines to produce an increased rate of cellular metabolism. Brown fat is extremely important in this mechanism owing to the large number of mitochondria in its cells.

3. The final mechanism is a general up-regulation of metabolism by the increased secretion of the thyroid gland, again mediated by the hypothalamus, which increases secretion of thyrophin-releasing hormone and is perhaps another form of the chemical thermogenesis.

A side from these inherent physiological systems for controlling body temperature humans posses an even more-potent mechanism-behavioral control. A human adult can increases its temperature by putting on warm clothes, getting out of the cold environment, drinking hot drinks and turning the central heating up. The converse is obviously true for the human in the warm environment.

Can you describe the body's response to hypothermia?The response is mediated via the autonomic and somatic nervous systems:Somatic response:


Increased voluntary muscle activity and curling up. Shevering (can increase basal metabolic rate (BMR) fourfold.

Autonomic response: Vasoconstriction (directly, via skin thermoreceptors). Hair stands up (horripilation). Sweat glands inhibited. tBrown fat activated (in infants).

The thermoregulatory centre is situated in the pre-optic region and the anterior hypothalamus The body has central and peripheral receptors

Central receptors monitor core temperature. whereas The peripheral receptors consist of warm and cold receptors whose discharge

increases with increasing and falling temperature repectively.The other mechanisms involved in the control and maintaince of temperature, include

Control of skin blood flow. Venous circulation. Shivering and sweating.

How does thermoregulation differ in Eskimos and children ?Brown fat plays an important role in chemical thermogenesis. Unfortunately, adult humans posses almost no brown fat; only infants do, in small patches between the scapulae. In children chemical thermogenesis can increase heat production by 100 %, which may be in compensation for the inability of babies to shiver. Eskimos have very high basal metabolic rates mediated by thyroid gland in an attempt to maintain adequate heat production. Children lack the behavioral control to allow them to modify their environment as circumstances dictate.

Which anatomical sites are commonly used for measuring temperature and are there variations according to site?The most commonly used sites and their normal readings are:

Oral (37 oC). Tympanic (37.5 oC). Axillray (35-36 oC).

And these variations should be borne in mind when examining patient charts. More accurate readings of core temperature (37 oC) can be obtained by rectal and oesophageal measurements; an oesophageal probe is often used intraoperatively.

How do you mange a hypothermic patient? Check airway, give oxygen and ventilate if needed. Set up an intravenous infusion of warm fluids and send off blood.


Monitor the patient:Accurate per rectal temperature probeECG-j waves and arrhythmiasUrinary catheter

Actively rewarm at half a degree Celsius per hour unless rapidly cooled. Thermal blanket, Bair hugger, infusion of warm fluids into the peritoneal

cavity of bladder, haemodialysis, cardiopulmonary bypass. Investigate the reason for the hypothermia and deal with this (including home

or social situation if applicable).

What is sweat?Sweat is a hypotonic solution containing approximately 60 mmol of sodium chloride.

What controls its production ? Its secretion is stimulated by the sympathetic system. How much sweat can one produce?Up to 1.5 L of sweat may be secreted in one hour, but this may be rise to 4L per hour in a heat acclimatized subject.

What physiological changes occur following acclimation in a hot climate?Following acclimation there is:

Increased rate of sweating. Decreased core temperature. Decreased heart rate. Expansion of plasma volume. Decreased sodium content of sweat.

What hormonal changes are seen following changes in temperature?In the cold, the adrenal medulla is stimulated so releasing catecholamines into the circulation. There is also inhibition of anti-diuretic hormone, (NB. Thyroid function does not change).

Is human body temperature constant?The temperature of the resting body varies throughout the day, exhibiting a diurnal or circadin rhythm. It is lowest at night often falling to 36 oC and rises by up to 1.5 oC during the day.Women have a monthly rhythm of temperature and the basal temperature rises by a bout 0.5 oC at ovulation and remains at this high level until the onset of the next menstruation.

Pyrexia

What conditions can cause a rise in body temperature? Infection (swinging pyrexias from abscesses), eg subpherenic abscess.


Inflammation ( radiotherapy, chemotherapy, thrombombolism, post-surgical). Malignancy. Drug reactions. Menstrual cycle. Malignant hyperplasia.

How is pyrexia mediated?Circulating pyrogens reset the thermostatic mechanism in the hypothalamus

Endogenous pyrogens (macrophage activate and release interleukin 1, 6 promoting the production of endogenous pyrogenic proteins from liver, brain and other organs) or

Exogenous pyrogens (eg bacterial debris).

What is malignant hyperthermia and how is it treated? A genetic muscle disorder of muscle, presenting at the time of operation. Affects 1 in 15.000 paediatric patients and 1 in 40.000 adult patients. Can have either autosomal dominant or autosomal recessive inheritance (50%

have a mutation of the calcium release-channel gene on chromosome 19). Acute onset of skeletal muscle rigidity, metabolic, acidosis and malignant

hyperpyrexia). Triggered by halogen-containing anaesthetic agents. Immediate treatment with dantrolene prevents tissue damage and death.

Pain

How pain sensed and tranmitted?Pain is sensed free nerve endings.


In the skin, they are widespread and densely packed; in most internal tissues, however, they are more widely dispersed. They react to different types of painful stimuli- thermal, mechanical or chemical-and there is often much overlap between receptors. Involved chemical mediators include bradykinin, serotonin, prostaglandins, histamine, potassium and acetylcholine. It should be noted that the body recognize 2 different types pain acute and slow pain.

Acute pain is that pain which begins within 0.1 second of the stimulus and is typified by a needle puncture of the skin. It is transmitted A δ pain fibres, which are small and transmit at between 6 and 30 m/s. Slow pain begins a second or so after application of the stimulus, but continues to increase over seconds and minutes. It is typified by a throbbing pain and is transmitted in larger diameter C fibres at speed of 0.5- 2.0 m/s.

Each type of pain fibre ends in different parts of the posterior horn grey matter before mostly crossing over and ascending in the anterolateral sensory pathway to the brainstem reticular formation before further ascending into the thalamus and higher cortical areas for processing and integration.

By what mechanisms can we modify the pain response?Stimulation of peripheral tactile receptors, perhaps by rubbing the skin, transmits sensory input in large sensory fibres and depresses the transmition of pain signals from the locality; it is this mechanism that is invoked when footballers have linament rubbed on injuries and is probably the basis for acupuncture. In a similar fashion, TENS (transcutaneous electrical nerve stimulation) has much the same effect.The body has an intrinsic analgesia system that allows damping down of pain signals-direct stimulation of these areas; the periaqueductal grey area of the mesencephalon, raphe nucleus magnus and part of the dorsal horn of spinal cord will block pain transmission. Implicated in this pathway are arises of optiate-cord substances which are naturally secreted and loosely grouped as endorphins and encephalins. When these are injected experimentally into the periaqueductal grey area, they produce profound analgesia. What is the pain relief ladder?

The pain relif ladder is a stepwise approach to controlling pain (WHO). Additional drugs are added until pain is fully controlled. The first step of the ladder uses non-opioid drugs, such as paracetamol or non-

steroidal anti-inflammatory drugs(NSAIDs). If this is insufficient to control the pain, then weak opioid drugs, such as

codeine are added. In the final step of the ladder, strong opioid drugs are used such as morphine.

What other drugs can be used in conjunction with the pain relief ladder? Anti-emetics to ease nausa and vomiting particularly with opioid drugs. Anxiolytics such as diazepam. Neurological pain-use drugs such as carbazepine, amitriptyline or gabapenitin.


Steroids such as prednisolone or dexamethasone, increase the efficacy of analgesia especially for terminally ill patient.

What are the goals of treatment in the terminally ill patient?The aim of terminal care is to provide appropriate relief and support from physical and psychological discomfort when cure is not possible. The important areas are to:

Provide the patient with as much control over their symptoms as possible. Keep the patient comfortable. Help the patient, their families and careers organize their lives and deal with

issues and concerns. Prepare them for death.

How do local anaethetics work?All local anaesthetic are esters or amides of benzoic acid and are membrane stablizers. They plug the membrane sodium channels, prohibiting generation of an action potential and stopping transmission of sensory signals. This is reversible. As they are non-specific membrane stablizers, they will also stabilize other excitable tissues, such as myocardium, if inadvertently injected intravenously.

What is the safe dose of lignocaine and bupivacaine?Maximum dosage is designed to take account of inadvertent intravascular injection; thus in theory a patient can have an intravenous injection of up to the maximum safe dose of local anaesthetic without side effects. As these anaethetics diffuse into the surrounding tissue and are then gradually absorbed, and are, in general, vasodialatory, addition of a vasoconstrictor, such as adrenaline, will slow down the rate of diffusion and consequently increase the safe maximum dose.For lignocaine, the safe dose is 3 mg/kg body weight increasing to 7 mg/kg with the addition of 1:200000 adrenaline.

0.5 % lignocaine contains 5 mg/ml of lignocaine. 1 % contains 10 mg/ml, and 2 percent contains 20 mg/ ml. Bupivacaine has a maximum dose of 2 mg/kg or 2.5 mg/kg with adrenaline.

What happens in overdose and why is the described therapeutic range for bupivacaine much less than for lignocaine?In systemic toxicity, all excitable tissues become membrane stabilized. The earliest features are:

Parasthesia around the nouth and on the tongue. followed by


Light-headedness, drowsiness and anxiety. Tinnitus is not uncommon.

If untreated and serum concentration continue to rise: Loss of consciounsness. Convulsions supervene.

Either as a consequence of this or due to a direct myocardial effect cardiovalcular collapse and cardiac arrest may follow. Bupivacaine has a tendency to be more cardiotoxic than other local anaesthetics and deosnot have the warning neurological signs before cardiovascular collapse occurs. Additionally, the myocardial depression tends to be more resistant to treatment compared to that initiated by lignocaine.

Micturition

Can you briefly describe the structure of the bladder?The bladder may be anatomically described in two parts- the trigone and the fundus.


o The trigone is a relatively fixed triangular base of the bladder neck at the internal urethral meatus. One of the ureters enters the bladder at the upper to angles. It is supported by stout fibro-muscular ligaments which extend from the inferior aspect of the pubic bones in the region of the bladder neck. There are pubo-prostatic ligaments in the male and pubourethral ligaments in the female which aid fixation of the trigone and maintain the osition of the bladder as the fundus expands and contracts.

o The fundus of the bladder consists of 3 layers, an outer adventitial, a middle muscular and an inner mucosal layer.

The adventitial layer is mainly composed of loose connective tissue. The bladder mucosa is of the transitional type of epithelium. The smooth muscle of the bladder, called the destrusor and is the

principle component of the bladder wall.

Can you briefly describe the initiation and control of voiding?Once the threshold of filling has been reached in the bladder, there is increased afferent activity which reaches conscious level and one becomes aware that the bladder is filling.The spinal cord integrates this afferent information from the bladder and also receives afferent inputs from the pelvic, hypogastric and lumbar nerves which run to the brain stem.The centres responsible for the co-ordination of micturition lie in the brain stem, impulses that facilitate reflex are throught to originate in the pontine micturtion centre. There is a complex series of reflexes which involve many areas of the brain with inputs to the brain stem micturition centre. There are major descending pathways that led from the brain stem and converge on the sacral micturition centre, which is a group of cells lying in the grey matter (Onuf's nucleus) in the ventral horn of the sacral spinal cord(S2). These cell bodies are the motor neurons which supply the external uretheral sphincter. The cerebral cortex is important in the control of micturtion having an overall inhibitory effect on the desrusor muscle.

What is the innervation of the detrusor muscle?The detrusor muscle receives:

Parasympathetic innervation via the pelvic nerves (S2-S4) and is responsible for bladder contraction.

Sympathetic innervation via the hypogastric nerves T10-L2 which produces destrusor relaxtion.

How does the bladder store urine?The bladder is able to store urine because it possesses intrinsic tone and exhibits receptive relaxation, i.e. the vesical lumen can expand without a concomitant rise in intra-vesical pressure. These viscoelastic properties of the bladder and intrinsic ability of muscle to retain a constant tension over a wide range of stretch allow the bladder to store urine. The other major factor controlling bladder storage is neural inhibitory control.


Cerebrospinal fluid

Discuss the formation of cerebrospinal fliud?


Cerebrospinal fliud is mainly produced by the choroid plexuses, which line the third, fourth and lateral ventricles with some being generated from the other cerebral capillaries. Although the total volume of CSF is only 130 ml or so, about 500 ml per day is produced, reflecting a constant circulation and resorption of fliud. It can exchange substances with the extracellular fliud, but this is regulated by the tight junctions of blood-brain barrier; the overall composition of CSF is determined by the secretory role of the choroids plexus.

Describe the pathways by which CSF flows and is resorbed?The CSF flows in a caudal direction from the lateral ventricles into the third ventricle via the interventricular foramen of Monro, and then

through the Sylvian aqueduct of the midbrain into the fourth ventricle from here, CSF then reaches the subrachnoid space via the foramina of Luschka and Magendie, passing into the pontine cistern and cerebromedullary cistern, respectively. Once within the subrachnoid space, it circulates around the surface of the brain and spinal cord before being resorbed into the venous circulation by the arachnoid villi. These herniate through the arachnoid mater and lie within the major venous sinuses, especially the superior sagittal sinus, and thus lie in the subdural space. Over time, the discrete arachnoid villi coalesce into clumps known as arachnoid granulation.

What are the contents of the CSF?Normal CSF is crystal clear and contains:

Water. Protein: 0.15-0.45 g/l.


Glucose: 0.45-0.7 g/l. Small numbers of white cells (leucocytes, neutrophils and monocytes) < 5

white cells/mm3.

What are the functions of the CSF?1. It acts as a shock absorber for the brain.2. It reduces the effective weight of the brain. It provides a route for excretion of

waste products from the brain.3. It delivers glucose to the brain, & is important in its homeostasis.

What are the abnormalities of the CSF?In meningitis:CSF samples are turbid in bacterial meningitis. The CSF contains several neutrophil polymorphs and depleted glucose levels.

In subarachnoid Hge:There is xanthochromia (CSF looks yellow when spun down in the lab).

What is hydrocephalus? How is it classified and how is it caused?Hydrocephalus is defined as an increase in the volume of CSF within the cerebral ventricles. It is usually although not always, caused by impaired absorption rather than excessive secretion. It may be classified as an obstructive or communicating hydrocephalus, depending on the site of absorption to flow:

I. The obstructive type: there is a blockage to CSF flow within the ventricular system itself.

II. The communication type: whereby the blockage is outside the ventricular system.

Hydrocephalus may also be described as congenital or acquired.

Table: causes of hydrocephalusTypes Pathology Cause

Aquired obstructive

o Aqueductal stenosis Infection. Haemorrahge.


o Mass effect/ compression Tentorial herniation. Tumors. Abscess. Granulomata.

o Obstructing lesion Intraventricular haematom. Arachnoid colloid cyst.

Congenital obstructive

o Structural anomalities Chiari II malformation Dandy-walker syndrome-atresia

of IVth ventricle oulet foramina Aqueductal stenosis

Communicating o Leptomeningeal thickening

Infection Haemorrhage carcinomatous

depositiso Increased CSF production Choroid plexus papllimoao Hypersensitivity of CSF.

How would you obtain a sample of CSF for analysis?By performing a lumbar puncture. The patients is placed on left side with knee drawn up and the neck flexed. The preferred level is at L3,L4. This level is easily identified as being level with the iliac crests. It can be checked by counting up from the lumosacral junction, and is marked. It is essential that lumber puncture is a sertile procedure.

The skin is prepared with antiseptic solution. Hand scrubbing, masking and gowning are as for any other sterile procedure.

Up to 5 ml of 1 % lignocaine are injected into the skin and paravertebral muscles as local anaesthetic.

A spinal needle is advanced forward, aiming for the previously identified vertebral space.

A "give" is felt as the needle pierces the tough ligamentum flavum and then passes through dura and arachnoid layers to enter the spinal canal.

The stylet is withdrawn from the needle and the CSF specimen(s) collected, noting its colour and turbidity.

The needle can now be connected to a manometer, if required to measure the pressure within the cerebrospinal system.

The blood brain barrier:It selectively controls the entry of substances into the extracellular fluid of the CNS and the rate of their entry. This limits access of toxins but also of immune mechanisms.


It is located in the smallest capillaries supplying the brain and consists of tight junctions and transport mechanisms. Fat-soluble drugs (e.g. diamorphine) cross quickely, andd glucose and anaesthetic agents can also cross.Hydrogen ions don't usually cross and this has implications for control of respiration and acid-base balance.The blood brain barrier is absent in a number of areas:

1. Median eminence of the hypothalamus: where hypothalamic neurons release hormones that act on the anterior pituitary into the portal system of capillaries.

2. Posterior pituitary: where ADH- and oxytocin-secreting neurons secrete directly into the blood.

3. Circumventricular organs: adjacent to the 3rd & 4th ventricles. This areas is adjacent to the chemotrigger zone.

The blood-brain barrier may be compromised in severly raised ICP and is often disrupted in the context of aggressive intra-axial tumours.


C.V.S.


Cardiac cell physiology

Which 2 ions are associated with the cardiac action potential?Na+, K+ and Ca++.

What are the intracellular and extracellular conteration of each of these?Ions Extracellular

concentration (mM) Intracellular concentration (mM)

K- 4 135Na- 145 10Ca2- 2 10 -4

What is the resting potential of a cardiac cell and how do you account for this?Approximately -80 ml.The cell membrane is permeable to K+ but less permeable to anions (e.g. proteins) within the cells. In the resting state K+ ions leave the cell and anions are left behind, making the anterior of the cell electronegative.

Can you describe the movement of these ions across the cardiac cell membrane during depolarization?Triggering of the action potential by the pacemaker cells results in a brief increase in cell membrane permeability to Na ions. There is rapid influx of Na+ ions making the transmembrane potential positive. K+ then diffuse out of the cell to restore negative transmembrane potential (repolarization). Restoration of membrane potential is delayed by influx of Ca++ ions (plateau phase of action potential). This means that there is an obligatory period during which the cell cannot be depolarized-this prevents tetany.

What are the effects of hypokalamia on the heart?A large increase in extracellular K++ results in loss of cell excitation, decreased rate of conduction and slowing of the heart with dysrythmias.


Cardiac cycle

What is the cardiac cycle?The cardiac cycle relates events within the heart to simple body-surface measurements. The opening and closing the heart valves and pressure changes within the chambers of the heart (and aorta and jugular vein) are drawn in relation to the timing of the heart sounds and changes on an electrocardiography (ECG) trace

{Volume, pressure changes in A, V, great vessels in each cycle + heart sounds +ECG}

How long is the cardiac cycle in seconds?It is 0.4 seconds.

With regard to the left ventricle, what are the phases of the cardiac cycleLeft ventricular contraction and relaxation. Left ventricular contraction can be further divided into phases of:

Isovolumetric contraction. Rapid ejection. Slow ejection.

Left ventricular relaxation can be further subdivided into phases of: Reduced ejection. Isovolumetric relaxation. Rapid filling and slow flling.


What is the difference between cardiological and physiological left ventricular systole?Cardiological left ventricular systole is defined as the period between closure of the mitral and aortic valve. Physiological left ventricular systole is defined as isovolumetric contraction to the end of the rapid ejection phase.

On an ECG, what do the P wave and QRS complex represent?The P wave represents atrial depolarization. Atrial systole begins shortly after the onset of the P wave.The QRS complex represents ventricular depolarization. Ventricular systole begins at the peak of R wave and ends just after T wave.

What does the dicrotic notch represent?The dicrotic notch is seen on the descending limb of the aortic pressure curve and marks the division between ventricular systole and diastole. The aortic valve closes at this point.

Can you desribe the opening and closing of the mitral valve in relation to the cardiac cycle?Closure:

It closes at the end of artrial systole when the pressure in the left ventricle exceeds that of the left atrium.

This marks the beginning of the ventricular systole (the peak of the R wave).Opening:

It opens in early ventricular diastole, when the pressure in the left ventricle is below that of the atrium.

It is the end of isovolumetric relaxation of the ventricle. Opening of the mitral valve results in rapid ventricular filling.

Can you describe the opening and the closing of the aortic valve in relation to the cardiac cycle?Opening:

It opens in early ventricular systole when the pressure in the left ventricle exceeds that of the aorta.

This marks the end of the period of isovolumetric contraction of the left ventricle- a short period at the start of ventricular systole when both the mitral and aortic valves are closed).

Closure: It closes when the pressure in the aorta in greater than the left ventricle. This marks the end of ventricular systole.


What produces the heart sounds ?Simplicitically, the closing of the coronary valves produces the heart sounds. To be more precise, after the valves have snapped shut, a backflow of blood against them causes them to bulge taut into the adjacent chambers and then rebound, forcing blood back into the chamber in turbulent flow. It is the rebound of the taut valve cusps and turbulent flow that causes the heart sounds.

1) The first sound is caused by the closure of the atrioventricular valves, namely the tricuspid and mitral valves.

2) The second heart sound is caused by the closure of the semilunar (aortic and pulmonary) valves.

3) The third heart sound is caused by the inrush of blood into the ventricles in the mid-third of diastole.

4) Fourth heart sounds is caused by the inrush of blood into the atirum during atrial contraction,


Cardiac function

What other ways can you investigate cardiac function ? Continuous ambulatory ECG monitor. ECG with exercise (treadmill). Echocardiology utilizes ultrasound to give dynamic information about

ventricular wall thickness and movements, flow across valves and kinetics segments.

Thallium scanning uses a radioisotopes, which is taken up by myocardial muscle in proportion to its blood supply; thus well-perfused areas show up brightly on the gamma camera, whilst infracted areas show up as holes.

Coronary artery angiography has revolutionized pre-operative assessment of ischaemic heart disease. Access is either by placement of a transvenous catheter to give information about the right heart or arterial catheter placement allwing angiography of the coronary arteries and exact visualization of occlusive disease, which is studied closely by the cardiac surgeon prior to coronary artery bypass grafting.

What are the differences between the right and left ventricles?Unsurprisingly, the differences between the two ventricles are a representation of their differing functions and requirements. The right ventricle:

It's thin walls are a reflection of the low afterload, i.e. the low-pressure pulmonary circulation.

It is able to cope with large changes in preload. One example being the changes in venous return between lying and standing.

It is not, however, very good at coping with an increase in afterload, and rises in pulmonary pressure badly affect right heart function.

The left ventricle: It is thick walled because of the high afterload. and consequently, It can deal with changes in afterload relatively easily-but it is sensitives to

change in preload, i.e. it needs filling. This description of the right ventricle explains some of the problems of ventilating asthmatics. To overcome the high airway pressures associated with intermittent positive pressure ventilation of an asthmatic, high pressures are needed. This will compress the pulmonary blood vessels, resulting in an increased right heart afterload, this in turn, can lead to right heart failure in this group of patients


Cardiac output

How do you calculate cardiac output (CO) and what percentage is delivered to each organ system?CO= strike volume x rate (usually 70 ml x 70 bpm = 51 minute).

Heart 5%Brain 14%Muscle 20%Kidney 22%Liver 25%The rest 14%

What formula is typically used to represent this value?Q = HR x SV

Where Q = CO (1/ minute)HR = Heart rate (beats/ minute)SV = Stroke volume (1)

What governs cardiac output?Cardiac output is the product of heart rate and stroke volume, i.e. how much blood does the heart eject at each contraction and how many times a minute does it do it?Cardiac ouput is also related to the blood pressure (BP) and systemic vascular resistance (SVR) according to the equation.

BP= CO/ SVR

How can the contractility of the heart be described?It is the amount of force generated for a given inotropic state. It is described by starling curves that plot force generated against initial fibre length. A rise in the inotropic state will move the curve into a higher position, indicating greater contractility. It is an intrinsic property of the myocardium.

What are the effects of sympathetic stimulation and CO?Increased myocardial contractility and increased heart rate and therefore, a rise in CO.

How is cardiac output regulated?Cardiac output is regulated through factors that affect heart rate and stroke volume. These include:

Neural mechanisms: sympathetic, parasympathetic. Intrinsic mechanisms to the heart: starling's law of contractility (preload is

proportional to vardiac output). Hormonal mechanisms: adrenaline, glucagons (less important), thyroxine.


How can you measure the cardiac output?1. Clinically through:

Conscious level. Blood pressure. Heart rate. Temperature. Urine ouptput. Peripheral perfusion.Capillary refill.

2. Fick principle: Requires samples of mixed veous and arterial blood Cardiac output (litres/ minute):

O2 absorbed per minute by lungs (mL/min)-----------------------------------------------------------------------------

Artetiovenous O2 difference (ml/l of blood)

The fick principle states that the amount of a substance taken up by an organ per unit of time is equal to the arterial level of the substance minus the venous level multiplied by the blood flow.

The fick principle can be used to calculate blood flow (cardiac output) and CO2 consumption.

3. Dilution technique (using a Swan-Ganz cardiac catheter): A. Dye dilution:

Know amount of dye is injected and its concentration measured peripherally (photoelectric spectrometer), indocyanine green (low-half and toxicity)

B. Thermodilution: It uses cold saline infused through a CVP line and analysed via a

modified arterial line containing a thermistor. Data represented as temperature drop against time; cardiac output is

inversely proportional to the area under the curve. Thermodilution method based on thr fick principle.

o CO= HR x SVo BP= CO x SVR

(CO: cardiac output; SV: stroke volume; HR: Heart rate; BP: Blood pressure; SVR: Systemic vascular resistance).

4. Echocardiology: Not a continous technique and operator dependent but allows direct visualization of the myocardium and an assessment of ejection fraction.

5. Echo Doppler: Measures blood flow in the aorta using an oesophageal probe. CO can be derived from the doppler waveform.


Are you aware of any other methods of measuring cardiac output?1. Impedance plethysmography.2. Echocardiography. 3. Electromagnetic flow measurement (probe on aortic root during

surgery).4. Cardiac catheterization.5. Oesophageal Doppler:

Doopler probe into the oesophagus to measure blood flow velocity in the descending aorta.

A velocity time waveform is created and the total ventricular stroke can be calculated from the area under the waveform. From this, cardiac output may be determined.

What is Straling's law?The force of contraction of the heart is proportional to the length of its muscle fibres, i.e. increasing venous returm to the heart results in increase stretch of the muscle fibres and in turn a greater force of contraction, therefore increasing SV. There is, however, an optimum fibre length and excessive stretch will depress pumping capacity.

In the transplanted heart, does Straling's law apply? What is resting heart rate?Yes, Starling's law of the heart- force generated is proportional to initial fibre length- is a local mechanosensitive mechanism that is intrinsic to the cardiac muscle fibres. The resting rate is about 80-90 beats per minute, which represents the intrinsic rate of the pacemarkers without any vagal slowing.

How well does a cardiac transplant function? What is the rate of developing angina?Postoperative function is usually good; enabling normal day to day activity. Survival rates are 90 % at 1 year and 70 % at 5 years. There is no angina, because by definition the the transplanted heart has been completely disconnected from any nerves and as such, there is no pain pathway to transmit the sensation of angina; that is not to say that coronary ischemia does not occur.

What facctors affecting the working of the transplanted heart?As stated Starling's law still holds, as does the Bainbridge reflex (increased venous return causing right atrail distension and a reflex increase in heart rate). Although separated from neural autonomic influences, the heart will respond to circulating catecholamines and may mount a response to stress or exercise.

What are the cardovascularn effects of cross-clamping the aorta in AAA repair?1. CO = SV HR.2. BP = CO SVR.

TPR increases markedly, pushing up blood pressure.To compensate, there is a reflex bradycardiacto reduce CO and hence BP.


What happens to your capillaries when you stand up/ perform valsalva manouever?

1. CO = SV HR.2. BP = CO SVR.3. Draw Starling's curve.

Standing up leads to pooling of blood, and a decrease in venous return.This leads to a decrease in SV and hence CO (Starling's curve).This leads to a decrease in BP.This drop in BP is sensed by the baroreceptors and there is a reflex constriction of the capillaries and arterioles to maintain BP as the CO component of equation has dropped. There is also a reflex bradycardia and an increase in contractility caused by sympathetic activation of the heart.A valsalva manoeuver (forced expiration against a closed glottis) causes increased intrathoracic pressure and hence a decrease in venous return as above.

Why would an anaestheist be worried about a patient with heart block?1. CO = SV HR.2. BP = CO SVR.3. Draw Starling's curve.

This equation needs lateral thinking.Induction agents cause vasodilation and a decrease in SVR.This causes the BP to drop.To maintain reflexly the BP, SVR & HR need to increase, but the heart block prevent a reflex tachycardia.


Oxygen flux equation

What is the oxygen flux equation?This equation represnts the amount of oxygen delivered to the tissue per minute.

Do2 = CO x arterial content.= CO x (O2 bound to Hb + O2 dissolved in plasma)= CO x (10x Hbx Sao2x 1.34)+ (10 x Pao2 x 0.0225)

Where CO = Cardiac output Hb = Haemoglobin concentration in g/ dl Sao2 = Arterial oxygen saturation of haemoglobin 1.34 = Hufner's constant Pao2 = Arterial partial pressure of oxygen 0.0225 = ml of oxygen dissolved/ 100 ml plasma/ k Pa (0.003 mm Hg)

Normally, the Do2 is 850-1200 ml/minute.

The factor of 10 is included to ensure uniformity of units as haemoglobin is in g/dl but cardiac output is in L/min. In practice, the amount of oxygen in direct solution is minimal (~ 1 % ) and is generally ignored in this calculation.

What is shock?Shock can be defined as an acute circulatory disturbance resulting in inadequate tissue perfusion and tissue hypoxia.

What is the revelence of the oxygen flux equation to the management of shock?The oxygen flux equation tells you how much oxygen is being delivered to the tissue. Shock is by definition an inadequate amount of oxygen delivered to the tissues, thus the management of skock is the maximization of the flux equation in practice. Sequential analysis of the equation and comparison to clinical events will make sense of this.In order to maximize DO2, any one of the individual terms could be maximized, hence If the shock is haemorrhagic in nature, there will be a decrease in the haemoglobin concentration and the (Hb) term of the equation will be lower than previously. The solution would be transfuse blood to restore the haemoglobin concentration, thus increasing the value of DO2. similarly, giving the patient supplemtal oxygen will serve to increase the SaO2 phrase of the equation. Cardiac output is defined as heart rate multiplied by stroke volume , thus maximization of these parameters by manipulation of inotropes is another important method of increasing oxygen delivery. Additionally, if cardiac output is considered mathematically as blood pressure over systemic vascular resistance (BP/SVR); then inotropic manipulation of these will also allow manipulation of DO2. in occasional situations, hyperbaric therapy may be used to increase the final. And normally ignored, part of the flux equation, although this is more likely to be in a case such as carbon monoxide poisoning than hypovolaemic shock management.


Discuss the role of "goal-directed therapy" in the of the critically ill?Goal-directed therapy stems from work by Shoemaker in the early 1980s when he noted that patients in intensive treatment units who achieved a certain level of oxygen delivery according to the flux equation did better than those who did not. This led to patients being aggressively fluid filled and inotropically driven to cheive preset goals of oxygen delivery, and was the vogue in many ITUs for a while.Later work has shown that achievement of these goals in itself does not improve outcome and the current view is that patients who reach these goal without heavy inotrope support do indeed do better; this is more likely a natural reflection of the fact that they are physiologically able to reach that target. Forcing physiologically incapable patients to meet preset goals by inotropic manipulation has a deletrious effect.

What is an inotrope? What do they do and give examples?An inotrope is a substance that alters the inotropic state of the heart i.e. it affects the myocardial contractility. The phrase is commonly used to refer to those agents that increase contractility, although negative inotropes do exist. Exogenous inotropes are analogues or derivatives of endogenous catecholamines and act on variety of receptors including the α, B1, B2 adrenergic and dopamine receptors.

Adrenaline acts mildly at α receptors, but mainly at B1 and B2 receptors to increase heart rate and contractility and causes vasodialtion because of relaxation of smooth muscle.

Noraderaline acts predominantly at te α receptor causing peripheral vasoconstriction and increase in systemic vascular resistance. It also has some mild B1 stimulatory properties.

Dobutamines is a synthetic derivatives of dopamine and causes mainly B1 effects.


Blood pressure

What is blood pressure ?Blood pressure is the force exerted by the blood against any unit area of the vessel wall and is traditionally measured in millimeters of mercury. It may be expressed as:

A mean arterial pressure (MAP) about which there are oscillations. or A systolic and diastolic pressure. These represent the biphasic output of the

heart with high pressure on ventricular contraction and a lower pressure due to vascular recoil while the ventricles refill.

As the blood pressure is closer to diastolic pressure for a greater proportion of the cardiac cycle, the mean arterial pressure is not simply an average of the diastolic and systolic pressures; it is given by the equation:

How can blood pressure be monitred?Non-invasive:

1. Traditional shygnomanometer: Intermittent, cumbersome and time-consuming. Non-invasive method is mannual (using stethoscope)

2. Dynamap system (still uses arm cuff but based on oscillometry) Automatic, quicker, less time-consumeing. Probably slightly less accurate than manual measurment. Intermittent but can be set to retake BP every minute.

3. Radia artery tonometry: Based on superficial pressure sensors and therefore highly positional. New technology but may eventually replace an arterial line for short-term

monitoring (e.g. in local anaesthetic procedures such as carotid endarterectomy).

Continous monitoring, produces BP waveform as with an arterial line.4. Finometer:

Largely for research, based on measurement of "finger blood pressure".Invasive:

1. Arterial line: Vommonly a 20 G catheter inserted into the radial artery. Invasive – risks of clotting of liine, infection. Most accurate, beat to beat assessment of Map and BP. Allows assessment of arterial waveform to see if it is swinging, indicating

underfilling. Allows regular aspiration of arterial blood for ABGs.

What factors determine arterial blood pressure?In broad terms, the factors determining arterial pressure can be divided into:

Physical factors (blood volume and compliance). Physiological factors (cardiac output (CO), heart rate, stroke volume (SV),

vascular resistance, etc).

MAP= (2X diastolic pressure) + systolic pressure---------------------------------------------------------------------------

3


Can you define mean arterial pressure using a simple equation?MAP = COX TPR

Where CO = cardiac output TPR= total peripheral resistance (dyne seconds/Cm5)

Which sites account for the majority of resistance in the circulation? The capillaries: have a narrow caliber, a large surface area and are numerous. The arterioles: are lined with smooth muscle which can contact, narrowing the

vessel and increasing resistance.

How can CO and systemic vascular resistance (SVR) affect blood pressure?Essentailly , in any given artery the MAP will be proportional to the volume of blood. CO and SVR can be understood to affect MAP by how they might alter the volume of blood. CO is the inflow of blood to the artery (CO= inflow) and SVR is inversely proportional to the outflow of blood from the artery (SVR= 1/ outflow). An increase in either CO or SVR will, therefore, increase blood volume and therefore MAP. Or the other words, MAP= COXSVR.

What is pulse pressure (PP)PP is the difference between SBP and DBP (PP= SBP-DBP).

What dactors affect PP and why they are important?Two main factors determine PP:

SV. Compliance. As pressure is proportional to the volume of the blood in the artery, an increase in SV will produce a proportionate increase in PP, provided compliance is normal.Therefore, PP can give information about SV (therefore PP is reduced in patients who have suffered severe haemorrhage for example). A reduction in compliance will increase PP for a given SV. This is significance in patients with atherosclerosis as a greater workload is placed on the left ventricle. A similar situation arises in hypertensive is patients as compliance is reduced at higher pressures.

What mechanisms are involved in the control of blood pressure?The main mechanisms comprise:

Baroreceptors. Autonomic nerve pathways. Vasomotor centre. Cardioinhibitory centre.

Two additional intrinsic cardiac regulatory mechanisms influence the blood pressure: The Anrep effect : a response to acute increase in afterload, leads to initial

reduction of stroke volume. The Bowditch effect : a response to change in heart rate, the contractility

increasing as the rate increases.


What factors control blood pressure?Blood pressure controlling factors can be categorized into immediate, early and long term. I. Immediate factors are:

1. The central nervous system response occurs if blood flow to the vasomotor centre falls below 60 mmHg, at which level the centre is excited and the blood pressure is raised by sympathetic control.

2. Barorecptors in large arteries relay impulses to tractus solitarius, which as pressure increases, inhibits the vasomotor centre and excites the vagal centre, leading to the blood pressure falling.

3. Chemoreceptors of the aortic and carotid bodies are sensitive to decreased PaO2 and increased PaCO2, which excite the vasomotor centre and raise blood pressure.

II. Early control mechanisms act within 30 minutes in response to changes in blood pressure, they consist of: 1. Rennin-angiotensin system, increases in renal perfusion pressures cause less

angiotensin II to be produced, causing a decrease in vascular resistance. 2. Stress relaxation occurs as high arterial pressures cause relaxation in blood

storage areas. 3. Capillary fliud shift allows decreased capillary fliud loss with lower blood

pressure allowing an increase in blood volume. 4. Adrenaline/ Noradrenaline cause sympathetic vasoconstriction to raise blood

pressure.5. ADH secretion is increased with hypotension and has a direct vasoconstriction

effect, and decreases fluid loss.

III.Long-term control occurs through: The renal control of body fluid. As blood pressure increases, the kidney

loses more fluid and Na+. in the long term, changes to the renal output curve develop.

What are baroreceptors and where are they found?Baroreceptors are stretch receptors which respond to distension and are present in:

Carotid sinus. Aortic arch. Atrium. Ventrivle.

Other centres intrinsic to barorecptor function: Vasomotor centre: a group of neurons in the ventrolateral medulla that

maintain the tone of vascular smooth muscle. Cardioinhibitory centre (ventral medulla): inhibits the vasomotor centre; tone

increased by baroreceptor discharge.


How do these receptors respond to a fall in blod pressure?These stretch receptors respond to a fall in pressure by reducing afferent signals carried via the IX and X cranial nerves to the cardiac and vasomotor centres in the medulla. This results in increased sympathetic activity via the autonomic system and reduced vagal tone. The consequence of this is vasoconstriction, increased heart rate and stroke volume. This raises both peripheral resistance and CO, restoring blood pressure.

How does transection of the cord at the level of T6 lead to "spinal cord"?Loss of sympathetic tone results in profound vasodilatation and a fall in total peripheral resistance. In addition, unpaired vagal drive causes bradycardia and contributes to lowering the blood pressure.

What hormonal mechanisms influence the long term control of blood pressure?Hormonal mechanisms involved in longer-term blood pressure control:

Rennin-angiotensin system. Aldosterone. Vasopressin (ADH). Atrail natriuretic peptide (ANP).

Why is hypertension relevant to surgical practice ?Uncontrolled hypertension will result in cancellation of a surgical patient from theatre owing to the increased risks of cerebrovascular events and cardiac failure.Severe hypertension may rarely result in aortic dissection, particularly of the thoracic aorta, and this brings the patient to the attension of the cardio-thoracic surgeons as it may need emergency surgical repair. For the majority of patients. Hypertension is controlled by oral mediation but the surgeon should recognize that a labile blood presuure pre-operative may indicate widespread atherosclerosis. Diuretic treatment often gives rise to fluid and electrolyte dis-turbances, which should be assessed and corrected prior to embarking on surgery. Most antihypertensives are cardioprotective and should continue to be given pre-operatively with a sip of water, even when patients are ' nil by mouth '.


What causes of hypertension can be treated surgically ? 90 % of people with hypertension have no obvious cause; this idiopathic or

essential hypertension. The treatment of these cases lies with the physician and his plethora of medications.

Only 10 % of cases have a discernible cause, some of which are amenable to surgical correction and should be sought before the diagnosis of essential hypertension is accepted, particularly in young patients. Dysfunction of the adrenal gland is a potent cause of hypertension:

Excess cortisol from Cushing's syndrome, driven by either a pituitary or adrenal tumour is amenable removal.

Aldosterone-secreting tumour of the adrenal gland, Conn's syndrome, may be surgically cured.

Renovascular hypertension causes, by means of a reduction in juxta-glomerular perfusion, a potent stimulus to the rennin-angiotensin system, causing profound hypertension. This is readily to surgical treatment by excision of the stenosed segment with primary anastomosis or by radiological angioplasty techniques.

Phaeochromocytoma also causes hypertension , which is usually paroxysmal, by release of huge quantities of catecholamines, causing marked vasoconstriction. Most are surgically removable .

What compensatory mechanisms are activated in severe haemorrhage ?Four interlinked mechanisms are activated following haemorrhage 1.Following haemorrhage there is a fall in mean arterial pressure and this produces a

baroreceptor response (stretch receptors in the aortic arch and carotid sinus send afferents to the brain stem).

2.Vagal (parasympathetic) tone is decreased resulting in ↑ Heart rate.3.The ↑ in sympathetic tone causes:

Peripheral vasoconstriction leading to ↑ systemic vascular resistance. ↑ Inotropic effect. ↑ Chronotropic effect. ↑ Stroke volume and thus cardiac output.

There is ↓ blood flow to the skin, skeletal muscle and splanchnic circulation.4.The rennin-angiotensin-aldosterone axis is also activated due to the fall in renal

perfusion and glomerular filtration rate. This leads to arteriolar vasoconstriction and sodium retension, which increases plasma osmolarity and stimulates thirst and ADH release from the posterior pituitary leading to water retension.


How does the body respond to an acute fall in blood pressure due to a large gastrointestinal bleed, for example ?The body responds in such a way as to try to normalize its internal environment and maintain tissue perfusion of essential organs at a normal level, and this varies with the degree of shock.

Physiological changes in response to haemorrhageDegree of

shockProportion of

blood volume lostResponse

Class 1 < 15 percent(< 750 ml)

Minimal signs and symptoms. There may be a slight tachycardia

Class II 15-30 percent(750 – 1500)

Tachycardia increases. Narrowing of the pulse pressure due to

catecholeamine induced peripheral vasoconstriction.

Anxiety may become manifest Class III 30-40 percent

(1500 – 2000)Tachycardia.Tachypnoea.A fall in systolic blood pressure.Mental confusion. The skin is cool and plate as blood is diverted to

essential organsClass VI >40 percent There is a marked drop in systolic pressure.

Diastolic pressure is often unobtainable. Urine output negligible . If >50 % blood volume is lost, unconsciousness

ensues, and the pulse and blood pressure become unrecordable ( > 2000 ).


Autoregulation

What is autoregulation and give an example of it at work ?Autoregulation is the ability of an organ to maintain a constant blood flow over a widw range of mean arterial pressures within certain limits. It is seen in the heart and kidney but is best demonstrated by examining cerebral blodd flow.

Cerebral perfusion pressure (CPP) = Mean arterial pressure ( map)

- [intracranial pressure ( ICP ) +Central venous pressure( CVP) ]

This curve shows that, up to a CPP of 60 mmHg ( pointA), an increase of pressure will increase cerebral blood flow (CBF). Between pressures of 60 and 160 mmHg (A to B), any increase in CPP does not result in alteration of CBF.But, with a CPP of over 160 mmHg, the blood flow increases with pressure again.


Draw the brain compliance curve and explain what it means in practical terms As volume increases, compensation occurs so that almost no rise in intracranial pressure ( ICP) follows (A to B on the curve). This works up to a critical point (C), after which even a small increase in volume causes a rapid rise in ICP (C to D).

How do you manage a patient with raised intracranial pressure after closed head injury ?The Munro-Kelly doctrine points out that the cranium is a fixed-volume box, the contents of which brain, CSF and blood are not compressible. Rises in volume cause a rapid rise in ICP at that point on the compliance curve.

The brain constitutes 85 % of the intracranial volume but is the least amenable to manipulation of its volume.

CSF represents 10 %. Blood, the most accessible 5 % .

The following measures all aim to reduce the volume of one or other of the three contents of the box, and thus protect adequate cerebral oxygen delivery:

1. Posture: 15˚ of head up tilt will reduce venous congetion. The avoidance of venous obstruction also helps, such as keeping the head central without tapes or lines around the neck.

2. Ventilation: protection of the airway and maintainance of good oxygenation are essential. Avoid hypercarbia as CO2 is a potent vasodilator, which at first seems like a good idea in order to maintain cerebral oxygen delivery, but the increased blood volume actually increases ICP and is counterproductive. Aim for low normal CO2 levels.

3. Mannitol: an osmotic diuretics. It increases colloid osmotic pressure, and draws water into the vascular space and is a potent free-radical scavenger. It


causes a decrease in CSF production and causes a reduction in blood viscosity allowing increased CSF. Too much mannitol, however, may cause a rebound phenomenon, as the leaky capillaries allow mannitol into the inter-stitium reversing the colloid gradient.

4. Steroids: are only useful when dealing with organized masses, such as tumours and the inflammatory reaction that accompanies them. They are not indicated in closed head injury.

5. CSF drainage: placement of an interventricular catheter not only allows accurate measurement of ICP, thus allowing calculation of cerebral perfusion pressure, but allows therapeutic drainaige.

Whilst these measures are aimed at ensuring adequate O2 delivery, the patient will also be helped by decreasing O2 demand. Thus a sedated well-analged patient with adequate anti-epileptic prophylaxis will have lower oxygen demands than an awake, anxious, fitting patient. Similarly, surface cooling will reduce the overall metabolic requirements.


Blood flow dynamics

What are the resistance vessels ?The arterioles are the main resistance vessels in the body. They offer the greatest resistence to the flow of the flow of the blood pumped by the heart. The main component of their walls is smooth muscle which is sensitive to a variety of factors, such as nitric oxide which reduces vascular tone and increases luminal diameter , and hence decreases resistance to flow.

What is the importance of these resistance vessels ?These vessels provide a mewchanism for controlling the systemic vascular resistance (SVR) and therefore the blood pressure (BP). (BP = Cardiac Output × SVR) Thus, these vessels influence perfusion to all parts of the body.

How are these resistance vessels regulated ?These resistance vessels are regulated by both neutral and metabolic factors:

1. Neutral regulation: is predominantly through the sympathetic vasoconstrictor fibres to the blood vessels.

2. Metabolic regulation: is achieved by vasodilator metabolites produced locally by the tissue when metabolically active or during anaerobic conditions. The metabolic factors producing vasodilatation include CO2 , H+ ,K+, adenosine and nitric oxide.

What processes are involved in controlling the movement of fluids across the capillary bed?The movement of water and small solutes across the capillary endothelial wall occurs by three processes: diffusion, filtration and absorption.The relationship between filtration and absorption is dependent on Starling's forces.

The principal force in capillary filtration is the capillary hydrostatic pressure. The main force that prevents fluid loss from the capillaries is the osmotic

pressure of the plasma proteins otherwise known as the colloid osmotic or oncotic pressure.

The capillary filtration pressure is the capillary hydrostatic pressure minus the interstitial hydrostatic pressure.

The hydrostatic pressure within the capillaries is regulated by the arterial pressure, venous pressure and the resistance of the arterioles.


What influences the coronary artery blood flow ?Coronary artery blood flow is influenced by a combination of physical, metabolic and neutral factors.

1. Physical factors: the main ones are aortic pressure, myocardial rate and contractility. Aortic pressure plays a primary role in determining myocardial perfusion .

it itself is dependent on heart rate and stroke volume. Thus, during early diastole coronary inflow is maximal, and minimal during early ventricular systole.

2. Metabolic factors: Myocardial metabolic activity closely parallels coronary blood flow (this relationship is preserved in the denervated heart). Increased myocardial oxygen demand stimulated the release of vasodilator substances from the myocardium into the interstitial fluid causing relaxation of the coronary vessels and so increasing blood flow.

3. Neutral factors: The direct neutral influence on coronary blood flow is through the sympathetic nervous (β1 receptors). However, Stimulation of the sympathetic nervous sytem itself causes release of circulating catecholamines thereby increasing heart rate and contractility (β2 receptors) and so influences coronary blood flow indirectly.

How is the cerebral circulation regulated ?The cerebral circulation is regulated by physical (main influence), metabolic and neutral factors.

1. Physical factors: The cranium should be considered a rigid, fixed box, so increases in the volume of the blood, extracellular fluid, cerebrospinal fluid or cerebral material (a tumour for example) would increase the intracranial pressure.Cerebral perfusion pressure (CPP) = mean arterial pressure (MAP) – ICP. Cerebral blood flow itself is autoregulated between a certain range, thus blood flow is kept relatively constant despite changes in the CPP. The changes in blood volume are influenced by changes in arteriolar diameter which are in turn affected by the PaCO2 level.

2. Metabolic factors: Cerebral blood flow is autoregulated so that total cerebral blood flow is constant. However, Regional cortical blood flow is also related to local cortical activity. This is influenced by metabolic factors, especially carbon dioxide, potassium, adenosine and hydrogen ions. High levels of these metabolites cause vasodilatation and increased blood flow.

3. Neutral factors : The cerebral vessels receive a sympathetic supply but their influence in regulating blood flow is minimal.

How is the cerebral circulation affected by changes in ventilation?Ventilation produces its main effect on the cerebral circulation through changes in arterial PaCO2 levels causing cerebral vasoconstriction with a subsequent lowering of ICP.


This technique is used to reduce the ICP in patients with head injury, The lowered ICP helps to maintain the CPP and reduce cerebral ischaemia.


Hydratic filter

What is the principle function of the arterial system ?To distribute blood to the capillary beds throughout the body ensuring tissue perfusion.

What do you understand by the term "hydraulic filtering" in relation to the arterial system?Hydraulic filtering reduces the amount of work required to perfuse tissues.

What features of the arterial system produce hydraulic filtering ?There are two features: the compliance of the great vessels and regulation of flow by high resistance arteiorles.

Do you know of any classic analogies to hydraulic filtering ?Hydraulic filtering has classically been compared to the Windkessel of a steam engine which is a compressible air trap which converts the intermittent flow of water to a steady outflow.


Blood flow in a vessel

What is flow and can you distinguish the different types of flow ?Flow is the amount of fluid moving per unit of time.Flow may be :

Laminar: in which flow is smooth, without eddy currents. Molecules at the periphery move more slowly than those in the centre.

Turbulent: when tube is unevently shaped (e.g. flow through a narrow orifice); or during laminar flow when flow velocity exceeds critical velocity.

Reynold's number describes the relationship between tube and fluid characteristics and the velocity at which turbulent flow occurs: Reynold's number < 2000 – flow likely to be laminar. Reynold's number > 3000 – flow likely to be turbulent.

How do you measure flow ?Gaseous flow: flow meters. Liquid flow:

Dilution techniques. Electromagnetic flow measurement. Fick principle.

How is flow related to the radius of a tube ?Flow is proportional to R4 (radius to the power of 4).The Hagen –poiseuille equation describes laminar flow :

Flow = (P × R4 ×Π) / ( 8 × η × l)Where:

P = pressure gradient across the tube. R= radius of the tube. η= viscosity of the tube. L = length of the tube.

Poiseuille's law : determines the flow of fluids through cylindrical tubes . It is applicable to Newtonain fluids with steady laminar flow .Poiseuille's law statics .

Are there any other laws relating to blood flow that can be applied ?Yes, Ohm's law can be applied:

∆ P = Flow × SVR. If this law is applied to the systemic circulation then BP = CO × SVR

Where is the greatest vascular resistance in the systemic circulation ?The small arteries and arterioles. SVR is regulated mainly by the arterioles.

What is the significance of a parallel arrangement of capillary beds?A parallel arrangement of capillary beds allows for oxygenated blood to perfuse all beds and there can be independent of regulation of blood flow to each individual bed. Also, the total SVR is determined by the collective the resistance in all capillary beds in the following way: 1/SVR= 1/R1 + 1/R2 + 1/R3 etc. (R1,2,3, are the resistances in the respective capillary beds)


What is meant to be velocity and flow in a blood vessel? and how are these two properties related?Velocity refers the speed of individual components of blood (m/second). whereas Flow refers to the quantity of blood pressure through the vesse perunit time. They are related in the following way: Flow = velocity × cross-sectional area.

How does arterial stenosis affect blood flow and velocity ?Stenosis causes increased resistance to flow and produces a pressure drop across the stenosed area (pressure proximal to stenosis > pressure distal to stenosis). Assuming that flow remains constant, velocity will increase through the area of stenosis. As velocity increases there is a risk that smooth lamina flow will change to turbulent flow Reynold's number (NR is used to estimate the likehood of turbulent flow (when NR > 3000 flow will be turbulent).

What is meant by critical stenosis and when does it occur ?Arterial stenosis is said to be critical when the flow rate reduces through the area of stenosis. This point usually occurs when there is around 70% stenosis.

Can you name some circulating factors that can cause vasodilatation and some that cause vasoconstriction?

Vasodilatation : somatostatin, histamine and bradykinin. Vasoconstriction : angiotensin II and adrenalin.

Can you do the same for endothelial-derived factors ? Vasodilatation: nitric oxide; prostaglandin I2 (PGI2). Vasoconstriction: endothelin and thromoxane.

Can you do the same foe neurotransmitters? Vasodilatation: adenosine triphosphate (ATP), vasoactive intestinal peptide

(VIP) and substance P. Vasoconstriction : noradrenaline.

Can you do the same foer metabolic factors ? Vasodilatation : k+ and Co2. Vasoconstriction : Ca 2+.

Are there any important key elements in the control of vascular smooth muscle tone?There is an intimate relationship with the endothelial lining with a number of signals from the circulation being transmitted to VSM through an effect on the endothelium. The contractile elements in VSM are more disorganized than those instriated muscle and this may facilitate longer periods of contraction in VSM.There are a variety of voltage – and receptor-operated channels (VOC's and ROC's, respectively) which allow an influx of Ca 2+ into VSM cells. Types of VOC's and ROC's in different capillary beds will all different responses to the same stimulus.

Starling's Forces


How do Starling's forces affect the capillary level?Starling's forces: it is the Factors determining the movement of fluid across the capillary wall endothelium.Movement of water into the interstitium is produced by the hydrostatic pressure gradient and counteracted by the colloid osmotic gradient.

How do these forces interact ?Pc= Capillary hydrostatic pressure (varies from artery to vein). Pif = Interstitial hydrostatic pressure. Пp = Oncotic pressure due to plasma proteins (28 mmlHg).Πif= Oncotic pressure due to interstitial proteis (3 mmHg).Net filtration = (pc – pif ) – (Пp – Πif).

What factors can lead to the development of oedema ?Definition: Generalised or local excess of extracellular fluid.

A. Increased leakiness of capillaries: Occurs in burns, sepsis or ARDS.

B. Inceased hydrostatic pressure at the venous end: This leads to increased hydrostatic pressure throughout the capillary and more net movement of fluid into the interstitial space.Occurs in:

DVT. Venous hypertension (which often accompanies varicose veins and ulcers). Pelvic venous compression (by tumours). Liver cirrhosis. Renal cell carcinoma infilteration and right sided heart failure.

C. Decreased colloid oncotic pressure: Basically any cause of hypoalbuminaemia.Occurs in:

Liver failure (lack of synthesis). Increased loss, nephrotic syndrome, protein losing enteropathies, poor

nutirtion.D. Failure of lymphatic system to drian = lymphoedema:

Primary lymphoedema: unknown aetiology. Secondary lymphoedema: damage of lymphatic system caused by surgery

(especially breast), radiotherapy or carcinoma.Capillary Dynamics


What is the major determinant of blood flow in capillaries ?Blood flow is dependent on the contractile state of the arterioles.

Which processes govern movement of substances across capillaries ? Diffusion. Filtration. Pinocytosis.

How is the hydrosratic pressure within the capillary determined ?This depends on arterial pressure, post-capillary venous pressure and the tone of pre- and post-capillary sphincters. Increase in arterial or venous pressure increases hydrostatic pressure. Increase in sphincter tone lowers hydrostatic pressure.

Which is the major force retaining fliud within the capillary ?This colloid osmotic pressure exerted by the plasma proteins that are retained within the capillary.

How does the interplay between hydrostatic and oncotic presuure determine net fluid movement across the capillary ?

This can be represented by Starling's law:Fluid movement = k [(pc + Пi) – ( pi + Πp)]Where

k = Filtration constant for capillary membrane. Pc = Capillary hydrostatic pressure. Πi = Interstitial fluid oncotic pressure. Pi = Interstitial fluid hydrostatic pressure. Πp = Plasma protein oncotic pressure.

If the net figure is positive filtration out of the capillary occurs, if negative absorption into the capillary takes place.

Arterial waveform


What are the important features of the arterial waveform? Systolic pressure. Diastolic pressure. Dicrotic notch. Pulse pressure. Mean arterial pressure (the pressure at which the area above the mean equals

the area below the mean).

What information can be gained from studing the arterial waveform? Arterial blood pressure. Stroke volume and cardiac output: from the area under the systolic part of the

waveform. Myocardial contractility: from the slope of the upstroke (change in

pressure/change in time). Outflow resistance: from the slope of diastolic decay:

o A slow fall suggests vasoconstriction.o A rapid fall suggests vasodilatation.

Hypovolamia: suggested:o A low dicrotic notch.o A large variation in pesk pressures in patients who are being ventilated.

How does the arterial waveform changes in the presence of aortic valve? Aortic stenoids – slow –rising waveform with a prolonged plateau. Aortic incompetence – excessive pulse pressure, low diastolic pressure.

Central venous pressure


What are the indications for gaining central venous access? Vascular access. Measurement of central venous pressure (CVP). Insertion of pulmonary artery wedge catheter. Transvenous pacing. Parentral feeding (long-term).

What problems can be associated with central venous access ? Infection. Arrhythmias. Air embolism. Cardiac/lung perforation. Central vein thrombosis. Neurovascular damage.

What are the components of the venous waveform?o a wave: atrial contraction.

o c wave : tricuspid valve bulges back into the atrium during ventricular

isometric systolic phase.o x descent : atrial relaxation.

o v wave : rise in atrial pressure before the tricuspid valve opens.

o y descent : atrial emptying into the ventricle.

Notes: No a wave in atrial fibrillation. Enlarged a wave in tricuspid stenosis, pulmonary hypertension. Enlarged v wave in tricuspid regurgitation. Cannon waves (not corresponding to a , v, or c waves) in :

1. Complete heart block (irregular).2. Junctional arrhythmias (regular).

Lymphatics


What is the function of the lymphatic system ?The function of the lymphatic system is to return plasma, capillary filtrate and protein to the vascular system. The lymphatic system also:

Filters the lymph nodes thereby removing foreign particles including bacteria. Carries nutrients absorbed from the gastrointestinal tract including

chylomicrons (fats) back to the circulation.

What is the difference between lymphatic and blood capillaries ?Lymphatic capillaries are similar to blood capillaries in many ways, but have two important differences:

1. Tight junctions are not present between capillary endothelial cells.2. Fine filaments anchor lymph vessels to the surrounding connective tissue.

What tissues in the body do not contain lymphatic vessels ?Cartilage, bone, CNS tissue and epithelium do not contain lymphatic vessels.

What factors affect lymphatic flow ?Lymphatic flow is influenced by any mechanism that enhances the rate of capillary filtration. Thus, increased capillary pressure or capillary permeability or decreased plasma osmotic pressure all have an effect.Lymph flow also varies in proportion to the degree of muscular activity and is almost nil in resting skeletal muscle.

Valsalva manoeuvre


What is malsalva manoeuvre ?Sustained expiratory effort against a closed glottis, i.e. a sustained increase intrathoracic pressure against a closed or occluded glottis.

Can you give some examples ? Voluntary increased abdominal pressure against a closed glottis. Coughing. Mechanically induced by an anaethetist in a ventilated patient.

What happens to SBP as a result of a voluntarily induced vasalva manoeuvre?At the initiation of the manoeuvre there is an initial increase, followed by a decrease back towards normal . At the end of the manoeuvre there is another transient increase in SBP.

Can you explain these changes? Initial rise in SBP: due to compression of the abdominal aorta by voluntary

staining. Reduction in systolic back towards normal: sustained pressure on the inferior

vena cava results in reduced venous return and, due to the frak-Starling relationship, there is a reduced CO. As blood pressure = cardiac output × total peripheral resistance (BP = CO × TPR) there is a reduction in blood pressure.

Rise in systolic at the end of the manoeuvre release of pressure on the inferior vena cava increases venous return and, therefore, for the same reasons outlined above, an increase in CO and SBP.

What happens to the heart rate and systemic vascular resistance during the valsalva manoeuvre ?They both increase steadily.

Can you explain this?Reduced venous return due to pressure on the inferior vena cava results in a reduced CO (Frank-Starling relationship). This results in a reduction in Baroreceptor stimulation and, therefore, an increase in sympathetic outflow to the heart and peripheral vasculature.

What happens to your capillaries when you stand up/ perform valsalva manouever?

1. CO = SV HR.2. BP = CO SVR.3. Draw Starling's curve.

A valsalva manoeuver (forced expiration against a closed glottis) causes increased intrathoracic pressure and hence a decrease in venous return as above.This leads to a decrease in SV and hence CO (Starling's curve).This leads to a decrease in BP.This drop in BP is sensed by the baroreceptors and there is a reflex constriction of the capillaries and arterioles to maintain BP as the CO component of equation has dropped. There is also a reflex bradycardia and an increase in contractility caused by sympathetic activation of the heart.


Respiratory


Mechanics of respiration

What do you understand by the trem mechanical breathing ?It is the movements of the thorax that enable ventilation of the lung tissue. There are two types of mechanical breathing:

Quiet breathing: which occurs at rest. Forced breathing: which occurs during exercise or when there is diseased lung

tissue, requiring extraventilation to oxygenate the blood.

Can you describe the mechanical process of breathing?There are two phases of breathing:Inspiration :

The thorax expands in three dimentions. During inspiration, the thorax expands mainly in its vertical diameter, as a

result of the contraction and flattening of the diaphragm (known as diaphragmatic breathing) supplied by the phrenic nerve (C3, C4, C5).

Thoracic breathing involves movement of the upper 2 to 7 ribs in a 'pump-handle' action, which increases the anteroposterior diameter of the chest.

The lower 8 to 12 ribs move in a 'bucket-handle' manner, thereby increasing the lateral diameter of the chest.

These movements of the ribs are brought about by the contraction of the external and internal oblique intercostals muscles.

This causes the pressure in the pleural cavity to drop to -4 mmHg, causing air to flow into the lungs down the pressure gradient.

The accessory muscles of respiration are used in forced and in deep inspiration (sternocleidomastoid, scalene muscles, pectoralis minor and major and serratus anterior).

Expiration: Elastic recoil of the lungs and chest wall rather than muscular contration is

responsible for quiet expiration. Forced expiration involves theo abdominal muscles and latissimus dorsi.


Control of respiration

What is the respiratory centre ?The respiratory centre is formed by two groups of neurons in the medulla near the floor of the IV ventricle.

The dorsal group contains mostly inspiratory neurons. The ventral group, expiratory and inspiratory nuclei.

Where are the respiratory centres?Respiratory centres are located in the pons and the medulla .

What are the main sensors controlling respiration ?The main sensors are the central and peripheral chemoreceptors.

Central chemoreceptors are situated on the ventral surface of the medulla and are sensitive to fluctuations in the PH of the cerebrospinal fluid (CSF).

Peripheral chemoreceptors are situated in the carotoid bodies and aortic arch and are primarily sensitive to fluctuations in PaO2.

There are also mechanical receptors in the lungs and in muscles which help regulate respiration.

What factors control breathing ?Non-chemical and chemical factors are thought to have an important influence on the control of breathing:

The cortex (impulses from higher centres may be important in increasing ventilation in voluntary exercise).

Proprioceptive impulses from the muscles of repiration Blood pco2 and pH. Respiration is finely regulated by paCo2 levels (central chemo-receptors) which when increases stimulates ventilation. A fall in blood pH also stimulates ventilation.

Hypoxia itself stimulates breathing indirectly via the aortic and carotid body receptors. It does not have a direct effect on the chemoreceptors of the reticular formation.

How do fluctuations of CSF pH relate to respiration ?Unlike H+ ions, CO2 reasdily crosses the blood-brain barrier. As PCO2 rises in the periphery it crosses into the CSF and results in an increase in H+

ion formation, thereby stimulating the central chemoreceptors.

What is the most important determination of repiratory control ?PaCo2 is the most important factors in controlling respiration. Increase in paCo2 leads to increase in respiration.

What is the main control of repiration in longstanding lung disease ?In longstanding lung disease, changes in CSF pH compensate for the rise in H+ and after a prolonged period the central chemoreceptors reset. When this has happened the main drive for respiration is paO2 detected by the peripheral chemoreceptors.

Why is pure oxygen contraindicated in patients with COPD?


In COPD, the central chemoreceptors are chronically exposed tp high levels of CO2 as a result of poor gas exchange in the lungs. Hence, the set point for PCO2 increases for the centeal chemoreceptors, and they no longer respond to small changes in PCO2.These patients therefore purely rely on hypoxia to stimulate the peripheral chemoreceptors, which in turn stimulates the respiratory centers to increase the drive to breath.If 100% oxygen is given, there is no hypoxia to stimulate the peripheral chemoreceptors and because the central chemoreceptors also no longer respond to a build-up of CO2 (as H+), the patient has no drive to breath.Note that, in practice, however, it is more dangerous to leave the patients in life-threating hypoxia than to adminster oxygen.

What factors govern respiratory gas exchange in the lungs?Respiratory gas exchange in the lungs depends on three factors-ventilation, diffusion and pulmonary capillary blood flow:

Ventilation: involves the volume and distribution of the inspired air which ventilates the alveoli.

Diffusion: involves the passage of gases between the alveoli and blood in the alveoalar capillaries.

Pulmonary capillary blood flow: involves the total volume of blood and its distribution to all the ventilated alveoli.

What effects does general anesthesia have on the respiratory system?General anaesthesia produces a rise in paCO2 due to a direct depressant effect of anaesthetic agents on the brain. In the post-operative period, there may be partial collapse of the small airways, resulting in a reduced ventilation-perfusion ratio, so leading to segmental collapse.General anaesthesia may also cause increased sputum production, impairment of the cough reflex and reduced ciliary action. Aspiration may occur during or after anaesthesia, so causing respiratory distress.

Pulmonary dynamics


What do you understand by the terms compliance and hysteresis ?They are both measures of the change in lung volume per unit change in pressure (∆V/∆P) during the breathing cycle. They are, therefore, measures of the degree of elasticity of the lungs. Compliance is measure of lung elasticity as the lung inflates.Hysteresis is a measure of lung elasticity as the lung deflates.

What is lung compliance and in what situations is it decreased ? Compliance refers to the elasticity of the lungs. (Defined as change in lung volume per unit change in pressure). Poor lung compliance occurs in:

o Lung disease, eg in pulmonary fibrosis.o Disease of the chest wall, eg in thoracic scoliosis.

What are the values of compliance and hysteresis different in the same lung?This is direct result of the action of surfactant (a detergent-like substance rich in lecithin) which lowers alveolar surface tension and decreases the work of breathing.

What are the implications of this difference when making pressure-volume measurements in the lung?The volume of the lung at any given pressure will be greater if measured during expiration than if measured during inspiration. This results in the classic pressure-volume loops.

What is meant by the term " work of breathing "?To expand the lung the inspiratory muscles must overcome the elastic recoil of the lungs and the resistance of the airways to flow.

Is there any way of measuring this work?Yes, by measuring intrapleural pressure.

Pulmonary gas exchange and blood gas transport


How is oxygen transported?Oxygen is carried in two ways:

1. Attached to haemoglobin.2. As dissolved oxygen in the blood.

What barriers must oxygen travers to pass from the air in the alveolus to attach to haemoglobin?

1. Surfactant.2. Plasmalemma of alveolar epithelium (outer surface of epithelium).3. Cytoplasm of alveolar epithelium4. Plasmalemma of alveolar epithelium (inner surface of epithelium).5. Basement membrane of epithelium.6. Interstitium.7. Basement membrane of endotheLium.8. Plasmalemma of endothelium (outer surface of endothelium).9. Cytoplasm of endothelium.10. Plasmalemma of endothelium (inner surface of endothelium).11. Plasma.12. Plasmalemma of red erythrocyte.13. Cytoplasm of erythrocyte.

What do you understand by impairment of diffusion?Impaired equilibrium between the alveolar gas and the capillary blood.

What diseases can cause impaired diffusion of oxygen?Asbestosis, sarcoidosis and interstitial fibrosis.

Oxygen delivery


In what ways can oxygen be delivered to the patients ? The patient can breathe room air as normal with an inspired oxygen

concentration of 21 % . Increased concentrations can be inspired using a mask system attached to an

oxygen supply, but this gives a very variable concentration of inspired oxygen (FiO2) owing to a dilutional effect of the oxygen escaping around the mask.

High air flow oxygen entainrment (HAFOE) uses the Venturi principle with a high-flow low-pressure system to suck in oxygen to give a known FiO2.

A reservoir bag uses the oxygen in the bag effectively to "dilute" the inhaled mixture, increasing FiO2.

To deliver FiO2 greater than 40 % reliably , endotracheal intubation and ventilation is required. It should be noted that prolonged exposure to FiO2 greater than 80 % is injurious to the lung.

Hyperbaric oxygen therapy also occasionally impinges on surgical practice in cases such as necrotizing fasciitis, It delivers 100 % oxygen at greater than 1 atmosphere of pressure in specially constructed tanks .

What is CPAP and what are its indications ?It stands for continuous airway pressure. Patients with impeding respiratory failure may be helped by this technique, which uses a one-way valve in a very closely appllied facemask. As the patient expires, gas is expelled through the valve until a certain pressure is reached, after which no further gas is allowed to escape. This has the effect of always maintaining a positive pressure in the airways-as the name suggests-preventing collapse of alveoli, and even recruiting previously collapsed ones. It is the stage of respiratory management before intubation and ventilation, but many patients find it very uncomfortable and are unable to tolerate the mask. There are also problems with the mask causing pressure necrosis of the face particulary over the nasal bridge.

If the patient requires ventilation, What modes of ventilation are you familiar with? Describe what parameters the ventilator can be set to? The patient can, of course, be allowed to ventilate spontaneously, but this is not common in the ITU setting. Intermittent positive pressure ventilation (IPPV):

It is the commonest mode, also known as continuous mandatory ventilation (CMV).

In this mode, there is no patient interaction and the gas mixture is forced into the lungs at regular intervals, which has important physiological consequences.

In normal breathing , there is a negative intrathoracic pressure in inspiration, whereas in IPPV the reverse is true, as there is a positive pressure in both inspiration and expiration . This has the effect of compressing the great vessels and impeding venous return cardiac output.

In this setting, a patient with borderline right heart function may well be tipped into right ventricular failure; conversely, it may help left ventricular failure by assisting the squeeze of blood into the aorta.

The machine can be set to give a set number of breaths per minute and to deliver either a set volume of gas or to provide gas at a given pressure or a


given flow rate, one can also set the ratio of inspiration to expiration and this can be varied according to the clinical need in ARDS or asthma, for example.

Synchronized intermittent mandatory ventilation (SIMV): It allows the patient to do some of the worse. The ventilator is set to the lowest acceptable parameters and, if the patient

does not breathe. The machine will cut in and perform that breath instead; it is used as a

weaning tool. Pressure support ventilation (PSV):

It allows the patient to breathe on their own, without a set respiratory rate but, if the patient's breath does not reach a pressure trigger point, then the ventilator will aid the breath-another weaning tool.

What is PEEP and autoPEEP?PEEP stands for positive end expiratory pressure. As air leaves the lungs in expiration, the alveoli will tend to collapse. In normal lungs, surface tension keeps the alveoli open and allows inflow of gas with the next breath. In the situation of poor repiratory function, alveoli will tend to collapse at the end of a breath . By setting the ventilator to a certain PEEP level , as the airway pressure falls, the closure of a valve in the circuit will not allow the pressure to fall back below that level- or to a negative pressure as happens in physiological ventilation- thus splinting the alveoli open. The stiffer the lungs, the higher the level of PEEP needed to achieve this aim. In actuely ill asthmatics, the pressures in the airway are so high that they are still exhaling when the next breath starts, thus splinting the airway open-so called autoPEEP.

Oxygen transport


Describe the relationship that governs O2 transport in the blood and draw the oxygen-haemoglobin dissociation curve .99% percent of oxygen is carried bound to haemoglobin with only 1 % carried in solution in plasma in proption to the partial pressure. The relationship between partial pressure (oxygen tension) and percentage saturation is given by a sigmoid-shaped curve.Point A:It is known as the p50 point.It is the oxygen pressure at which haemoglobin is 50 % saturated. It is important for two reasons:

1. It helps to draw the curve.2. It is often used to compare the effects of conditions that shift the curve to

either the right or the left. Point B:It is the normal mixed venous point.Point C:It is the normal arterial point.

There are three reference points on the curve: P50 = 3.6 kpa P75 =5.3kpa P100=13.3 kpa

Important points on the curve : The normal oxygen saturation of arterial blood is 98% when the PaO2 is 100 mmHg. The normal oxygen saturation of venous blood is 75% when the PaO2 is 40 mmHg. At a paO2 of 26 mmHg under normal physiological conditions, the saturation of Hb

is 50 %.

Why is the curve shaped like it is ?

4 memorable points: 97%- 80mmHg (10 kPa):normal arterial. 75%- 40mmHg (5.3 kPa) normal mixed venous. 50%- 25mmHg (3.6 kPa) P50. 10%- 10 mmHg (1.3 kPa).


It is a sigmoid curve because haemoglobin exhibits peculiar binding characteristics. Binding of one oxygen molecule to one haem molecule makes it easier for further binding to occur, which is represented by the steep mid-portion of the curve. It demonstrates large increases in percentage saturation for minimal increases in partial pressure, i.e. oxygenation of haemoglobin is relatively easy. This facilitation occurs until three out of four binding sites are occupied after which it gets slightly harder again, reflected by the curve flattening out at the higher saturations.

What is the physiological advantage of a sigmoid shaped curve ?A sigmoid shaped curve maximizes the quantity of oxygen taken up in the lungs at low alveolar oxygen tension but maximieses the quantity released in the system capillaries at a relatively high partial pressure.

What is the importance of the sigmoid shaped curve ? A fall in Po2 is tolerated provided the saturation remains above 90% (lie the

flat part of the curve). Increasing the Po2 above normal has little effect unless hyperbaric oxygen is

used, when the amount of oxygen in solution in the plasma becomes significant.

On the steep part of the curve, small decreases in Po2 lead to large falls in saturation (lie oxygen content).

What factors affect the affinity of haemoglobin for oxygen ? H+, PCO2 , tempreture and 2,3-diphosphoglycate: a rise of any of these

factors reduce the affinity of haemoglobin for oxygen and will result in a rightward shift of the oxygen-haemoglobin dissociation curve.

How do clinical conditions affect the shape of the curve ?The curve is shifted to the right (i.e. decreased affinity for oxygen ) by:

1. Acidosis.2. Increased 2,3-DPG.3. Increased tempreture.4. Hypercapnia (Bohr effect).

The curve is shifted to the left ( ie increased oxygen affinity) by :1. Fetal haemoglobin (HbF).2. Decreased 2,3-DPG.3. Alkalosis.4. Methaemoglobinamia.5. Carbon mnonxide poisoning. 6. Hyperthermia.7. Hypocapnia.

What is the effect of a right shift in the oxygen dissociation curve ?A shift of the curve to the right decreases the affinity of oxygen for Hb i.e. oxygen is released more readily from Hb at a given pO2. Therefore, at a given pressure of oxygen, say 26 mmHg, the standard Hb-oxygen dissociation curve has a saturation of 50% which is reduced to 40% with a small right shift.What are the Bohr and Haldane effects?


The Bohr effect:It is the shift in the curve due to changing (H+).(As the PH of blood decreases its affinity for oxygen descreases, this is related to deoxygenated haemoglobin having a greater affinity for H + than oxyhaemoglobin).It is due to binding effects with the imidazole groups of histidine. The Haldane effect:It describes the effect of the differing buffering capacities of CO2 for both oxyhaemoglobin and deoxyhaemoglobin. At the cell, deoxyhaemoglobin has a high buffering capacity for CO2 and accepts it readily. Once returned to the pulmonary circulation, the binding of oxygen converts it to oxyhaemoglobin, which has a low buffering capacity, and thus offloads CO2 readily.

What do the curves for myoblobin, carbon monoxide and fetal haemoglobin look like?

The implications are as follows: For myoglobin, it is positioned such that it will release its single molecule of oxygen only at low oxygen tensions, thus is not useful as a transport mechanism. Carbon monoxide has an avid affinity for haemoglobin, some 200 times that of oxygen: the molecule is saturated at even very low tensions of CO and is very difficult to displace. Fetal haemoblobin, which has δ instead of β globin moieties, has a left-shifted curve, increasing its affinity for oxygen at the lower tensions found in the fetus.

What happens to the oxygen dissociation curve in anaemia?Anaemia reduces the overall oxygen carrying capacity of the blood but does not affect the percentage saturation of Hb, therefore the curve is inchanged.

How is CO2 carried in the blood?


CO2 is transported in the blood by three means: 1. HCO3- buffer system: accounts for approximately 60% of CO2 carriage.2. Carbamino haemoglobin compounds: account for approximately 30% of

carriage of CO2. CO2 reacts with the amine groups in haemoglobin to form carbamino Hb. This reaction is faster if the Hb is deoxygenated, as in venous blood

3. Dissolved CO2. CO2 is 20 times more soluble in blood than oxygen. This represents approximately 10% of the total CO2 carriage.

What is the alveolar gas equation?The alveolar gas equation describes the relationship between alveolar ventilation and PaCO2.It is the PaCO2 that is constantly 'sensed' by the brain stem repiratory centre and used to regulate alveolar ventilation.The equation states that the product of alveolar ventilation and arterial P aCO2 is a constant at any given level of CO2 production.

What affect does a raised CO2 have on blood vessels?Raised CO2 concentrations have a moderate vasodilatory effect in most tissues, but have a marked dilatory effect on the cerebral and coronary vasculature. If CO2 is considered as the waste product of cellular respiration, any accumulation in areas, such as ischemic muscle, will have the effect of increasing blood flow through the area to try and reduce the tissue concentrations. What affect does a raised metabolic PaCO2 have on respiration?Raised metabolic CO2 gives rise to a metabolic acidosis because of combination with water forming carbonic acid, as detailed above.In order to attempt to correct this, the respiratory rate is increased to exhale more CO 2

and thus correct blood biochemistry. This is called respiratory compensation.

What happens to a patient with carbon monoxide inhalation?The carbon monoxide combines with haemoglobin to form carboxyhaemoglobin, stopping normal oxygen transport. Symptoms include:

1. Mental impairment. 2. Headache.3. Nausea. 4. Vomiting.5. Classic pink skin (usually rosy cheeked) due to the carboxyhaemoglobin. 6. Coma. 7. Respiratory distress.8. Cardiac arrhythmias develop, leading to death if untreated .

Treatment:1. Removal from the CO source.2. Administering high-flow oxygen; in some centre.3. Hyperbaric oxygen therapy is also used to increase the amount of oxygen held

in direct solution as a compensatory mechanism, whilst the CO is removed from the system.

What are the effects of hypercarbia?


Definition : PaCO2 > 6 KPa .

Central nervous system effects Increases cerebral blood flow (increased hydrogen ions). Stimulates sympathetic nervous system. Carbon dioxide narcosis at levels ≥ 12 Kpa.

Respiratory system effects: Carbon dioxide stimulates respiration at levels ≤ 13 KPa, above this level, it

acts as aaa depressant. Increases peripheral vascular resistance.

Cardiovascular system effects: Myocardial depressant (effect blunted due to sympathetic stimulation initially,

but at higher levels cardiac output is severely affected). Arrhythmias.

Renal effects: Constriction of glomerular afferent arterioles, leading to reduced urine output

with high levels of carbon dioxide.

What are the clinical features of carbon dioxide retention?1. Flushed skin.2. Characteristic coarse flap of the hands (asterixis).3. Bounding pulse.4. Muscle twitching.5. Hypertension.6. Ventricular ectopics.7. Convulsions.8. Coma.

Respiratory assessment


Draw a respiratory trace to show the volumes and capacities of the lung?

What is the difference between a volume and a capacity?A capacity represents the sum of two or mor volumes.

What is the functional sifnificance of the functional residual capacity ?The functional residual capacity (FRC):It is a effectively the body's reservoir. It is that volume of gas remaining in the lung after a normal exhalation. It is the volume in which gas exchange actually occurs and, as such, is of the utmost significance. In patients with repiratory failure, attemps are made to increase the FRC, by using continuous positive airway pressure (CPAP) or positive end expiratory pressure (PEEP), in order to recruit more alveoli for gas exchange.

What is meant by tidal volume?The volume of air entering/leaving the lungs during normal inspiration/expiration.

What is meant by forced vital capacity ?The volume of air expelled by maximal expiration following full maximal inspiration.

What is meant by expiratory reserve volume?The volume of air left in the lumgs following maximal expiration.

What is the FEV1/FVC ratio and why is it useful?It is the ratio of forced expiratory volume in one second over the total forced vital capacity. In a normal subject this ratio is 0.8. It provides a useful way of distinguishing restrictive lung disease (FEV1/FVC> 0.8) from obstructive lung disease (FEV1/FVC< 0.8).


At is the difference between anatomical and physiological dead space ?Anatomical dead space:

It is the portion the tidal volume that remains in the upper part of the respiratoyu tree that is not involved in gas exchange.

(the volume of gas exhaled before the CO2 concentration rises to its alveolar plateau).

It is not constant and is influenced by many factors, including: Size of the subject. Posture. Position of the neck and jaw. Hypoventilation. Drugs. Hypothermia. Age and the lung volume at the end of inspiration.

Physiological dead space: It includes all non-exchanging parts of the repiratory tree, i.e. anatomical dead

space and alveoli not taking part in gaseous exchange. It is defined as the sum of all parts of the tidal volume. It varies according to age, sex, size, posture , duration of inspiration and

breath-holding. It is well known that prolongation of inspiration reduces the deadspace,

allowing gas mixing to take place between deadspace and alveolar gas.

Vitalography is generally a laboratory tool. What other simple measurements may help you assess respiratory function? A good history:

It will allow you to make an assessment of respiratory function by gauging ability to perform everyday task.

Examination: Examination of the chest may reveal clunbing, barred chest,wheeze, or the

crackles of fibrosis or failure. Investigations:

A chest x-ray will reveal much in the way of pulmonary pathology, such as emphysema, basal fibrosis and right heart enlargement.

Arterial blood gas analysis will give useful information regarding the state of gas exchange in the patient.

A non-invasive measure of respiratory capacity can be provided by using a hand-held flow meter to measure peak expiratory flow rate (PEER).

What would you expect your PEER to be …… and that for an acute severe asthmatic?An average adult would have a PEER between 450 and 650 L/min depending on sex, build and degree of fitness. In acute severe asthma, the PEER falls to between 33 and 50 % of normal or best predicted for that patient. If the PEER falls below 33 % of best predicted, then it is termed life-threatening asthma and warrants careful consideration of ITU treatment.

Lung function tests


What is the peak expiratory flow rate (PEER)?It is maximal rate of air flow during a sudden forced expiration ( litres/minute)

1. Normal female PEER: 350-500 litres/minute.2. Normal male PEER: 450-700 litres/minute.3. Reduced in obstructive disease, eg asthma.

Can you define the values obtained in spirometry?FEV: Forced expiratory volume; volume of gas forcibly exhaled from full inspiration.FEV1: Forced expiratory volume ehhaled in 1 second (reduced in obstructive

pulmonary disease).FVC: Forced vital capacity; largest volume if air forcibly expired after maximum

inspiration (reduced in restrictive disease, if supine, elderly, muscle weakness, emphysema).

FEV1/FVC: expressed as a percentage; normal is > 70% (reduced in obstructive disease; increased/normal in restrictive disease).

What is lung compliance ?It is volume change per unit of pressure change, ie a measure of distensibility.

Normal lung compliance is 150-200 ml/cm H2O. Can be divided into:

Static compliance : i.e. alveolar distensibility (reduced in pulmonary fibrosis and pulmonary oedema).

Dynamic compliance : related to aiway resistance (decreased in chronic bronchitis).

What is the effect of PACO2 and PAO2 on minute volume and respiratory rate?

On a minute-to-minute basis, the PACO2 is proportional to the repiratory rate. This is brought about by the centeal chemoreceptors.The PACO2 brings about an increase in repiratory rate and minute volume only at quite low values, this being effected by the peripheral chemoreceptors.

What are the investigations for aasessing repiratory function?Non-invasive:

Repiratory rate

PAO2

Repiratory rate

PACO2


1. Peak flow: bedside measure of respiratory muscle function and airway resistance.

2. Pulse oximetery: estimated arterial oxygen saturation.3. Capnography: end-tidal CO2 is measured as a marker of ventillatory function.4. Spriometry: a measure of lung volumes and forced expiratory capacity.5. Gas transfer function: a measure of the diffusing capacity across the alveolus.6. V/Q scanning and CT pulmonary angiography if pulmonary emboli are

suspected.7. Echocardiography: assessment of PA pressure and right heart function in

pulmonary hypertension.Other imaging modfalities: plain radioglo. Ct and MRI.Invasive:

1. ABGs: gold standard measurment of arterial oxygenation and PaCO2.2. Also crucial formassessment of acid-base balance.3. Bronchoscopy: for assessment of lesions and/or secretions, can be flexible or

rigid.4. Lung biopsy: CT guided or open via thoracic procedure or open thoracotomy.

Flow-volume loops in obstructive & restrictive pulmonary disease?Plotting the relationship between airflow and lung volume over the respiratory cycle gives an indication of the type of pulmonary disease.

Obstructive disease , such as asthma, brochiectasis and COPD show an increase in the total lung capacity and residual volume as a result of air trapping and hyperinflation.

Restrictive disease shows a reduction of all volumes because of: An alteration inlung parenchyma (e.g. idiopathic pulmonary fibrosis,

fibrosing alveolitis). or Disease of the pleura. Chest wall (e.g. kyphoscoliosis). Neuromuscular apparatus as seen

Hypoxia


How do you classify hypoxia?1. Hypoxaemic hypoxia: reduced PaO2 due to hypoventilation, diffusion

impairment, shunt, V/Q mismatch.2. Stagnant hypoxia: inadequate blood supply to an organ; PaO2 and haemoglobin

may be normal. 3. Cytotoxic hypoxia : normal oxygen delivery but cells prevented from utilizing

it (cytochrome poisoning).4. Anaemic hypoxia : PaO2 normal, haemoglobin low.

Can you suggest methods of supplementary oxygen delivery ? Nasal cannula = 30%-40%. Face mask = up to 50%. Venture mask ( fixed performance) = up to 60%. Reservoir bag = up to 100%.

What are the problems and risks associated with oxygen therapy? Reduced hypoxic ventilator drive (be aware of this in COPD). Pulmonary toxicity (increased free oxygen radicals; decreased surfactant and

compliance. Atelectasis. Fire risk.

Physiological effects of altitude and diving


What are the main physiological effects of altitude ?The physiological effects include:

Hypoxia hyperventilation low PaCO2. Rise in cerebral blood flow cerebral oedema. Low O2 pulmonaryvasoconstrictionpulmonary

hypertensionpulmonary oedemaAs one ascends to high altitude, the first effect is a fall in PaO2.

This hypoxia stimulates a number of compensatory mechanisms.Hyperventilation is caused by stimulation of the peripheral chemoreceptors (mainly the carotoid bodies). This causes the PaCO2 and [ H+] to fall .

What are the changers at altitude?

A. Immediate changes: Repiratory & acid-base: Peripheral chemoreceptors detects a drop in PO2 which leads to a reflex

tachypnoea and increase in depth of repiration. This results in: Repiratory alkalosis and its associated features (tingling, fingers, etc.). Hypocapnia, which reduces the drive of the central chemoreceptos

(nont suitable). This is compensated for in the short team by removal of bicarbonate ions by the choroid plexus from the CSF.

Alkalosis has an adverse effect on oxygen delivery: Because alkalosis shifts the oxygen-haemoglobin dissociation curve to

the left, thus making it more difficult for the haemoglobin to give up oxygen at the tissues at a given PO2.

Reduced humidity can lead to a dry cough.Cardiovascular: Reflex tachycardia and cardiac output increase initially, via stimulation of the

peripheral chemoreceptors by hypoxia, to increase oxygen delivery to the tissues.

Cerebral blood flow increases to increase delivery of oxygen to brain.

B. Slow changes: Respiratory & acid-base: The alkalosis created by tachypnea is compenstaed for in the kidney by

increased excretion of HCO3- ions, a slow metabolic compensation.

Increased production of 2,3-diphosphoglycerate (DPG) compensates for the left shift of the O2-haemoglobin dissociation curve and facilitates releaase of oxygen to the tissues.

The chronic hypoxia leads to increased production of erythropoietin by the kidney, which causes increased haemoglobin synthesis. This improves oxygen carriage, and individuals chronically exposed to altitude become chronically polycythemic.

There is a blunted response to hypoxia as the individual acclimatizes and the alkalosis improves over time. There may also be an increase in the alveolar size and a decrease in the thickness of the alveolar membranes, leading to more efficient gas transfer.

Cardiovascular:


Chronic hypoxia leads to pulmonary vasoconstriction and hypertension, and this can lead to pulmonary oedema.

Blood viscosiy increases at altitude.

C. Other medical problems: Thrombosis. Retinopathy. Immunosuppression.

What physiological changes can be seen with acclimatization ?Initially in the acclimatation process there is an increase in respiratory drive (hyperventilation)Later:

Haemoglobin concentration increases which has the effect of increasing the oxygen carrying capacity.

2,3 DPG (diphosphoglycerate ) concentration rises, which in turn decreases the affinity of Hb for oxygen so causing a right shift of the O2 dissociation curve.

What are the main physiological effects of diving ?For every 10 m of depth in sea water, the ambient pressure increases by 1 atmosphere. The lung volume halves at a depth of 10 m and the partial pressures of the gases double. This may lead to nitrogen narcosis, oxygen toxicity, impairment of intellectual functions, tremors or drowsiness.

What are the main dangers of a fast ascent ?Barotrauma, air embolism and decompression sickness are the main dangers of fast ascent. Nitrogen escapes from solution and bubbles in the tissues may cause severe pains (especially joints), neurological symptoms and in more severe cases the bubbles may obstruct the cerebral, pulmonary and coronary vessels.


Kidney, Acid-base & Electrolytes


The kidney

What are the functions of the kidney?The important functions of the kidney include:

1. Maintaenance of body fluid osmolarity and volume, electrolyte and acid-base balance.

Osmolarity is regulated by the excretion of water and NaCl. Acid-base balance is achieved through secretion of H+ and absorption

of HCO3-.2. Elimination of water-soluble waste products of metabolism and foreign

substances: Metabolic products include urea (from amino acids) and creatinine

(from muscle protein). Foreign substances include breakdown products of drugs.

3. Hormone production and secretion. Hormones include: Rennin. 1,25 dihydroxycholecalciferol. Erythropoietin. Prostaglandins and kinins (such as bradykinin).

What are hormones are produced by the kidney? Rennin: released from the juxtaglomerular cells. Kallikrein: produced in the distal nephron. Hydroxylase production: converts 25-hydroxycholecalciferol into 1,25-

dihydroxycholecalciferol. Erythropoietin: produced in response to anemia. Prostaglandins: produced in the cortex and medulla.

What are the main buffers in the maintenance of acid-base balance? Proximal tubule: HCO3

-/H2CO3 buffer system. Distal tubule : HPO4

2-/H2PO4- buffer system.

The phosphate buffer is the most important in normal renal function. NH4

+ buffer system is the weast buffer but allows the excretion of acid without the loss of Na+.

Where are the sites of water reabsorbtion ?1. Proximal tubule: passive transport along osmotic gradient( 75% of resorbtion).2. Descending limb of loop of Henle : passive transport.3. Distal tubule : under the control of antidiuretic hormone (ADH).4. Collecting ducts : under the control of ADH.

How is the osmolarity of urine controlled?The concentration of urine is under the control of ADH on the collecting duct. ADH increases permeability and results in increased water resorbtion . Osmolarity varies between 50 and 1200 mosmol/1.

How does the kidney maintain a constant extracellular fluid ( ECF) osmolarity?


NaCl is the major determent of ECF osmolarity. Large variations of water and NaCl ingestion do not produce similar changes in ECF volume and osmolarity, as the kidney is able to compensate by excreting urine that is either hyperosmotic (concentrated) or hypo-osmotic (dilute) with respect to CSF.If ECF osmolarity increases:

The hypothalamus responds by increasing anti-diuretic hormone (ADH) release.

ADH increases the permeability of the collecting ducts of the kidney to water. Water is thus reabsorbed resulting in a small volume of concentrated urine

If the ECF osmolarity decreases: ADH secrestion and the sensation of thirst are both supported. This results in reduced water reabsorption from the collecting ducts and

production od a large volume of dilute urine.

How is ECF volume regulated?The ECF volume is regulated by low and high pressure sensors: High pressure sensors:

1. Baroreceptors (pressure sensors) in the aortic arch, carotis sinus. 2. And afferent arterioles of the kidneys send afferent impulses to the brain stem

via the vagus and glossopharyngeal nerves about the ECF volume. For example if ECF volume rises, there is decreased sympathetic activity and reduced ADH secretion. In addition, pressure receptors in the afferent arterioles of the kidney suppress renin secretion through a negative feed back loop. The net result is system vasodilatation and decreased renal Na+

absorption. Low pressure sensors (pulmonary vessels and atria) have the opposite effect so that sympathetic activity, ADH secretion and the Renin-Angiotensin-Aldesterone axis are all stimulated.

What is the glomewrular filtration rate (GFR) ?Definition: Volume (in ml) of plasma filtered by the kidneys per minute (normal is 120 ml/minute).

How do you measure GFR?The GFR is measured by infusion of a substance that is freely and neither reabsorbed nor secreted by renal tubules:The basic formula for clearance (Cx) of a substance x is :

GFR (Cx) = (urine concentration of x (mg/dl) x urine volume /time) / plasma concentration of x

Inulin can be used but is difficult to measure.An alternative is to use creatinine clearance (approximates to the GFR), averaged over 24 hours (normal range is 90-130 ml /minute).

What are the indications for dialysis haemofilteration?


The indications are: Symptoms of uraemia. Complications of uraemia e.g pericarditis. Severe biochemical derangement in the absence of symptoms (e.g. rising trend

in an oliguric patient). Hyperkalemia not controlled by conservative measures. Severe acidosis. Removal of drugs causing acute renal failure (gentamicin, lithium, aspirin

overdose).

Glomerulus


Can you describe the glomeulus ?The glomerulus is formed by a group of capillaries, supplied by an afferent arteriole, invaginnating into the Bowman's capsule and drained by an efferent arteriole.

What is the anatomy of the nephron?

The blood is filtered at high pressure in the glomerulus, the large proteins and cells remain in the blood and water, and solutes pass into the bowman's capsule and the

nephron; 170-180L of plasma are filtred a day.Several solutes are actively reabsorbed in the proximal tubules, including sodium, glucose, calcium, phosphate and chloride. Water is also reabsorbed as are amino acids.The renal medulla contains a gradient of sodium, which is most concenterated at the center and more dilute at the periphery. More sodium is pumped out actively at the thick ascending limb of the loop of henel to maintain the sodium gradient.

What is the function of the glomerular membrane?The glomerular membrane allows passage of neutral substances up to 4mm in diameter into the Bowman's capsule and excludes substances with a diameter of over 8 mm, though the charge of the substance affects its passage across the membrane. (The endothelium of the glomerulus is fenetrated and contains pores 70-90 nm wide and the glomerular epithelium contains filtration slits 25nm).

How is the glomerular filtration rate (GFR) measured ?The GFR can be measured by measuring the extraction and plasma level of a substance that is freely filterd through the glomerular and is neither secreted nor reabsorbed by the renal tubules. The total amount of plasma filtred through the glomeruli is 170-180 1/day. GFR is approximately 125ml/minute. What substances can be used to measure GFR?Inulin can be used to measure GFR (inulin is a fructose polymer).What are the factors that increase GFR?


Increased renal blood flow. Increased capillary hydrostatic pressure. Increased afferent arteriolar pressure. Decreased efferent arteriolar pressure. Increased glomerular permeability. Hypoproteinemia.

What factors decrease GFR?The opposite of any of the factors listed in the question above , and :

Decreased systemic blood pressure (< 90mmHg). Ureteric obstruction. Oedema of the kidney. Dehydration. Decreased in effected filtration surface area.

Loop of Henle


What is the function of the loop Henle? Descending limb: water , Na+ and Cl – are reabsorbed. Ascending limb: impermeable to water but Na+ and Cl- are reabsorbed. Formation of countercurrent multipliers.

What are the different types of loop of Henle?Long (juxtamedullry nephrons) and short (cortical nephrons) loops. In man 15% of nephrons have long loops.

Which are important in the formation of a countercurrent multiplier?The long loops, the longer the loop the greater the osmolarity at its tip.

What is the advantage of this countercurrent multiplier ?A high osmotic gradient is formed across the kidney with the cortex being isotonic and the medulla hypotonic. This allows a very dilute urine to be produced in the distal tubule.

Countercurrent multiplier formation:The thin desecending limb of the loop of Henle is permeable to water and the thick asecending limb is not. Sodium is pumped actively from the tubular fluid in the ascending limb of the loop of Henle to the interstitium (at the centre of the loop). Fluid moves from left to right through the loop. The sequence of events is as follows:

1. All concentrations are equal.2. Sodium is prepared out of the ascending limb .3. The increased concentration of sodium in the interstitium equilibrates with the

fluid in the descending limb.4. Fluid moves around the loop of Henle.5. Again , fluid is pumped from the thick ascending limb into interstitium.6. The fluid concentrations equilibrates as before.7. The fluid moves once again.

A gradient has started to form. This is maintained by the sodium pumps and the constant delivery of the sodium to the loop of Henle.The fluid leaving the loop of Henle is very hypotonic because sodium has been pumped away from it. Water is later reabsorbed through water channels in the collecting system.This sodium gradient, together with the coutercurrent multiplier arrangement of the loop of Henle and the blood supply, allows the urine to be concentrated, because water follows sodium, the main anion in the blood. As the fluid filtered by the Bowman's capsule enters the loop of the Henle and progress through the permeable descending limb, water enters the more concentrated interstitium by osmosis.Sodium and chloride are reabsorbed here.


How do loop and thiazide diuretics work?As water follows sodium, blocking of the sodium channels in the proximal tubule, loop of Henle or distal tubule causes a dieresis (sodium not reabsorbed, so excreted with water); this is the basis of the action of different types of diuretic.In the loop of Henle, blocking of the sodium channels dissipates the sodium gradient and the kidney cannot concentrate urine (loop diuretics such as frusemide).In the proximal tubule, if sodium reabsorption is blocked (thiazide diuretics such as bendrofluazide) more water and sodium are excreted.

DISTAL TUBULEIn the distal tubule, potassium is excreted under the control of aldosterone, in exchange for sodium.In the collecting duct, water is reabsorbed via water channels, the synthesis of which is mediated by ADH. Some urea is passively reabsorbed, but the main contents of the urine here are urea, sodium and water.

Renal failure


Classify renal failure and give examples each type ?It can be easily classified into pre-reanl, renal and post-renal renal faiklure. Pre-renal failure:

It is due to inadequate renal perfusion due to reduced intravascular volume or lowerd effective arterial circulation Commonest surgical causes include:

1. Gastrointestinal losses.2. Haemorrahge.3. Sepsis.4. Third-space losses.

May lead to acute tubular necrosis if untreated.

Renal: Acute tubular necrosis. Glomerulonephritis. Drugs.

Post-renal failure ocuurs due to: Blockage of the passage of urine:

It may be within the kidney, such as when myoglobin blocks the glomeruli.

The blockage is extra-renal by neoplasms, calculi, prostatic enlargement, strictures or catheter occusion.

You are asked to see a catheterized, male, postoperative surgical patient who hasn't passed any urine for 4 hours. How are you going to assess the problem?True anuria is generally only caused by a blocked outflow tract-commonly a blocked catheter, and so this is likely to be oliguria rather than anuria, oliguria being defined as a urine output less than (0.5 ml/kg per hour). Initially, a history is taken and the patient examined.

Specific evidence of previous renal insufficiency an enlarged bladder and the state of circulatory filling is sought.

The catheter should be flushed to ensure it is not blocked. Examination of his fluid input/output charts would indicate, along with his

pulse, blood pressure and pulse pressure, whether he was likely to be underfilled.

All recent urea and electrolyte results should be examined and a new set requested.

All information is interpreted in light of the patient's operation and operative fliud losses. In general, post-renal causes should be excluded and any evidence to suggest intrinsic renal failure is sought.

What is the management of postoperative oliguria?


In the evident, the patient appeared fluid depleted increased intravenous fluid are prescribed, giving due regard to his cardiovascular status and the patient's ability to accept fluid loading.

If fluid filling within the limits of clinical monitoring did not abate the oliguria, then more invasive monitoring in the form of a central venous pressure line is appropriate. With a CVP line in situ, a fluid challenge is given to the patient to gain an indication of the state of filling.

If clinically and with CVP readings the patients is well filled but still oliguric, then the use of diuretics may be appropriate, normally in the form of intravenous frusemide. 'Low-dose renal' dopamine has not convincingly been shown to help this type of oliguric patient beyond acting as an additional diuretic.

If the patient were well filled and remained oliguric after diuretics, and outflow obstruction from rare conditions, such as bilateral uretic obstruction was excluded, then the ITU should be contacted for assistance. In the face of deteriorating reanl function, as witnessed by rising urea and potassium concentrations and fliud accumulation, then renal dialysis should be considered. In patients with compressed renal function, NSAID should be avoided as should ACE inhibitors if possible.Gentamicin is nephrotoxic and should be changed to another antibiotic if possible.

What are the indications for renal replacement therapy?Renal replacement therapy (RRT) is indicated in:

Renal failure of whatever aetiology. Uncontrollable rising serum potassium, sympathetic uraemia or its

complications. Severe acidosis or pulmonary oedema from fluid overload.

How can RRT be achieved ?Available methods are haemodialysis, peritoneal dialysis and haemofiltration. In haemodialysis:The patient's blood is pumped through an artificial kidney with a dialysis to 'filter' the blood by ultrafiltration. Both hydrostatic pressure from the pump and an osmotic pressure generated from the glucose present in the dialysis fluid are used to drive the ultrafiltration process. Peritoneal dialysis:It allows a dialysis fluid to reside in the peritoneal cavity with exchange of metabolites by diffusion alone. Haemofiltration:The patient's blood is driven through a filter by the patient's arterial pressure, and a dialysis added around the filter and diffusion of waste metabolites occurs into the dialysis. it is, in essence, a slow haemodialysis.

Acute renal failure


How do you define acute renal failure?Acute renal failure in adults may be defined as a creatinine > 125 μmol/l recoreded within the last 48 hours and oliguria of < 135 ml in the last 8 hours.

In practice what should the normal urinary output be above?0.5 ml/kg per hour.

What does the picture of oliguria and high urine osmolarity indicate?This indicates that the kidneys are concentrating urine appropriately and indicates a pre-renal cause for the oliguria. If you have oliguria and a urine osmolarity similar to serum osmolarity, i.e.300 μmol/l, this suggests established renal failure.

Can renal failure occur without oliguria ?Yes, particularly if diuretics are used to maintain urine flow.

What are the common causes of acute renal failure in a surgical patient?The common causes of acute renal failure in surgical patients are sepsis and hypotension.

Can you list any risk factors that predispose a surgical patient to developing post-op acute renal failure?The potential risk factors are factors are:

Pre-existing renal disease. Diabetes mellitus. Pre-existing cardiac failure. Evidence of reno-vascular disease and hypertension.

The older patient is also more prone to developing renal failure. Diuretics, antibiotics such as amino-glycosides (gentamicin), non-steroidal anti-inflammatory agents, cyclosporine and contrast media will exacerbate renal failure. In addition, jaundice or myoglobinaemia will have detrimental effects on the kidneys.

How may examination of the urine be useful in the management of acute renal failure?

The presence of white cells suggests infection or inflammation. Haematuria suggests stones or tumor. Whole castsd suggests intrinsic disease (e.g. glomerulonephritis). Protein suggests glomerular injury. Specific gravity > 1.022 suggests intact concentrating ability. Spot urinary sodium concentration may help differentiate prerenal failure from

acute tubular necrosis (fractional sodium excretion in prerenal failure is <1% fractional sodium excretion in acute tubular necrosis is >1%).

Urine culture for infection.

Can you outline the principles of management of acute renal failure ?


The management of acute renal failure is not restricted to the kidney but the management of the patient as a whole. It is important to treat any multiple organ dysfunction.

The patient should be resuscitated. Hypoperfusion must be corrected, with the use of fluids, blood and inotropes as necessary.

Invasive cardiovascular monitoring may be of advantage depending on the patient's condition. T

reatment of any underlying sepsis should be commenced. Appropiate antibiotics must be given having adjusted for reduced excretion

rates due to renal failure. Nutrtitional support should also be considered.

Are diuretics of any use in the treatment of acute renal failure?Diuretics may be useful in some patients to maintain urine volume. However, if they are used inappropriately they may precipitate acute renal failure.Furosemide:

It has theoretical benefit in that it may reduce medullary work thereby reducing tubular oxygen demand.

It acts on the loop of Henle' and reduces chloride and hence sodium re-absorption.

Some studies have shown that a continuous infusion of Furesemide rather than boluses is more beneficial, as blousing may induce further hypovolaemia.

Mannitol: It has also been used and is often described as a renal protective agent due to

its osmotic-diuretic, free-radical scavenger and renal vasodilatory effects. However, protective trials have not demonstrated any clear benefit. It is of

great importance when considering using diuretics in patients with acute renal failure to ensure that cardiovascular resuscitation and fluid loading has been performed before instituting diuretic treatment.

Renin-Angiotensin-Aldosterone system


What is rennin and what stimulates its release? Rennin is a proteolytic enzyme (molecular weight 40.000 Da). Synthesized and stored in the juxtaglomerular apparatus. Released in response to decreases in circulating volume:

Decreased afferent arteriolar pressure. Decreased sodium delivery at the macula densa.

What are the actions of angiotensin II? Vasoconstriction: intrarenal and systemic. Increased proximal tubular sodium reabsorption. Aldostrerone release from the adrenal cortex. Increased distal tubular sodium reabsorption. Stimulates thirst. Antidiuretic hormone release: leads to water retension.

What are the causes of hyperalsosteronism?Primary: adrenal cortical tumour (Cronn's syndrome).Secondary:

Pregnancy. Heart failure. Chronic diuretic therapy. Dietary salt restriction. Cirrhosis with ascitis. Nephrosis.

What is the body's primary mineralocorticoid? Describe its synthesis and control of its secretion?Aldosterone is the major mineralocorticoid. It is synthesized in the zona glomerulosa of the adrenal cortex by 18-hydroxylation of a cholesterol skeleton. It is under the control of the rennin-angiotensin system and not the hypothalamic-pituitary axis. A decrease in the glomerular filtration rate (GFR) stimulates release of rennin from the juxtaglomerular apparatus which in turn cleaves angiotesinogen to angiotensinI. This is, in turn, acted upon by angiotensin-converting enzyme (ACE) to cleave the decapeptide into an octapeptide, angiotensinII , one of the most potent vasoconstrictors yet isolated. The effect of angiotensin II:

Increase peripheral resistance, particulary at the efferent renal arteriole. Stimulate synthesis of aldesterone.

The primary role of aldesterone is regulation of sodium. It increases sodium resorption in the kidney and water will follow by osmosis,

thus increasing extracellular volume and hence correcting GFR. It should be noted that when sodium is resorbed under the control of aldesterone, it exchanges at the cell membrane with either potassium or hydrogen ion; thus aldosterone excess can lead to hypokalaemia. Alternatively, if potassium is already low, the Na+ will exchange for H+, which increases bicarbonate production leading to hypokalemic alkalosis. Aldosterone is metabolized by hepatic conjugation and urinary excretion.


What is Conn's syndrome and how does it present?Conn's syndrome is primary hyperaldosteronism:

Over half of the cases are due to a single benign adrenal cortex adenoma. 10 % are multiple adenomata. One-third due to bilateral hyperplasia.

Secretion from a carcinoma is extremely rare. Excess plasma sodium, freed from normal negative feedback control, stimulates increased antidiuretic hormone (ADH) secretion. ADH acts in response to increased extracellular fluid osmolarity by increasing distal tubular permeability and increasing the volume of resorbed water; thus ADH excess leads to water retention and an expanded extracellular fluid volume.The clinical features of this are:

1. Hypervolaemic hypertension.2. Hypokalaemic alkalosis which may be so severe as to lead to tetany owing to

the effect on calcium binding. 3. Muscle weakness and even paralysis due to the hypokalaemia.4. Increased plasma bicarbonate, hypernatraemia and low urinary sodium

contentration also occur.

What are the causes of secondary hyperaldosteronism?Secondary hyperaldosteronism occurs when there is a low GFR in spite of normovolaemia. Good examples are:

Damaged renal vessels from either hypertension or renal artery stenosis. Reduced colloid osmotic pressure, as in the nephritic syndrome or cardiac

failure, causing poor renal perfusion. In secondary hyperaldosteronism plasma rennin is elevated because of the mechanisms described overstimulating the juxtaglomerular apparatus. In the primary condition, aldosterone is elevated, which increases plasma volume and therefore, results in low levels of plasma rennin.

Outline your management of an adrenal lesion identified as an incidental finding on CT scanning So-called "incidentalomas" are thought to arise with an incidence of up to 10 %. I. Initial investigation is to determine whether the lesion is functional or not:

Serum aldosterone and cortisol. Urinary catecholamines and cortisol. Low-dose dexamethasone suppression test.

Neither biochemical markers nor scanning will reliably distinguish benign from malignant tumors in most cases. In most centres, management depends on the size of the lesion and age of the patient:

Lesions greater than 4 cm in size in patients under the age of 50 should be surgically removed.

Smaller lesions should be monitored closely with serial scanning.The risks of malignancy increase with the size of the lesion and the relative risks for a given size of tumor are higher the younger the patient's age.


Acid-Base Balance

Interpret the arterial blood gas readings shown?Blood gas value

PH 7.268


PO2 24.3 KPaPCO2 5.05 KPa

Acid-base statusc Base (Ecf)c – 8.9 mmol/Lc HCO3

-(p,st) c 17.1 mmol/LElectrolyte values

cK+ 5.0 mmol/LcNa+ 137 mmol/LcCa+2 1.16 mmol/LcCl- 115mmol/LcK+ 5.0 mmol/L

Metabolite valuescGlu 9.0mmol/Lc Lac 0.9 mmoll/L

Oximetry valuesctHb 5.3g/dlFO2Hb 97.6%FMetHb 0.7%F HHb 0.5%Hct 16.8%FCOHb 1.2%

PH is log10 1/(H+) and is a measure of hydrogen ion concentration, i.e. acidity or alkalinity. Normal blood PH is 7.35-7.45

pO2/pCO2 measure the partial pressures of oxygen and carbon dioxide in the blood. They are affected by changes in respiratory function, and the pCO2 is particularly affected by acidity, since H+ ions will combine with CO2 to form bicarbonate and water. Normal ranges are pO2 10-13.3 kPa and pCO@ 4.8-6.1 kPa.

Standard bicarbonate is the amount of HCO3- in the sample when equilibrated

at 370C, pO2 13.3 kPa and pCO2 5.3 kPa. Normal values are 22-30 mmol/L. lower values imply a metabolic acidosis.

Base excess the amount of acid or alkali that needs to be added to the sample at 37oC to achieve a PH of 7.4 with pO2 13.3 kPa, and pCO2 5.3 KPa. Positive base excess is an alkalosis and negative base excess is acidosis. Normal value are -2 to +2.

Tissues metabolizing glucose with an inadequate oxygen tension produce lactate. Lactate rises with decreased tissue perfusion or with tissue ischaemia. Normal values are less than 1.0 mmol/L.

The patient has a profound acute metabolic acidosis. The PH is low with a low bicarbonate and a significant base deficit. The pO2 is high (this patient is receiving oxygen therapy) and the pCO2 is in the normal range. Common potential causes of this picture are shock, renal failure and tissue ischaemia, such as ischaemic bowel.

What is the normal PH range in the blood?The normal PH range is 7.35-7.45.

Why is the PH maintained within such a narrow range?


The purpose of regulating the PH within this narrow range is to maintain the shape and structure of enzyme which control numerous metabolic reactions in the body. Failure of regulation leads to cellular damage.

How is this PH maintained ?Any PH changes are buffered to minimize any immediate effects. The kidney and lungs are then involved in further modification through the excretion of "acid".

What is the main buffer system in the extracellular fluid?The CO2/HCO3

- buffer is the most important system in the body.CO2 + H2O → H2CO3→H+ + HCO3

-

Carbonic anhydrous (CA) catalyses the first (rate limiting) step. The second step is instantaneous.

What is an acid, a base and a buffer? An acid is a proton donor. A base is a proton acceptor. A buffer is a combination of a weak acid and its conjugate base. It works

best at a PH equal to its PKa, i.e. when it is maximally dissociated.

What is acidosis, alkalosis & base excess?Acidosis (or acidaemia) is an excess of H+ ions in the blood.Alkalosis (or alkalaemia) is a deficiency of H+ in blood.Base excess (normal value 0): measures how far removed bicarbonate is from its normal value.Acidosis:

If PCO2 > 5.3 kPa = repiratory acidosis. If HCO3

- < 24 mmol/L = metabolic acidosis.Alkalosis:

If PCO2 < 4.8 kPa = repiratory alkalosis. If HCO3

- > 28 = metabolic alkalosis.

What is acidosis and how is it classified? Acidosis occurs when the PH of the arterial blood is less than 7.35 It may be classified into metabolic and non-metabolic causes. This distinction is made via the anion gap which is defined as the sum of the

major cations (i.e. sodium and potassium) minus the sum of the major anions (bicarbonate and chloride). The normal range for the anion gap is between 12 mmol/L and 20 mmol/L.

An acidosis with a normal anion gap results from the replacement of bicarbonate by chloride, causes by:

1. Gastrointestinal losses-diarrhoea, pancreatic fistula, ileostomy2. Renal- renal tubular acidosis typesIII and IV.

An acidosis with an increased anion gap signifies that there has been addition of exogenous or endogenous fixed acids, as in:

1. Lactic acidosis. 2. Diabetic ketoacidosis.

How is acid produced in normal metabolism?


Two forms of "acid" are produced in normal metabolism. Metabolism of carbohydrates and fats produce CO2 which is called a " volatile

acid" because it can be excreted from the lungs. The metabolism of many foods, particularly those that have a high protein

content produce "non-volatile acids" such as sulphuric, hydrochloric and phosphoric acid.

What do you understand by the term metabolic acidosis?Metabolic acidosis is the condition where the plasma PH falls below 7.35 following a decrease in the plasma HCO2

-.

What are the common causes of metabolic acidosis?1. Anaerobic metabolism secondary to poor oxygen delivery to the tissue (The

commonest cause):1) Metabolic shock (post-MI).2) Hypovolaemia (trauma, septic shock).3) In situation of increased oxygen demand (sepsis, trauma).

2. Diabetic ketoacidosis.3. Body can't get rid of acid: renal failure.4. Poisoning with acid (e.g. aspirin).5. Loss of bicarbonate (e.g. diarrhea).

What are the causes of respiratory acidosis?Any cause of hypoventillation - cardiac arrest, COPD, pneumonia, asthma.

What are the harmful effects of acidosis?1. Suboptimal enzyme action.2. Decreased myocardial contractility/arrhythmia.3. Decreased oxygen carrying ability of haemoglobin.4. Decreased response to vasopressor agents.5. Hyperkalemia and impaired potassium secretion.6. Hyperventillation and exhausion.

How would you interpret these arterial blood gases? PH 7.30, HCO3 18 mmol/L, pCO2 30mmHg.

The PH is > 7.35 so this represents an acidosis. To determine whether this is a metabolic or respiratory acidosis we must look at the PCO2 and HCO3. the PCO2 here is low, so a respiratory acidosis may be excluded. Therefore, the only other condition that this could be is a metabolic acidosis. This is also suggested by the fact that the HCO3, the lungs compensate by increasing the excretion of CO2 (thus PCO2 falls).

What are the causes of respiratory alkalosis?Increased respiration (e.g. hyperventillation, PE).What are the causes of metabolic alkalosis?Loss of H+ (e.g. vomiting).

What is an anion gap?Is a calculation used to detect an unmeasured concentration of anion (acid) in the blood.


It helps in differential diagnosis of causes of metabolic acidosis.The number of anions and cations in the blood should be equal.The main anions & cations (Na+, K+, HCO3-, Cl-) are measured when calculating the anion gap, so:{(Na+) + (K+)} – {(Cl-) + (HCO3-)} = (unmeasued anions) – (unmeasured cations)Normal range is 10-18 mmol/L because there are more unmeasures anions than cations.If the anion gap is increased, an unmeasured anion is present in the blood in increased quantities.Causes of metabolic acidosis with increased anion gap include lactic acidosis, ketoacidosis and salicylate poisoning.Causes of metabolic acidosis with normal anion gap include diarrhea and RTA.

What are the major buffering system in the human body?1. The bicarbonate system is the major buffer in the blood2. Others include the phosphate and the ammonia systems. 3. The proteins in the body also buffer changes in PH (eg. Globin chains in the

blood and cytoplasmic proteins intracellularly). These factors make up the immediate buffers.

Acutely, the respiratory system can assist in PH homeostasis by reducing the concentration of volatile acid (by blowing off carbon dioxide).

In chronic states, buffering occurs in the kidney, where filtered bicarbonate and phosphate are replaced with regenerated bicarbonate, and new bicarbonate is formed from glutamine.

Bone also buffers protons in exchange with anions from its mineral matrix and the liver can secrete new bicarbonate and ammonia, again from glutamine.

How does the kidney handle bicarbonate ion?Bicarbonate is freely filtered at the glomerulus and is reabsorbed by the renal tubular cells but these cells are actually impermeable to bicarbonate. The mechanism of bicarbonate resorption is as follows:

Cellular hydrogen ion is exchanged through an ion transport mechanism with sodium in the filtrate.

The H+ combines with HCO3- forming H2CO3, which then dissociates into CO2

and water. CO2 freely diffuses into the renal tubular cell where upon it reforms H2CO3,

catalysed by carbonic anhydrase and the sequence starts again. This works in a steady state but, if the kidney is presented with acid to excrete,

then it must generate more bicarbonate.

Explain the role of phosphate and ammonium as urinary buffers?These come into play when the kidney has to excrete a hydrogen load.

The hydrogen ion transported out of cell in exchange for sodium combines with the phosphate ion which is excreted in the urine.


The conversion of cellular water and carbon dioxide, again catalysed by carbonic anhydrous, provides the stream of hydrogen ions for excretion and generates one molecule of bicarbonate each time.

In the case of ammonium buffering, glutamine in the renal tubular cells splits into glutamate into ammonium ion, which further dissociates into ammonia and H+. this hydrogen ion is incorporated into 2-oxyglutarate formed from the continued deamination of glutamine to form glucose and the mmonia couples with the free H+ ion to be excreted as ammonium chloride.

Discuss renal tubular acidosis?Renal tubular acidosis (RTA) may be acquired or inherited and both types are rate in adults. There are four types described.

1. RTA type I: is a distal tubular defect and is often referred to as classical RTA. The luminal cells are abnormally permeable to H+ and cannot establish an ion gradient across which the normal cellular mechanisms can excrete hydrogen ion.

2. RTA type II: is a proximal tubular abnormality in which sodium bicarbonate cannot be resorbed proximally. This loss of bicarbonate leads to systemic acidosis and excretion of bicarbonate in the urine.

3. RTA type III : is a combination of I and II and is very rare indeed. 4. RTA type IV : is the condition of hyporeninaemic hypoaldosteronism and is

commonly caused by non-steroidal anti-inflammatory drugs.

Potassium

How is potassium distributed in the body?


Most potassium is intracellular. The normal serum potassium concentration is 3.5-5.0 mmol/L.

How is potassium homoestasis maintained?Extracellular potassium concentration is controlled primarily by the kidney. Filtered potassium is almost completely reabsorbed in the proximal tubules.

What are the major mechanisms involved in maintaining K+ homeostasis?K+ homeostasis is primarily maintained by the kidney. The GI tract plays a smaller role. In the kidney:

Filtered K+ is almost completely reabsorbed in the proximal tubule. Urinary K+ excretion is mainly a passive process. However, fine adjustments to K+ balance are made through active secretion in

the distal convoluted tubule. This regulation is under the aldesterone control. Aldosterone stimulates the renal tubular cells to secrete K+ (and absorb Na+

concurrently) causing reduction in plasmaK+.The amount of K+ lost in the urine depends on several factors

1. The amount sodium available for reasorption in the distal convoluted tubule.2. The availability of hydrogen and K+ ions in the cells of the distal convoluted

tubule.3. The renal tubular fluid flow rate (a decreased flow rate results in a decreased

secretion of K+ and an increase in plasma K+).Other endogenous substances have an effect on K+ levels in the body and they include:

Insulin and adrenaline which cause K+ to pass from the extracellular fluid into the cells resulting in a reduction in plasma K+, through its action on the Na/K+ ATPase pump.

ADH also has an effect on K+ levels.

How does acid-base balance affect the distribution of K+ ions? In metabolic acidosis, hydrogen ions are secreted in preference to K+, thus

there is a tendency for K+ levels to rise. In contrast, in alkalosis, fewer hydrogen ions are available for excretion, therefore more K+ is excreted.

Acid-base disturbances due to respiratory disorders have a negligible effect on K+ homoestosis.

A patient of yours has a potassium of 6.9 mmol/L. in general, what are the causes of hyperkalaemia and which are commonest in surgical patients?

1. Artefactual is the commonest cause of hyperkalaemia, caused by a haemolysed sample. Potassium is predominantly an intracellular ion and, if a sample is mishandled, cell lysis release large amounts of potassium.


2. Increase of total body potassium caused by overenthusiastic potassium therapy or failure to stop potassium treatment.

3. Redistributive cause. Severe injury (Rhabdomyolyis, Burns) particularly crush injuries release huge amounts of potassium after reperfusion, again due to cell injury. This could be classed as a.

4. A rare condition known as hyperkalaemic familial periodic paralysis is also in this category.

5. Oliguric renal failure.6. Sodium depletion and the causes thereof will tend to cause hyperkalaemia, as

potassium excretion is dependent on the amount of sodium available to exchange with.

7. Any form of glomerular dysfunction can be responsible as can any mineralocorticoid deficiency such as addison's disease or congenital adrenal hyperplasia, where 21-hydroxylase deficiency ensures no aldesterone is synthesized.

8. ACE inhibitor by reduction in aldosterone secretion, owing to interference in the rennin-angiotensin pathway.

9. Both acidosis and hypoxia impair the Na+/K+ pump and cause a net gain of ECF potassium.

10. Insulin normally enhances the passage of potassium from the ECF into the cell, but in situations of deranged glucose metabolism, such as diabetic ketoacidosis, potassium remains in the CSF space, resulting in the hyperkalaemia. If glomerular function is intact, however, urinary potassium loss continues but at an insufficient rate to correct the hyperkalaemia. There is a decrease in total body potassium but a rise in serum potassium.

What are the ECG changes of hyperkalaemia? Hyperkalaemia increases the risk of cardiac arrhythmia. Initially, there are:

High peaked T waves. Widened QRS complex. ST depression ensues followed by disappearance of the T waves.

Cardiac arrest may supervene.

How would you treat hyperkalaemia? Exogenous potassium therapy should be halted immediately. Calcium will temporarily antagonize the depressive effect of potassium on the

myocarcardium, so where the potassium is grossly raised, the emergency measure of priority is the administration of 10 ml of 10 % calcium gluconate as a cardioprotective agent.

Glucose and insulin (50g glucose and 20 units human actrapid IV) will reduce potassium levels by driving the K+ back into the cells.

A total of 40 ml 8.4 % sodium bicarbonate will also reduce hyperkalaemia. A 5-mg salbutamol nebulizer can be tried as salbutamol activities the Na+/K+

ATPase, again moving extracellular potassium into the cells. The underlying cause should be sought. If it is a chronic condition, then calcium resonium orally will bind gut

potassium and reduce absorption. If these measures fail and potassium continues to rise, then consideration

should be given to haemodialysis.


What are the causes of hypokalaemia? Diuretics. Diarrhea and vomiting. Pyloric adenoma of the rectum. Villous adenoma of the rectum. Intestinal fistulae. Cushing's syndrome. Conn's syndrome. Purgative abuse.

How do you treat hypokalaemia? If the serum potassium is < 2.5mmol/l, it needs urgent treatment, with cautious

intravenous potassium with continuous electrocardigraphy (ECG) monitoring. If the serum potassium is mild >2.5mmol/l, potassium may be given orally.

Distribution of body water

What are the different fluid compartments of the body?Total body water accounts for 50-70% of body weight. It is distributed into:

I. Intracellular fluid (3-40% of body weight).


II. Extracellular fluid (20% of body weight): Interstitial fluid (15% of body weight). Intravascular fluid (5% of body wight).

How do you determine the size of the fluid compartments?Total body water comprises approximately two-thirds of body weight. Of this:

I. Two thirds is intracellular.II. One third is extracellular:

Two-thirds is interstitial. One-third is intravascular.

However, there is a higher percentage of water in the young, thin and men, and a lower percentage in the elderly, obese and women.

What is meant by osmolarity and osmolality ?Osmolarity is a measure of concentration per litre of solution. Osmolality is a measure of concentration per kilogram of solvent. Osmolality of plasma is maintained at 280 - 305 mosmol/kg. it may be estimated by

mosmol/kg = glucose + urea + (2 x sodium) (mmol/l)

How do you intravenous fluids distribute when infused into the body?Normal saline:

It rapidly distributes across the entire extravascular compartment, which is 4 times as large as the intravascular compartment.

So of 1000 ml of normal saline, only 250 ml would remain in intravascular compartment.

5 % dextrose: It distributes across both intracellular and extracellular compartments. The

intravascular compartment represents only 5/40 this of the fluid compartments as a whole.

So only 8% or 80 ml of 5% dextrose would remain in the intravascular compartment.

What are the common causes of water excess? The infusion of 5% dextrose. Transurethral bladder irrigation with 1.5% glycin solution. Excess antidiuretic hormone (ADH) secretion. Inappropriate (lung cancer, central nervous system (CNS) disorders and

pulmonary sepsis). Appropriate (following surgery).

Sodium

Definition: plasma sodium < 135 mmol/l.

What is the distribution of sodium in the body?The adult body contains approximately 3000 mmol of sodium:


70% of which is free. 30% is complexed in bone.

The majority of free sodium is extracellular. The normal extracellular sodium concentration is 134-145 mmol/l. The normal intracellular sodium concentration is 4-10 mmol/l.

How is sodium homoeostasis maintained ?The volume of the ECF is directly proportional to the total body sodium content. ECF volume is controlled by:

Carotid sinus baroreceptors The juxtaglomerular apparatus Atrial natriuretic peptide

What are you actually measuring when you measure the serum sodium?The ration of extracellular sodium (mmol) to extracellular water(1).

How do you asses fluid status?Examine the patient, paying particular attention to:

Blood pressure (especially postural drop). Jugular venous pressure (JVP). Basal crackles (interstitial compartment). Peripheral perfusion and oedema (interstitial compartment).

Examine the charts for serial weights and fluid balance (input/output). Additional tools that may be useful include:

Chest radiograph (signs of pulmonary oedema). Central venous pressure (CVP) line (used dynamically). And/ or a swan-Ganz catheter.

Hyponatraemia

What are the causes of hyponatraemia?Hyponatraemia may be due to water excess or sodium deficit. Salt deficient may be caused by:

Large sodium losses from the gut:


Diarrhea. Vomiting. Fistula. Small bowel obstruction.

Renal salt loss in: Diuretic overuse. Osmotic diuresis in hyperglycemia. Tubulo-intersitial renal disease.

Volume overload: It is uncommon in a person with normal kidneys, but postoperative

overtransfusion of crystalloid is a common cause. It commonly presents in:

Heart failure. Hepatic cirrhosis. Nephritic syndrome. The syndrome of inappropriate anti-diuretic hormone secretion (SIADH)

occurs in conjunction with many other conditions, particularly pulmonary and central nervous system diseases.

ADH secretion may also be ectopic from malignant tumors and presents with hyponataemia with normal fluid volume.

What are the symptoms of hyponatraemia?Symptoms:

Headache. Nauses. Confusion. Coma. Convulsions (symptoms depend on the rate as well as the magnitude

of the fall in plasma sodium).

What investigations might help you?Investigations should include both a plasma and urinary sample for sodium analysis. This allow an assessment of whether the body is concentrating sodium or not. In volume overload: there is little sodium in the urine. whereas In sodium overload: There are usually normal to high amounts.

How would you treat hyponatraemia? Treat underlying cause. Correction should be gradual (otherwise, problems that may arise include

subdural haemorrhge, pontine lesions, cardiac failure); correct at a rate of 5-10 mmol/day (faster if plasma sodium < 120 mmol/l).

Salt-deficient hyponatraemia should be treated by: Oral " slow-sodium" or in patients who are vomiting by IV saline.

Volume excess hyponatraemia should be treated by: Restriction of fluid intake and review of diuretic therapy.

The clinical picture of continuing, uncorrected salt-deficient hyponatraemia, symptoms are neurological as water moves into the brain cells due to falling extracellular osmolarity. Symptoms are :

Confusion and restlessness. Followed by drowsiness, myoclonic jerks convulsions and coma.

What are the complications of correcting low plasma sodium levels?Fluid overload, secondary to excessive sodium administration which increases ECF volume and central pontine myelinosis.


What are the causes of hypernatraemia ?True sodium excess in very rare and is usually iatrogenic. Hypernatraemia can be due to:

1. Water loss in excess of sodium: Diarrhea. Vomiting. Burns.

2. Incorrect i.v. fluid replacement. 3. Diabetes insipidus (this may follow head injury) osmotic diuresis.

How do you treat hypernatraemia?1. Treat the cause. 2. Give water orally if possible. 3. Otherwise 5% dextrose or normal saline (which is hypotonic in

hypernatraemic patients to achieve normal sodium levels in 48 hours.).

Calcium

What is the normal plasma concentration of calcium?The normal range of calcium in plasma is 2.2-2.6 mmol/l (corrected for albumin concentration, as calcium is bound to albumin in blood).

What is the approximate distribution of Ca++ ions in the body? 99% bone. 0.9% intracellular.


0.1% extracellular. Approximately 40% of serum Ca++ is protein bound.

What are the functions of calcium in the body? Structural: bone and teeth. Neuromuscular: control of excitability, release of neurotransmitters, initiation

of muscle contraction. Enzymes: a co-enzyme for coagulation factors. Signaling: an intracellular second messengers.

What hormones are responsible for calcium homeostasis and can you briefly describe their actions?Parathyroid hormone increases serum calcium:

Stimulates osteclastic activity, leading to bone resorption. Increases renal phosphate secretion and decreases calcium excretion. Stimulates 1 α-hydroxylase activity in the kidney (enhances vitamin D

formation). Vitamin D3 cholecalciferol increase serum calcium and calcification of bone matrix:

To increase calcium and phosphate resorption from the gut. To increase calcium and phosphate resorption in the kidney. To enhance bone turnover. Inhibit PTH release.

Calcitonin decreases serum calcium: Inhibits bone resorption through inhibition of osteoclast activity. Stimulates excretion of calcium, phosphate, sodium and chloride in the

kidney.

How is serum calcium affected by PH?In alkalosis, hydrogen ions dissociate from albumin and calcium binding to albumin increases. There is also an increase in calcium complex formation. So, the concentration of ionized calcium falls. This is why hyperventilation causes tetany. In acidosis the opposite happens.

How is serum calcium affected by albumin?The plasma total calcium concentration must be corrected for changes in albumin concentration: For {albumin}< 40, corrected calcium= {calcium} + 0.02 x (40-{albumin})mmol/lFor {albumin}< 45, corrected calcium= {calcium} - 0.02 x ({albumin}-45) mmol/l

How does Ca++ influence the action potential? Ca+2 influences the relationship between the membrane potential and Na+ influx.

A higher extracellular Ca++ concentration stabilizes the membrane by decreasing excitability.

A lower Ca++ concentration increases the exitability of nerve and muscle cells by decreasing the amount of depolarization necessary to initiate the changes in Na+ and K+ flux that produce the action potential. Thus muscle cramps and tetany are seen.

How do you correct the serum calcium measurement and why?


As 45 % of serum calcium is albumin bound, the albumin concentration directly affects the total calcium concentration measured in plasma and variations in albumin concentration and therefore total plasma calcium may not accurately reflect the concentration of ionized calcium. It is variations in the plasma calcium ion content that give rise to symptoms, but unfortunately it is difficult to measure free calcium concentrations, so a standard correction is made to the total calcium concentration to account for variations in plasma protein.

For each gram per litre the albumin concentration is below 40, the calcium concentration is increased by 0.02 mmol/L. an identical negative adjustment is made for albumin concentrations above 40 g/L.

Outline the clinical presentation of hypercalcemia?Raised serum calcium may be the result of wide range of underlying pathologies.

1. Malignancy is the commonest cause.2. Hyperparathyroidism (primary & tertiary).

and these two causes are responsiple for more than 90 percent of all cases.3. Thyrotoxicosis.4. Addison's disease. 5. Sarcoidosis. 6. Milk-alkali syndrome. 7. Familial hypocalcuric hypercaalcemia.

Malignant neoplasms may elevated the calcium levels by direct osteolysis from secondary deposits or a primary tumor. Myeloma, for example, may mobilize skeletal calcium or may be a focus of ectopic PTH secretion, in common with other tumors, such as small cell lung cancer.

The clinical presentation is the classical student rhyme of " bones" stones, abdominal groans and psychic moan's. Bones changes range from:

Florid prepperpot skull. Subperisosteal erosions of the phalanges. and commonly present with pain.

The urinary tract: Susceptible to recurrent stone formation and the patient may display:

Polyuria. Haematuria. Hypertension from nephrocalcinosis.

Renal failure Gastrointestinal symptoms:

Abdominal pain Nauasea Vomiting Higher incidence of peptic ulceration owing to the gastrin-stimulating action

of calcium. Patients become prone to constipation and gallstone.

Psychic moan's: Psychiatric disoreders (lethargy and depression).


How might hypercalcaemia present to the surgeon? Incidental findings. Non-specific musculoskeletal symptoms. Osteoporosis. Ureteric colic. Peptic ulcer. Epigastric pain. Acute pancreatitis.

What is the treatment of hypercalcaemia?Treatment of hyprecalcaemia is an emergency, because it can cause arrthymias.

It is treated in short term by vigrous fluid resuscitation and adminstration of pamidronate, which lowers the calcium levels.

The cause should be sought and treated where possible.

What are the features of hypocalcaemia? Paraesthesia around the mouth and of the fingers. Seizures. Tenaty. Trousseau's sign (twitching of facial muscles on tapping facial nerve). Chvostek's sign (Carpopedal spasms). Malaise. Hyperreflexia. Hypotension, bradycarias, dysrhythmias and congestive cardiac failure. Prolonged QT interval.


What are the causes of hypocalcaemia? Hypoparathyroidism (primary, secondary or most commonly post-surgical). Renal failure. Vitamin D deficiency. Pseudohypoparathyoidism. Severe magnesium deficiency. Acute complexing or sequestration of calcium. Acute pancreatitis. Rhabdomylysis.

How would you mange post-parathyroidectomy hypocalcamia? Post-parathyroidectomy, mild hypocalcemia normally results. This requires

observation only, in the absence of symptoms. A nadir occurs at day 5 post-operatively.

However, in patients who have parathyroid bone disease, a profound hypocalcaemia may occur shortly after the parathyroids are removed. This may cause a profound and severe hypocalcaemia which requires several days' treatment:

If symptomatic administer 10 ml of 10% calcium gluconate. Long-term therapy is with oral calcium and activated vitamin D

(alfacacidol). The serum calcium should not exceed 2.30 mmol/l because of an increased risk of nephrolithiasis.

How would you treat acute severe hypercalcemia?Hypercalcaemia has an enormous range of consequences, including renal tubular damage, peptic ulceration, hypertension, cardiac arrythmias and bone pain. As an acute severe event:

Volume repletion is the mainstay of therapy, as patients are usually markedly dehydrated.

Frusemide will help to increase renal clearance. Biphosphonate infusion binds hydroxyapatite in bone and decreases bone

turnover. After which attention must be turned to identifying the cause of the

hypercalceamia.

How is vitamin D formed and what are its metabolites?There are two sources of vitamin D:

Produced in the skin by UV light (vitaminD3). Ingested in the diet (vitamin D2).

Both D2 and D3 have identical biological actions and so both forms are known as vitamin D. The active metabolites of vitamin D are produced by the 25-hydroxylation step in the liver (forming 25 hydroxy cholecalciferol) and 1α hydroxylation in the kidney (forming 1,25 DHCC or 1,25 dihydroxycholecalciferol). The 1,25 DHCC is the most active metabolite of vitamin D and is almost entirely responsible for the actions of vitamin D.


What is the role of vitamin D?Vitamin D acts on The intestine to increase Ca++ and phosphate absorption and skeletal mineralization.Bone, stimulating osteoclastic resorption. Kidney increases calcium and phosphate resorption.Hence, vitamin D deficiency results in the formation of unmineralised osteoid.

In children, this will affect the bony growth plates resulting in bowing of the extremities and collapse of the chest wall (rickets).

In adults, bone pain, vertebral collapse and stress fractures will ensue (osteomalacia).

What are the possible causes of vitamin D deficiency? Insufficient sunlight exposure to the skin of individuals who have a diet poor

in vitamin D. Liver disease ( affects the 25 hydroxylation step) Renal failure (affects the 1 α hydroxylation step and hence production of the

most active metabolite 1,25 DHCC).

Classify hyperparathyroidism?Hyperparathyroidism represents an increase in the concentration of circulating parathyroid hormone, and it may be calssified as primary, secondary or tertiary. Primary hyperparathyroidism :

It occurs with excess PTH production, so PTH and serum calcium are both elevated.

1. 80 % of cases are due to a single adenomatous gland.2. 15 % of cases are due to generalized parathyroid hyperplasia.3. 5 %. of cases are due to multiple adenomata. 4. Parathyroid carcinoma may also the cause of primarily elevated PTH

but with an incidence of loss than 1 in 100 cases. Secondary hyperparathyroidism :

It occurs when there is excess calcium loss, usually in renal failure. Calcium is normal or low, but PTH is raised in an attempt to increase calcium mobilization.

Tertiary hyperparathyroidism :It occurs in patients who have had their cause of secondary hyperparathyroidism treated, typically individuals whose renal failure was treated by transplantation. Although the stimulus has been removed, the parathyroids remain hyperplastic and secrete excess PTH, i.e. autonomously; both PTH and calcium are elevated.

Hyperparathyroidism may occur as part of the multiple endocrine neoplasia syndromes and as such may be familial with an autosomal dominant inheritance. Both parathyroid hyperplasia and adenoma are included in the disease, which is common to MEN types I and II.


Magnesium

What is the distribution of magnesium in the body?The adult body contains approximately 1000 mmol/l:

Half of which is in bone. One quarter in muscle. One quarter in other soft tissues.

Only 15-29 mmol is found in the ECF. The plasma concentration is 0.8-1.2 mmol/l

What are the physiological roles of magnesium?1. Magnesium acts an essential cofactor for some 300 enzymes, involved in

protein synthesis, glycolysis and transmembrane ion transport.


2. A magnesium-adenosine triphosphate (ATP) complex is the substrate for many enzymes requiring ATP.

3. Magnesium is important in the maintenance of the structures of ribosomes, nucleic acids and some proteins.

4. Magnesium, by its interactios with calcium, affects the permeability of excitable membranes and their electrical properties.

When might you measure serum magnesium? Severe or intractable diarrhea and/or malabsorption (e.g. short bowel

syndrome and inflammatory bowel disease). Life-threatening alcohol withdrawal. Refractory cardiac dysrhthmias (especially ventricular). Hypocalcaemia and tetany unresponsive to calcium. Refractory hypokalamia . Neuromuscular symptoms after cisplatin or mannitol. Renal failure. During parentral nutrition.

What are the causes of hypermagnesaemia? Hypermagnesaemia is uncommon. At concentration of:

2.5-5.0 mmol/l: Cardiac conduction is affected. Very high concentration (> 7.5 mmol/l) cause respiratory paralysis and cardiac

arrest. Hypermaneseamia may be ssen in renal failure.

What are the causes of hypomagnesaemia?1. Malabsorption, malnutrition and

fistulae. 2. Alcoholism.

3. Diuretic therapy (especially loop diuretics).

4. Cirrhosis.

5. Renal tubular disorders. 6. Chronic mineralocorticoid excess.

How do you treat hypomagnesaemia ? Mild magnesium deficiency is treated with oral supplementation. In severe deficiency and with malabsorption, magnesium may be given by

slow intravenous infusion.

How do you treat hypermagnesaemia ?Intravenous calcium may give short-term protection against hypermagnesaemia. In renal failure, dialysis may be necessary.


Endocrine Physiology

Thyroid gland

Briefly describe the synthesis of tri-iodothyronine (T3) and thyroxine (T4).Iodide in the blood is taken up by the iodide pump present in thyroid follicular epithelial cells. The iodide is oxidized by thyroidal peroxidase and is transported within the cell. Here, the newly formed iodine is linked to tyrosine residues in the protein thyroglobulin.


It is then secreted into the colloid at the centre of each follicle (a thyroid follicle is colloid surrounded by thyroid follicular cells). At the junction of the follicular cells and the lumen further action by peroxidase converts the tyrosine residues to mono-iodotyrosine (MIT) and di-iodotyrosine (DIT). MIT then couples with DIT to form T3 and DIT coupled to DIT to form T4. Thyroglobulin is stored within the colloid until the gland is stimulated to secrete thyroid hormone. The stores typically last for 2 months. When thyroid hormones are required, thyroglobulin is redirected into the follicular cell by pinocytosis. Proteases act on thyrpglobulin to produce T3 and T4, which are then released into the circulation. Thyroid-stimulating hormone (TSH) stimulates each step in the synthesis of T3 and T4. the remaining MIT and DIT is deiodinated by thyroid deiodinase. The I 2 released is recycled to synthesis more thyroid hormones.

How are T3 and T4 transported in the blood stream? In the bloodstream T3 and T4 are bound predominately to thyroxine binding globulin (TBG) but also to albumin and thyroid binding prealbumin. More T4 is produced than T3 and in the peripheral tissue T4 converted to T3 by 5-iodinase.

Which is more biologically active, T3 or T4?T3 is at least 4 times as potent as T4. however, T3 has a much shorter half-approximately 1 day compared with 1 week for T4.

How is thyroid hormone secretion controlled?TSH has a direct positive effect on thyroid hormone production. TSH is secreted from the anterior pituitary and is itself regulated by thyroid releasing hormonr (TRH) secreted by the hypothalamus. TRH is produced in response to low circulating thyroid hormone concentration and a fall in external temperature. The hypothalamus pituitary thyroid axis works by negative feedback, i.e. thyroid hormone production inhibits TRH secretion from the hypothalamus and TSH secretion from the anterior pituitary. The thyroid gland itself shows some ability to autoregulate depending on the iodine supply. High iodine circulating levels are inhibitory to thyroid hormone production. Deficiency states in endemic regions are associated with goiter as the glands infrastructure swells in an attempt to produce thyroid hormone.

What are the effect of thyroid hormones in the body ?Thyroid hormones are steroid hormones and work by increasing DNA transcription in cells with a resultant increase in new mRNA. The new mRNA is translated into the production of new specific proteins that have physiological actions. These effects are widespread in the human body and can be summarized as follows;

Central nervous system (CNS) maturation : This is totally dependent on thyroid hormone production in the perinatal

period.


Lack of hormone or deficiency can result in mental retardation and cretinism and as result hypothyroidism is screened for in the neonatal period.

Growth and skeletal maturation : Thyroid and growth hormones act synergistically to promote bone

formation and maturation. Regulation of basal metabolic rate (BMR) and temperature regulation :

Thyroid hormones cause increased oxygen consumption by mitochondria with a subsequent increase in (ATP) formation in most organs of the production indirectly and therefore explains why thyrotoxic patients complain of heat intolerance.

Thyroid hormones influence (BMR) directly i.e. patients with hypothyroidism have a low BMR and vice versa.

Metabolic effect : There is a net increase in protein breakdown and hence thyroid hormones

are catabolic. There is an increase in fat mobilization and degradation. Glucose absorption is promoted from the gastrointestinal tract and there is

an increase in glycogenolysis and gluconeogenesis. Sympathomimetic :

Many effects of thyroid hormone are analogous to B adrenegenic stimulation. This explains how thyrotoxic patients can get some symptomatic relief with B blockers.

Other effects : Thyroid hormones cause an increase in stroke volume and heart rate. Since

these two parameters have an effect on cardiac output, this too increases. This is combination with increased ventilation, another effect of thyroid hormones, promotes increased oxygen delivery to tissues.

Thyroid hormones also play a role in regulation of gut motility and skin/ hair development.

What is the pathophysiology of Graves' disease?Graves' disease is an autoimmune condition in which high circulating levels of thyroid-stimulating immunoglobulins or long acting thyroid stimulators (LATS) are present.These antibodies are directed at the TSH receptors and are stimulatory. As a result thyroid hormone levels in these patients are raised. They present with generalized hyperthyroid syndrome, symptoms specific to Graves' (exopthalmos, acropachy and pretibial myxoedema) or a combination of both. TSH levels are low due to the negative feedback mechanism.

Parathyroid gland

What actions does parathyroid hormone (PTH) have?PTH is secreted in response to a reduced sereum calcium.

It promotes resorption of bone. reasorption of calcium in the distal convoluted tubule of the kidney. increases production of 1,25-dihydroxy-holecalciferol.

All these processes act to increase the serum calcium.


Increased 1,25-dihydroxycholecalciferol production in the kidney has a direct effect on increasing intestinal absorption of calcium.The bone resorption effect promotes an increase in both phosphate and calcium in the extracellular fluid. Normally:

40% of calcium is bound to plasma proteins. 60% is filtered by the kidney.

The filtered load is either bound to anions or is free ionized calcium. PTH helps to increase free uncomplexed calcium, which is the biologically active form. What are the causes of primary hyperparathyroidism?

Parathyroid adenoma (85%). Parathyroid hyperplasia (14%). Parathyroid carcinoma (1%).

What is the net biochemical changes in primary hyperparathyroidism?1ry hyperparathyroidism leads to a raised serum calcium, PTH level and a decreased serum phosphate.

What are the signs and symptoms of 1ry hyperparathyroidism?Although some patients may be asymptomatic, many will show the effects of hypercalcaemia:

Weakness, fatigue, nausea and vomiting. Polyuria, polydepsia and dehydration. Renal calculi. Abdominal pain, peptic ulcer disease, pancreatitis & constipation. Cardiac dysrrhythmias. Renal impairment. Corneal & vascular deposits. Psychiatric illness (depression). Bony conditions: skeletal pain, fractures, subperosteal erosions especially of

phalanges and cystic fibrosis.

How can 1ry hyperparathyroidism be treated?Treatment can involve surgical exploration with removal of the offending gland in cases of adenoma or carcinoma.With hyperplastic glands, 3.5 out of 4 are removed in order for symptomatic control.In asymptomatic disease the debate still continues whether surgery be undertaken as long-term sequelae are still possible.

How does renal failure cause 2ry hyperparathyroidism and what serum biochemival will enuse?In renal failure glomerular filteration is reduced and phosphate excretion is hampered.As a result more phosphate is available to bing to calcium & thus the free or ionized calcium pool is reduced & patients tend to become hypocalcaemic.There is active vitmain D formation which also prevents intestinal absorption of calcium confounding the problem.


The body's response to this is to try & incease serum calcium. It achieves this by increasing parathyroid hormone and eventually this leads to secondary hyperparathyroidism (i.e. an increase in PTH in response to low serum calcium).The increased bone resorption in combination with reduced intestinal absorption eventually leads to osteomalacia and produces the apt named renal osteodystrophy seen in these patients.The biochemical will include a raised parathyroid hormone level and phosphate level with a decreased serum calcium level.

What are the causes of hypoparathyoidism and what biochemical changes would occur in primary disease?

Neck surgery (e.g. thyroid surgery). Congenital conditions (e.g. Albrights hereditary osteodystrophy). Primary hypoparathyroidism causes a low PTH, with a low serum calcium and

a raised serum phosphate.

Pitriotary gland

Describe the functional anatomy of the pituitary gland?Although named as one gland, functionally and embryologically it is two.

1. The anterior pituitary (Adenohypophysis): It is derived from Rathke's pouch, an outgrowth of pharyngeal epithelium.


It is connected to the hypothalamus via the pituitary portal system of blood vessels though which the hypothalamic releasing and inhibitory factors arrive at the anterior pituitary.

2. The posterior pituitary (Neurohypophysis): It is a downward projection of the hypothalamus. It is in direct neural connection with the hypothalamus above; indeed, the

cell bodies of the neural cells of the neurohypothysis reside in the hypothalamus ans the hormones are transported to the posterior pituitary down the axons.

What hormones are secreted from the pituitary?The anterior gland secrets:

1. Growth hormone (GH).2. Adrenocorticotrophic hormone (ACTH).3. Thyroid stimulating hormone (TSH).4. Prolactin.5. Follicle-stimulating hormone (FSH).6. Leutinizing hormone (LH).

The posterior pituitary secrets:1. Antidiuretic hormone.2. Oxytocine.

What is portal circulation?It is a circulation that connects 2 capillary beds but doesn,t receive a direct arterial supply nor drain into a venous system.The 2 of significance are the hypothalamic-hypophyseal & hepatic portal systems.

What is an acidophil adenoma and what are the endocrine consequences?Cells of the anterior pituitary are often classified according to their staining characteristics:

1. Acidophil: s the cells that secret growth hormone and prolactine. 2. Basophils: the cells secreting TSH, FSH, LH & ACTH.3. Chromophobes: The cells with neutral sstaining characteristic.

An acidophil adenoma is therefore, a tumour of the acidophil cells.The excess of GH and sometimes prolcactin which will give rise to:

o Gigantism, if present before epiphuseal fusion, oro Acromegaly after fusion.

Uncontrolled growth of an acidophil adenoma will also compress the rest of the gland and thus the patient may also suffer from hyposecretion of the basophil hormones.

What problems may result from an enlarging non-secretory pituitary tumour?An enlarging tumour can compress normal functioning glandular tisssue causing hyposecretion and a large non-secretory tumour may give rise to panhypopituitarism with a complete absence of all anterior pituitary hormones.


Owing to its anatomical location in sella tursica, enlargement by tumour can cause pressure on the optic chiasm above leading to visual defects, such as a bitemporal hemianopia and ultimately blindness. Lateral extension can cause compression syndrome on those cranial nerves running through the cavernous sinuses.Tumours that have grown to enormous proportion may obstruct the 3rd ventricle or produce through the sphenoid sinuses as a pseudo-nasal polyp.

What are the clinical manifestation of prolactinoma?The clinical manifestations typically depends on whether the tumour is a micro (< 10mm in diameter) or macro adenoma (> 10 mm in diameter).The clinical manifestations of a micro-prolactinoma are those of hyperprolactinaemia:

Galactorrhea. Menstrual irregularities in females/ Infertility in females. Impotence in males.

A macroadenoma usually presents with a mass effect, as it is usually non-secreting. It would therefore cause:

Headache. Paralysis of the extra-ocular muscles. Visual field abnormalities (bitemporal hemianopia). Anterior pituitary failure (secondary to compression).

What is the medical treatment for hypeprolcatinaemia?In the normal individual, dopamine is secreted from the hypothalamus and inhibit prolactin secretion from the anterior pituitary.Bromocriptine, a dopamine agonist can therefore be used to inhibit prolactin secretion from the anterior pituitary.Bromocriptine is also used to reduce the size of macroadenoma prior to surgery.

What is Sheehan's syndrome, and how does it present?Sheehan's syndrome is pituitary infarction following a postpartum haemorrhage.Symptoms are :

Those of panhypopiruitarism. Loss of libido. Amenorrahea. Galactorrhea. Secondary hypothyrpodsim & adrenal suppression lead to tiredness, mental

slowing & mild hypotension.The classic hypopituitary patient will be pale and hairless – the "alabaster skin" appearance.

Anterior pituitaryHormone Site of action Action Controlling

influencepathologies

Growth hormone

Liver.Peripheral

Hyperglycaemia.Secretion of IGF-1

GHRH is excitatory.

Acromegally (epiphyses


tissue which stimulates growth of unfused bone.Several anabolic, metabolic functions.

Somatostatin is inhibitory.

fused)Gigantism.Dwarfism.

TSH Thyroid gland

Promotes secretion of T4 & T3 and increases their synthesis.

TRH.T3 & T4 feed back –ve on the pituitary.

Hyper- and hypothyroidism.

PRL Breast Promotes breast development & milk production.

Dopamine has an inhibitory effect

Prolactinoma.

ACTH Adrenal cortex

Promotes secretion of cortisol.

CRH (corticotrophin-releasing hormone).-ve feedback by cortisol.

Cushing's disease, Addison's sisease.

FSH & LH Gonads Promotes secretion of estrogen & progesterone in female, in a cyclical fashion (menstrual cycle) and testosterone in the male.

GnRH.Complex feedback mechanisms by their target hormones.

Posterior pituitaryHormone Site of

acionAction Controlling

influencepathology

Vasopressin (ADH)

Controlling duct of the nephron

Water retension Its release is increased by increased tonicity of blood.

SIADH, D.I.

Oxytoxin UterusCollecting duct of the nephron.Smooth muscle cells in breast

Initiation of parturition/stretch receptors in uterine contractionMilk secretion.Water retension.

UterusNeural inputs from sucking child (breast) Milk ejection reflex.

Adrenal Gland & Addison disease

What imprtant hormones are secreted from the different layers of the adrenal gland?The adrenal cortex: has 3 distinct zones:


1. Zona glomerulosa: secrets aldosterone.2. Zona fasculata: secrets glucocorticoids (e.g. cortisol).3. Zona reticularis: secrets sex hormones (e.g. testosterone & oestrogen).

The adrenal medulla secrets catecholamines such as adrenaline and noreadrenaline.

What are the actions of costisol?Cortisol is a catabolic hormone and is essential in the body's response to stress.Its actions are as follows:

I. Anti-inflammatory:It induces synthesis of lipocortin which acts on the arachidoonic metabolite pathway inhibiting the enzyme phospholipase A2. This enzymes liberates arachidonic acid from free phospholipids and goes on to produce the mediators of pain and inflammation (leucotrienes, prostagglandins & thromboxanes). In addition, it inhibits proliferation of T lymphocytes, prevents the production of interleukin-2 and prevents mast cells and platelets causing histamine and serotonine sensitivity.

II. Promotes protein catabolism & lipolysis:This makes more amino acids and gltcerol are avaialabe in the liver for gluconeogenesis.

III. Reduction in insulin sensitivity.IV. Enhances the effect of catecholamines on the peripheral vasculature:

Noreadrenaline causes vasoconstriction in the peripheral vasculature and this effect is potentiated by cortisol.In addison's disease, where there is a distinct lack of cortisol, the peripheral effect of noreadrenaline is diminished and patients therefore tend to develop postural hypotension.

How is glucocorticoid secretion regulated?Cortisol level vary during a normal day, being highest in the morning.Cortisol secretion is dependent on stimulation of the adrenal cortex by ACTH.ACTH is secreted from the anterior pituitary in response to corticotrophin releasing hormone which is secreted from the hypothalamus.The system lke other hypothalamo-pituitary-end organ axis is governed by negative feedback such that raised cortisol levels will cause a suppression the amount of CTRH & ACTH released from the hypothalamus and anterior pituitary repectively.

What are the actions of aldosterone?o Increases Na+ reabsorption in the distal convoluted tubule and collecting

system of the kidney.o Increases K+ secretion in the distal convoluted tubules and collecting system

of the kidney.o Promotes secretion of H+ ions (acid) from the kidney.

How does aldosterone contribute to the homeostasis of the extracellular fluid compartment in the hypovolaemic states?A reduction in tissue perfusion of the kidneys secondary to a reduction in blood volume stimulates the renin-angiotensin system.


As a result a surge in renin production occurs which causes angiotensinogen to be converted to angiotensin I. This is then converted to angiotensin II by the action of angiotensin cenzyme.Angiotensin II is a potent vasoconstrictor (helping to maintain mean arterial pressure) and also acts on the zona glomerulosa of the adrenal cortex to stimulate secretion of aldosterone.Aldosterone promotes Na+ reabsorption in the kidney. Along with this shift comes a shift in water thereby restoring the ECF volume towards normal.

What is addison's disease?Addison's disease or primary adrenocortical insuffieciency is usually due to bilateral destruction of the adrenal cortex.Causes:

Autoimmune disease, which is the commenst. Tuberculosis. Adrenal adenoma/carcinoma. Sudden withdrawal of steroids. Haemochromatosis. Amyloidosis. Sarcoidosis. Fungal: balstomycosis. Iatrogenic: surgical removal in the treatment of Cushing's syndrome. Waterhouse-Fredreichson syndrome: meningococcal septicaemia can cause

adrenocortical infarction.As a result the adrenal gland is unable to produce the mineralocorticoid, aldosterone, glucocorticoids such as cortisol or sex hormones.Treatment is with mineralocorticoid and glucocorticoid replacement. Despite this patients tend to develop adrenal crises when the body undergoes furtheer stresses such as surgery, infection & immunosuppression.

What are the clinical features of Addison's disease?o General : nausea, vomiting, weight loss, anorexia, malaise & weakness.o ACTH related : in producing high circulating level of ACTH, melanocyte-

stimulating hormone (MSH) levels are also increased leading to hyperpigmentation which tends to manifest in the peripheral region.

o Aldosterone related : postural hypotension (Secondary to a reduction in ECF volume), hyperkalemia, metabolic acidosis (aldosterone promotes acid secretion and therfore conversely leads to acidosis in aldosterone deficient states).

o Hyponatraemia .o Cortisol related : hypoglycemia, losss of cortisol induced peripheral

vasoconstrictor effect with noreadrenaline (contribting to postural hypotension).

o Sex hormone related : reduced pubic & axillary hair in women.

Describe an addisonian crisis and its treatment?An acute presentation may be precipitated by:

Any intercurrent infection. Situation requiring the body to mount a stress response.


Acute withdrawal of the patient's normal corticoid supplements will also precipitate a crisis.

The primary features are: Massive hypovolaemia. Shock. Headache. Nausea & vomiting. Weakness. Abdominal pain. Confusion & coma. There is usually marked hypotension.

Biochemical analysis demonstrates: A profound hponataremia which may be as low as 115 mmol/L, hyperkalemia

& hypoglycaemia. There is often hyperglycaemia in addition.

Treatment:The resultant depletion of the intracellular and extracellular compartment may require enormous volumes of fluid.The major deficiencies of salt, steroid & glucose are addressed.Provided there is no cardiovascular disease, 1L of saline is given over 30-60 minutes.If hypoglycaemia, dextrose is infused concurrently.Subsequent fluid requiremrents may be high & a central line should be considered for monitoring.Hydrocortisone 100 mg I.V. is given 6 hourly until the patient is stable.Fludrocortisone isn't needed in the acute setting.

How is the diagnosis confirmed and what is the long-term treatment?The biochemical abnormalities should strongly suggest the diagnosis and further investigation used to confirm this.A short synacthen test should prove the clinical suspension.

A standard dose of synacthen is given parenterally and plasma cortisol measured at adminstration and between 30 & 60 minutes later. A normal subject will demonstrate a rise in plasma cortisol, which is absent in the addisonian patient.

It is important to prohibit hydrocortisone adminstration for 8 hours prior to the test, as this leads to erroneous results.

Long-term mangment:o The cause should be treated, if possible, such as tuberculosis or blastomycosis.o Treatment is by replacement therapy, typically fludrocortisone and

hydrocortisone.o The dose of glucocorticoid is judged on patient well-being and cortisol levels.o Mineralocorticoid dose is assessed by blood pressure response to standing i.e.

it shouldn't fall and suppression of plasma renin to normal activity.Patients should be educated to increase their hydrocortisone when ill to mimic a "stres response".

What is secondary hypoadrenalism?This is adrenal hypofunction due to non-adrenal causes.It occurs in:

Hypothalamic-pituitary disease.


Long term steroid use when hypothalamic-pituitary-adrenal suppression occurs.

It is rested for by long synacthen test with a higher dose of synacthen, and blood test at 0,1,2,3,4,5,8 & 24 hours.

Cushing's disease & Cushing's syndrome

What is the difference between Cushing's disease and Cushing's syndrome?


Cushing's syndrome: is any clinical condition resulting from excessive inapproprtiate exposure to glucorticoid.Cushing's disease: is where excess glucocorticoid results from a pituitary tumour.

What are the causes of Cushing's syndrome?1. Iatrogenic (the commenst) – patients on long term exogenous steroids for

immune suppression or treatment of diseases such as brittle asthma.2. Increased autonomous secretion of ACTH from a pituitary microadenoma

drives the adrenals into bilateral hyperplasia and hypercortisim with increased androgen secretion as well – this is cushing's disease.

3. A variety of extra-adrenal tumours produce ACTH-like substances, such as bronchogenic tumours and small carcinoid neoplasms; this gives the ectopic ACTH syndrome.

4. A primary adrenal tumour either adenomatous or carcinomatous, may produce excess cortisol directly with normal or usually low ACTH.

What are the typical manifestations and causes of hypercorticism?The clinical picture of hypercortisolism, commonly referred as Cushing's syndrome, is one of the most striking of all the endocrine diseases.

o Glucocorticoid action stimulates appetite and gluconeogensis resulting in obesity and fat deposition in particular sites, creating buffalo hump, moon face and central obesity.

o In association with muscle wasting owing to toxic effect of cortisol on muscle, the classical appearance of "a lemon on toothpick" occurs.

o Decrease in collagen synthesis give rise to thin skin, which bruises easily, heals poorly & stretches causing striase.

o Diabetes melliteus enuses owing to the glucocorticoid action.o The mineralocorticoid effect of cortisol causes marked salt & water retention

giving rise to hypertension.o Increased adrenal androgen secretion, if there is increased ACTH, accounts

for the acne and hirtism often seen.o If there is often marked osteoporesis and pathological fractures.

How would you diagnose Cushing's syndrome? Taking history and examination, bearing in mind that none of the above

clinical findings are diagnostic of Cushing's syndrome.


A methodical approach to the diagnosis is needed and initially confirm the diagnosis of hypercortisolism before attemping identification of the cause.

I. At first: serial plasma cortisol estimation looking for: Persistently raised levels. and Loss of diurnal variation as cortisol levels are highest at about 9 am

and lowest around midnight.

II. Then: an overnight dexamethasone suppression test by adminstering 1 mg dexamethasone at midnight and measuring the morning cortisol level.Failure to suppress cortisol levels to less than 50% of basal values points towards a diagnosis of Cushing's syndrome.

III. A high-dose dexamethasone suppression test (2mg 6 hourly for 48 hours): 2 mg of dexamethasone is given 6 hourly for 48 hours. Plasma corisol is measured at 09:00 on the morning following the last dose.It will suppress ACTH secretion in pituitary Cuching's, resulting in a decrease of at least 50% in plasma cortisol or urinary 17-hdroxy sterids.

If this test proves positive then arrange a cranial MRI to examine the pituitary fossa.

If the test was negative, suggests ectopic ACTHproduction or an adrenal tumour. Then assay plasma ACTH level.

Very high levels are consistent with ectopic ACTH secreting tumours.

Low plasma ACTH points to a primary cortisol secreting adrenal tumours.

Having differentiated between the two, CT or MRI scanning should be undertaken to image the lesion responsible.

What is nelson's syndrome and explain its pathogenesis?It is the combination of hyperpigmentation following bilateral adrenalectomy.In pituitary-dependent hypercortisolism treated by bilateral adrenalectomy, up to 30% of patients develop unrestrained growth of the pituitary tumomurs with enlargement of the sella tursica and very high levels of plasma ACTH. Residues 1-13 of the ACTH precursor molecules correspond exactly to α-melanocyte-stimulating hormone (α-MSH) and account for the skin pigmentation that is the striking feature of Nelson's syndrome.The syndrome may develop acutely but is more commonly a chronic event with the meantime from adrenalectomy to onset being 3 years.Bilateral adrenalectomy is less commonly performed these days, but anyone who has been treated in this way should be followed up regularly with cranial CT or MRI to look for an expanding sella tursica lesion.

Pheochromocytoma

Describe the synthesis and metabolism of catecholamine?


Catecholamines are synthesized by chromaffin cells of the adrenal medulla and sympathetic nervous tissue; both are derived from embryonic neural crest.Adrenaline is predominantly produced in the adrenal medulla and noreadrenaline in the sympathetic tissue.The pathway begins by hydroxylation of tyrosine to dihyroxyphenylalanine (DOPA) follwed by decarboxylation to dopamine.This is further hydroxylated to noreadrenaline and tjen methylated to adrenaline.They are metabolized in the liver by further methylation and then deamination into vanilyl mandelic acid (VMA), which is excreted in the urine.Urinary VMA & metanephrines may be measured.

How might an excess of catecholamines present clinically?Catecholamines excess, as in pheochromocytoma, presents with hypertension as the commenst symptom, which in 50% of patients.Other symptoms include:

Sweating & flushing. Hyperglycemia.

Pheochromocytoma is known as 10% tumour because: 10% of all tumours are extra-adrenal. 10% are bilateral. 10% are malignant. 10% are familial. 10% occur in children.

How is the diagnosis confirmatory?The presence of excess circulating catecholamines is confirmed by:

Raised urinary VMA & metanephrines (adrenaline, noradrenaline & dopamine) in a 24-hour urine collection.

After the diagnosis is established:The tumour must be localized by MRI scanning better than CT bacause:

Functioning & non-functioning adrenal tumours have different characteristics on MRI, unlike CT.

The need for contrst which may trigger a hypertensive crisis is avoided in MRI scanning.

If the tumour isn't localized by MRI, then MIBG (123I-metaiodobenzyllguanidine) scanning is both sensitive & spicific.

What consideration need to be taken into account before embarking on surgery in these instances?Operating for phaeochromocytoma isn't for the occasional surgeon or faint-hearted anaesthetist.Inadverent handling of the tumour can stimulate an enormous outpouring of catecholamines; even induction of anaesthesia in the unprepared patient can have the same effect. The patient must be fully α & β blocked before surgery.

The long-acting α blocker phenoxybenzamine is used along with a β blocker such as propranolol.The timing of β blockade isn't critical, but the α blockade requires careful optimization.


The patient is started on phenoxybenzamine 7-10 days before surgery, and the dose increased until hypertension is controlled and the patient develops orthostatic hypotension.

The surgery iteself is now routinely performed laparoscopically for tumours less than 6 cm. The approach is most commonly transabdominal but smaller tumours can be removed endoscopically by a posterior retroperitoneal approach. After removal of the tumour, the patien't venous tone may disappear altogether, causing a massive relative hypovolaemia. Thus the anaesthetic should be warned when removal of the tumour is imminent in order to maximize the circulating volume.

Might it be associated with other conditions?10% are familial, associated with MEN syndrome type II (Sipple's syndrome):The other components of MEN II are:

Hyperparathyroidism which may eb due to either parathyroid adenoma or hyperplasia.

Thyroid medullary carcinoma. The condition is autosomal dominant with the genetic defect located on chromosome 10. Afurther variant MEN IIb encompasses:

Same abnormalities, + Mucosal neuromatosis. Marfanoid habitu. Muscloskeletal abnormalities.

What is the prognosis for patients with malignant pheochromocytoma?Overall 10% of pheochromocytoma are malignant, but 50 % of all extra-adrenal pheochromocytoma are malignant.

MIBG scanning is useful to assess metastatic spread.Surgery is the mainstay of treatment as the tumours are unresponsive to chemotherapy, rediotherapy to bony metastases will provide local palliation.The 5-year survival is around 40%.

Pancrease

How much pancreatic fluid is secreted each day?Pancreatic fluid is secreted 1500 ml/day.


What do pancreatic secretions contain?Water, electrolytes (cations: Na+, K+, Ca2+ & Mg2+. Anions HCO3

-, Cl-,SO42-. PH

around 8) and enzymes.

What is the exocrine function of pancrease?It is to produce digestivenzymes, fluids & electrolytes to modify & optimise the PH environment.

What enzymes does the pancrease synthesize?It synthesizes 3 main groups of enzymes:

A proteolytic group which includes trypsinogen, procarboxypeptidases and proelastase.

The starch and polysaccharide enzymes (amylase). A lipolytic enzyme group consisting of lipase and phospholipase.

What are their function? The proteolytic enzymes of which trypsinigen is the most important, activate other

proteolytic enzyme precursors though an autocatalytic process. Pancreatic amylase hydrolyses starch, glycogen and other carbohydrates. Pancreatice lipases: it is regulated by 2 mechanisms neural and hormonal.

1. Neural control: It occurs during the cephalic phase and gastric phases of digestion.The pancrease is stimulated by impulses along the vagus nerve to pancreatic enzymes.It causes release of pancreatic secretions high in enzyme content.

2. Hormonal regulation:It is the most important mechanism. It is mediated by hormones released from the mucosa when chyme enters the duodenum: Secretin:

It is produced by endocrine cells in the duodenum and jejunum.It is released when acid enters the duodenum.This causes the pancreatic ducts to secrete large amounts of fluid with a high bicarbonate content (& low enzyme content).The bicarbonate neutralises the acid and creates the necessary luminal PH for activity of pancreatic enzymes.

Cholecystokinin :It is produced by endocrine cells in the duodenum & jejunum.It is released when food, particularly fatty acids, enters the duodenum. It stimulates secretion of pancreatic juice (high in enzyme content).

Acetylcholine : acts on acinar cells. Somatostatin :

It is released from pancreatic islet D cells.It inhibits pancreatic secretions.

What are the endocrine functions of the pancrease?The following hormones are secreted by the islets of Langerhans:Insulin:

It is produced by the β cells. It facilitates glucose uptake to muscle, glyogen and fat synthesis in the liver.


It also inhibits glycogen breakdown.Glucagon:

It is produced by the α cells. It stimulates glycogenolysis and glyconeogenesis in the liver.

Somatostatin: It is released from pancreatic islet D cells. It inhibits insulin and glucagon release. It also inhibit pancreatic & gastric secretions.

Pancreatic polypeptide: It has a role in gastrointestinal function.

What would the effects of subtotal pancreatectomy be?Removal of all or almost all of the pancreas will lead to a varying degree of malabsorption of fat.This will result in:

o Failure to absorb fat-soluble vitamins such as A, D, E & K and if not supplemented, may result in deficiency.

o Protein malnutrition may enuse and without proper glucose control pateints may develop gleucose intolerance and diabetes.

Acute pancreatitis

What is pancreatitis ?Acute pancreatitis : acute inflammation of the pancreas is a common cause of acute abdominal pain with considereable associated morbidity and mortality.


It can be divided into mild, moderate and severe, depending on presentation.

What are the possible causes of pancreatitis ?A mnemonic to remember the causes of pancreatitis is GETSMASHED: G: gallstones (probably the most common cause, impacted at the ampulla of

Vater and causig backwash of activated pancreatic enzymatic juice into the parenchyma of the pancreas, leading to pancreatic autolysis and haemorrhage).

E: ethanol (alcohol is a very common cause of pancreatitis and people with alcohol problems often develop chronic pancreatitis after number of bouts acutely).

T : trauma. S :steroids. M: mumps (paramyxoviruses). A: autoimmune ( panartetitis nodosa or PAN, systemic lupus erythematosus

or SLE). S: scorpion sting /snake bite. H: hypercalcaemia, hyperlipidaemia/ hypertriglyceridaemia and hypothermia. E: ERCP (endoscopic retrograde cholangiopancreatography). D: drugs (e.g. sulphonamides, furesemide, azathioprine, NSAIDs).

Less common causes: Carcinoma of the head of the pancreas. Pancreas divisum. Long common bile duct. Fat necrosis. Pregnancy. Pancreatic ischaemia as a result of bypass surgery.

What are the clinical features of pancreatitis ? Acute severe abdominal pain, usually constant, epigastric and radiating into

the back, and relieved by sitting forwards. Vomiting is early and profuse. Patient usually shocked with rapid pulse, cyanosis. Abnormal temperature: either subnormal or pyrexial. Examination of the abdomen reveals generalized tenderness and usually

garding with or without rebound tenderness. 30 % of cases have mild jaundice as a result of oedema of the pancreatic head

obstructing the common bile duct. After a severe attack, patient may develop a bluish discoloration in the loins

from extravasation of blood-stained pancreatic juice into the retroperitoneum (Grey Tuurner's).

Bluish discoloration and bruishing may occur in the periumbilical region (Cullen's sign).

What are the investigations?Tests confirm the diagnosis and utilize the creticria below to determine the severity. In addition to arterial blood gases and venous sampling for amylase, liver function tests (LFTs), full blood count (FBC) and urea and eletrolytrs ( U+Es) :


1. ECG: flattened T waves or arrhythmias may cause confusion with cardiac ischaemia

2. Abdominal radiograph :It isnot usually helpful inacute pancreatitis but can show pancreatic calcification in cases of acute on chronic pancreatitis. In some cases a ' sentinel loop ' of proximal jejunum may be seen to be dialted.

3. Erect chest radiograph to exclude a perforation , which can present in a similar manner.

4. Ultrasonography:It may show gallstones and/or dilated common bile duct and pancreatic duct. Often gives poor views of the pancreas. Good for looking for collecting in the acute setting – can also be used to look for pleural effeusions.

5. Abdominal computed tomography (CT) is the investigation of choice.But is not usually performed before 48 hours of onset of the episode. Diagnostically , fat streaking is seen around the pancreas or fluid may be seen in the lesser sac, and this may be confirmatory in cases where the serum amylase is normal . Further, later imaging may reveal necrosis in the pancreas is normal. Further, later imaging may reveal necrosis in the pancreas or the formation of a pancreatic pseudocyst.

6. Serum calcium: may well be lowered as a result of fat saponification, and may lead to tetany and cardiac arrhythmias in severe cases.

ASSESSMENT OF PANCREATITIS SEVERITYo It is essential to perform arterial blood gas sampling in all patient with

pancreatitis to assess their acid-base status and to keep a regular check on their arterial Po2.

o Serum amylase is used as a diagnostic criterion but, in 10% cases, it is normal, particulary in acute on chronic pancreatitis, where there is a loss of acinar cell mass, or in severe pancreatitis with pancreatic necrosis.

o Scoring system: two very well-known and used methods are the Ranson and the Glasgow cretiria.

Glasgow criteria for severe pancreatitis The following criteria are assessed over the first 48 hours. 3or more indicate severe pancreatits with a high mortality:

Age > 55 years.


Hyperglycaemia (glucose >10 mmol/L in the absence of a history of diabetes). Leukocytosis ( 15 x 10 9 /L). Urea > 16 mmol /L after adequate rehydration. Ρo2 < 8 kPa on arterial blood gases. Calcium > 2.0 mmol /L. Albumin < 32 /L. Lactate dehydrogegenase (LDH) > 600 IU/L. Raised aspirate tranaminase (AST)> 100 IU/L.

Ranson's criteria for pancreatitisRanson's criteria on admission

Age > 55 years. White blood cell count ( WCC ) > 16 000 μL. Glucose > 11 mmol /L ( > 200 mg/dL). Serum LDH > 400 IU/L. Serum AST > 250 IU/L.

Ranson's criteria after 48 hours of admission: Fall in haematocrit by more than 10 %. Fluid sequestration of > 6 L. Hypocalcaemia (serum calcium < 1.0 mmol/L ( 8.0 mg /dL)). Hypoxaemia ( PO2 < 80 mmHg). Increase in urea to > 1.98 mmol /L (> 5 mg /dL) after intravenous fluid

hydration. Hypoalbuminaemia (albumin < 3.2 g/dL) in the firast 48 hours of admission. Base deficit of > 4.

The prognostic implications of Ranson's criteria are as follows: Score 0-2 = 2 % mortality rate. Score 3-4 = 15 % mortality rate. Score 5-6 = 40 % mortality rate. Score 7-8 = 100 % mortality rate.

Pathophysiology of markers of severity: Hypoxia : a result of (ARDS) and pleural effusions. Hypocalcaemia : calcium is chelated after the saponification of omental fat by

pancreatic lipases. Acidosis : anaerobic respiration of tissues as a result of poor perfusion leads to

a lactic acidosis. High urea: reflects dehydration. High WCC: acute inflammatory response and probable pancreatic necrosis ±

superventing bacterial infection.

Treatmwnt:This is largly conservative and non-surgical but aggressive, consisting of :

Fluid resuscitation and replacement with either colloid or blood transfusion to treat profound shock that can result from acute pancreatitis.


Electrolyte replacement is often required, with particular attension to potassium and calcium if necessary. All patients should be catheterized and a urometer should be used to produce a strict record of hourly urine output. Fluid sequestration can be very svere in acute pancreatitis, requiring many litres of fluid replacement to keep up. It is not uncommon for initial rescuscitation volumes of an individual with acute pancreatitis to be of the order of 10-15 L over several hours .

Analgesia : pain relief with pethidine commonly. Morphine is said to produce sphincter of Oddi spasm but there is little evidence to support this theory.patient- controlled analgesia (PCA) can be useful in this contex.


GIT


Swallowing and oesophageal physiology

What is the sequence of events in swallowing?Oral phase:

Food is chewed and a bolus is formed, which is pushed to the posterior pharynx by the tongue.

Here, afferent impulses in cranial nerves IX and X are transmitted to the swallowing centre ( medulla), which refluxly triggers swallowing via efferent impulses in cranial nerves IX and X.

Respiration is also refluxly inhibited.Pharyngeal phase:

The soft palate is pulled upward and palatopharyngeus helps to close the nasopharynx and prevent reflux.

The true vocal folds are apposed and larynx elevates . The bolus pushes against the epiglottis to close the entrance to the respiratory tract and prevent aspiration.

Upper oesophageal sphincter (cricopharyngeus muscle ) relaexes. The constrictor muscles (superior, middle, inferior) sequentially contract and

force the bolus down into the oesophagus.Oesophageal phase:

Bolus is propelled along the oesophagus by a primary peristaltic wave behind the bolus.

Takes 9-10 seconds to transverse the oesophagus. Secondary waves can occur if the bolus is not cleared. Tertiary contractions are non-propulsive and their presence is pathological.

What sphincteric mechanisms are there in the lower oesophagus and how is reflux normally prevented ?Lower oesophageal sphincter:This is a physiological sphincter (there is no anatomical sphincter here), located at the lower 2 cm of the oesophagus . It is an area of high pressure. Its finction is to prevent reflux of acid into the oesophagus. The factors preventing reflux are as follows:

Acute angle of entry to the stomach acts like a valve. Right crus of diaphragm acts as sling around the lower oesophagus. Intra-abdominal pressure acts on segment of oesophagus below the diaphragm. Mucosal folds act as valve. Lower oesophagus is normally contracted.

A degree of reflux occurs through this sphincter in normal individuals. However, several factors can lead to disruption of this sphincter, and hence reflux:

Te upper stomach can herniated through the diaphragm (hiatus hernia). Increased intra-abdominal pressure in pregnancy or after a large meal can

cause reflux. Some individuals have an incompetent lower sphincter


The stomach

What volume of gastric secretions are produced each day by a healthy adult?Approximately 2500 ml.

What are the contents of gastric secretions? Hydrpchloric acid. Pepsin. Gastric li[ase. Intrinsic factor. Mucus. Water. Ions (e.g. Na+, K+, Mg2+, HPO4

2+, SO42+).

What is the function of hydrochloric acid?1. Activate pepsinogen to pepsin.2. Convert ferric acid to ferrous form.3. Acid environment aids the absorption of calcium.4. Killing of ingested bacteria.

Which cells secret pepsin>The chief cells secrete it as an inactive precursor pepsinogen.

What is the function of pepsin?Breaks down food proteins to peptides and polypeptides.

Which cells secrte intrinsic factor?The parietal cells.

What is the function of intrinsic factor?Binds to vitamin B12 so that it can be absorbed by the ileal mucosal epithelial cells.

How is acid secretion regulated?There 3 phases to acid secretion:

A. Cephalic phase : initiated by the site, smell, taste or thought of food. Vagally mediated, acetylcholine directly stimualates the production of acid and indirectly causes acid secretion by stimulating secretion of gastrin (from G cells) and histamine (enterochromaphin-like cells).

B. Gatric phase : the mechanical effect of food in the stomach, distension of the body, antrum and pyloric are leads to the release of gastrin and also causes vagal stimuation leading to stimulation of pareital cells. Protein digestion products, calcium ions, caffeine, alcohol and amino acids in the antrum stimulate gastric secretion.

C. Intestinal phase : duodenal distension, presence of peptides and amino acids stimulate gastric secretion mainly by G cells in the duodenum. Acid in the duodenum leads to the release of secretin, fatty acids in the duodenum causes the release of cholecyctokinin (CCK) and gastric inhibitory peptide all of which inhibit gastric secretion.


What happens to gastric acid secretion when large parts of small intestine are removed ?Gastric acid secretion is increased and the amount is roughly proportional to the mount of intestine removed.

Do you know of any other factors that may influence acid and pepsin secretion?Hypoglycemia can stimulate acid and pepsin secretion via cerebral and vagal influences. In addition, stimulants such as alcohol and coffee can act directly on the gastric mucosa.

What are the functions of the stomach ?1. Reservoir for food, mixing of food with gastric secretions to form chime.2. Endocrine function: secretion of gastrin.3. Exocrine functions:

o Production of acid: digestion of food and immune function.o Enzyme production ( pepsin) for protein digestion, intrinsic factor and

mucous.

1. Reservoir & mixing functions: Its volume can increase to 1.5 L without an increase in pressure. It performs mixing and rudimentary digestion of proteins and

carbohydrates. It is able to deliver smaller, more manageable quantities of material to

the duodenum as required and reject potentially harmful subsrances before absorption.

It renders the ingested contents relatively free of bacterial contamination by way of the bactericidal action of hydrochloric acid.

2. Endocrine function: The stomach produces a hormone called gastrin ( G cells of the antral mucosa).This hormone is released in response to the cephalic phase controlling acid secretion in the stomach.Gastrin acts to increase the secretion of acid by partial cells in the stomach. It also causes histamine release, which potentiates the release of acid.H2- receptors such as ranitidine and cimetidine reduce gastric acidity by blocking this mechanism.

3. Exocrine functions: A. Acid secretion.B. Intrinsic factor.


Based on your knowledge of the functions of the stomach , what are the effects of a total gastrectomy ?

Early dumping syndrome : food of high osmolarity, not mixed in the stomach, causes rapid fluid shift and oligaemia. This causes fainting and sweating from hypovolaemia

Late dumping syndrome: caused by rebound hypoglycaemia, or high insulin levels experienced after a high carbohydrate load is presented and absorbed by the duodenum. Similar symptoms to above.

Pernicious anaemia and iron deficiency anaemia. Early satiety: loss of reservoir function. Bilious vomiting: loss of pyloric sphincter. Hypocalcaemia and iron deficiency. Gastric stump carcinoma : cancers occur at the gastrojejnal anastomosis 20

years or so after surgery. This may be a result of chronic irritation of gastric mucosa by duodenal secretions

Gallstones: caused by increased gallbladder motility post-vagotomy Which tumor can lead to the development of multiple sever peptic ulcers?

Gastrinoma Due to gastrin-secreting adenomas in the pancreas, duodenum, stomach,

or elsewhere (eg. Cystadenoma of the ovary) or simple islet-cell hyperplasia.

50%-60% of tumors are malignant of 50% are multiple. 30% of cases are associated with autosomal dominant disorder of multiple

endocrine neoplasia (MEN 1) Overproduction of gastrin leads to Zollinger-Elison syndrome, with

widespread peptic ulceration and diarrhea.

What is pernicious anaemia?The parietal cells of the stomach that secret HCL also secrete a glycoprotein known as intrinsic factor, which is essential for vitamin B12 absorption. Intrinsic factor binds to B12:

1. Protects it from acid digestion in the stomach.2. Aids its absorption by pinocytosis at the intestinal brush border of the terminal

ileum. Deficiency of intrinsic factor either as a result of chronic atrophic gastritis or the generation of autoantibodies to the parietal cell, gives rise to a megaloblastic anaemia known as pernicious anaemia. A similar event occur after gastric resection.It is easily treated by 3-monthly vitamin B12 injections. There is a lag period of several years between abolition of intrinsic factor function from whatever cause and the development of pernicious anaemia as the body's reserves of vitamin B12 are considerable.

What factors increase the risk of developing gastric carcinoma?


Certain factors are recognized as risk factors for the development of gastric cancer not least of which is a geographical distribution of the disease with a high prevalence in the japenease. Whether this is diet-related or not is unclear. The other notable risk factors are:

Pernicious anaemia Chronic atrophic gastritis Gastric polyps Family history: a small group of patients have a defect of E-cadherin gene,

which predisposes them to gastric carcinoma at a young age. The postgastrectomy/ gastrotomy stomach Intestinal metaplasia Cigarette smoking Blood group A Gastric ulceration.

Where in the stomach do most cancers occur?Two-thirds occur in the pyloric region, one-quarter in the body, with only 6 percent occurring in the cardia. A further 3 percent will be the diffuse infilterating carcinoma known as linitis plastica involving the whole stomach. However, these figures are contiously changing, since the distribution of gastric cancers has been changing over the last decade with a gradual decrease in distal cancers and an increase in proximal cancers.

What are the biochemical abnormalities that commonly occur in a case of pyloric stenosis? Explain them?The typical biochemical upset is a hypokalaemic alkalosis associated with hypovolaemia and haemoconcentration. The urine is acidic .The gastric parietal cells generate H+ and HCO3- via the carbonic anhydrase reaction.H+ enters the gastric lumen, with chloride ions as hydrochloric acid and the HCO3- enters the extracellular fluid (ECF) to be subsequently secreted into the duodenum in bicarbonate-rich biliary and pancreatic juice. Thus, when vomiting occurs with free connection between stomach and duodenum, the body loses volume, H+CL-, HCO3-, Na+ and K+. The clinical problem is one of volume deficit and electrolyte disturbance rather than H/HCO3 disequilibrium. Now consider the setting of pyloric stenosis in which free connection between stomach and duodenum does not occur; vomiting will loss volumes and H+CL- only causing a relative gain of HCO3-.The loss of H+ drives the carbonic anhydrase reaction to produce more H+/HCO3-; thus, the bicarbonate gain increases and as renal compensation is slight metabolic alkalosis ensues. The kidney is a sodium-preserving organ and in the proximal tubules as there is less chloride for sodium to be absorbed with, owing to decreased chloride from vomiting, Na+ exchanges for H+ giving rise to acidic urine and worsening alkalosis. As H+ becomes scarter, Na+ then exchange with K+, giving rise to potassium- rich urine and hypokalameia.

What is the epidemiology of this condition in the paediatric setting?


It is classically a condition affecting the male infant, usually the first-borne and with an increased incidence in children of affected parents. The incidence in caucasions is about 4 per 1000.It presents at between 4 and 6 weeks with projectile vomiting, continuing hunger even after feeds, poor stools and weight loss. Dehydration and wasting is now only seen in extreme cases of delayed presentation.

Describe the diagnosis and management of a child with congenital hypertrophic pyloric stenosis?

The history is usually higher suggestive of the diagnosis. Witnessing a test feed is usually enough evidence, as the baby feeds hungrily

and a projectile vomit follows. The hypertrophic pylorus can often be palpated in the epigastrium as a firm

olive sized swelling. Ultrasound confirms the diagnosis.

Treatment:By correction of biochemical abberations and scheduling the child for urgent surgery.Ramsted's pyloromyotomy:

A transverse or even periumbilical incision. The pylorus is identified and the hypertrophic muscle fibers divided until the

intestinal mucosa is seen to pout through the incision. The abdomen is then closed.

Small bowel


What substances are absorbed or digested by the small intestines? Water and electrolytes. Carbohydrates. Protein. Fat. Iron. Folate. Calcium. Vitamin B12.

What are the functions of the duodenum? Control of gastric contents. Stimulation of gastric acid. Reduction in gastric acid output. Pancreatic secretion stimulation. Stimuates bile formation. Stimualtion of gall bladder contraction. Absorption of carbohydrates, amino acids, fatt acids, calcium and some

vitamin.

How is gastric acid output affected by the duodenum?Gastrin released by the duodenal G cells stimulates gastric acid secretion.Secretin and gatric inhibitory peptides secreted by duodenal S and M cells respectively reduce the secretion of gastrin in the stomach and therefore reduce gastric acid secretion.

How does the duodenum control gastric acid?The mucosa of the duodenum is more resistant to the gastric acid.The duodenum is where neutralization of gastric acid occurs.

How does neutralization of gastric acid occur?Pancreatic secretion containing HCO3- are stimualted by secretin and CCK released from duodenum.CCK also stimulates gall bladder contraction and bile formation.HCO3- is also secreted from the glands of Brunner in the submucosa.

What are the effects of duodenectomy? Acid contents reaching the jejunum can causeulceration. Incomplete neutralization leading to decreased absorption of iron, calcium and

phophate. Loss of control of gastric emptying can lead dumpting syndrome. Loss of pancreatic and biliary stimulation leads decreased fat absorption.

What is dumping syndrome?


It can be caused by excessive volumes of food entering the small intestine to fast. This leads to large volumes of extrscellular fluid into the lumen of the intestine and uncontrolled carbohydrate absorption leading to rapid changes in serum glucose.Symptoms include faintness, sweating, abdominal pain and tachycardia.

What is the function of jejunum?It has 5 broad functions namely:

1. Transport of chyme between duodenum and ileum.2. Mixing of this digextive fluid.3. Absorption of various nutrients and electrolytes and water.4. Secretion both exocrine & endocrine.5. Lymphoid function.

1. Transport function: It is obvious as the jejunum provides the continuuity of the gastrointestinal tract

2. Mixing function: As the repetitive chuming is accompained by contraction of the villi to help pump nutrient rich lymph away from the brush border. Interspersed with this action are propulsive contraction of the jejunum to propel the bolus of chyme down the gut.

3. The Absorption: Of carbohydrate, protein, iron and folic acid as well as most of the water

and electrolytes. Fat and fat-soluble vitamins are absorbed mainly in the jejunum. Zinc and copper have been shown to be absorbed mainly in the upper

gastrointestinl tractResorption is driven by the osmotic forces generated by nutrient absorption.Large proportion of electrolytes (Na+, Cl-, HCO3-) are resorbed, in part by simple diffusion, in part by active transport mechanism and partly due to the osmotic pull of nutrient absorption an effect known as solvent drag.

4. Secretion both exocrine & endocrine: Such as somatostatin, secretin and motilin which is implicated in the intrinsic rhythmicity of the various gut segments.

5. Lymphoid function: The entire gut performs an important immune function and is endowed with its own system of lymphoid tissue collectively known as mucosa-associated lymphoid tissue (MALT).It occurs in concentereated areas suchas the peyer's patches as well as diffuse distribution of intraepithelial lymphocytes and mucosal mast cells which help protect the gut from the constant exposure to antigens within the gut lumen.

How would you differentiate jejunum from ileum in a pathology specimen? The gut wall of jejunum is thinner, but with thicker more vascular mucosa

than ileum. The jejunum has a larger circumference. Under microscope, the villi are taller and more numerous in the upper gut. The arterial arcades supplying the jejunum are more obviously arborizes (tree-

like) and plentful. There is much more fatty infilteration of the ileal mesentery than in the

jejunum, where the mesentery is often transparent.


Describe the functions specific to the terminal ileum and the consequences of resection?Effective absorption of bile salts and vitmain B12 onl occurs in the terminal ileum, since they acquire specific transport channels that areonly situated there. The bile salts are normally returned to the liver and recycled- this is known as the enterohepatic circulation.Resection of the terminal ileum prevents this pathway from functioning and an excessive loss of bile salts occurs. This in turn leads to malabsorption of fats and steatorrhea owing to the diminshed bile salt pool.Vitamin B12 isnot absorbed when the terminal ileum has been resected and patients who have undergone resection should have regular blood cheecks, and receive parenteral B12 regularly if needed.

What are the causes of malabsorption?1. Abnormal digestion in the intestinal lumen.2. Pyloroplasty: dumping syndrome (inadequate mixing of food with pancreatic

secretion and bile).3. Small bowel resection: reduced absorptive area.4. Chronic pancreatitis.5. Cystic fibrosis.6. Blockage of bile duct (stone & carcinoma).7. Excess gastric secretion: leading to inadequate lipolysis.8. Blind loop syndrome: causes bacterial overgrowth decreasing conjugated bile

salts.9. Celiac disease.10. Disaccharide deficiency.11. Abnormal fat transport in the lymphatics.

What are the consequences of small bowel resection?After loss of most of jejunum fat, protein and carbohydrate absorption is reduced due to loss of absorptive area. This leads to diarrrhoea with loss of water and electrolytes.The ileum over several weeks adjusts taking over most of the functions of the jejunum after resection.

When over 1 m of terminal ileum is resected bile salts and vitamin B12 absorption is reduced and the jejunum is not able to compensate.Stores of vitamin B12 last over 3 years, the bile slat pool however declines, this leads to increased gallstone formation, steatorrhoea and decreased absorption of fat-soluble vitamin (A, D, E & K).


What are the causes and features of "short bowel syndrome"?Short bowel syndrome occurs when there is insufficient bowel remaining to support the absorptive function required for normal growth and life.The minial amount of small bowel needed for normal absorption is approximately 100cm, although as little as 50 cm may be adequate, if a complete functioning colon is in situ. The symtpoms are due to the intestinal decompensation from both reduction in absorptive area and a greately reduced transit time.

Absorption of fats and proteins are most severly affected followed by carbohydrates.

The patient is malnourished and underweight, with diarrhoea or steatorrhoea. There are deficiencies of most vitamins and trace elements. With time, the bowel adapts with increased numbers of enterocytes and

heightened villi in the remaining bowwel, and compensation to some degree can occur.

The principal reason for short bowel syndrome is extensive small bowel resection; indications include:

Crohn's disease. Mesenteric infarction. Radiation enteritis. Mid gut volvulus. Small bowel tumours. Loss of bowel length from congenital atresias and loss of functional length due

to multiple fistulae may also be responsible.


Iron absorption and transport

What is the role of iron in the body?Iron is an absolute requirement for the synthesis of haemoglobin, so its deficiency leads to hypochromic microcytic anaemia.

What is the usual daily requirment of iron?Approximately 25 mg of iron is required daily for haemopoiesis.The majority of iron in the body is recycled and only 1 mg of iron is absorbed per day.The normal diet contains between 10 and 25 mg a day.

How does iron deficiency occur?It generally results from increased losses.Only in very rare instances does it occur as a result of failure of absorption or dietary deficiency.

Where is iron absorbed?It occurs in the upper small intestine.

How is it absorbed?It ossurs when iron is in the reduced ferrous form (Fe2+). Haem iron is also relatively well absorbed (20%).In the epithelial cell, iron is split from haem by the enzyme haemoxidase.Once Fe2+ enters the epithelial cell, it is bound to a cytosolic protein called mobilferrin at the basolateral membrane of epithelial cells.Transferrin receptors mediate the transfer of the Fe2+ from mobilferrin to transferrin, and this Fe2+ transferrin complex is released into the extracellular fluid which then diffuses into the blood.

Where is iron absorbed?Iron is stored in the liver, bone marrow and spleen, where it is stored as ferritin and haemosiderin.


Vitamin B12

What is the function of vitamin B12?It is involved in the maturation of red blood cells and deficiency leads to:

Pernicious anaemia. Subacute combined degeneration of the cord. Irritation. Depression. Memory loss.

Where is vitamin B12 stored?It is manly stored in the liver, with small amount present in the bile.

How long will the body store of vitamin B12 last if absorption totally ceases?The bosy's store of vitamin B12 is very large and will last 3-6 hours.

Where is vitamin B12 absorbed?It absorbed in the distal ileum.

Can you describe the mechanism by which vitamin B12 is absorbed?Following ingestion of food:

Pepsin in the stomach releases free vitamin B12 from proteins. This free vitamin B12 rapidly binds to a number of glcoproteins called R

proteins.During the intestinal phase of digestion:

Pancreatic proteases start to degrade the complexes between the R proteins and vitamin B12.

The free vitamin B12 then rapidly binds to intrinsic factor (which has been secreted by the parietal cells), Once bound to this complex is taken up by the ileal cells and is slowly transported into the circulation.

Absorption of vitamin B12 normally occur in the presence of intrinsic factor. However 1-2% occurs via instrinsic facot independent mechanisms.

What other substances are absorbed in the distal ileum?Fat soluble vitamins A, D, E & K and bile salts.

What factors reduce absorption of intrinsic factors? Lack of instrinsic factors (pernicious anaemia and gastric resection). Loss of terminal ileum (resection and crohn's disease). Blind loop syndrome.


Large intestine

What are the main functions of the large bowel?1. Absorption.2. Secretion.3. Motility.4. Storage.

What does the large bowel absorb? Water: 1-2 L enter the colon a day and only 100-200 ml are excreted. Electrolytes: Na+ is actively absorbed. Amino acids. Fatty acids. Vitamin K and B complex vitamins.

What is secreted from large bowel? Electrolytes: K+ and HCO3

- are secreted. Mucus: secreted by the goblet cells.

What is stored in the colon?Faeced are stored mainly in the transverse colon until defecation occurs.Gas mainly consisting of nitrogen, it also contains oxygen, carbon dioxide, methane (only 1% of the population) and hydrogen sulphide.

What are the consequences of diarrhoea? In the acute situation absorption of Na+ and water is reduced. Secretion of K+ & HCO3

- is reduced.This leads to dehydration and merabolic acidosis.In chronic diarrhea: Aldosterone leads to increase K+ loss from the kidenys and large bowel causing hypokalemia and a metabolic alkalosis.

What are the causes of diarrhoea? Reduced absorptive capacity (bowel resection and colitis). Malabsorption. Excess bile. Increased peristalisis. Infection. Tumours (carcinoid). Drugs (laxatives and antibiotics).


Liver and hepatic failure

What are the function of the liver?1. Production of bile2. Protein , fat and carbohydrate metabolism3. Storage of glycogen and vitamins ( A,D,E,K,B12)4. Detoxification of drugs , hormones and toxins5. Reticulonoendothelial and haematopoietic ( fetus ) functions.6. Kupffer cells (macrophage function).7. Blood reservoir and production of heat.

1. Production of bile.2. Metabolism:

Protein metabolism Muscle is broken down in starvation to amino acids and transported to the

liver for glucuneogenesis. Protein is broken down in the liver to form nitrogegous waste products such as

urea via the urea cycle. The liver is responsible for the synthesis of all non-essential amino acids. It is

also responsible for the synthesis of protein, such as albumin, clotting factors and complement proteins

Fat metabolism: The liver is responsible for synthesis of transport proteins for fatty acids , and

in starvation it synthesizes ketone bodies. Fatty acids are cleaved to produce acetyl-CoA for the production of ATP. In starvation, the brain requires glucose to function but can also metabolize

ketone bodies for energy. The liver can produce ketone bodies from fatty acids (which cannot be used to produce glucose).

Carbohydrate metabolism: This occur during gluconeogenesis.

In 'times of plenty', glucose is converted into glycogen, for storage (glycogenesis). The breakdown of glycogen to glucose takes place in the liver in early starvation (fasting), and is called glyconeogenolysis.

3. Storage:The liver stores glycogen, vitamins A, D, E, K and B12, iron and copper.

4. Detoxification:Peptide hormones (e.g. insulin) and steroid hormones (e.g. testosterone) are degraded in the liver. The cytochrome P450 system is involved in their metabolism, which includes increasing water solubility.Drugs that increase or decrease the activity of the cytochrome P450 system may have an effect on other drugs being administered concomitantly.


What is the role of the liver in starvation ?o Early starvation : glycogenolysis and gluconeogenesis (muscle breakdown to

form amino acids).o Late starvation : breakdown of fatty acids.

Formation of ketone bodies, for use by the brain. Ketosis occurs when the liver's glycogen reserves are used up and the liver metabolizes fat to produce ketones. These are used as an energy source by respiring tissue, sparing glucose for the brain, which relies on a proportion of glucose for metabolism but can also use ketone bodies.

What plasma proteins are synthesized by the liver? Acute phase proteins. Albumin. Proteins that transport steroids. Proteins that transport hormones. Clotting factors V, VII, IX & X.

How are substances inactivated and excreted by the liver?The liver reduces the toxicity and biological activity of substances and increases their water-solubility.The cytochrome P450 system is involved in increasing water-solubility.The formation of glucoronides of a vareity of substances including bilirubin, steroids and some drugs is catalyzed by the glucuronyl transferase system.

What substances affect the cytochrome P450 system? Increase activity is caused by: barbituates, phenytoin & rifampicin. Decrease activity is caused by: erythromycin, ketoconazole and cimetidine.

What drugs interact with warfarin and how ?Erythromycin inhibits the cytochrome P450 system and phenytoin increases it, so warfarin, which is metabolized via this system, would have its effects potentiated if administered together with erythromycin, and reduced if admintered with phenytoin.

What cells carry out the reticuloendothelial function in the liver?Kupffer cells remove bacteria, toxins and abnormal erythrocytes.

What complications of liver disease are relevant in the perioperative peroid?1. Bleeding:

Prolonged prothrombin time (PT). Thrombocytopenia. Oesophageal and gastric varices.

2. Encephalopathy.3. Hypoglycaemia.4. Ascitis due to portal hypertension, sodium and water retention and low

albumin.5. Depressed immune function.6. Renal failure.

What is child's classification?


It is a system of classifying the risk of mortality for surgery and anaesthesia in hepatic failure, based on:

1. Bilirubin.2. Albumin.3. Prothrombin time.4. Ascitis.5. Encephalopathy.6. Nutrition.

Bile


How much bile is produced a day?It is produced 500-1500 ml/day and is stored in the gall bladder between meals.

What is the function of bile? Bile salts are required for lipid digestion. HCO3

- aids neutralization of gastric acid as it enters the duodenum. Excretory route for bile pigment, cholesterol, steroids and fat-soluble drugs.

How do bile salts function?Hepatocytes form primary bile salts (steroid molecules) from cholesterol. Primary bile salts are dehydroxylated by intestinal bacteria to secondary bile salts.Bile salts are detergents (containing a fat and a water-soluble end), in aqueous solution bile salts form micelles (hydrophobic ends in the centre and the hydrophilic ends on the surface) this enables them to solubalise and assist the absorption of lipids.

Where are bile salts absorbed?80 % of bile salts are absorbed actively in the distal ileum and pass back to the liver via the portal circulation.The remaining bile salts enter the colon where they are converted to secondary bile salts (deoxycholate-soluble and lithocholate-insoluble) and the soluble deoxycholate is absorbed.The bile salts are not absorbed (mainly lithocholate) are excreted in the faeces.Bile salts are recycled up to 8 times a day.

What are bile pigments and how they excreted? Degradation of the haem group of haemoglobin leads to the formation of

biliverdin. This is then reduced to unconjugated bilirubin and is taken to liver attached to

albumin. Unconjugated bilirubin is conjugated with glucuronic in the liver. This is now water-soluble and is excreted in bile. Intestinal bacteria reduce the conjugated bilirubin to urobilinogen (absorbed

abd returns to the liver and is excreted into the bile) and stercobilinogen (excreted in faeces).

What is a "straberry gall bladder"?When cholesterol precipitates from bile on the gall bladder wall, it forms yellow submucous collection of cholesterol with an appearance similar to a trawberry skin.These are usually associated with cholesterol stones.

What different types of gallstones do you knw and what are they made from?There three common varieteies of stones:


1. Mixed (75%): Most common type, often mutliple, pale &faceted. Major component is cholesterol. Cut surface is laminated with alternate dark & light zones of pigment and

cholesterol respectively.

2. Colesterol (20%): Often large solitary stones. Cut surface shows crystal radiating from the centre of the stone. Surface is yellow and greasy to touch.

3. Pigment (5%): Small, black, irregular and multiple, associated with haemolytic anaemia. Composed of calcium bilirubinate and calcium carbonate.

What problems may gall stones cause? The majority of gallstones are asymptommatic. Those that do cause problems they may do so withihn the gallbladder itself,

within biliary tree or outside of the biliary system altogether. The site of the stones determines the further manahement of the patient.Predisposing factor for carcinoma of the gallbladder.

Within the gallbladder:Biliary colic: obstruction of the gallbladder neck by a gallstone gives rise to a sever colicky pain, which may in contrast to most colics last for several hours.Cholecystitis: the stones cause inflammation of the gallbladder wall. Presents as right upper quadrant pain, fever, leucocytosis and systemic upset.Mucocele: impaction of a stone in Hartmann's pouch can completely occlude the cystic duct. The gallbladder fills with mucus.Empyema: infection of an obstructed gallbladder; it turns into a bag of pus.

Within the biliary tree:Obstructive jaundice: bacause of occlusion of the common bile duct by a stone.It tends to be painless as there is no muscle in the common duct wall to produce colic.Ascending cholangitis: is produced by infection in the stagnant bile of an obstructed system. The duct fills with pus and the patient is markedly unwell and septic.Pancreatitis: due to impaction of a stone at the ampulla.

Outside the gallbladder:Gallstone ileus: erosion of the stone through into the duodenum and passage through the small bowel may present wwith small bowel obstruction owing to the blockage of the ileocaecal valve by the gall stone. X-rays reveal the stone in the right lower quadrant and gas in the biliary tree, which is pathognomonic of this condition.

When is a T-tube used and for how long?A T-tube is a rubber used to drain the common bile duct after surgical exploration. It gives the bile a safe route to the surface, and forms a tract. The tube can be used to perform cholangiogram, and can be removed after 10-14 days by which time a track will have formed.


In the event of bile duct stones remaining, they can sometimes be removed by the use of mechanical graspers down the tract under radiological control.

Inflammatory bowel disease


Describe the typical pathological features of Crohn's disease?It is a segmental discontinous full thickness inflammation of the bowel affecting the whole gastrointestinal tract from mouth to anus, which may have associated extraintestinal manifestations.Terminal ileitis is the commenst gastrointestinal lesion.The mucosa is reddened with small apthous ulcers that develop into superficial spreading ulcers with submucosal oedema and an increase in lymphoid tissue.This process may progress to deep narrow transmural ulcers and may result in fistulation – a common features of Crohn's disease.Extensive fissuring may leave islands of raised mucosa – cobblestonning.In advanced disease, the bowel wall becomes fibrotic, giving rise to small bowel stricture or even longer "hosepipe" segements. Although Crohn's is recognized as a chronic granulomatous condition, granulomata are only found in about 70% of speciemen.

What is a granuloma?It is a collection of activated macrophages.

What surgical interventions are common in Crohn's disease?As Crohn's is a disease of the whole gastrointestinal tract, no resectional procedure is likely to be reliably curative as compared to ulcerative colitis. Surgical intervention should, therefore, be kept to a minimum and the maximum legnth of bowel preserved.However, it should be noted that recurrence rates are independent of resection extent and not increased if there microscopic, but not macroscopic, Crohn's disease at the resection margrins.Patients should be considered for surgery before advanced disease occurs, because mortality and morbidity are reduced and more conservative resection are possible with early surgical intervention.

o Localized terminal ileal disease may be treated by a limited ileocaecal resection, which in many cases turns out to be the only surgical intervention necessary.

o Small bowel strictures should ideally be treated by strictureplasty; as opposed to resection and anastomosis, as this will preserve intestinal length.

o Perianal sepsis with fistulation is a particular problem associated with Crohn's disease and surgical intervention should be weighed against the risk of perianal recurrence. It should be treated by clinicians with specialist interest in the condition.

A presentation of multiple/recurrent fistula should always raise the question of Crohn's disease involvement.

What are the typical clinical features of ulcerative colitis?The commest presentation is with diarrrhea with marked faecal urgency.


There is often blood present with the diarrhoea. This may be associated with abdominal pain although pain is more often a

feature of Crohn's disease. There is associated malaise, anorexia and weight loss. There are several well-recognized extraintestinal manifestations of the disease,

some of which are related disease activity such as:Pyoderma gangrenosum. Erythema nodosum.Musouc apthous ulcers. Iritis.Large joint arthritis.

Those not related to disease activity include:Sacroileitis/ankylosing spondylitis. Chronic active hepatitis.Cirrhosis. Sclerosing cholangitis.Primary biliary cirrhosis. Clubbing.

How common is ulcerative colitis (UC)?The incidence of UC approximately 1:10,000 population in the UK.

Is there any familiar tendency?Yes, there is evidnece of increased risk in families of affected individuals. The risk is between 10-20% for individuals who have a first degree relative with UC.

What is the relationship between smoking and UC?Smoking is protective against UC, stopping smoking increases the risk of developing the disease and causes exacerbations in those patients in remission.

How would you define an acute sever attack of UC?Acute sever attack nay be defines clinically by the presence of:

6 or more bloody diarrhoeal stools per day. Pyrexia. Tachycardia. Anaemia. Weight loss. Abdominal pain/tenderness.

What blood tests would you request to assess the activity of UC? Haemoglobin. Platelet count. ESR. C-reactive protein. Serum albumin.

What other tests can be used to assess extent and activity of UC?1. Plain abdominal X-ray looking for colonic dilatation & thumb printing.2. Erect chest X-ray or lateral decubitus abdominal film if you suspet perforation.3. Radio-labelled whhite cell scan (99Tc-HMPAO).4. Rigid or flexible sigmoidoscopy without excessive air insufflation.

What is the initial supportive treatment for acute active UC? Intravenous fluid replacement ± blood transfusion.


Nutritional support (enteral or parenteral depending on the clinical state). DVT prophylaxis (UC patients are at high risk of developing

thromboembolism). Avoidance of drugs such as NSAIDs, anti-diarrhoeal (loperamide, codeine

phosphate), opoid analgesic, anti-spasmodics and anti-cholinergic agents as they may provoke colonic dilatation.

What is the specific medical treatment of acute sever UC?1. Intravenous corticosteroids form the cornerstone of treatment.

Hydrocortisone or methylprednisolone may be used.They are used to induce remissionn, which is then maintained by 5-aminosalicylic acid (5-ASA) derivatives, such as mesalazine.

2. Cyclosporin and heparin are still undergoing evaluation.3. Oral azathioprine and 6 mercaptopurine work too slowly to be effective in the

acute episodes. Localized proctitis may be treated by foam enemata of either steroids or 5-

ASA. But widespread disease requies oral or I.V. therapy. Treatment including oral budesonide and azathioprine have been used to

reduce the impact of standard steroid therapy.

What are the indications for surgery in UC?In the emergency situation:

Perforation. Bleeding. Toxic dilatation. Failure of aggressive medical treatment.

In the elective situation: Malignant transformation. Steroid dependence. Recurrent acute exacerbations. Growth retardation in children. Prophylaxis: UC increases the risk of colonic adenocarcinoma; the risk is

calculated at 1% per year after 10 years of disease.

What surgical options are available for elective management of UC?

Operation Advantages Disadvantages Proctocolectomy &

ileostomySingle operation.No surveillance needed.

Permanent end stoma.All disease removed.

Colectomy & ileorectal anastomosis (if rectal

sparing)

Single procedure.No stoma.

Residual rectum with recurrent disease & cancer risk needing surveillance.

Proctocolectomy & pouch reconstruction

Usually continent.All disease removed.

Often > 1 operation.Complications are common (30%).

Hiatus hernia


What is a hiatus hernia? Which types are you aware of? A hiatus hernia is an acquired form of diaphragmatic hernia. There are two types:

Sliding: the gastro-esophageal junction slides through the esophageal opening diaphragm, predisposing to reflux and Barrett's oseophagitis.

Rolling or paraoseophageal: junction remains in position, but an area of stomach and peritoneum slides up alongside the esophagus into the thorax.

What are the principles of management of gastro-esophageal reflux?Clinical history is aided by the following basic investigastions:

Upper gastrointestinal endoscopy with biopsy to detect oesophagitis and Barrett's osophagus.

24-hour lower oesophageal pH recording.Uncomplicated reflux can be managed by the following lifestyle changes:

Weight loss. Avoidance of alcohol and smoking. Avoidance large meals at night. Elevating the head of the bed.

Medical treatment is successful in most patients, and includes the following: Antacids. H2 antagonist. Proton-pump inhibitor (PPIs).

The indications for surgery are as follows: Persistent regurgitation. Sever reflux symptoms despite the compliance with medical advice. Patient choice.

What surgery can be performed?Nissen's fundopolication is performed in over 95% of patients.Other operations include:

Belsy Mark IV (fundopolication through a thoracotomy). Hill gastropexy (securing the cardia to pre-aortic fascia).

Describe the principles of Nissen's fundoplication?This can be performed either laparoscopically or via an upper midline incision.The pateint's consent is obtained and preoperative investigations are confirmed. The patient is placed in a supine position, given a general anaesthetic, and the head end of the table is elevated.

surgical phsyiology

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