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1996 Integrated Body Function 536-022: Volume III By Duy Thai
2nd Year Medicine Page 1 of 24
Integrated Body Function

1996
Volume IV
CONTENTS
TOPIC PAGE NO.

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ACID BASE METABOLISM
Concept 1
• The body pH is maintained within a narrow range of 7.35 - 7.45
• Any value outside these ranges (i.e. too alkaline or too acidic) will lead to poor enzyme functioning.
• Physiological values which are important in acid-base analysis are:
pH...........................7.35 - 7.45 (7.4)

PaCO2.....................38 - 42 mmHg (40mmHg)
[HCO3-]...................24mmol
Concept 2
• Henderson-Hasselbach equation is useful in any acid base analysis
−
[HCO 3 ]
pH = 61
. + log10
0.03 × PaCO 2
• Using the normal values, the pH works out to be:
24
pH = 61
. + log10
0.03 × 40
pH = 7.4
Concept 3
• CO2 is being generated all the time.
• It is a byproduct of oxidative metabolism
• It is also a product of the buffering of non volatile acids (e.g. lactic acid)
• Non volatile acids e.g. lactic acid do not travel in the blood in that form. In the blood lactic acid dissociates into
H+ and its corresponding anion (lactate). It is the free H+ which causes any acidic effects.
• The H+ is buffered by HCO3-: H+ + HCO3- → H2CO3 → CO2 + H2O
• As you can see, CO2 is the product, along with H20
• CO2 is excreted by the lungs so that there is no buildup of CO2 in the blood.
• Any excess H+ is excreted by the kidney's in exchange for HCO3- in the tubule cells
Concept 4
• Acidosis
• Respiratory
• An increase in PaCO2 (due to hypoventilation, airway obstruction)
• Metabolic
• A decrease in HCO3- (due to excess acid, i.e. H+, in the body or excess loss as in diarrhea)
• Alkalosis
• Respiratory
• A decrease in PaCO2 (due to hyperventilation)
• Metabolic
• An increase in HCO3- (often due to ingestion)
Concept 5
• Compensatory mechanisms occur to maintain the pH at the required levels.
• Compensatory mechanisms act by manipulating the levels of CO2 and HCO3- (see Henderson-Hasselbach equation,
concept 2).
• e.g. An increase in CO2 will be met with an increase in HCO3- (via increased absorption in the kidney's).
• Note that even though the pH is maintained, the values of the chemicals in question are abnormal.
Metabolic acidosis
• The ways of getting metabolic acidosis are:
• Being silly and ingesting acids
• Buildup of lactic acid due to anaerobic metabolism (poor tissue perfusion in shock, cardiac failure)
• Ketoacidosis in the diabetic who is generating excess Acetyl CoA as a result of fatty acid metabolism
• Metabolic acidosis is distinguished by a fall in plasma HCO3- (i.e. a value < 24mmol)
• Compensation to metabolic acidosis occurs in stages, from the immediate response to more prolonged responses for
chronic acidosis.
• Buffer mechanisms are the immediate response to a rise in plasma H+
• Proteins (e.g. Hb) can act as buffers to “soak up” H+ ions in the blood but the most important buffer
system is the bicarbonate buffer.
• The fall in HCO3- is due to excess H+ combining with HCO3- as a buffer mechanism.
H+ + HCO3- → H2CO3 → H2O + CO2
• CO2 can travel dissolved in the blood or bound to Hb as a carbamino compound
• Respiratory compensation occurs next
• The bicarbonate buffer produces CO2
• The excess CO2 is transported to the lungs to be breathed out.
• Excess CO2, along with a decreased pH both act on the respiratory centers to increase ventilation.
Hence, one important compensatory mechanism for metabolic acidosis is hyperventilation to blow off
excess CO2.
• For those with chronic, compensated acidosis:
• The pH will be normal
• HCO3- levels are reduced (primary disorder)
• PaCO2 is lower than normal (i.e. < 40mmHg) due to hyperventilation (compensatory
mechanism)
• Renal mechanisms to try and conserve HCO3- and prevent it from dropping lower
• H+ is normally secreted by the nephron
• This intracellular H+ is derived from CO2 which enters the cell and reacts with H2O.
• 90% of H+ secretion occurs in the proximal tubule via a Na+-H+ countertransport.
• Although this represents the major site of secretion of H+, it is not the most
significant because a large concentration of H+ cannot be set up in the tubular fluid
(what will become the urine).
• The remaining site of H+ secretion occurs in the intercalated cells of the distal nephron.
• The H+ is actively pumped out into the tubular fluid by a H+ ATPase pump. This
enables a huge concentration gradient to be set up in the tubular fluid.
• Under normal conditions, when H+ is secreted out into the tubular lumen, it binds to filtered HCO3- in
the tubular fluid.
• H+ reacts with HCO3- to form H2CO3 which dissociates into CO2 and H2O.
• CO2 and H2O pass freely into the tubular cell and react once again (due to the presence of
carbonic anhydrase) to form H2CO3. This then dissociates into H+ and HCO3-. The H+ is
recycled by being secreted and the HCO3- passes through the basal surface to enter the
circulation.
• This mechanism allows reabsorption of HCO3- for every H+ secreted.
• Under normal conditions, the rate of H+ secretion is enough to reabsorb virtually all the
HCO3- present in the tubular fluid.
• In metabolic acidosis, the levels of H+ are relatively high and so the amount of H+ secretion is more
than the amount of HCO3- in the tubular fluid. This is good because what we want to do is try and
push the HCO3- levels in the blood back up again by reabsorbing as much as possible. But what
happens once we have reabsorbed all there is to reabsorb in the tubular fluid?
• High levels of H+ secretion by the tubular cells into the lumen is due to increased levels of
CO2. Aldosterone also has an effect by stimulating the release of H+.
• The tubular fluid cannot contain much H+ in it’s free form. The minimum pH the tubular
fluid can handle is 4.5. Hence in order for the urine to be an effective way of excreting
excess H+, there must be some way to convert the H+ into an alternative form to be excreted
safely, rather than in its free form (which is limited).
• There are 2 mechanisms to do this, and an extra bonus is that they both produce HCO3- in the
process, aiding our quest to search and capture precious HCO3-.
• H+ can bind to HPO42- in the tubular fluid to form H2PO4- which is readily
excretable in urine
• The H+ which is used is formed by the reaction of CO2 with H2O, which
also produced HCO3- as a byproduct.
• H can also bind to NH3 in the tubular fluid to form excretable NH4+.
+
• The H+ which is used is formed by the reaction of CO2 with H2O, which
also produced HCO3- as a byproduct.
• NH4+ can also be produced by the metabolism of glutamine in the tubular

cells. Glutamine produces NH4+ as well as 2 molecule of badly needed
HCO3- as a bonus.
• A useful method of determining whether you have a metabolic acidosis is to use the anion gap
• The anion gap works on the principle that all the cation concentrations in the plasma must balance the anion
concentrations.
• In practice, this is not always true because we are limited in the types of ions we can measure in plasma. The
typical ions used are Na+, K+, Cl- and HCO3-.
• The sum of all the positive cation concentrations minus the sum of all the anions give you the anion
gap.
• Normally, the difference is < 15.
• If there is an additional acid added, the concentration of HCO3- will be reduced and so the anion gap
will get bigger, indicating a metabolic acidosis.
Metabolic alkalosis
• Causes:
• Ingestion of bases
• Diarrhea, vomiting where there is increased loss of H+ in the fluids
• Characteristic feature:
• In metabolic alkalosis, the distinguishing feature is an elevated HCO3- concentration, i.e. a value > 24mmol.
• .The main compensatory mechanisms are:
• Hypoventilation to try and raise CO2 levels in the blood to counter the effects of a raised HCO3- (use
Henderson-Hasselback equation).
• Increased levels of CO2 cause an increase in H+ due to the reaction:
H2O + CO2 → H2CO3 → H+ + HCO3-
• There is also a reduced secretion of H+ from the renal tubules. This prevents any HCO3- from being reabsorbed
back into the circulation from the tubular fluid. Hence, an analysis of the urine will show high levels of HCO3-.
• For those with chronic, compensated alkalosis:
• HCO3- levels are high (primary disorder)
• PaCO2 is greater than normal (i.e. > 40mmHg) due to hypoventilation (compensatory mechanism)
Respiratory acidosis
• In any form of respiratory acid base disorder, the primary disorder is one of PaCO2 levels
• In respiratory acidosis, there is an increased PaCO2 due to:
• Deliberate hypoventilation (holding your breath)
• Pathological hypoventilation
• Airway obstruction
• Poor gas exchange (e.g. pulmonary oedema)
• In respiratory acidosis, the best compensatory change is to start breathing again. This is good if you were stupid enough
to hold your breath. But in some cases, breathing is so shallow that every breath is difficult and there is no way the lungs
can breathe off the excess CO2.
• When this occurs, the kidney’s are often recruited to increase the loss of CO2 (indirectly) by converting CO2 into H+
which is secreted and reabsorbing HCO3- to maximum capabilities.
• The compensatory mechanisms is virtually identical to metabolic acidosis except for the fact that the person is unable to
hyperventilate and so the respiratory compensation is ignored.
• Hence the For those with chronic, compensated respiratory acidosis:
• HCO3- levels are high (compensatory mechanism)
• PaCO2 levels are high (primary disorder)
Respiratory alkalosis
• This is due to a low PaCO2 resulting from:
• Hyperventilating
• The primary abnormality is a reduced PaCO2.
• With time, compensatory mechanisms will come into play and cause reduced reabsorption of HCO3- from the
tubular fluids.
• Hence the For those with chronic, compensated respiratory alkalosis:
• HCO3- levels are low (compensatory mechanism)
• PaCO2 levels are low (primary disorder)
• Note that in all cases, chronic compensated cases all have a normal pH.
PULMONARY CIRCULATION
Concept 1
• The pulmonary circulation is a low pressure, low resistance, thin walled system.
• It receives all the cardiac output (5L/min) per systole
• During systole when the hear contracts, the left ventricle pushes blood out into the aorta and the right ventricle
pushed blood out into the pulmonary arteries.
• The normal, resting cardiac output is 5L/min. During exercise, the cardiac output can rise to as much as
25L/min.
• The unique characteristic of the pulmonary circulation is that when there is an increase in blood flow through the
pulmonary circulation (due to an increased cardiac output), the pressure in the system remains relatively constant.
• Compare this to the systemic circulation where an increase in blood volume leads to an increase in arterial
pressure (hypertension).
• The reason for the constant pressures in the pulmonary circulation is that when there is an increased blood flow
to the lungs, there is a compensatory vasodilation of the pulmonary capillaries and recruitment of new
(previously closed) vessels.
• In some disease states where there is a loss of the vascular bed (less capillaries available), an increase in blood
flow will result in an increased pressure in the pulmonary circulation.
Concept 2
• Like any other capillary bed, the pulmonary capillaries are subject to Starling's forces.
PIF πIF
Arteriolar end Pc πc Venous end
• In the pulmonary circulation, the oncotic pressures remain relatively stable and the only really significant factors which
can go wrong are:
• An increase in the capillary hydrostatic pressure (forcing fluid out into the interstitium)
• A change in capillary permeability
• Under normal conditions, the capillary hydrostatic pressure is small and the pressure in the interstitial spaces is negative
(due to the negative pressures in the thoracic cavity). This negative pressure will tend to suck fluid out of the capillaries.
• Note that in normal systemic capillaries, the interstitial pressure is usually in the direction which forces fluid
into the capillaries (opposing the capillary hydrostatic pressure).
• The net result of the capillary hydrostatic pressure and the negative interstitial pressure is to favour the loss of
fluid from capillary to interstitium.
• The alveoli must be kept dry and so any fluid leaking out into the interstitial spaces must be mopped up quickly. This is
achieved by the lymphatics which drains the fluid from interstitial spaces into the venous circulation.
• Any disorder which results in fluid entering the lungs (alveoli) is known as pulmonary oedema.
Concept 3
• Ideally, the ventilation-perfusion ration (V/Q) should remain at 1. That means that the rate of ventilation is matched to
equal the rate of perfusion, thus enabling efficient gas exchange.
• If the ventilation is reduced, you would get a decrease in V/Q. This means that the rate of perfusion is greater than the
ventilation and so you have wasted blood flow to the alveolus (i.e. you have too much blood for the level of ventilation).
• As a result, the arterioles supplying a lung segment with decreased ventilation will constrict to reduce the blood flow
(perfusion) in order to match the reduced ventilation.
Concept 4
• If the compensatory mechanisms is too excessive, then that itself can lead to a problem.
• The ventilation can be decreased too much due to:
• Hypoventilation (e.g. sleep apnoea)
• Obstructed airflow
• The compensatory mechanisms is to have pulmonary vasoconstriction
• This decreases the volume of the vascular bed (to match the decreased ventilation) but also leads to a buildup of
blood in the pulmonary arteries. (The vasoconstriction effectively increases the pressure in the pulmonary
circulation).
• An increase in blood in blood in the pulmonary arteries results in an increase in pulmonary pressure
(pulmonary hypertension).
• The pulmonary arteries are connected to the right ventricle and so the right ventricle has to pump harder to
force blood through the high pressure pulmonary circulation.
• The right ventricle was not made for this job, it was made to pump against a low pressure pulmonary
circulation.
• As a result, you get right ventricular failure.
Clinical cases - Pulmonary oedema

• Pulmonary oedema means fluid in the alveoli
• The normal pulmonary unit (capillary + alveoli) is like so:
Arteriole Venule
• Say now, we have a myocardial infarct which destroys the function of the left ventricle.
• You would get a backlog of blood in the left atrium which is directly connected to the pulmonary veins. The backlog of
blood increases the pressure in the left atrium which is then transferred to the pulmonary veins. Hence, the pressure at the
venous end of the pulmonary capillary is increased.
• As a result of the increased capillary hydrostatic pressure, more fluid will leak out the capillary than normal.
• The amount of fluid is too much for the lymphatics to handle and so fluid leaks into the alveoli.
• Effects of pulmonary oedema include:
• Creates a low V/Q since the fluid in the alveolus reduces the volume of air which is available (and hence
reduces the ventilation).
• Oxygen cannot diffuse effectively across the fluid so you have diffusion impairment.
• If the situation is so bad, the capillary will constrict completely, creating a shunt which bypasses the blood flow
to the lung segment.
• The lungs are soaked and so they become stiffer (less compliant). You need to increase the work of breathing in
order to expand the lungs sufficiently to generate a negative pressure.
• Other causes of pulmonary oedema are:
• An increase in capillary permeability makes the capillary more leaky.
• More fluid will be able to leak out into the interstitium and flood the lymphatics.
• This type of oedema is known as non cardiogenic pulmonary oedema.
• It can be caused as a result of chemicals released by the endothelial cells (e.g. prostaglandins) in
response to sepsis, trauma or shock.
Clinical cases - Pneumonia

• Pneumonia is essentially similar to pulmonary oedema in that the alveoli become filled with stuff other than air - in this
case puss.
• This results in:
• Decreases ventilation for reasons identical to pulmonary oedema. Leads to low V/Q.
• Compensation results in vasoconstriction at that lung segment. (Reduced perfusion)
• As a result of some capillaries being shut off, you get redirection of blood to other, more healthy parts of the
lung.
• You also get hypoxia due to impaired oxygen diffusion/ventilation and so the body responds by increasing the
respiratory rate.
Loss of the vascular bed

• You need to lose approximately 80% of the pulmonary vascular bed to get any noticeable effect on breathing at rest.
• The loss the vascular bed means a reduction in the number of capillaries through which the blood can be distributed.
When the numbers are reduced, it means that the remaining capillaries need to handle a greater volume load of blood
since the extra blood they receive used to be handled by the now "dead" capillaries.
• Loss of vascular bed can be due to:
• Vasospasm
• An excessive compensatory response to low ventilation may result in too many capillaries
vasoconstricting.
• Obstruction from pulmonary emboli

• An embolus lodges in the pulmonary capillaries and effectively stops blood flow through the capillary
to the lung segment is supplies.
• Destruction of the vasculature by fibrosis or emphysema.
• The results of a loss of vascular bed are:
• The remaining capillaries need to handle a larger volume of blood than they did previously.
• As a result, the pressure in the pulmonary vasculature increases (pulmonary hypertension).
• The right ventricle needs to pump harder in order to push blood through the high pressure circulation. Right
ventricular failure ensues.
• Right ventricular failure causes blood to pool up in the right atrium and into the systemic venous
circulation.
• As a result of the increased volume of blood, you get an increase in systemic venous pressure
(detectable by looking at the height of the jugular venous pulse).
• A rise in central venous pressure can cause an increased hydrostatic pressure in the peripheral
capillaries and oedema can result. This is especially evident in the feet since the venous pressure here
is highest since there is a large column of blood above it.
• There is also a poor cardiac output which results in lassitude and breathlessness.
SLEEP RELATED BREATHING DISORDERS
Obstructive sleep apnoea

• Obstructive sleep apnoea is due to upper airway narrowing as a result of loss of muscle tone to the muscles which
support and hold open the airways. Note that this occurs in everybody.
• The condition becomes pathological if the airways are physically more narrower than normal. Hence, when you get
relaxation of the muscles, there will a higher risk of the airways being totally obstructed.
• The common places of muscle relaxation during sleep is:
• At the level of the soft palate
• A the base of the tongue
• The cycle of breathing which occurs in obstructive sleep apnoea is:
• At the onset of sleep, the muscles in the airway lose their tone and block the airway.
• In susceptible people, this results in airway blockage and apnoea (stop breathing).
• The hypoxia and hypercapnia results leads to a reflex arousal and so the person wakes up and they lose sleep
because they have to wake up multiple times during the night (sleep fragmentation).
• The patient thus presents with:
• Complaints of snoring during sleep
• Excessive daytime drowsiness due to lack of sleep.
• Decreased productivity and other disorders (both physical and psychological) due to sleep deprivation.
Cardio-respiratory effects of obstructive sleep apnoea

• Hypoxia, leading to pulmonary hypertension
• Increased susceptibility of heart attack (since the heart must work harder)
• Arrhythmias
• Increased erythropoietin (as a result of the hypoxia) leading to polycythemia.
Diagnosis
• We diagnose sleep apnoea by measuring the sleep patterns of a patient and look for any arousals during sleep.
• It is important to note that during obstructive sleep apnoea, there is still movement of the chest wall, but no ventilation
can occur due to airway obstruction.
• The chest and abdomen move out of phase (normally the chest and abdominal rise and fall in sync).
Treatment
• Refrain from smoking, drinking, sedatives
• Reduce weight
• Continued positive airway pressure (positive pressure ventilation) i.e. forcing air into the lungs rather than rely on the
negative pressure (suction) mechanisms of the lung.
• Surgery to widen the airway.
Central sleep apnoea

• This is also known as periodic breathing or Cheyennes-Stoke respiration
• In this disorder, there is no problem with the airways. The problem lies in the central mechanisms of respiration.
• The apnoea is due to the respiratory center of the brainstem failing to keep respiration going due to depression
of its activity during sleep.
• In contrast to obstructive sleep apnoea where there is a normal chest wall movement during the stages of
apnoea, obstructive sleep apnoea is characterised by no movement of the chest wall during an apnoeic episode.
• Central sleep apnoea can also be due to heart failure.
• In this case, it takes longer for the blood to reach the peripheral chemoreceptors and so there is a delay in the
feedback control.
• Another reason for central sleep apnoea is due to a neurologic delay.
• The respiratory center takes longer to respond to a signal from the peripheral chemoreceptors regarding blood
gas levels.
• This can be a result of a medullary stroke or CNS depression (due to drugs).
• This pattern of breathing (where you get periodic sequences of non breathing) is also seen transiently in normal people
and also in people with acute mountain sickness.
Why does this occur?

• When we go to sleep, there is a decrease in the set point between alveolar ventilation and CO2 (and O2) levels. As
ventilation falls during sleep (due to removal of the wakefulness drive to breathe), there is a fall in O2 levels which
stimulates the peripheral chemoreceptors into increasing ventilatory rate. Central respiratory centers are also stimulated
due to the high CO2 levels. The ventilation increases to such an extent that too much CO2 is blown off, resulting in a
low PaCO2. Remember that CO2 stimulates central respiratory centers to breathe, so a decrease in CO2 levels stops you
breathing. As a result, the CO2 starts to rise once again and re-stimulate the central respiratory centers to cause
ventilation. However, the ventilatory response is too great and so we hyperventilate to the point where the CO2 levels in
the blood are too low and stop respiration.
• The cycle then repeats itself
• e.g..
Depression of breathing
Hypoxia/high CO2 levels
Central respiratory centers activated
Resumption of breathing
Hyperventilate
Blow off too much CO2 leading to

depression of breathing
• An important concept to grasp:

• There are 2 control mechanisms in the body to control respiration.
• Central respiratory centers
• These are located in the medulla and respond to the level of CO2 in the blood. These are the
primary mechanisms the body uses to control respiration under normal conditions. Note that
they DO NOT respond to the O2 levels.
• CO2 does not act directly on the centers, they act indirectly via H. The CO2 in the
circulation combines with H2O to form H2CO3. This is able to diffuse through the blood
brain barrier and once in the CSF, the H2CO3 dissociates to H and HCO3. The H then acts
directly on the center to stimulate respiration. (This also suggests that an acidotic CSF, i.e.
low pH, can stimulate respiration.)
• However, under chronic hypercapnia, the CSF cannot keep this up, because the acidic CSF
will start to have bad effects on brain tissue. Hence, after prolonged hypercapnia, the body
adjusts by enabling HCO3 ions to pass through the blood brain barrier and buffer the H.
Hence, there will be an increase in pH due to a reduction in H and subsequently a loss of
central respiratory drive.
• However, peripheral chemoreceptors which were of secondary importance under normal
conditions now take up the role of the primary respiratory control center.
• Because hypercapnia invariably means a corresponding hypoxia, there will be a low O2 in
the blood, which stimulates the chemoreceptors to increase respiration.
• Note that hypercapnia always means that you have hypoxia as well, but hypoxia
does not necessarily mean you have hypercapnia.
• Why? Because the only way you can get hypercapnia is via hypoventilation or
airway obstruction. These conditions also lead to hypoxia.
• To get hypoxia without hypocapnia, you can have a low V/Q, so that ventilation is
reduced but blood perfusion is not. Therefore, CO2 can be removed from the blood
quite happily, but O2 does not enter the blood in great amounts. Another way of
getting hypoxia is via high altitude, where the PO2 in the air is less.
• This condition is known as hypoxic drive and is important in treatment because the only
thing keeping the person alive is their hypoxia. If you try to correct the hypoxia by giving
them O2, the PaO2 will increase and so the peripheral chemoreceptors will no longer be
stimulated. The respiratory rate drive will thus be abolished because the central mechanisms
need time to recover back to their old self. The patient will thus stop breathing.
• Peripheral chemoreceptors
• As mentioned above, peripheral chemoreceptors respond to PaO2. A fall in PaO2 results in

an increased respiratory rate.
• Peripheral chemoreceptors are located in the carotid bodies and aortic arch.
Conditions required for cyclic breathing (apnoeas)

1. The system must exhibit an apnoeic threshold for CO2
• This means that there must be a threshold level for CO2. Any level below this would result in a failure of the
central respiratory centers to become activated.
2. The ventilatory response to hypoxia and hypercapnia (hyperventilate) mediated by the central and peripheral
chemoreceptors must be great enough to drive the CO2 levels in the blood below the apnoeic threshold (point 1 above).
• In other words, you need a brisk carotid body response to have a strong ventilatory drive.
3. There must be sufficient hypoxia to activate the carotid body effectively.
Acute mountain sickness

• Acute mountain sickness occurs in people who travel to high altitudes quickly without having time to adjust to the low
O2 tension in the air (see lecture on hypobaric conditions).
• The person has recurrent bouts of central apnoea due to hypoxia, followed by excess ventilation (brisk carotid body)
which results in a decrease in CO2, depressing the central desire to breathe.
• Note that in this case, the initial hypoxia is not associated with hypercapnia because the airways are fine - it is just the
level of O2 which is decreased in the atmosphere.
• The reduction in the central respiratory centers results in cessation of breathing which gradually increases the levels of
CO2 in the blood to a level which allows resumption of breathing.
• People who live at high altitudes all their life are aclimatised to it. The physiological adaptations include:
• Less active (less brisk) peripheral chemoreceptors
• i.e. The body is able to cope with small degree of hypoxia.
• Increased red blood cells
• Increased pulmonary arterial pressure due to vasospasm of the pulmonary capillaries to match the ventilation
with perfusion.
• Enlarged right ventricle as a result of it working harder to pump blood against a high pressure pulmonary
circuit.
• Reduced arterial pressure due to a reduction in cardiac output.
THE BENDS AND HYPOBARIC MEDICINE
Hyperbaric conditions
• Hyper = High
• Baro = Pressure
• Therefore hyperbaric conditions are conditions where the ambient pressure (the pressure around our bodies) is greater
than normal.
• At sea level, the normal ambient air pressure is 1atm.
• 1atm = 760mmHg
= 101.3 kPa
= 1 Kg/cm^2
= 10 m below sea level
Boyle's law
• A number of gas laws have been devised but only some of these will be relevant to us.
• Boyle's law states that pressure and volume of a gas are inversely proportional.
• This means that as the ambient pressure increases, the volume of space a gas occupies is reduced (the gas is
compressed).
• This only applies if the gas is contained in an open container which will allow equalisation of pressure. If a gas
is in a sealed container, a rise in ambient pressure will not affect the pressure in the container. If the ambient
pressure rises to a level which greatly exceeds the pressure in the container, the container will be crushed.
• The body cavity housing the lungs is like an open container (provided we keep our mouth open - but
underwater that would not be very applicable).
• To overcome this pressure difference between the lungs and the ambient pressure in deep sea divers, the person
breathes air from a pressurised tank which delivers air at high pressures to the lungs. This enables the lung to be
at pressures equal to the ambient pressure.
Deep sea diving

• At 10m below the surface of the water, a person will be subject to an ambient pressure of 2atm.
• Recall above that 10m of water = 1atm.
• A person 10 below water will be subjected to a pressure of 1atm due to the water above him and also subjected to
another 1atm due to the air above the water. Hence, a total of 2atm.
• There is a linear relationship between pressure and depth.
• Therefore, at 20m the pressure will be 3atm, 30m a pressure of 4atm, etc...
• The fact that the diver will be breathing air at high pressures to keep the lung volume constant means that they will be
breathing an average of 6L of air (the same as on land since the lung volume is around 6L). However, 6L of air on land
contains much less air molecules than 6L of air under pressure (since the air molecules are squashed up closer to each
other). i.e. The air in the lungs is denser.
• We will see the results of this after considering other gas laws.
Physical effects
• At depths where the ambient pressure is very high, the pressure is large enough to cause the blood vessels to leak.
• The extreme pressures can collapse the teeth, causing dental fractures
Dalton's and Henry's law

• Dalton's law states that all partial pressures of a gas must add up to the total pressure of the gas as a whole.
• Air is not uniform. It is composed of a number of different gases, each with a partial pressure of its own. The total partial
pressures of the gases in air must add up to 1atm (760mmHg).
• The percentage of oxygen in air is 20%. Therefore the partial pressure of oxygen is:
• 20% of 1atm (760mmHg) = 0.2atm (152mmHg)
• This is what we normally breathe in every day, however the body does not use all of this 152mmHg of
oxygen.
• The partial pressure of oxygen in the alveolae/arterioles is 95-100mmHg.
• The partial pressure of oxygen in the venous blood is 40mmHg
• Is a diver who breathes 20% oxygen at a pressure of 20atm safe?

• 20% of 20atm = 4atm. (a huge 3000mmHg)
• Hence, the partial pressure of oxygen in the blood will be 4atm. This is obviously way too high because the
normal level is only 0.2atm.
• High levels of blood oxygen can lead to the formation of free radicals, especially superoxide.
• Therefore, a diver subjected to a pressure of 20atm must breathe air with an oxygen concentration of 1% to get
a partial pressure of oxygen at 0.2atm.
• 1% of 20atm = 0.2atm.
• What about a person at 0.5atm breathing air at 20% oxygen?
• 20% of 0.5atm = 0.1atm (76mmHg)
• This is clearly not enough
• Henry’s lay states that the amount of gas dissolved in a liquid is proportional to its partial pressure.
• As the partial pressure of oxygen increases the deeper you go down, more of it will dissolved in the blood.
• Therefore, when underwater, you will have blood which is supersaturated with oxygen and can only keep that
oxygen in solution provided that you remain at that pressure.
• If you rise to the surface too quickly, the gas comes out of solution and so you get bubbles forming in the circulation.
• This condition is known as decompression illness and comprises of 2 conditions:
• Arterial gas embolism
• The gas can literally burst through the capillaries in the lungs and enter the pleura, forming
a pneumothorax (air in the pleural cavity)
• The gas can also escape up the mediastinum and pass up into the neck.
• The bubbles will tend to rise up (gas rises) if you are standing, and this means that they head
towards the cerebral vasculature. This would result in an air blockage and prevent blood
from supplying some parts of the brain.
• Decompression sickness
• Decompression sickness involves mainly nitrogen.
• Nitrogen comes out of solution and is quickly absorbed by tissues which have high blood
flow.
• Nitrogen which is absorbed in the neurons can cause pins and needles, loss of sensations.
• Treatment of decompression illness is via a hyperbaric chamber which keeps the person at high pressures to
prevent gas from coming out of solution.
• The pressure in the chamber is then reduced slowly to allow the body to breathe out the extra gas that comes
out of solution in small amounts.
Hypobaric conditions (high altitude)

• In hypobaric conditions, the ambient air pressure is reduced below the normal 1atm.
• As you ascend, the ambient air pressure drops in a logarithmic manner (unlike hyperbaric conditions where the ambient
pressure increases linearly).
• At around 18 000 feet the ambient air pressure is 0.5 atm (360mmHg)
• I will continue on about the effects of decreased gas tensions later. Now, lets consider the body’s response when
subjected to acceleration forces.
Acceleration forces
• A good example to illustrate acceleration forces is with fighter pilots.
• As a pilot pulls out of a dive, he pulls positive g’s (to use pilot terminology).
• Positive g’s means that the body is subjected to a larger gravitational force that it would be on land. On land 1g
= 9.8m/sec2
• Say for example the pilot pulls 6g’s. This means that the body will feel as though it is in an environment where
the gravitational force is 6 times larger than on land. As a result, the blood in the body will feel 6 times heavier.
• The blood will pool in the veins of the legs and parts of the body above heart level will receive a reduced
cardiac output because the heart cannot pump the heavier blood effectively against the increased gravity. This
causes decreased blood flow to the brain and leads to what is known as a “black out”.
• At 4g’s the effect is not great enough to cause a black out but you will get a “grey out” (the vision goes hazy)
because the blood vessels of the eye, being externally located (the vessels of the brain are protected by the
skull), a subject to being compressed.
• To avoid black out’s the pilot must:
• Lie down to lower the head
• This reduces the height to which the heart must pump the blood to the head. Lying horizontally at the
level of the heart is best because the heart does not need to pump harder to counter the effects of
gravity.
• Valsalva manouver - contract leg and abdominal muscles
• These manouevers contract the muscles which in turn contract the veins. This forces the blood from
the veins and prevents them from pooling in the legs. Venous return is hence aided.
• These days, the suits worn by pilots have straps around the legs which contract when the pressures in
the cabin increase.
• A reduction in cardiac output leads to a decrease in blood pressure. Physiological mechanisms are initiated to correct the
condition:
Veins Arterioles Heart
Constrict Constrict Sympathetic stimulation to

increase strength and rate
of contraction
Aids venous return increases TPR Increases SV
Increased SV Increased CO
Increased CO
Increased blood pressure
Changes in air pressure

• The aircraft cabin is pressurised to equal the air pressure outside the plane.
• Because the air pressure at high altitudes is below normal, a cabin at normal pressure (1atm) would just blow the
plane apart because the cabin is high pressure compared to the outside air which is low pressure.
• If the plane suddenly descends quickly to a lower altitude, the air pressure will increase.
• The pilot may experience ear and forehead pain
• This is because there is a pressure difference between the cabin and the body cavities.
• The body cavity was initially at a low pressure altitude and so it had become equal to the low
pressure. However, doing a quick descent, the outside pressure rises too quickly and so the body
cavity pressure becomes less. This pressure difference affects the tympanic membrane most of all.
The hi pressure on the outside forces the tympanic membrane in.
• To counter this, breathing against a closed glottis (valsava) increases the pressure in the inner ear,
equalising the outside pressure.
• Unlike hyperbaric conditions, breathing concentrated (100% oxygen) is safe at high altitudes. This is because the
partial pressure of oxygen is quite low and if you were breathing normal air, a lot of the air is made up of wasted
nitrogen. We want to maximise oxygen content and so breathing 100% oxygen prevents wasted space in the
alveolae being occupied by gases other than precious oxygen.
• The situation is quite different underwater where the partial pressures of oxygen are high and so we need to be
careful not to get an oxygen overdose (oxygen toxicity) by breathing oxygen at a high concentration.
Altitude acclimatisation
• Increased ventilation
• Hyperventilation allows for an increased PAO2
• Since you are breathing more, you tend to blow off more CO2 and so PaCO2 is reduced.
• Polycythemia
• Hypoxic conditions stimulate erythropoietin release from the kidneys to increase the number of red blood
cells
• Increase in capillary recruitment in tissues and lungs
• Increases the diffusing capabilities because there is a greater surface area for oxygen to diffuse across
• Depression of central respiratory centers
• The reduced CO2 levels (and consequently and increase in pH - alkalosis) will initially inhibit the central
respiratory center. This opposes the effects of hypoxia which acts to stimulate the peripheral
chemoreceptors. Over time, the central respiratory center will not be responsive to CO2 levels any more
because HCO3- will start to diffuse out of the CSF to bring the pH of CSF down.
• No change in cardiac output
• There is an increase in HR but a decrease in SV due to the increased viscosity of blood (CO = HR × SV)
• There is a shift in the oxygen saturation curve to the left
• The oxygen saturation curve displays the percentage of oxygen bound to Hb at a given PaO2.
• Normally, a PaO2 of 60mmHg is sufficient to give a Hb saturation of 90%. However, below 60 the curve
starts to drop off rapidly.
• By shifting the curve to the left, a PaO2 of 50mmHg will enable a Hb saturation of 85%. Normally, a PaO2
of 50mmHg may only give a Hb saturation of 80%.
100
90
80
Hb saturation %
70
60
50
40
30
20
10
0
1 2 3 4 5 6 7 8 9 10 (×10)
11
Oxygen partial pressure (mmHg)
MUSCULAR FUNCTION
(PREVIOUSLY: ABNORMAL NEUROMUSCULAR FUNCTION 1& 2)
Muscle damage
• Muscle can be damaged in many ways and not all of them directly involve the muscle itself.
• Disease
• Can be progressive and chronic
• Acute or localised damage
• Direct mechanical damage
• Chemical damage
• From toxins in the blood
• Ischemia due to poor blood flow
• Neuropathies
• A muscle needs to be innervated in order to survive
Development of muscle
• Myoblasts fuse together to form primary myotubes. The plasma membrane of each myoblast cell fuses with another so
that the cytoplasm of each cell becomes continuous with the other.
• There may be more than one type of myoblast cell and myoblasts of the sane type group together to form
specific types of myotubes. e.g. Fast fatiguable myoblasts aggregate together to form fast fatiguable myotubes
which then develop into fast fatiguable muscle fibres.
• Primary myotubes act as the backbone on which more myoblast cells aggregate to form secondary myotubes which are
stuck to the primary myotube.
• A basal lamina surrounds the 1 and 2 myotube.
• 2 myotubes bud off (separate) from the 1 myotube and eventually becomes and individual muscle fibre with its own
basal lamina.
• Left over myoblast cells which are not incorporated into myotubes become satellite cells which lie between muscle fibre
and basal lamina.
• Satellite cells and basal lamina are important in the repair process of damaged muscle.
Muscle damage due to overactivity

• Muscle damage often results from overuse of eccentric contractions.
• Normal contraction mechanisms:
• Electrical stimulation of a muscle fibre causes Ca2+ to be released from the sarcoplasmic reticulum
• Ca2+ binds to troponin, a molecule which is bound to tropomyosin.
• The troponin-tropmyosin complex is wrapped around the actin filament and covers all the active sites on the
actin
• When Ca2+ binds to troponin, the troponin-tropmyosin complex undergoes a conformational change which
uncovers the active sites on the actin
• Myosin can then act on the active sites and cause contraction (provided ATP and Mg is around)
Muscle contraction
• Excitation of a muscle causes muscle contraction. This contraction can either shorten or lengthen the muscle.
• Normal contraction is associated with muscle shortening. However, the muscle can be lengthened provided that there is
an external force which is in the opposite direction to muscle shortening and also of greater force.
• An isometric contraction is when the external load has a force which is equal and opposite to the force of contraction.
Hence no movement will take place. If however, the tension in the muscle increases further so that it will exceed the
force of the load, you will get concentric contraction (muscle shortening)
• If the force of the load increases above the tension force in the muscle, the muscle will be stretched (lengthened) and
undergo eccentric contraction.
What happens to the muscle?

• With eccentric contraction, there is a delay in the onset of muscle soreness. Unlike a knife wound where the pain is
immediate.
• Stretching a muscle fibre causes stress on the plasma membrane, making them more leaky.
• This increases the permeability of the cell membrane and allows molecules to pass in and out of the muscle cell.
• The things that leak out of the cell into the plasma are used to test for muscle damage. These are:
• Creatine kinase (CK)
• There are many isoforms of this enzyme (one in skeletal muscle and one in cardiac muscle).
• Tests to analyze the levels of CK-skeletal in plasma can determine is muscle damage has occurred.
Tests for CK-cardiac can determine whether a heart attack has occurred.
• Myoglobin levels may be increased in the plasma
• There is a large concentration gradient for Ca2+ to leak into the cell, causing excess intracellular Ca2+ concentrations.
• Normal levels of intracellular Ca2+ stimulate contraction
• Excess levels saturate to ability of the sarcoplasmic reticulum to mop up Ca2+. The excess Ca2+ activates
enzymic pathways which can eat away at the sarcolemma (the plasma membrane of a muscle fibre).
• The cell will be trying very hard to pump out the excess Ca2+ but it has to do so against a large concentration
gradient. Heaps of ATP must be used.
• Over time, after the muscle has healed, remodeling of the muscle has effectively made the muscle more resistant to the
effects of eccentric contraction.
Muscle repair
• Muscle repair is dependent on an intact basal lamina and satellite cells.
• Muscle repair is essentially a repeat process of muscle formation.
• Satellite cells divide profusely to become myoblasts which aggregate at the site of muscle damage to patch
things up.
• The basal lamina is essential because it provides the template on which the myoblasts work with. The basal
lamina demarcates the boundaries of the muscle cell and so the myoblasts can only grow within those
boundaries.
• In cross section, a muscle fibre undergoing repair will have characteristic centrally located nuclei of the
myoblasts. When the myoblast fuse, the nuclei migrate to their usual peripheral location.
• In muscular dystrophy, there is heaps of muscle damage and subsequent repair. Sometimes you may get abnormal repair
where myotubes may branch out from the main fibre because the basal lamina was damaged.
Muscular diseases
• Exercise and direct trauma to muscle is handled relatively easily because we can then relate the muscle damage to
something tangible. However, muscle damage due to disease states is harder to comprehend.
• Diseases may damage:
• Muscle (myopathy)
• Nerve supply to muscle (neuropathy)
• Blood supply to muscle
• The most commonest form of muscular disease is muscular dystrophy, in particular Ducenne muscular dystrophy
(DMD)
Ducenne muscular dystrophy

• There is heaps of muscle destruction going on and subsequent repair.
• In a muscle biopsy, you can see fibres of small calibre with centrally located nuclei (indicative of a muscle in repair).
• As the disease progresses, you can see a variety of muscle fibre sizes and a large proportion of non contractile connective
tissue.
• As the disease progresses even more, you eventually run out of satellite cells and the muscle will be unable to repair
itself.
• In DMD, there is a selective targeting of large, fast fatiguable muscle fibres to destroy. These fibres are the ones which
generate the most force during contraction.
Mechanism of DMD
• In DMD, there is a genetic mutation which results in a lack of dystrophin being produced. (The gene for dystrophin is
poorly expressed).
• Dystophin is a protein bound to the inner surface of the sarcolemma.
• It alters the membrane properties by altering the membrane permeability. A lack of dystrophin results in
membrane fragility and so any slight eccentric contraction will damage the membrane and lead to an influx of
Ca2+.
• Other muscles can be involved, e.g. cardiac muscles and so DMD can lead to cardiac failure, although many die before
these abnormalities can take place.
• The most common cause is damage to the respiratory muscles.
Dystrophin is also present in neuronal membranes, so a lack of it can lead to abnormal neuronal functioning.
BLEEDING
Bleeding disorders
• Bleeding disorders can occur via 5 means:
1. Poor vascular structural integrity
2. Low platelet numbers
3. Poor platelet function
4. Disorders of blood clotting
5. Excessive fibrinolysis
Differences between a platelet plug and a coagulation plug

• A platelet plug if formed when there is damage to the endothelium.
• A coagulation plug is formed when you have a large scale damage, where platelet plugs are simply not enough to stop
blood loss.
• Hence, a platelet plug is formed either during minor or severe vascular damage.
• For minor damage, the platelet plug is enough to stop blood loss
• For severe damage, blot clot formation is required to strengthen the platelet plug and eventually replace the
platelet plug with a stronger fibrin clot..
Formation of a platelet plug

• Damage to the endothelial wall leads to the exposure of underlying collagen.
• VWF:Factor VIII complex attaches itself to the collagen and any platelets which come close, are attracted to the VWF
complex.
• The VWF:Factor VIII complex bind to a receptor site on the platelet membrane (glycoprotein Ib, GpIb).
• This allows for platelet adhesion.
• The platelet releases TxA2 which initially constricts the damaged blood vessel.
• Shortly later, the endothelial cells themselves release prostacyclin which acts to dilate the damaged blood vessel
(opposing the constrictor effects of TxA2)
• The platelets release TxA2 and ADP which plays a part in platelet aggregation, attracting more platelets to come and
help in the formation of the platelet plug.
Formation of a coagulation plug

• The platelet plug will suffice for minor injuries, but the plug itself is very unstable.
• For major injuries, after the formation of the platelet plug, coagulation starts to take place to gradually replace the platelet
plug with a stable fibrin clot.
• The initial platelet plug forms a surface for which coagulation can take place.
• There are 2 mechanisms for coagulation to take place:
• Extrinsic pathway
• Intrinsic pathway
• Both these pathways converge upon a common pathway
Differences in coagulation in arteries and veins

• Arteries:
• High flow rate in which the sheer forces can induce platelet aggregation.
• Platelets must be able to stop and adhere to the site of damage against a high flow rate. It does this by literally
"anchoring" itself to the damaged area. This is achieved by the link between VWF and GpIb on the platelet
membrane.
• Coagulation tends to form white clots because the high flow rate prevents RBC's from being trapped in the
fibrin mesh.
• Veins:
• There is a low flow rate and so the platelets do not have to fight against fast moving blood in order to remain
fixed to an area of damage.
• The platelets are able to bind directly to the collagen and also fibronectin, as well as anchor itself via VWF.
• Since the flow is low, RBC will be able to become trapped in the fibrin mesh, forming a red clot.
Tests which can be performed on a patient

• Visual examination and a detailed case history
• We need to know the extent of the bleeding and where it is one the body.
• Petechiae
• Small, little red, brown dots on the arm and legs due to structural changes in the vascular endothelium,
making them leaky.
• May be an indication of low circulating platelets because platelets are required to maintain normal
structural integrity of the endothelium.
• Purpura
• Patches of bleeding which goes into the tissues. A more severe form of petechiae.
• Hematoma
• Large bruises which go into the subcutaneous tissues to form a lump of blood under the skin.
• Often a result of poor coagulation.
• Excess blood can extravasate into the joints and large cavities and cause pressure effects as the blood
builds up.
• Platelet counts
• These are obtained to confirm any suspicions if we have a lengthened bleeding time, which would indicate low
levels of platelets.
• The normal values are 150,000 - 400,000 per mm3
• Bleeding times
• Measures how long it takes for a small pinpric to stop bleeding. Because the damage is tiny, coagulation is not
involved and so all we are measuring is how long it takes to form a simple platelet plug.
• Normal values are 2-4 min
• Coagulation times
• Prothrombin time
• Measures the time of the extrinsic and common pathways
• Normal times are 13-18 sec
• Partial thromboplastin time
• Measures the time of the intrinsic and common pathways.
• Normal times are 25-40 sec
• Specific tests
• e.g. radioimmunoassay for levels of a particular clotting factor we are interested in.
Causes of abnormal bleeding

• Structural abnormality (defect in the endothelium)
• Generally acquired.
• Can be due to corticosteroid treatment
• Corticosteroids break down the subcutaneous fat so people tend to bruise easier
• Inflammation
• Inflammatory reagents (often prostaglandins) cause the endothelium to become leakier than usual
• Immune reaction
• The endothelium can be attacked by the body's own immune system.
• Low platelet count
• Platelets are required for the integrity of the endothelium.
• Platelets
• Platelet dysfunction
• Failure of platelets to adhere
• e.g. Von Willerbrand's disease (lack of VWF) so platelets will be unable to bind to the site of
lesion.
• Failure of platelets to aggregate
• One of the processes that lead to positive feedback mechanisms which aid in aggregation are
deficient. e.g. abnormal granule formation. Remember that granules in the platelets give rise
to chemicals such as ADP, TxA2, serotonin which all aid in attracting more platelets to the
site.
• In this case there are normal numbers of circulating platelets.
• Thrombocytopenia
• Low platelet count
• Can be due to:
• increased production time from the megakaryocyte. The normal production time is 4 days
and this can be lengthened due to bone marrow failure or megakaryocytopoiesis (low
numbers of megakaryoctes in the bone marrow).
• Reduced survival time of platelets in the blood. Normal platelets can live up to 8 - 10 days.
An infection of autoimmune response which selectively destroys platelets can reduce their
lifespan.
• Normally, 20% of all circulating platelets are found in the spleen. Any disease state which
leads to an enlarged spleen will increase the percentage of platelets which are pooled in the
spleen (and hence reduce the percentage of circulating platelets). Therefore, proper physical
examination for enlarged spleen or liver can tell us a lot about the possible defects in
bleeding.
• Coagulation
• Deficient coagulation factor synthesis
• Abnormal coagulation factor synthesis
• Inhibition of coagulation factor activity
• All 3 of these may present with an abnormal clotting time
• An abnormal prothrombin time indicates a defect in the clotting factors which mediate the
intrinsic pathway. (Factor VII, X, V Prothrombin).
• An abnormal PTT time indicates a defect in the clotting factors which mediate the extrinsic
pathway (XII, XI, IX, VIII, X, V, prothrombin).
• A radioimmunoassay may indicate normal levels of coagulation factors, however functional
tests will enable us to determine if the factors are defective in any way.
• Excessive fibronolysis
• Activation of the plasmin system is greater than the rate at which fibrin is being made.
• Plasmin is an enzymatic molecule which dissolves the cross linking which holds the fibrin clot together, hence
making the clot weaker.
• Normally the ratio of antiplasmin:plasmin is 10:1.
• If this ratio is reduced (decrease in antiplasmin), then we have plasmin floating around waiting for a clot to
dissolve.
• The normal mechanism is that any free plasma is bound to antiplasmnin.
• Plasmin is derived from an inactive precursor - plasminogen. Plasminogen activator catalyses this conversion.
• If PA is excessively produced, we have increased levels of plasmin.
• If PA is not broken down quickly enough, we get prolonged action of PA in catalysing plasminogen to
plasmin, and hence we get excess plasmin. The liver is the site of PA breakdown and so liver diseases
can lead to this disorder.
The role of the liver in affecting the levels of coagulation factors

• What can cause a lowered blood level of coagulation factors?
• Diseased liver
• The liver is the site of production for nearly all of the clotting factors (I,II, V, VII, IX, X, XI, XII,
XIII).
• The only exception is Factor VIII which is derived from the site of injury by endothelial cells or via
platelets.
• Poor gene expression of a gene coding for a coagulation factor
• Hemophilia A
• Known as classic hemophiia & Von Willerbrand's disease
• Due to a deficiency of factor VIII and VWF
• Hemophilia B
• A deficiency of factor IX
• Deficient vitamin K absorption in the terminal ileum.
• The clotting factors which are dependent on Vit K for their proper formation are the so called "TV
factors" because they represent the TV channels we see.
• The factors are: II, VII, IX, X.
• What does vitamin K do?
• Vit K acts as a cofactor in the reaction which adds a carboxylate group to the gamma carbon
of glutamic acid which is present in each of these factors. This allows for Ca to be able to
bind and affect the factor’s function.
• It just so happens that the same TV factors need Ca2+ in order to work effectively (hence the
need for the gamma carboxylation
Causes of vitamin K deficiency

• Inadequate intake of green leafy vegetables
• Rare that this would cause Vit K deficiency because bacteria in the gut is also capable of making Vit K for us.
In the newborn, the baby is reliant on the vitamin K stores it has gotten from the mother in utero (because the
gut is sterile). Hence mothers who don't have vitamin K adequately during pregnancy can give birth to a child
with vitamin K deficiency. This is no problem, so long as the baby does not die. If during the labour process it
gets any form of hemmorhage, the baby may very well die because it literally bleeds to death.
• Depletion of tissue stores of vitamin K
• Obstructive jaundice
• No bile acids entering gut so no reabsorption of fat soluble vitamins in the terminal ileum
ANAEMIA
• Anaemia is defined as poor oxygen transport to tissues which is insufficient for the tissue’s metabolic needs.
• In the population, the hemoglobin values form a normal distribution, with 5% of the population having Hb levels
below normal.
• Normal hematological values which need to be remembered are:
Hb concentration:M 13-18 g/100ml
F 11-16 g/100ml
Hematocrit: M 42 - 52 %
F 37 - 47 %
Mean cell volume 90 ± 8
Mean cell Hb conc 34 ± 2
Mean cell Hb 30 ± 3
• In very young children, the Hb concentration is higher than normal

• In elderly, Hb concentration is lower than normal
• Low values indicate anaemia. High values indicate polycythemia
• If the Hb concentration drops below normal, many people can still function normally due to compensatory
mechanisms. There is only a problem if you have physical exertion which required increased oxygen demand from
the tissues.
Compensatory mechanisms
• Compensatory mechanisms ensure that the major organs have adequate oxygenation.
• The various compensatory mechanisms are:
• Flow distribution
• Shunting of blood away from minor organs an distributing them to major organs.
• Major organs are:
• Heart
• Brain
• Muscle
• Minor organs are
• Kidney
• Skin
• Gut
• The shunting is coordinated by the ANS and local vasoconstriction
• One of the first signs is loss of blood supply to the tongue, so a diagnostic feature is to look at the
tongue to see if it is a healthy pink colour or pale, indicating anaemia.
• Oxygen extraction
• The oxygen saturation curve is shifted to the right
• This enables more efficient unloading of oxygen from the Hb to tissues
• This is due to the increased production of 2,3BPG
• Erythropoeitin production
• Decreased oxygen saturation of the blood results in the kidneys to release erythropoeitin (epo).
• Epo acts on the bone marrow to increase the production of more RBC
• Also stimulates the release of reticulocytes (immature RBC) into the circulation
• Ventilation
• Reduced Hb can result in an increase in pCO2, which stimulates the central respiratory center to
increase respiration.
• Reduced pO2 stimulates the peripheral chemoreceptors only if the oxygen saturation drops below
60mmHg
• Cardiac output
• Low blood viscosity due to low RBC
• Increased HR, SV resulting in increased CO
Compensation in anaemia
• Moderate anaemia ( 8 - 10 g/100ml)
• Blood shunting
• Increased levels of 2,3 BPG
• Severe anaemia (< 8 g/100ml)
• Same as above but increased HR (tachycardia)
• Hyperventilation
Clinical tests
• Clinical tests measure the values shown in the table on pg. 1
• In addition to those values, other values measured are:
• Reticulocyte count
• Increased levels of anucleate reticulocytes but they still have mRNA
• Fe concentration
• Measured if suspect iron deficiency
• RBC turnover (normal is 120 days)
• Faster turnover indicates hemolytic anaemia
• Transferrin levels
• Bone marrow morphology
Classification of anaemia
• Hypoproliferative
• Reduced levels of erythropoeitin due the renal disease
• Iron deficiency (most common one)
• Due to chronic bleeding
• Lack of Fe in the diet
• Results in microcytic, hypochromic RBC
• Bone marrow damage
• Due to toxins, drugs
• Maturation abnormality
• Megaloblastic
• Lack of vitamin B12, folate
• Large, immature RBC
• Normoblastic
• Normal sized RBC
• Due to growth of fibrous tissue in the bone marrow, resulting in the decreased capability of
marrow to produce RBC
• Microcytic
• Thalassemia
• Sideroblastic anaemia
• Due to lack of vitamin B6 in the diet (pyridoxal)
• Pyridoxal is required for the formation of the protoporphyrin ring
• Results in the inability to incorporate iron into protoporphryin to form heme due to a
lack of protoporphyrin (as opposed to iron deficiency microcytic anaemia where the
limiting factor was iron)
• Hemolytic anaemia
• RBC turnover of less than 120 days
• Autoimmunity (phagocytosis of RBC)
• Lack of vitamin E, resulting in increased membrane fragility
• Fragmentation
• Intravascular clotting traps RBC in the fibrin mesh
• Intravascular hemolysis
• H2O toxicity resulting in reduced osmolality of blood. Fluid enters RBC due to osmotic balance,
causing the RBC to burst
• Heat stress
Clinical classification of anaemia

• Microcytic ↓ MCV
• Hypochromic ↓ MCHC
• Normocytic normal MCV Due to acute blood loss, hemolytic anaemia

• Normochromic normal MCHC (i.e. RBC are normal in morphology)
Use if the reticulocyte index

• Level of reticulocytes in circulating plasma
• Normal values are 1 -1.5 %
• If the reticulocyte index is > 3 % then this indicates hemolytic anaemia
• Why????
hemolytic anaemia breaks the
↑ RBC cycle here
↑ erythropoeitin ↑ Hb
-ve feedback
Kidney detects low O2 saturation
• Increased epo levels, in addition to increasing the levels of RBC, also increase the levels of reticulocutes. If you
have hemolytic anaemia, the RBC are destroyed earlier and so cannot feedback on the kidney to tell it to stop
releasing epo. Hence, the kidney continues to produce epo, resulting in a high reticulocyte index.
End of Volume IV
5D=PbO "HH
'KHGO

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1996 Integrated Body Function 536-022: Volume III By Duy Thai

2nd Year Medicine Page 1 of 24

Integrated Body Function

TOPIC PAGE NO.

ACID BASE METABOLISM

pH...........................7.35 - 7.45 (7.4)

• NH4+ can also be produced by the metabolism of glutamine in the tubular

• PaCO2 levels are low (primary disorder)

Arteriolar end Pc πc Venous end

Clinical cases - Pulmonary oedema

Clinical cases - Pneumonia

Loss of the vascular bed

• Obstruction from pulmonary emboli

SLEEP RELATED BREATHING DISORDERS

Obstructive sleep apnoea

Cardio-respiratory effects of obstructive sleep apnoea

Central sleep apnoea

Why does this occur?

Hypoxia/high CO2 levels

Central respiratory centers activated

Blow off too much CO2 leading to

• An important concept to grasp:

• As mentioned above, peripheral chemoreceptors respond to PaO2. A fall in PaO2 results in

Conditions required for cyclic breathing (apnoeas)

Acute mountain sickness

THE BENDS AND HYPOBARIC MEDICINE

Deep sea diving

Dalton's and Henry's law

• Is a diver who breathes 20% oxygen at a pressure of 20atm safe?

Hypobaric conditions (high altitude)

Veins Arterioles Heart

Constrict Constrict Sympathetic stimulation to

Aids venous return increases TPR Increases SV

Increased blood pressure

Changes in air pressure

Muscle damage due to overactivity

What happens to the muscle?

Ducenne muscular dystrophy

Differences between a platelet plug and a coagulation plug

Formation of a platelet plug

Formation of a coagulation plug

Differences in coagulation in arteries and veins

Tests which can be performed on a patient

Causes of abnormal bleeding

The role of the liver in affecting the levels of coagulation factors

Causes of vitamin K deficiency

• In very young children, the Hb concentration is higher than normal

Clinical classification of anaemia

• Normocytic normal MCV Due to acute blood loss, hemolytic anaemia

Use if the reticulocyte index

Kidney detects low O2 saturation

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