14. Hypoxia

Question 1

State the 3 main oxygen delivery calculations

Answer 1

Oxygen delivered = cardiac output (litres/min) * oxygen content (ml/litre)

(O2delivered = CO * O2content)

Oxygen uptake/consumption = cardiac output (litres/min) * arterio-venous difference (60ml)

(O2uptake = CO * AVdifference)

Respiratory quotient (R.Q.) = carbon dioxide output / oxygen uptake

(RQ = CO2output / O2uptake)

Question 2

Outline hypoxia

Answer 2

Hypoxia: lack of oxygen

Hypoxaemia: reduced arterial oxygen (also known as hypoxic hypoxia):

o If arterial PO2 is < 10.7kPa, 80mmHg

o If arterial O2 saturation is < 93%

o If arterial O2 content is reduced (i.e. the ml O2 per 100ml blood reduced)

Cause: alveolar hypoventilation; this may be due to impaired gas exchange in the lung, or reduced barometric pressure (which occurs at high altitude)

There are other causes of hypoxia where the arterial PO2 oxygen saturation and content are normal (i.e. non hypoxaemic hypoxia)

These include:

o Anaemic hypoxia

o Stagnant hypoxia

o Histotoxic hypoxia

Compensatory mechanisms of the body for hypoxia include:

o Alveolar hyperventilation

o Increased cardiac output

o Improved pulmonary perfusion

o Changes in regional blood flow

o Polycythaemia

o Anaerobic metabolism

Question 3

Outline polycythaemia

Answer 3

An abnormally increased concentration of haemoglobin in the blood, either through reduction of plasma volume or increase in red cell numbers

It may be a primary disease of unknown cause, or a secondary condition linked to respiratory or circulatory disorder or cancer

Question 4

Outline gaseous transport and exchange within erythrocytes

Answer 4

Oxygen is transported around the body in erythrocytes, bound with Hb to form HbO2

Some CO2 is sequestered (isolated/stored) in erythrocytes and bound with Hb to form HbCO2, but most CO2 is transported in the blood plasma as bicarbonate ions (HCO3- )

Question 5

Outline gaseous transport and exchange within erythrocytes in the lungs

Answer 5

O2 in:

• Inhaled O2 diffuses across from the alveolar wall across the pulmonary capillary wall and is taken up by red blood cell:

o It is then bound with Hb (previously bound to a H+ ion) to form HbO2, displacing the H+ ion

CO2 out:

• CO2 bound with Hb is released from the Hb molecule and the erythrocyte, diffusing across the pulmonary capillary wall into the alveolus, where it is then exhaled:
• HCO3- ions that have been transported in the blood plasma from the tissues is taken up by the red cell; the H+ ion (that was previously displaced from the HbH molecule on oxygen binding) then binds with the bicarbonate ion to form H2CO3 (hydrogen bicarbonate):

o This is then dehydrated by carbonic anhydrase to form CO2 and H2O

o Via coupled transport, using the chloride shift of Cl- ions into the red cell, this CO2 is then released from the erythrocyte back into the plasma, where it diffuses across the pulmonary capillary wall into the alveolus where it is exhaled

Question 6

Outline gaseous transport and exchange within erythrocytes in the tissues

Answer 6

O2 out:

• H+ ion displaces oxygen from oxyhaemoglobin:

o It is then released from the red cell into the blood plasma where it diffuses across systemic capillary walls into the tissue cell

CO2 in:

• CO2 diffuses out of the tissue cell, across the systemic capillary wall across the blood plasma, where coupled with the chloride shift, it is taken up by the red cell:

o Some of the CO2 is then sequestered by haemoglobin to form carbamino-Hb; this reaction releases oxgen from the Hb molecule

The rest of the CO2 then binds with a water molecule to form H2CO3 (involves carbonic anhydrase):

o This hydrogen bicarbonate then dissociates to form HCO3- and H+ ions

o The HCO3- are then released by the red cell into the blood plasma, where they are transported back to the lungs

Question 7

Outline haemoglobin

Answer 7

Molecular weight is 64.5kDa

Globular protein; consists of two alpha and two beta
polypeptide globin chains:

o Each chain has an associated haem molecule
comprising a prophyrin and ferrous ion (Fe2+)

Each haemoglobin molecule can combine with 4
molecules of oxygen

In deoxyhaemoglobin, there are tight electrostatic
bonds between the globin chains; the haem molcules are placed in crevices within the tight conformational shape, and have a low affinity for oxygen; this means that at low surrounding partial pressures of oxygen, the increase in Hb oxygen uptake for increased pO2 is small

However, once one molecule of oxygen is taken up,
there is a conformational change in the Hb molecule; this renders the other oxygen binding sites very easily accessible, leading to a steep increase in Hb, therefore oxygen uptake for small pO2 increases, producing a sigmoidal-shaped oxygen dissociation curve

Other factors leading to changes in the binding of oxygen to the haem group are: pH, pCO2, temperature, concentration of 2,3-diphosphoglycerate (DPG)

Oxygen dissociation curve:

o Bohr effect - shown by the red line on the graph; a decrease in oxygen affinity of deoxyhaemoglobin
is seen when pH decreases or pCO2 increases

o Haldane effect - describes how O2 displaces CO2 from Hb, i.e. oxygenated blood has a reduced carbon dioxide carrying ability, and vice versa

Question 8

Outline ‘Daltons’ (the unit of molecular weight)

Answer 8

The unified atomic mass unit or dalton (symbol: u, or Da) is a standard unit of mass that quantifies mass on an atomic or molecular scale (atomic mass)

One unified atomic mass unit is approximately the mass of one nucleon (either a single proton or neutron) and is numerically equivalent to 1 g/mol

Question 9

Outline factors which affect the oxygen affinity of Hb

Answer 9

Factors which decrease oxygen affinity:

• pH ↓
• pCO2 ↑
• Temperature ↑
• Anaemia
• Pregnancy
• 2,3-bisphoglycerate (DPG) ↑

> This leads to a shift in the oxygen dissociation curve to the right

Factors which increase oxygen affinity:

• pH ↑
• pCO2 ↓
• Temperature ↓
• Store blood
• Foetal blood
• 2,3-biphoglycerate (DPG) ↓

> This leads to a shift in the oxygen dissociation curve to the right

Question 10

Which directional change on an oxygen dissociation curve results in a decrease in affinity for O2?

Answer 10

A shift to the right

Question 11

Which directional change on an oxygen dissociation curve results in an increase in affinity for O2?

Answer 11

A shift to the left

Question 12

Outline the effect of exercise on gaseous transport and exchange in the erythrocyte

Answer 12

The increased production of CO2 with exercise leads to an increase in the tissues of PCO2 and fall in pH

This reduces oxygen affinity and increases oxygen release.

The disadvantage of this change in affinity leads to a reduction in oxygen uptake in the lung, and a fall in
arterial PO2:

o This disadvantage is offset by the increase in ventilation associated with exercise which reduces a rise in
alveolar PO2 and prevents a fall in oxygen saturation

Question 13

Outline the effect of carbon monoxide (CO) on gaseous transport and exchange in the erythrocyte

Answer 13

Carbon monoxide affinity for Hb is 250x higher for Hb than Oxygen

In the presence of CO, the oxygen dissociation curve is shifted to the left (high affinity) impairing oxygen unloading in the tissues, therefore leading to ischaemia (dangerous)

Note the lower affinity in anaemia (low Hb) and the difference in shape

Question 14

Outline the effects of high altitude on hypoxia

Answer 14

Hypobaric hypoxia

An increase in altitude leads to a decrease in pO2, resulting in a decrease in pO2(alveolar) and pO2(arterial), leading to reduced oxygenation of arterial blood

Respiratory response:

• To ensure an adequate uptake of oxygen in the lungs at the reduced PaO2, alveolar ventilation increases and there is an increased arterial oxygen affinity:

o This leads to a fall in PaCO2, with an associated rise in pH

• The rise in pH is known as respiratory alkalaemia, and its effect is to stop the respiratory response to hypoxaemia:

o This means that over the next few days at high altitude renal compensation for the alkalaemia leads to a return of the pH to normal, removing the inhibition of breathing

• The result is a further increase in alveolar ventilation and rise in PaO2; oxygen affinity tends to return to the same level as that which operated at sea level due to correction of the alkalaemia due to renal compensation, and increased production of 2-3,DPG

Question 15

Outline there role of 2,3-bisphoglycerate

Answer 15

Binds deoxyhaemoglobin in the tissues leading to its increased production via bisphoglycerate synthase, leading to its accumulation in erythrocytes

Question 16

Outline the acclimatisation of lowlanders to areas of high altitude

Answer 16

In Lowlanders (residents at sea level)m the ventilatory response to hypoxia at altitude does not restore the PaO2 to sea level, leading to hypoxaemia, resulting in feeling unwell with headaches, anorexia, photophobia and poor sleep

These symptoms are often mild but when severe the condition is referred to as Acute Mountain Sickness (AMS)

Acclimatisation occurs over the next 2 to 10 days with resolution of symptoms and improved physical and mental performance; it is associated with a gradual rise in ventilation and PaO2

At altitudes above about 5500m (18,000ft) the strength of the hypoxic stimulus leads to a marked respiratory alkalaemia with increased oxygen affinity and uptake of oxygen in the lung; however this impairs unloading of oxygen in the tissues and limits exercise capacity

The initial unpleasant effects of ascent to altitude can be improved by slowing the ascent; drug prophylaxis against the unpleasant effects is achieved with acetazolamide leading to a mild metabolic acidosis with respiratory compensation and a rise in PaO2

Question 17

Outline HAPE and HACE

Answer 17

HAPE: High Altitude Pulmonary Oedema

HACE: High Altitude Cerebral Oedema

Serious medical emergences; untreated mortality of about 50%

Approximately 1% of lowlanders suffer from these conditions; usually proceeded by AMS

Patients with HAPE suffer from severe breathlessness, dry cough, chest pain and occasionally with haemoptysis

A chest X-ray shows patchy pulmonary oedema

The alveolar hypoxia leads to reflex pulmonary artery constriction and pulmonary hypertension
which may lead to right heart failure.

It is assumed that the oedema is due to ‘Capillary Leak’ due to endothelial damage from hypoxia

There is no evidence of left ventricular failure

HACE usually follows AMS with severe headache, impaired cognition and physical function with clouding of consciousness which may proceed to coma; upon ophthalmoscopy, retinal haemorrhages are often seen and less commonly papilledema (optic disc swelling)

Successful treatment of HAPE and HACE depend on transferring the patient on oxygen to the lowest possible
altitude in the shortest possible time

Nifedipine is used in HAPE because it leads to relaxation of pulmonary artery smooth muscle and reduction in pulmonary artery hypertension

Question 18

Define haemoptysis

Answer 18

Haemoptysis is the coughing of blood originating from the respiratory tract below the level of the larynx

Question 19

Outline respiratory failure (RF)

Answer 19

RF is associated with a failure of alveolar ventilation and/or gas exchange

The limits defining failure are an arterial oxygen tension, less than 60 mmHg (8 kPa) and a carbon dioxide tension above 50 mmHg (6.7 kPa), the patient being at rest and breathing air

Question 20

Outline the 3 groups/types of respiratory failure

Answer 20

Type 1 Hypoxaemic failure:

• A disturbance of ventilation to perfusion relationships (leading to gas exchange problem) within the lung, whilst overall alveolar ventilation remains normal (point B):

o Low PaO2

o Normal (or low) PaCO2

Type 2 Ventilatory failure:

• A condition results from alveolar hypoventilation:

o Raised PaCO2

o Low PaO2 (point A)

Type 3 Combined hypoxaemic and ventilatory failure:

• In which features of type 1 and 2 are mixed, the defect including both alveolar hypoventilation and a disturbance of ventilation-perfusion (V/Q) relationships within the lung:

o Raised PaCO2

o Low PaO2 (point C)

In a normal ventilated lung, the arterial PO2 and PCO2 are inversely proportional, a result of which is the linear
relationship shown on the graph

Therefore, if PCO2 goes up due to alveolar hypoventilation, PO2 goes down (vice versa for hyperventilation); this allows type R failure to be identified easily as it will fall on the same linear relationship:

NB: if PCO2 and PO2 are added at any point on the graph, they will come to the same value (approximately 16kPa); this is very useful for characterising type 2 failure

[See http://www.icsmsu.com/exec/wp-content/uploads/2011/12/ABS-Respiratory_System.pdf Page 66 for the references graph]

Question 21

Outline the V/Q relationship

Answer 21

Ventilation-perfusion relationship

NB: V/Q

‘V’ - ventilation; the air which reaches the alveoli

‘Q’ - perfusion; the blood which reaches the alveoli

Question 22

Outline CO2 dissociation with regards to the V/Q relationship

Answer 22

The increase in partial pressures of CO2 leads to an increase in PaCO2

This relationship is nearly linear

N is the PCO2 and CO2 content of blood leaving a normal lung with normal V/Q ratios averaged at 0.8 (see N in the figure)

In diseases of the lung there are low V/Q areas (H) and normal and high V/Q areas (L)

When blood from these areas mixes in the left side of the heart the areas of high V/Q compensate for the low V/Q areas

This results in an arterial PCO2 that is slightly raised by within the normal range

This normality is achieved because the CO2 dissociation curve is nearly linear and also because any rise in PCO2 stimulates the chemoreceptors leading to an increase of ventilation of the high V/Q areas

[See http://www.icsmsu.com/exec/wp-content/uploads/2011/12/ABS-Respiratory_System.pdf Page 67 for the reference figure]

Question 23

Outline O2 dissociation with regards to the V/Q relationship

Answer 23

Consider two equal volumes of blood with the same gas with Po2 of 80 mmHg (10.7 kPa); each aliquot will have an oxygen saturation of 95% (point N)

Equilibrate one with a gas of PO2 of 40 mmHg (5.3 kPa) and the other with a Po2 of 120 mmHg (16 kPa); the mean tension is still 80 mmHg (10.7 kPa)

If the O2 dissociation curve was linear, one would expect that when the two bloods were mixed the resulting tension and saturation would be 80 mmHg (10.7 kPa) and 95%

However, an increase in PO2 to 120mmHg only raises the saturation by 4% (point H), and a decrease to 40mmHg lowers the saturation by 20% (point L)

When the two equal volumes of new blood (point H + L) are mixed anaerobically, the O2 tension (pressure) and saturation of the mixture are 53 mmHg (7.1 kPa) and 86.5% respectively (point F):

o This is because the increase in oxygen saturation, and, therefore, oxygen content (ml of O2 per 100ml of blood) of sample H is less than the fall in O2 saturation of sample L

o This result outside the normal range is due to the sigmoidal shape of the oxygen dissociation curve

[See http://www.icsmsu.com/exec/wp-content/uploads/2011/12/ABS-Respiratory_System.pdf Page 67 for the reference figure]

Question 24

Outline air travel with regards to the V/Q relationship

Answer 24

The pressurisation of cabins is equivalent to breathing 15% of oxygen at sea level

This has no adverse effects in people free of respiratory and cardiovascular disease; in patients with lung disease or respiratory muscle weakness it may be necessary to arrange for in-flight O2 availability

Assessment for need of in-flight oxygen is usually based on the arterial oxygen saturation (measured by
pulse oxymeter) and the FEV1

The recommendations of The British Thoracic Society are (at sea level):

o O2 saturation of >95%; not required

o O2 saturation of 92-95%, with FEV1 > 50% predicted; not required

o O2 saturation of 92-95%, with FEVl < 50% predicted; perform the hypoxic challenge test

o O2 saturation of <92%; O2 required

Question 25

Outline the hypoxic challenge test with regards to air travel

Answer 25

Hypoxic challenge test: patient breathes an inspired O2 of 15% through a mask for approximately 20 min with arterial blood gases measured at the start and end:

o If the oxygen saturation falls to 85% and the PaO2 to below 6.6 kPa in-flight O2 is recommended:

o No in-flight oxygen is required if the PaO2 remains above 7.4 kPa

o This leaves a borderline range of 6.6 to 7.4 kPa when it is helpful to add one of the walk tests to the
assessment of the need for in-flight oxygen

A walk test, which is judged as satisfactory on clinical grounds, would obviate the need for in-flight oxygen