Sc04 L04 Gaseous Diffusion and Transport 2

02 February 2012 17:03

How does increased CO2 or lactic acid affect haemoglobin? decreases haemoglobins affinity for O2

Decreases pH which

With increases in CO2 or lactic acid, pH decreases. This changes haemoglobins affinity for O2 (decreases). Hyperventilation doesnt improve O2 delivery to blood. Doesnt change saturation.

What affects the quaternary structure of haemoglobin? PCO2, pH, temperature What does this result in? Changes in affinity of haemoglobin for oxygen How does increased PCO2 shift the curve? Towards the right, Bohr shift What else can cause this shift? Fall in pH, increase in temperature, increase in 2,3-DPG Why is this beneficial as arterial blood flows into tissue capillaries? Haemoglobin exposed to reduced PO2 and decreased pH, increased temperature, etc (in active muscle) and so affinity for oxygen is reduced and oxygen is released Why is this beneficial in the lungs? Reverse changes happen as PCO2 falls, pH rises and temperature falls. Affinity of haemoglobin for oxygen rises aiding oxygen uptake What is the haemoglobin graph shaped like and why? Sigmoid curve which steepens because the 2nd haem group binds O2 more readily due to conformational change caused by previous binding Notes on oxyhaemoglobin dissociation curve shifts The quaternary structure of haemoglobin is altered by changes in PCO2, pH and temperature and this in turn affects the affinity of haemoglobin for oxygen. Increased PCO2 reduces the affinity of haemoglobin for oxygen, so that at any given PO2 the oxygen saturation reduced. This is reflected by a 'rightward' shift of the oxyhaemoglobin dissociation curve, known as the 'Bohr shift'. A fall in pH, an increase in temperature and a rise in the red cell metabolite 2,3 diphosphoglycerate also cause a rightward shift of the oxyhaemoglobin dissociation curve. As arterial blood flows into the tissue capillaries the haemoglobin is exposed to a reduced PO2 and this causes the haemoglobin to release oxygen. At the same time the haemoglobin is also exposed to increased PCO2, reduced pH and if the tissue is metabolising heavily (e.g. skeletal muscle in exercise) there will also be an increased temperature. These changes will reduce the affinity of haemoglobin for oxygen, aiding unloading of oxygen. In the lungs the reverse changes happen as PCO2 falls, pH rises and temperature falls. The affinity of haemoglobin for oxygen rises, aiding the oxygen uptake that is occurring as the blood is exposed to increased PO2 in the alveolus Double pressure doubles dissolved oxygen (in plasma). With haemoglobin, there is a sigmoid curve which steepens because the 2nd haem group binds O2 more readily due to conformational change due to previous binding. How does the graph change with anaemia and CO poisoning? With anaemia, shifts down, still sigmoidal. With CO poisoning, shifts down, less sigmoidal, steeper curve at lower O2 content

No O2 saturation scale as patients would have different saturations. At point B, high enough to match O2 needs exercise intolerance, breathlessness in exertion, fine at rest.

What does normal HbA consist of? 2alpha, 2beta protein chains What about HbF? 2alpha, 2gamma protein chains What about myoglobin? Single haem group and protein chain

Hyperbolic, no cooperative binding What is cyanosis? Blue tinge in a tissue due to high conc of deoxyHb What is peripheral cyanosis? Reduced blood flow to regions Arterial O2 content is decreased in this, T/F?False, it may be normal. What are the causes of cyanosis? Local obstruction or (more commonly) low CO What does cyanosis depend on, high percentage or high content of deoxyHb? Absolute concentration What is central cyanosis? Arterial hypoxaemia buccal mucosa and lips are best sites How much deoxygenated haemoglobin would the arterial blood contain for cyanosis to be observable? >15-20g/l At what O2 saturation does this occur? About 85-90% if [Hb] is normal (150g/l) In what patients does it appear more easily (at higher O2 sat)? In polycythaemic patients Why is central cyanosis impossible in severe anaemia? It would require an O2 saturation incompatible with life
Cyanosis is a blue tinge in a tissue due to a high concentration of deoxygenated Hb Peripheral cyanosis = reduced blood flow to region(s) Arterial O2 content may be normal

Usually low CO rather than local obstruction High absolute concentration of deoxyhaemoglobin, it isnt the percentage that matters.
Central cyanosis = arterial hypoxaemia - buccal mucosa and lips are best sites. When the arterial blood contains >15-20g/l of deoxygenated haemoglobin cyanosis is observable even in well-perfused tissues. Occurs when O2 saturation = about 85-90% if [Hb] normal (150g/l)

It appears more easily (higher O2 saturation) in polycythaemic patients. In severe anaemia central cyanosis is impossible as it would require an O2 saturation incompatible with life.

High O2 levels damage lungs = toxic Notes on 'The Oxygen Cascade' One of the main roles of the cardiovascular and respiratory system is to deliver oxygen to the mitochondria of the tissue cells where it is used. Fortunately, they evolved to work in quite a low PO2 environment and need local tissue PO2 to be kept above about 0.3kPa (2mmHg) to keep working. Normal tissue PO2 is about 2-5kPa (15-40mmHg) The process of delivering oxygen from the air (PO2 about 21kPa to the tissues and their mitochondria involves a series of step falls in PO2 as shown in the diagram. Previously viewed as the inevitable inefficiency of the system, it may be a necessary process to 'step down' the PO2 to provide the correct tissue PO2 and protect the cells from the effects of a PO2 that is too high. (Life on earth emerged in a very low PO2 atmosphere.) However, too low a PO2 is also obviously harmful and the diagram also helps us understand the places where problems may lead to tissue hypoxia. Carbon dioxide carriage Dissolved CO2 Solubility CO2 = 0.0052 ml.ml-1.kPa-1 Ie. 20 times more soluble than O2 In normal arterial blood, PCO2 = 5.3 kPa Therefore dissolved CO2 = 0.0274 ml.ml-1 Carbonic acid - bicarbonate

Reaction 1 is slow in plasma but fast in RBC because of presence of carbonic anhydrase (c.a.) Rightward reaction aided by buffering of [H+] by Hb Bicarbonate formed within the RBC diffuses out down its concentration gradient into the plasma in exchange for Cl- (the chloride shift)

HCO3- diffuses out down concentration gradient

Carbamino Compounds RNH2 + CO2 <=> RNHCOOH e.g. lysine, arginine side chains Mostly formed with haemoglobin (Hb) a little with plasma proteins Reaction affected by oxygenation of Hb, little affected by PCO2 CO2 not competing with O2 Haldane effect = at any given PCO2 the quantity of CO2 carried is greater in deoxygenated blood than in oxygenated blood. Due to: 1. Hb forms carbamino compounds more readily when doxygenated 2. Hb is a better buffer when deoxygenated. Therefore increased formation of HCO3Relative importance of mechanisms of CO2 carriage Of the CO2 evolved at the mouth, about: 60% comes from HCO330% comes from carbamino compounds 10% comes from dissolved CO2

Breathing air (CO2-free), alveolar and therefore arterial PCO2 is determined by the balance between CO2 production and alveolar ventilation:

Hypercapnia = high PaCO2 due to hypoventilation (possible causes of hypoventilation are head injury, anaesthetics, drugs, chronic lung disease)

The effects of a high PCO2 are: Flushed skin Full pulse, extrasystoles BP often raised Muscle twitching, 'hand flap' Very high PaCO2 (>10kPa or 75 mmHg) result in: Confusion Convulsions Coma Depressed ventilation (positive feedback, increases PaCO2) Death Hypocapnia = low PaCO2 due to hyperventilation (caused by: anxiety, pain, low PaO2, acidosis, excessive mechanical ventilation) Symptoms: Dizziness, visual disturbances, pins and needles, still muscles, tetany (all especially in hands and feet) Mechanisms: Low PaCO2 --> Cerebral vasoconstriction --> Cerebral hypoxia Low PaCO2 --> alkalosis --> plasma *Ca2++ --> nerve and muscle excitability