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1. OXYGEN CASCADE OXYGEN FLUX OXYGEN HEMOGLOBIN DISSOCIATION CURVE MODERATOR – DR ASHWINI H DR SATHEESH

2. OXYGEN CASCADE It is a step wise reduction of oxygen tension {PO2} from Environment to tissues. PO2 reaches the lowest level in the mitochondria. ATMOSPHERE ALVEOLI ARTERIES TISSUES

3. Atmosphere to alveolus The air (atmosphere) around us has a total pressure of 760mmhg. Air is made up of 21% oxygen, 78% nitrogen and small quantities of CO2, argon and helium. P B at sea level is 760mmhg and FiO2 of dry air is 20.93%. Atmospheric PO2 is calculated as follows PO2 = P B X FiO2 PO2 = 760 X 20.93% = 160mmhg

4. However By the time inspired air reaches the carina, it has become fully saturated with water vapour. Water has a saturated vapour pressure P SVP water of 47mmhg at 37°C. The PO2 of humidified air at the carina is calculated as follows: PO2= {PB - P SVP water} x FiO2 ⇒PO2 = {760– 47} x 20.93% = 150mmhg

5. Alveolus. PaO2 is mainly dependent on FiO2, P B and V̇ A , as described by the AGE : PaO2 can be calculated by PaO2 = FiO2{PB−P SVP water} - PaCO2/ Rq RQ? PaCO2 = 40mmhg and Rq = 0.8 PaO2 = 20.93% [760 − 47] – 40/0.8 PaO2 = 100mmhg

6. Factors affecting PiO2

7. STEPS IN OXYGEN CASCADE - step reduction in PO2 between alveolus and systemic arteries results in 1.Diffusion across alveolar capillary membrane 2.Shunts 3.V/Q mismatch

8. A.Diffusion across alveolar capillary membrane barrier Normally there is sufficient time for oxygen to diffuse across the alveolar capillary membrane barrier. that is, for PaO2 and pulmonary capillary PO2 to equilibrate at 100mmhg Transfer of O2 is then said to be perfusion limited. Chap 10 However, in lungs with thickened alveolar capillary barrier or a decreased alveolar surface area, oxygen may become diffusion limited, pulmonary capillary PO2 then becomes a step lower than PaO2.

9. B.Shunts There is normally a small anatomical right to left shunt arising from bronchial circulation and thebesian veins. chap 14 Deoxygenated blood enters systemic circulation without getting oxygenated. It might lead to atelectasis,consolidation or airway closure

10. C.Ventilation perfusion mismatch For optimal gas exchange, ventilation and perfusion must match each other in all the lung regions. Here by both ventilation and perfusion increase downward through the lung. However, perfusion increases more than ventilation, it shows the difference between the upperzone and lowerzone segments. These segments being threefold more for ventilation and tenfold for perfusion. This change results in a mean V/Q ratio.

11. In TISSUE CAPILLARIES the PO2 falls progressively from Arterial end to venous end of capillary, Where as in mitochondria the Mitochondrial PO2 is much lower than that of arterial blood and is related to the metabolic activity of the tissues. Example – The person who does exercise the oxygen utilisation will be more and the mitochondrial PO2 will be low. Therefore there Exists a large oxygen partial pressure gradient between the capillary blood and mitochondria increasing the rate of oxygen diffusion.

12. Clinically If the mitochondrial PO2 falls below the critical point there is insufficient of oxygen tension for aerobic metabolism. Anaerobic metabolism then takes over as the dominant mechanism for ATP production. This threshold is called the Pasteur point. It can occur if any of the steps of the cascade are greater than normal. examples such as 1. High altitude, 2.Pneumonia, 3.Hypoventilation

13. Arterial – venous Difference Factors that increase the arterial venous difference are 1.Increased O2 Consumption 2.Exercise 3.Shivering 4.Hyperthermia Factors that decrease the arterial-venous difference are 1.Skeletal muscle relaxation (drugs) 2.Poisons The difference between oxygen content of arteries and veins is said to be as arterial-venous difference – {C( a-v )02}

14. H ow is oxygen transported in blood? Oxygen is carried in blood as 2 forms. In combination with haemoglobin Dissolved in plasma

15. A. WHEN COMBINED WITH HAEMOGLOBIN Accounting for 98% of 02 carried by the blood . Each gram of hb contains 1.34 ml of O2 this is called huffners constant. B.DISSOLVED IN PLASMA In dissolved form, it is accounting for 2% of 02 carried by the blood.. The volume of O2 dissolved in blood is proportional to the partial pressure of O2 this is called HENRY’S LAW. Oxygen content per 100ml is more in arterial blood than venous blood.

16. OXYGEN FLUX The amount of oxygen leaving the left ventricle per minute in the arterial blood and also the amount of oxygen delivered to peripheral tissues. Oxygen flux = oxygen bound to haemoglobin + dissolved oxygen Oxygen bound to haemoglobin = Hb x SaO2 x K ( Huffner’s constant ) which is equal to 1000ml oxygen/ minute. Dissolved oxygen= PO2 x 0.03 = 0.003ml of oxygen/mm hg.

17. FACTORS INFLUENCING OXYGEN FLUX Oxygen flux decreases in 1. anemia 2.CCF Oxygen flux increases in 1.exercise 2.Thyrotoxicosis 3.Pain 4.Shivering

18. OXYGEN HEMOGLOBIN DISSOCIATION CURVE The oxygen carrying capacity of haemoglobin is given by oxygen hemoglobin dissociation curve i.e. the curve relating percentage oxygen saturation of the hemoglobin to the pO2. The curve is sigmoid shaped curve.

19. Why the curve is in sigmoid shape ? In deoxyhaemoglobin, the globin portion is tightly bound in a Tense configuration (T) thereby it reduces the affinity of the molecule for oxygen. Combination of molecule with oxygen releases the bond holding the globin units producing a relaxed configuration (R). This results in exposure of more oxygen binding sites and the affinity of haemoglobin molecule with oxygen increases. However all four atoms of ferrous do not combine with oxygen immediately and simultaneously. If it is combined the line will be in vertical.

20. The combination is a stepwise process and affinity for oxygen is different at different steps. Eg. , Combination of first haem in the hemoglobin molecule with oxygen increases the affinity of the the second haem for oxygen , and oxygenation of the second increases the affinity for the third and so on. Therefore the affinity of haemoglobin for fourth oxygen molecule is many times that for the first. This shifting affinity of hemoglobin for oxygen due to T-R interconversion produces characteristics sigmoid shape. T- tense configuration R- Relaxed configuration

21. P50 P50 means the pO2 at which heamoglobin is half (50%) saturated with O2. It’s normal value is 26mm Hg, It tells the hemoglobin affinity for oxygen. Hemoglobin affinity for oxygen is an inverse function of P50 i.e., Higher the p50, lower the affinity of hemoglobin for oxygen.

22. Factors affecting oxygen dissociation curve

23. SHIFT TO LEFT: Affinity of haemoglobin to combine with oxygen increases, causing less release of oxygen to tissues. CAUSES : CARBON MONOXIDE : Carbon monoxide shifts the curve to left due to inhibition of of synthesis of 2,3 DPG. Affinity of CO to combine with haemoglobin is 210 times more than that of oxygen. Higher affinity of CO for hemoglobin producers large proportion of hemoglobin as carboxyhemoglobin therefore hemoglobin is unavailable for oxygen carriage.

24. 2. FOETAL HEMOGLOBIN : affinity of fetal hemoglobin for 2,3DPG is considerably less than that of HbA Therefore HbF shifts the curve to left i.e., a lower pO2 is required to bind a given amount of oxygen. Thus affinity of HbF to combine with O2 is more than that of HbA At pO2 20mm Hg where HbA is only 35% saturated with O2, HbF is more than 70% saturated, that is why HbF can store more oxygen. However foetus never suffers from hypoxia, as it requires less oxygen for having low metabolic activities.

25. 3. MYOGLOBIN : It is a iron containing pigment found in in greater quantities in muscles specialised for sustained contraction. Eg. Muscles of leg and heart muscles. It contains only one heam group up with one polypeptide chain i.e., one atom of iron per molecule, therefore its molecular weight is 1/4 that of hemoglobin . It takes up O2 at low pressure much more readily than does blood i.e., rate of association of Myoglobin with oxygen is very fast. Thus its dissociation curve is a rectangular hyperbola rather than a sigmoid curve.

26. The causes of Shift of right can be remembered using the  Mnemonic , " CADET , face Right!" C O 2 ,  A cid, 2,3- D PG,  E xercise and  T emperature

27. SHIFT TO RIGHT: At any pO2 , O2 content that can be held by blood decreases, causing unloading of O2 . CAUSES : Fall in blood pH due to increased CO2 or presence of any acid in blood Increase in body temperature Exercise Anaemia Drugs like digoxin, propranolol Increase in concentration of 2,3 DPG