WINDSOR UNIVERSITY SCHOOL OF MEDICINE

1. WINDSOR UNIVERSITYSCHOOL OF MEDICINE RespiratoryPhysiology Dr.Vishal Surender.MD. Gas Transport

2. • The blood transports oxygen and carbon dioxide between the lungs and other tissues throughout the body. • These gases are carried in several different forms: 1. dissolved in the plasma 2. chemically combined with hemoglobin 3. converted into a different molecule

3. TRANSPORT OF OXYGEN BY BLOOD Oxygen Is Transported In Two Forms In The Blood— 1. physically dissolved [2 %] 2. chemically bound to the Hemoglobin, Hb, molecule [98 %] OXYGEN PHYSICALLY DISSOLVED IN BLOOD Compared to carbon dioxide, oxygen is relatively insoluble in the blood-- at PO2 = 100 mmHg, 100 ml blood contains 0.3 ml of O2

4. Oxygen Content of Plasma • Solubility of oxygen – 0.003 ml O2 per 100 ml of plasma • [O2]dissolved = PO2 x s • Therefore [O2]dissolved = 100 x 0.003 =0.3 ml O2 100 ml-1 • Since O2 consumption >250 ml min, would need to pump 83 L blood min-1 to suppy needs! • Dissolved oxygen is not the answer. Blood oxygen content is increased by oxygen carrier molecule – hemoglobin

5. TRANSPORT OF OXYGEN BY BLOOD Chemically Bound to the Hemoglobin Molecule Hb can combine rapidly & reversibly with O2. • The reversibility of this chemical reaction allows O2 to be released to the tissues. Hb + O2 <---------> O2Hb Deoxyhemoglobin oxygen oxyhemoglobin a.k.a reduced hemoglobin

6. Hemoglobin • Tetramer (4 units) • Each monomer contains a heme group (porphyrin ring with Fe held in the center) and a polypeptide (globin) which is either a or b in form • Tatramer is aHeme2, bHeme2 – and each heme group can bind 1 O2 molecule

7. O2 O2 O2 O2 • O2 Saturation-fraction of O2 binding sites that are actually occupied by oxygen the total amount of binding sites is therefore simply the amount of Hb molecules x 4 (a lot!). 25% Sat 50% Sat 75% Sat 100% Sat

8. O2 Content • This is the mass of oxygen per unit volume, e.g. ml O2/dl blood. This is the important quantity as far as the • body is concerned as this is how much oxygen is available to the tissues. • 1 g of hemoglobin can bind 1.36 ml O2 • Blood contains 15 g /100 ml-– so what is O2content? • Therefore – 1.36*15 = 20.4 ml O2 /100 ml blood is full capacity of HbO2 • Blood also carries 0.3 ml 100 ml-1 dissolved O2 (100 mm Hg PO2) • Total = 20.4+0.3 = 20.7 ml O2 100 ml-1 blood • If breathing 100% O2 with PO2 of (e.g. 600 mm Hg) then [O2]dissolved = 1.8 ml + 20.4 = 22.2 ml 100 ml-1

9. Saturation and Oxygen Content Oxygen content = (1.36*Hb content)x(measured saturation/maximum saturation) saturation Max possible saturation ml O2 g-1 g Hb 100ml-1

10. PULSE OXIMETER A Non-invasive Device Measuring Percentage of Oxyghemoglobin in the arterial blood [Hb Saturation/SaO2/SpO2] These monitors can be clipped on to the finger and continuously record saturation. These monitors rely on the fact that blood changes color with oxygen content. Deoxygenated blood is dark red, whilst oxygenated blood becomes vibrant cherry red – the pulse oximeter simply measures blood color and calculates saturation based on this parameter! This type of monitor is useless when the patient has CO poisoning – since Hb bound to CO is the same color as oxygenated blood – vibrant red!

11. Co-operativity The binding of O2 to hemoglobin can be considered in terms of affinity – i.e. how easy it is for O2 to bind to Hb • If it is difficult for O2 to bind, then Hb has a low affinity for O2 – and a lot of O2 is needed to get. • If it is easy for O2 to bind, then Hb has a high affinity for O2 – and very little O2 is needed to get, e.g. 50% of Hb molecules bound to O2. • Hemoglobin has a low affinity for O2 when no oxygen is bound, however, when the first oxygen binds to hemoglobin, the protein changes shape slightly and enters a higher affinity state, thus the next O2 molecule can bind more easily than the first. • This property is called co-operative binding.

12. P50 The partial pressure of oxygen required to get 50% Hb bound to O2, and is thus an index of the affinity of Hb for O2 – and is termed the P50. ↑ P50 means a lot of PO2 is needed for 50% binding – thus ↓ affinity ↓ P50 means little PO2 is needed for 50% binding – thus ↑ affinity

13. Each hemoglobin molecule can transport up to 4 oxygen molecules because each iron atom can bind one oxygen molecule. When 4 oxygen molecules are bound to hemoglobin, it is 100% saturated; when there are fewer, it is partially saturated. polypeptide chain iron atom heme group Oxygen binding occurs in response to the high partial pressure of oxygen in the lungs. cooperative binding affinity of hemoglobin

14. oxygen–hemoglobin dissociation curve/Saturation Curve- 22 lungs 20 oxygen–hemoglobin dissociation curve 18 tissues 16 14 12 • % Hb saturation *flat slope at high PO2's * steep slope at low PO2's 10 O2 content ml 100 ml-1 8 6 4 2 0 • PO2 (mm Hg)

15. In the lungs of a hiker at higher elevations or a person with particular cardiopulmonary diseases, the PO2 may be 80 mm Hg. At this PO2, hemoglobin is 95% saturated, O2 content of just less than 20 ml/dl Hemoglobin Saturation at High PO2's In the lungs at sea level, a typical PO2 is 100 millimeters of mercury. At this PO2, hemoglobin is 98% saturated and O2 content of ~20 ml/dl 22 20 18 16 14 12 Notice that even though the PO2 differs by 20 millimeters of mercury there is almost no difference in hemoglobin saturation. This means that although the PO2 in the lungs may decline below typical sea level values, hemoglobin still has a high affinity for oxygen and remains almost fully saturated. 10 O2 content ml 100 ml-1 8 6 4 2 0 The plateau phase of the O2 saturation curve means that good loading of O2 will occur despite small changes in PO2 at the alveolus

16. Hemoglobin Saturation at Low PO2's 20 A PO2 of 40 millimeters of mercury is typical in resting organs. 18 16 • • At 40 millimeters of mercury, hemoglobin has a lower affinity for oxygen and is 75% saturated., carry ~11 ml/dl O2. 14 12 10 O2 content ml 100 ml-1 8 In vigorously contracting muscles, you would expect the PO2 is lower than in resting muscle because an actively contracting muscle uses more oxygen, so it has a lower PO2 than a resting muscle, typically 20 millimeters of mercury. At this PO2, hemoglobin is only 35% saturated. (~5 ml/dl) 6 4 2 The steep part of this curve allows large amounts of O2 to be offloaded from blood for a small decline in PO2.

17. Factors Affecting Hb affinity for O2 O2 binding to Hb – biochemical process and is strongly affected by the bio-environment • pH • PO2 • PCO2 • Temperature • 2,3-DPG (diphosphoglycerate) • CO (carbon monoxide)

18. pH, temperature and CO2 all right shift the curve

19. Right shift ↑P50 • Increased temp • Decreased pH (acidic) • Increased PCO2 (Bohr effect) • All factors alone or in concert result in right-shift and ↑P50 (note effects are ‘concentration’ dependent i.e. bigger stimulus gives bigger right-shift) • To remember think of a working muscle – it gets hot, produces CO2 and gets acidic – the right-shift ↑P50 helps this situation in that it facilitates oxygen unloading to the tissue that needs it

20. pH Bohr effect Bohr effect The right-shift in the saturation curve in response to CO2 is called the Bohr effect , increased CO2 causes an acidification which accounts for the majority of this effect. end result is a right shift in the saturation curve, i.e. ↑P50. ↑PCO2 = low affinity and oxygen offloading 100 80 Hb(O2)4 + 2H+ ↔ Hb(H+)2 + 4O2 ↓pH = low affinity and oxygen offloading 60 % Hb saturation 40 pH 7.6 pH 7.4 pH 7.2 20 0 0 20 40 60 80 100 600 PO2 (mm Hg)

21. ↑2,3-DPG • Organic phosphate compound present in blood cells • Its biogenesis is enhanced by hypoxia and exercise • Living at high altitude increases 2,3-DPG in red blood cells • When ↓PO2 in Red Blood Cells – glycolysis is stimulated and 2,3-DPG is produced • 2,3-DPG binds to Hb and holds it in the ‘Tense’ state with a low O2 affinity (i.e. ↑P50) • This helps to offload oxygen to tissues – clinically it is a feature of chronic hypoxia (e.g. COPD, high altitude, anemia, shunts, emphysema etc) • This also means that O2 loading is slightly reduced – but this occurs in the plateau phase and is a small effect

22. Remember!Saturation is not O2 content 24 100 22 Normal 15 g 100ml-1 20 80 18 16 14 60 O2 content ml 100 ml-1 12 % Hb saturation 100% 10 40 8 Anemic patient has e.g. half the Hb and therefore can carry 0.5 times the O2 6 20 4 2 0 0 % 0 0 20 40 60 80 100 600 PO2 (mm Hg)

23. O2 O2 O2 O2 O2 O2 O2 O2 O2 O2 O2 O2 Anemia • Saturation will not fall – all of the available O2 binding sites are full (SaO2 normal) • PaO2 remains normal – PaO2 depends on PAO2 and diffusion not Hb • It is just that there are less binding sites in total – therefore the O2 content falls – but the saturation is not effected Patient 1 has 1 Hb molecule Patient 2 has 2 Hb molecule 8 binding sites – 8 occupied – 100% Sat O2 content = 8 O2 4 binding sites – 4 occupied – 100% Sat O2 content = 4 O2

24. Carbon Monoxide • Has very high affinity for Hb – producing carboxyhemoglobin HbCO (P50 for CO >200 times lower than O2) – therefore CO can compete with O2 even at very low concentrations • Occupation of Hb sites by CO prevents O2 binding to those sites although it increases the affinity of the other sites for O2 • The P50 is actually reduced (i.e. oxygen now has greater affinity for Hb) – making it harder for Hb to offload the oxygen to tissues that need it • CO effectively reduces the carrying capacity of Hb for O2 by binding O2 sites • CO can be driven off Hb – by breathing 100% O2 and increasing ventilation

25. Saturation Curve (SaO2) 24 100 22 20 80 18 16 14 60 O2 content ml 100 ml-1 12 % Hb saturation 100% 10 40 8 50% CO Hb 6 20 4 2 0 % 0 0 0 20 40 60 80 100 600 PO2 (mm Hg)