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OXYGEN DELIVERY TO THE TISSUES
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Oxygen delivery, or by definition, the volume of oxygen delivered to the systemic vascular bed per minute, is the product of the cardiac output and the arterial oxygen concentration. The ability to deliver O2 in the body depends on both the respiratory and the cardiovascular systems. O2 delivery to a particular tissue depends on the amount of O2 entering the lungs, the adequacy of pulmonary gas exchange, the blood flow to the tissue, and the capacity of the blood to carry O2. Blood flow to an individual tissue depends on cardiac output and the degree of constriction of the vascular bed in the tissue. The amount of O2 in the blood is determined by the amount of dissolved O2, the amount of hemoglobin in the blood, and the affinity of the hemoglobin for O2.
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REACTION OF HEMOGLOBIN & OXYGEN
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The dynamics of the reaction of hemoglobin with O2 make it a particularly suitable O2 carrier. Hemoglobin is a protein made up of four subunits, each of which contains a heme moiety attached to a polypeptide chain. In normal adults, most of the hemoglobin molecules contain two α and two β chains. Heme (see Figure 31–7) is a porphyrin ring complex that includes one atom of ferrous iron. Each of the four iron atoms in hemoglobin can reversibly bind one O2 molecule. The iron stays in the ferrous state, so that the reaction is oxygenation (not oxidation). It has been customary to write the reaction of hemoglobin with O2 as Hb + O2 HbO2. Because it contains four deoxyhemoglobin (Hb) units, the hemoglobin molecule can also be represented as Hb4, and it actually reacts with four molecules of O2 to form Hb4O8.
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The reaction is rapid, requiring less than 0.01 s. The deoxygenation of Hb4O8 is also very rapid.
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The quaternary structure of hemoglobin determines its affinity for O2. In deoxyhemoglobin, the globin units are tightly bound in a tense (T) configuration, which reduces the affinity of the molecule for O2. When O2 is first bound, the bonds holding the globin units are released, producing a relaxed (R) configuration, which exposes more O2 binding sites. The net result is a 500-fold increase in O2 affinity. In tissues, these reactions are reversed, resulting in O2 release. The transition from one state to another has been calculated to occur about 108 times in the life of a red blood cell.
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The oxygen-hemoglobin dissociation curve relates percentage saturation of the O2 carrying power of hemoglobin (abbreviated as SaO2) to the Po2 (Figure 35–1). This curve has a characteristic sigmoid shape due to the T–R configuration interconversion. Combination of the first heme in the Hb molecule with O2 increases the affinity of the second heme for O2, and oxygenation of the second increases the affinity of the third, and so on, so that the affinity of Hb for the fourth O2 molecule is many times that for the first. Especially note that small changes at low Po2 lead to large changes in SaO2.
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When blood is equilibrated with 100% O2, the normal hemoglobin becomes 100% saturated. When fully saturated, each gram of normal hemoglobin contains 1.39 mL of O2. However, blood normally contains small quantities of inactive hemoglobin derivatives, and the measured value in vivo is thus slightly lower. Using the traditional estimate of saturated hemoglobin in vivo, 1.34 mL of O2, the hemoglobin concentration in normal blood is about 15 g/dL (14 g/dL in women and 16 g/dL in men). Therefore, 1 dL of blood contains 20.1 mL (1.34 mL × 15) of O2 bound to hemoglobin when the hemoglobin is 100% saturated. The amount of dissolved O2 is a linear function of the Po2 (0.003 mL/dL blood/mm Hg Po2).
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In vivo, the hemoglobin in the blood at the ends of the pulmonary capillaries is about 97.5% saturated with O2 (Po2 = 100 mm Hg). Because of a slight admixture with venous blood that bypasses the pulmonary capillaries (ie, physiologic shunt), the hemoglobin in systemic arterial blood is only 97% saturated. The arterial blood therefore contains a total of about 19.8 mL of O2 per dL: 0.29 mL in solution and 19.5 mL bound to hemoglobin. In venous blood at rest, the hemoglobin is 75% saturated and the total O2 content is about 15.2 mL/dL: 0.12 mL in solution and 15.1 mL bound to hemoglobin. Thus, at rest the tissues remove about 4.6 mL of O2 from each deciliter of blood passing through them (Table 35–1); 0.17 mL of this total represents O2 that was in solution in the blood, and the remainder represents O2 that was liberated from hemoglobin. In this way, 250 mL of O2 per minute is transported from the blood to the tissues at rest.
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FACTORS AFFECTING THE AFFINITY OF HEMOGLOBIN FOR OXYGEN
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Three important conditions affect the oxygen-hemoglobin dissociation curve: the pH, the temperature, and the concentration of 2,3-diphosphoglycerate (DPG; 2,3-DPG). A rise in temperature or a fall in pH shifts the curve to the right (Figure 35–2). When the curve is shifted in this direction, a higher Po2 is required for hemoglobin to bind a given amount of O2. Conversely, a fall in temperature or a rise in pH shifts the curve to the left, and a lower Po2 is required to bind a given amount of O2. A convenient index for comparison of such shifts is the P50, the Po2 at which hemoglobin is half saturated with O2. The higher the P50, the lower the affinity of hemoglobin for O2.
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The decrease in O2 affinity of hemoglobin when the pH of blood falls is called the Bohr effect and is closely related to the fact that deoxygenated hemoglobin (deoxyhemoglobin) binds H+ more actively than does oxygenated hemoglobin (oxyhemoglobin). The pH of blood falls as its CO2 content increases, so that when the Pco2 rises, the curve shifts to the right and the P50 rises. Most of the unsaturation of hemoglobin that occurs in the tissues is secondary to the decline in the Po2, but an extra 1–2% unsaturation is due to the rise in Pco2 and consequent shift of the dissociation curve to the right.
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2,3-DPG is very plentiful in red cells. It is formed from 3-phosphoglyceraldehyde, which is a product of glycolysis via the Embden-Meyerhof pathway. It is a highly charged anion that binds to the β chains of deoxyhemoglobin. One mole of deoxyhemoglobin binds 1 mol of 2,3-DPG. In effect,
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In this equilibrium, an increase in the concentration of 2,3-DPG shifts the reaction to the right, causing more O2 to be liberated.
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Because acidosis inhibits red cell glycolysis, the 2,3-DPG concentration falls when the pH is low. Conversely, thyroid hormones, growth hormones, and androgens can all increase the concentration of 2,3-DPG and the P50.
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Exercise has been reported to produce an increase in 2,3-DPG within 60 min (although the rise may not occur in trained athletes). The P50 is also increased during exercise, because the temperature rises in active tissues and CO2 and metabolites accumulate, lowering the pH. In addition, much more O2 is removed from each unit of blood flowing through active tissues because the tissue Po2 declines. Finally, at low Po2 values, the oxygen-hemoglobin dissociation curve is steep, and large amounts of O2 are liberated per unit drop in Po2. Some clinical features of hemoglobin are discussed in Clinical Box 35–1.
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An interesting contrast to hemoglobin is myoglobin, an iron-containing pigment found in skeletal muscle. Myoglobin resembles hemoglobin but binds 1 rather than 4 mol of O2 per mole protein. The lack of cooperative binding is reflected in the myoglobin dissociation curve, a rectangular hyperbola rather than the sigmoid curve observed for hemoglobin (Figure 35–3). Additionally, the leftward shift of the myoglobin O2 binding curve when compared with hemoglobin demonstrates a higher affinity for O2, and thus promotes a favorable transfer of O2 from hemoglobin in the blood. The steepness of the myoglobin curve also shows that O2 is released only at low Po2 values (eg, during exercise). The myoglobin content is greatest in muscles specialized for sustained contraction. The muscle blood supply is compressed during such contractions, and myoglobin can continue to provide O2 under reduced blood flow and/or reduced Po2 in the blood.
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CLINICAL BOX 35–1 Hemoglobin & O2 Binding In Vivo Cyanosis
Reduced hemoglobin has a dark color, and a dusky bluish discoloration of the tissues, called cyanosis, appears when the reduced hemoglobin concentration of the blood in the capillaries is more than 5 g/dL. Its occurrence depends on the total amount of hemoglobin in the blood, the degree of hemoglobin unsaturation, and the state of the capillary circulation. Cyanosis is most easily seen in the nail beds and mucous membranes and in the earlobes, lips, and fingers, where the skin is thin. Although visible observation is indicative of cyanosis, it is not fully reliable. Further tests of arterial oxygen tension and saturation, blood and hemoglobin counts can provide more reliable diagnoses.
Effects of 2,3-DPG on Fetal & Stored Blood The affinity of fetal hemoglobin (hemoglobin F) for O2, which is greater than that for adult hemoglobin (hemoglobin A), facilitates the movement of O2 from the mother to the fetus. The cause of this greater affinity is the poor binding of 2,3-DPG by the γ polypeptide chains that replace β chains in fetal hemoglobin. Some abnormal hemoglobins in adults have low P50 values, and the resulting high O2 affinity of the hemoglobin causes enough tissue hypoxia to stimulate increased red cell formation, with resulting polycythemia. It is interesting to speculate that these hemoglobins may not bind 2,3-DPG.
Red cell 2,3-DPG concentration is increased in anemia and in a variety of diseases in which there is chronic hypoxia. This facilitates the delivery of O2 to the tissues by raising the Po2 at which O2 is released in peripheral capillaries. In banked blood that is stored, the 2,3-DPG level falls and the ability of this blood to release O2 to the tissues is reduced. This decrease, which obviously limits the benefit of the blood if it is transfused into a hypoxic patient, is less if the blood is stored in citrate-phosphate-dextrose solution rather than the usual acid-citrate-dextrose solution.
THERAPEUTIC HIGHLIGHTS Cyanosis is an indication of poorly oxygenated hemoglobin rather than a disease, and thus can have many causes, from cold exposure to drug overdose to chronic lung disease. As such, proper treatment depends on the underlying cause. For cyanosis caused by exposure to cold, maintaining a warm environment can be effective, whereas supplemental oxygen administration may be required under conditions of chronic disease.