TRANSPORT OF RESPIRATORY GASES IN BLOOD
O2 is carried in blood in two forms: dissolved in solu-tion and in reversible association with hemoglobin.
The amount of O2 dissolved in blood can be derived from Henry’s law, which states that the concen-tration of any gas in solution is proportional to its partial pressure. The mathematical expression is as follows:
Gas concentration = α × Partial pressure
where α = the gas solubility coefficient for a given solution at a given temperature.
The solubility coefficient for O2 at normal body temperature is 0.003 mL/dL/mm Hg. Even with a Pao2 of 100 mm Hg, the maximum amount of O2 dissolved in blood is very small (0.3 mL/dL) com-pared with that bound to hemoglobin.
Hemoglobin is a complex molecule consisting of four heme and four protein subunits. Heme is an iron–porphyrin compound that is an essen-tial part of the O 2-binding sites; only the divalent form (+2 charge) of iron can bind O2. The normal hemoglobin molecule (hemoglobin A1) consists of two α and two β chains (subunits); the four subunits are held together by weak bonds between the amino acid residues. Each gram of hemoglobin can theo-retically carry up to 1.39 mL of O 2.
Each hemoglobin molecule binds up to four O2 molecules. The complex interaction between the hemoglobin subunits results in nonlinear (an elon-gated S shape) binding with O2 (Figure 23–22). Hemoglobin saturation is the amount of O2 bound as a percentage of its total O 2-binding capacity. Four separate chemical reactions are involved in bind-ing each of the four O2 molecules. The change in molecular conformation induced by the binding of the first three molecules greatly accelerates bind-ing of the fourth O2 molecule. The last reaction is responsible for the accelerated binding between 25% and 100% saturation. At about 90% saturation, the decrease in available O2 receptors flattens the curve until full saturation is reached.
Clinically important factors altering O2 binding include hydrogen ion concentration, CO2 tension, temperature, and 2,3-diphosphoglycerate (2,3-DPG) concentration. Their effect on hemoglobin–O2 inter-action can be expressed by P50, the O2 tension at which hemoglobin is 50% saturated (Figure 23–23). Each factor shifts the dissociation curve either to the right (increasing P50) or to the left (decreasing P50).
A rightward shift in the oxygen–hemoglobin dissociation curve lowers O 2 affinity, displacesO2 from hemoglobin, and makes more O2 available to tissues; a leftward shift increases hemoglobin’s affinity for O 2, reducing its availability to tissues. The normal P 50 in adults is 26.6 mm Hg (3.4 kPa).An increase in blood hydrogen ion concen-tration reduces O 2 binding to hemoglobin (Bohr effect). Because of the shape of the hemoglobindissociation curve, the effect is more important in venous blood than arterial blood (Figure 23–23); the net result is facilitation of O2 release to tissue with little impairment in O2 uptake (unless severe hypoxia is present).
The influence of CO2 tension on hemoglobin’s affinity for O 2 is important physiologically and is secondary to the associated rise in hydrogen ion concentration when CO2 tension increases. The high CO2 content of venous capillary blood, by decreasing hemoglobin’s affinity for O 2, facilitates the release of O2 to tissues; conversely, the lower CO2 content in pulmonary capillaries increases hemoglobin’s affin-ity for O2 again, facilitating O2 uptake from alveoli.
2,3-DPG is a by-product of glycolysis (the Rapoport–Luebering shunt) and accumulates dur-ing anaerobic metabolism. Although its effects on hemoglobin under these conditions are theoreti-cally beneficial, its physiological importance nor-mally seems minor. 2,3-DPG levels may, however, play an important compensatory role in patientswith chronic anemia and may significantly affect the O2-carrying capacity of blood transfusions.
Carbon monoxide, cyanide, nitric acid, and ammo-nia can combine with hemoglobin at O2-binding sites. They can displace O 2 and shift the saturation curve to the left. Carbon monoxide is particularly potent, having 200–300 times the affinity of O2 for hemoglobin, combining with it to form carboxyhe-moglobin. Carbon monoxide decreases hemoglo-bin’s O2-carrying capacity and impairs the release of O2 to tissues.
Methemoglobin results when the iron in heme is oxidized to its trivalent (+3) form. Nitrates, nitrites, sulfonamides, and other drugs can rarely result in significant methemoglobinemia. Methemoglobin cannot combine with O2 unless reconverted by the enzyme methemoglobin reductase; methemoglo-bin also shifts the normal hemoglobin saturation curve to the left. Methemoglobinemia, like car-bon monoxide poisoning, therefore decreases the O2-carrying capacity and impairs the release of O 2. Reduction of methemoglobin to normal hemoglo-bin is facilitated by such agents as methylene blue or ascorbic acid.
Abnormal hemoglobins can also result from variations in the protein subunit composition. Each variant has its own O2-saturation characteristics. These include fetal hemoglobin, hemoglobin A2, and sickle hemoglobin.
The total O2 content of blood is the sum of that in solution plus that carried by hemoglobin. In reality, O2 binding to hemoglobin never achieves the theoretical maximum (see above), but is closer to 1.31 mL O2/dL blood per mm Hg. Total O2 content is expressed by the following equation:
O2 content = ([0.003 mL O2/dL blood per mm Hg]
Po2) + (So2× Hb × 1.31 mL/dL blood)
where Hb is hemoglobin concentration in g/dL blood, and So2 is hemoglobin saturation at the given Po2. Using the above formula and a hemoglobin of 15 g/dL, the normal O 2 content for both arterial and mixed venous blood and the arteriovenous differ-ence can be calculated as follows:
Cao2 = (0.003 × 100) + (0.975 × 15 × 1.39)
= 19.5 mL/dL blood
= (0.003 × 40) + (0.75 × 15 × 1.31)
= 14.8 mL/dL blood
vo2 = 4.7 mL/dL blood
O2 transport is dependent on both respiratory and circulatory function. Total O 2 delivery (Do2) to tis-sues is the product of arterial O2 content and cardiac output:
Do2 = Cao2 × Qt
Note that arterial O 2 content is dependent on Pao2 as well as hemoglobin concentration. As aresult, deficiencies in O2delivery may be due to a low Pao2, a low hemoglobin concentration, or an inadequate cardiac output. Normal O 2 delivery canbe calculated as follows:
O2 delivery = 20 mL O2/dL blood× 50 dL per blood/min
1000 mL O2/min
The Fick equation expresses the relationship between O2 consumption, O2 content, and cardiac output:
Rearranging the equation:
the arteriovenous difference is a good measure of the overall adequacy of O2
delivery.As calculated above, the arteriovenous difference (Cao2−C
is about 5 mL O2/dL blood (20 mL O2/ dL – 15 mL O2/dL).
Note that the normal extraction fraction for O2[(Cao2−C vo2)/Cao2]
is 5 mL ÷ 20 mL, or 25%; thus, the body
normally consumes only 25% of the O2 carried on hemoglobin. When O2
demand exceeds supply, the extraction fraction exceeds 25%. Conversely, if O2
supply exceeds demand, the extrac-tion fraction falls below 25%.When Do2 is even moderately reduced, Vo2extraction (mixed
venous O saturation decreases); Vo2
remains independentof delivery. With fur ther reductions in Do2,
however, a critical point is reached beyond which Vo2 becomes directly proportional to Do2. This
state of supply-dependent O2 is typically associated with progressive lactic
acidosis caused by cellular hypoxia.
The concept of O2 stores is important in anesthesia. When the normal flux of O2 is interrupted by apnea, existing O2 stores are consumed by cellular metabo-lism; if stores are depleted, hypoxia and eventual cell death follow. Theoretically, normal O2 stores in adults are about 1500 mL. This amount includes the O2 remaining in the lungs, that bound to hemoglobin (and myoglobin), and that dissolved in body fluids. Unfortunately, the high affinity of hemoglobin for O2 (the affinity of myoglobin is even higher), and the very limited quantity of O2 in solution, restrict the availability of these stores. The O2 contained within the lungs at FRC (initial lung volume during apnea), therefore, becomes the most important source of O2. Of that volume, however, probably only 80% is usable. Apnea in a patient previously breathing room air leaves approximately 480 mL of O2 in the lungs. (If Fio2 = 0.21 and FRC = 2300 mL, O2 content = Fio2 × FRC.) The metabolic activity of tissues rapidly depletes• this reservoir (presumably at a rate equiva-lent to Vo2); severe hypoxemia usually occurs within 90 sec. The onset of hypoxemia can be delayed by increasing the Fio2 prior to the apnea. Following ven-tilation with 100% O2, FRC contains about 2300 mL of O2; this delays hypoxemia following apnea for 4–5 min. This concept is the basis for preoxygenation prior to induction of anesthesia.
Carbon dioxide is transported in blood in three forms: dissolved in solution, as bicarbonate, and with proteins in the form of carbamino compounds (Table23–6). The sum of all three forms is the total CO2 content of blood (routinely reported with elec-trolyte measurements).
Carbon dioxide is more soluble in blood than O2, with a solubility coefficient of 0.031 mmol/L/mm Hg (0.067 mL/dL/mm Hg) at 37°C.
In aqueous solutions, CO 2 slowly combines with water to form carbonic acid and bicarbonate, according to the following reaction:
In plasma, although less than 1% of the dis-solved CO2 undergoes this reaction, the presence of the enzyme carbonic anhydrase within erythro-cytes and endothelium greatly accelerates the reaction. As a result, bicarbonate represents the largest fraction of the CO 2 in blood (see
Table 23–6). Administration of acetazolamide, a car-bonic anhydrase inhibitor, can impair CO2 transport between tissues and alveoli.
On the venous side of systemic capillaries, CO2 enters red blood cells and is converted to bicar-bonate, which diffuses out of red cells into plasma; chloride ions move from plasma into red cells to maintain electrical balance. In the pulmonary capil-laries, the reverse occurs: chloride ions move out of red cells as bicarbonate ions reenter them for con-version back to CO2, which diffuses out into alve-oli. This sequence is referred to as the chloride or Hamburger shift.
Carbon dioxide can react with amino groups on proteins, as shown by the following equation:
At physiological pH, only a small amount of CO2 is carried in this form, mainly as carbamino-hemoglobin. Deoxygenated hemoglobin (deoxy-hemoglobin) has a greater affinity (3.5 times) for CO2 than does oxyhemoglobin. As a result, venous blood carries more CO 2 than does arterial blood (Haldane effect; see Table 23–6). Pco2 normally has little effect on the fraction of CO2carried as carbaminohemoglobin.
The buffering action of hemoglobin also accounts for part of the Haldane effect. Hemoglobin can act as a buffer at physiological pH because of itsChigh content of histidine. Moreover, the acid–base behavior of hemoglobin is influenced by its oxy-genation state:
Removal of O 2 from hemoglobin in tissue cap-illaries causes the hemoglobin molecule to behave more like a base; by taking up hydrogen ions, hemo-globin shifts the CO2–bicarbonate equilibrium in favor of greater bicarbonate formation:
As a direct result, deoxyhemoglobin also increases the amount of CO2 that is carried in venous blood as bicarbonate. As CO2 is taken up from tissue and converted to bicarbonate, the total CO2 content of blood increases (see Table 23–6).
In the lungs, the reverse is true. Oxygenation of hemoglobin favors its action as an acid, and the release of hydrogen ions shifts the equilibrium in favor of greater CO 2 formation:
Bicarbonate concentration decreases as CO 2 is formed and eliminated, so that the total CO2 content of blood decreases in the lungs. Note that there is a difference between CO2 content (concentration per liter) of whole blood (see Table 23–6) and plasma (Table23–7).
A CO2 dissociation curve can be constructed by plotting the total CO 2 content of blood against Pco2.
The contribution of each form of CO2 can also be quantified in this manner (Figure23–24).
Carbon dioxide stores in the body are large (approximately 120 L in adults) and primarily in the form of dissolved CO 2 and bicarbonate. When an imbalance occurs between production and elimination, establishing a new CO2 equi-librium requires 20–30 min (compared with less than 4–5 min for O2; see above). Carbon dioxide is stored in the rapid-, intermediate-, and slow-equilibrating compartments. Because of the largercapacity of the intermediate and slow compart-ments, the rate of rise in arterial CO2 tension is generally slower than its fall following acute changes in ventilation.
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