After studying this chapter, you should be able to:
Describe the manner in which O2 flows “downhill” from the lungs to the tissues and CO2 flows “downhill” from the tissues to the lungs.
List the important factors affecting the affinity of hemoglobin for O2 and the physiologic significance of each.
List the reactions that increase the amount of CO2 in the blood, and draw the CO2 dissociation curve for arterial and venous blood.
Define alkalosis and acidosis and list typical causes and compensatory responses to each.
Define hypoxia and describe differences in subtypes of hypoxia.
Describe the effects of hypercapnia and hypocapnia, and give examples of conditions that can cause them.
The partial pressure gradients for O2 and CO2, plotted in graphical form in Figure 35–1, emphasize that they are the key to gas movement and that O2 “flows downhill” from the air through the alveoli and blood into the tissues, whereas CO2 “flows downhill” from the tissues to the alveoli. However, the amount of both of these gases transported to and from the tissues would be grossly inadequate if it were not for the fact that about 99% of the O2 that dissolves in the blood combines with the O2-carrying protein hemoglobin and that about 94.5% of the CO2 that dissolves enters into a series of reversible chemical reactions that convert it into other compounds. Thus, the presence of hemoglobin increases the O2-carrying capacity of the blood 70-fold, and the reactions of CO2 increase the blood CO2 content 17-fold. In this chapter, physiologic details that underlie O2 and CO2 movement under various conditions are discussed.
FIGURE 35–1 Po2and Pco2values in air, lungs, blood, and tissues. Note that both O2 and CO2 diffuse “downhill” along gradients of decreasing partial pressure. Est, estimated. (Redrawn and reproduced with permission from Kinney JM: Transport of carbon dioxide in blood. Anesthesiology 1960;21:615.)
OXYGEN DELIVERY TO THE TISSUES
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.
REACTION OF HEMOGLOBIN & OXYGEN
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 . 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.
The reaction is rapid, requiring less than 0.01 s. The deoxygenation of Hb4O8 is also very rapid.
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.
The oxygen–hemoglobin dissociation curve relates percentage saturation of the O2 carrying power of hemoglobin (abbreviated as SaO2) to the PO2(Figure 35–2). This curve has a characteristic sigmoid shape due to the T–R 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.
FIGURE 35–2 Oxygen–hemoglobin dissociation curve. pH 7.40, temperature 38°C. Inset table relates the percentage of saturated hemoglobin (SaO2) to PO2 and dissolved O2. (Redrawn and reproduced with permission from Comroe JH Jr, et al: The Lung: Clinical Physiology and Pulmonary Function Tests, 2nd ed. Year Book, 1962.)
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).
In vivo, the hemoglobin in the blood at the ends of the pulmonary capillaries is about 97.5% saturated with O2. 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.
TABLE 35–1 Gas content of blood.
FACTORS AFFECTING THE AFFINITY OF HEMOGLOBIN FOR OXYGEN
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 35–3). 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.
FIGURE 35–3 Effects of temperature and pH on the oxygen—hemoglobin dissociation curve. Both changes in temperature (left) and pH (right) can alter the affinity of hemoglobin for O2. Plasma pH can be estimated using the modified Henderson–Hasselbalch equation, as shown. (Redrawn and reproduced with permission from Comroe JH Jr, et al: The Lung: Clinical Physiology and Pulmonary Function Tests, 2nd ed. Year Book, 1962.)
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.
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,
In this equilibrium, an increase in the concentration of 2,3-DPG shifts the reaction to the right, causing more O2 to be liberated.
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.
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 CO2and 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.
CLINICAL BOX 35–1
Hemoglobin & O2 Binding In Vivo
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.
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 upon 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.
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 35–4). 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.
FIGURE 35–4 Comparison of dissociation curves for hemoglobin and myoglobin. The myoglobin binding curve (B) lacks the sigmoidal shape of the hemoglobin binding curve (A) because of the single O2 binding site in each molecule. Myoglobin also has greater affinity for O2 than hemoglobin (curve shifted left) and thus can release O2 in muscle when PO2 in blood is low (eg, during exercise).
CARBON DIOXIDE TRANSPORT
MOLECULAR FATE OF CARBON DIOXIDE IN BLOOD
The solubility of CO2 in blood is about 20 times that of O2; therefore, considerably more CO2 than O2 is present in simple solution at equal partial pressures. The CO2 that diffuses into red blood cells is rapidly hydrated to H2CO3because of the presence of carbonic anhydrase (Figure 35–5). The H2CO3 dissociates to H+ and , and the H+ is buffered, primarily by hemoglobin, while the enters the plasma. Some of the CO2 in the red cells reacts with the amino groups of hemoglobin and other proteins (R), forming carbamino compounds.
FIGURE 35–5 Fate of CO2 in the red blood cell. Upon entering the red blood cell, CO2 is rapidly hydrated to H2CO3 by carbonic anhydrase. H2CO3 is in equilibrium with H+ and its conjugate base, . H+ can interact with deoxyhemoglobin, whereas can be transported outside of the cell via anion exchanger 1 (AE1 or Band 3). In effect, for each CO2 molecule that enters the red cell, there is an additional or Cl– in the cell.
Because deoxyhemoglobin binds more H+ than oxyhemoglobin and forms carbamino compounds more readily, binding of O2 to hemoglobin reduces its affinity for CO2. The Haldane effect refers to the increased capacity of deoxygenated hemoglobin to bind and carry CO2. Consequently, venous blood carries more CO2 than arterial blood, CO2 uptake is facilitated in the tissues, and CO2 release is facilitated in the lungs. About 11% of the CO2 added to the blood in the systemic capillaries is carried to the lungs as carbamino-CO2.
Because the rise in the content of red cells is much greater than that in plasma as the blood passes through the capillaries, about 70% of the formed in the red cells enters the plasma. The excess leaves the red cells in exchange for Cl– (Figure 35–5). This process is mediated by anion exchanger 1 (AE1; also called Band 3), a major membrane protein in the red blood cell. Because of this chloride shift, the Cl– content of the red cells in venous blood is significantly greater than that in arterial blood. The chloride shift occurs rapidly and is essentially complete within 1 s.
Note that for each CO2 molecule added to a red cell, there is an increase of one osmotically active particle in the cell—either an or a Cl–(Figure 35–6). Consequently, the red cells take up water and increase in size. For this reason, plus the fact that a small amount of fluid in the arterial blood returns via the lymphatics rather than the veins, the hematocrit of venous blood is normally 3% greater than that of the arterial blood. In the lungs, the Cl– moves back out of the cells and they shrink.
FIGURE 35–6 CO2 dissociation curves. The arterial point (a) and the venous point (v) indicate the total CO2 content found in arterial blood and venous blood of normal resting humans. Note the low amount of CO2 that is dissolved (orange trace) compared to that which can be carried by other means (Table 35–2). (Modified and reproduced with permission from Schmidt RF, Thews G [editors]: Human Physiology. Springer, 1983.)
SPATIAL DISTRIBUTION OF CARBON DIOXIDE IN BLOOD
For convenience, the various fates of CO2 in the plasma and red cells are summarized in Table 35–2. The extent to which they increase the capacity of the blood to carry CO2 is indicated by the difference between the lines indicating the dissolved CO2 and the total CO2 in the dissociation curves for CO2 shown in Figure 35–6.
TABLE 35–2 Fate of CO2 in blood.
Of the approximately 49 mL of CO2 in each deciliter of arterial blood (Table 35–1), 2.6 mL is dissolved, 2.6 mL is in carbamino compounds, and 43.8 mL is in . In the tissues, 3.7 mL of CO2 per deciliter of blood is added; 0.4 mL stays in solution, 0.8 mL forms carbamino compounds, and 2.5 mL forms . The pH of the blood drops from 7.40 to 7.36. In the lungs, the processes are reversed, and the 3.7 mL of CO2 is discharged into the alveoli. In this fashion, 200 mL of CO2 per minute at rest and much larger amounts during exercise are transported from the tissues to the lungs and excreted. It is worth noting that this amount of CO2 is equivalent in 24 h to over 12,500 mEq of H+.
ACID–BASE BALANCE & GAS TRANSPORT
The major source of acids in the blood under normal conditions is through cellular metabolism. The CO2 formed by metabolism in the tissues is in large part hydrated to H2CO3, resulting in the large total H+ load noted above (> 12,500 mEq/d). However, most of the CO2 is excreted in the lungs, and the small quantities of the remaining H+ are excreted by the kidneys.
BUFFERING IN THE BLOOD
Acid and base shifts in the blood are largely controlled by three main buffers in blood: (1) proteins, (2) hemoglobin, and (3) the carbonic acid–bicarbonate system. Plasma proteins are effective buffers because both their free carboxyl and their free amino groups dissociate:
The second buffer system is provided by the dissociation of the imidazole groups of the histidine residues in hemoglobin.
In the pH 7.0–7.7 range, the free carboxyl and amino groups of hemoglobin contribute relatively little to its buffering capacity. However, the hemoglobin molecule contains 38 histidine residues, and on this basis—plus the fact that hemoglobin is present in large amounts—the hemoglobin in blood has six times the buffering capacity of the plasma proteins. In addition, the action of hemoglobin is unique because the imidazole groups of deoxyhemoglobin (Hb) dissociate less than those of oxyhemoglobin (HbO2), making Hb a weaker acid and therefore a better buffer than HbO2. The titration curves for Hb and HbO2(Figure 35–7) illustrate the differences in H+ buffering capacity.
FIGURE 35–7 Comparative titration curves for oxygenated hemoglobin (HbO2) and deoxyhemoglobin (Hb). The arrow from a to c indicates the number of additional millimoles of H+ that Hb can buffer compared with a similar concentration of HbO2 (ie, no shift in pH). The arrow from a to b indicates the pH shift that would occur on deoxygenation of HbO2 without additional H+.
The third and major buffer system in blood is the carbonic acid–bicarbonate system:
The Henderson–Hasselbalch equation for this system is
The pK for this system in an ideal solution is low (about 3), and the amount of H2CO3 is small and hard to measure accurately. However, in the body, H2CO3 is in equilibrium with CO2:
If the pK is changed to pK’ (apparent ionization constant; distinguished from the true pK due to less than ideal conditions for the solution) and [CO2] is substituted for [H2CO3], the pK’ is 6.1:
The clinically relevant form of this equation is:
since the amount of dissolved CO2 is proportional to the partial pressure of CO2 and the solubility coefficient of CO2 in mmol/L/mm Hg is 0.0301. cannot be measured directly, but pH and PCO2 can be measured with suitable accuracy with pH and PCO2 glass electrodes, and can then be calculated.
The pK’ of this system is still low relative to the pH of the blood, but the system is one of the most effective buffer systems in the body because the amount of dissolved CO2 is controlled by respiration (ie, it is an “open” system). Additional control of the plasma concentration of is provided by the kidneys. When H+ is added to the blood, declines as more H2CO3 is formed. If the extra H2CO3 were not converted to CO2 and H2O and the CO2excreted in the lungs, the H2CO3 concentration would rise. Without CO2 removal to reduce H2CO3, sufficient H+ addition that would halve the plasma would alter the pH 7.4 to 6.0. However, such a H+ concentration increase is tolerated because: (1) extra H2CO3 that is formed is removed and (2) the H+ rise stimulates respiration and therefore produces a drop in PCO2, so that some additional H2CO3 is removed. The net pH after such an increase in H+concentration is actually 7.2 or 7.3.
There are two additional factors that make the carbonic-acid-bicarbonate system such a good biological buffer. First, the reaction proceeds slowly in either direction unless the enzyme carbonic anhydrase is present. There is no carbonic anhydrase in plasma, but there is an abundant supply in red blood cells, spatially confining and controlling the reaction. Second, the presence of hemoglobin in the blood increases the buffering of the system by binding free H+ produced by the hydration of CO2 and allowing for movement of the into the plasma.
ACIDOSIS & ALKALOSIS
The pH of the arterial plasma is normally 7.40 and that of venous plasma slightly lower. A decrease in pH below the norm (acidosis) is technically present whenever the arterial pH is below 7.40 and an increase in pH (alkalosis) is technically present whenever pH is above 7.40. In practice, variations of up to 0.05 pH unit occur without untoward effects. Acid–base disorders are split into four categories: respiratory acidosis, respiratory alkalosis, metabolic acidosis, and metabolic alkalosis. In addition, these disorders can occur in combination. Some examples of acid–base disturbances are shown in Table 35–3.
TABLE 35–3 Plasma pH, , and PCO2 values in various typical disturbances of acid–base balance.a
Any short-term rise in arterial PCO2 (ie, above 40 mm Hg, due to hypoventilation) results in respiratory acidosis. Recall that CO2 that is retained is in equilibrium with H2CO3, which in turn is in equilibrium with . The effective rise in plasma means that a new equilibrium is reached at a lower pH. This can be indicated graphically on a plot of plasma concentration versus pH (Figure 35–8). The pH change observed at any increase in PCO2 during respiratory acidosis is dependent on the buffering capacity of the blood. The initial changes shown in Figure 35–8 are those that occur independently of any compensatory mechanism; that is, they are those of uncompensated respiratory acidosis.
FIGURE 35–8 Acid–base nomogram. Changes in the PCO2 (curved lines), plasma , and pH (or [H+]) of arterial blood in respiratory and metabolic acidosis are shown. Note the shifts in and pH as acute respiratory acidosis and alkalosis are compensated, producing their chronic counterparts. (Reproduced with permission from Brenner BM, Rector FC Jr. (editors): Brenner & Rector’s The Kidney, 7th ed. Saunders, 2004.)
Any short-term lowering of PCO2 below what is needed for proper CO2 exchange (ie, below 35 mm Hg, as can occur during hyperventilation) results in respiratory alkalosis. The decreased CO2 shifts the equilibrium of the carbonic acid–bicarbonate system to effectively lower [H+] and increase pH. As in respiratory acidosis, initial pH changes corresponding to respiratory alkalosis (Figure 35–8) are those that occur independently of any compensatory mechanism and are thus uncompensated respiratory alkalosis.
METABOLIC ACIDOSIS & ALKALOSIS
Blood pH changes can also arise by nonrespiratory mechanism. Metabolic acidosis (or nonrespiratory acidosis) occurs when strong acids are added to blood. If, for example, a large amount of acid is ingested (eg, aspirin overdose), acids in the blood are quickly increased. The H2CO3 that is formed is converted to H2O and CO2, and the CO2 is rapidly excreted via the lungs. This is the situation in uncompensated metabolic acidosis (Figure 35–8). Note that in contrast to respiratory acidosis, metabolic acidosis does not include a change in PCO2; the shift toward metabolic acidosis occurs along an isobar line (Figure 35–9). When the free [H+] level falls as a result of addition of alkali, or more commonly, the removal of large amounts of acid (eg, following vomiting), metabolic alkalosis results. In uncompensated metabolic alkalosis the pH rises along the isobar line (Figures 35–8 and 35–9).
FIGURE 35–9 Acid–base paths during metabolic acidosis. Changes in true plasma pH, , and PCO2 at rest, during metabolic acidosis and alkalosis, and following respiratory compensation are plotted. Metabolic acidosis or alkalosis causes changes in pH along the PCO2 isobar line (middle line). Respiratory compensation moves pH towards normal by altering PCO2 (top and bottom arrows). (This is called a Davenport diagram and is based on Davenport HW: The ABC of Acid–Base Chemistry, 6th ed. University of Chicago Press, 1974.)
RESPIRATORY & RENAL COMPENSATION
Uncompensated acidosis and alkalosis as described above are seldom seen because of compensation systems. The two main compensatory systems are respiratory compensation and renal compensation.
The respiratory system compensates for metabolic acidosis or alkalosis by altering ventilation, and consequently, the PCO2, which can directly change blood pH. Respiratory mechanisms are fast. In response to metabolic acidosis, ventilation is increased, resulting in a decrease of PCO2 (eg, from 40 mm Hg to 20 mm Hg) and a subsequent increase in pH toward normal (Figure 35–9). In response to metabolic alkalosis, ventilation is decreased, PCO2 is increased, and a subsequent decrease in pH occurs. Because respiratory compensation is a quick response, the graphical representation in Figure 35–9 overstates the two-step adjustment in blood pH. In actuality, as soon as metabolic acidosis begins, respiratory compensation is invoked and the large shifts in pH depicted do not occur.
For complete compensation from respiratory or metabolic acidosis/alkalosis, renal compensatory mechanisms are invoked. The kidney responds to acidosis by actively secreting fixed acids while retaining filtered . In contrast, the kidney responds to alkalosis by decreasing H+ secretion and by decreasing the retention of filtered .
Renal tubule cells in the kidney have active carbonic anhydrase and thus can produce H+ and from CO2. In response to acidosis, these cells secrete H+ into the tubular fluid in exchange for Na+ while the is actively reabsorbed into the peritubular capillary; for each H+ secreted, one Na+ and one are added to the blood. The result of this renal compensation for respiratory acidosis is shown graphically in the shift from acute to chronic respiratory acidosis in Figure 35–8. Conversely, in response to alkalosis, the kidney decreases H+ secretion and depresses reabsorption. The result of this renal compensation for respiratory alkalosis is shown graphically in the shift from acute to chronic respiratory alkalosis in Figure 35–8. Clinical evaluations of acid–base status are discussed in Clinical Box 35–2 and the role of the kidneys in acid–base homeostasis is discussed in more detail in Chapter 38.
CLINICAL BOX 35–2
Clinical Evaluation of Acid–Base Status
In evaluating disturbances of acid–base balance, it is important to know the pH and HCO3– content of arterial plasma. Reliable pH determinations can be made with a pH meter and a glass pH electrode. Using pH and a direct measurement of the PCO2 with a CO2 electrode, concentration can be calculated. The PCO2 is ∼8 mm Hg higher and the pH 0.03–0.04 unit lower in venous than arterial plasma because venous blood contains the CO2 being carried from the tissues to the lungs. Therefore, the calculated concentration is about 2 mmol/L higher. However, if this is kept in mind, free-flowing venous blood can be substituted for arterial blood in most clinical situations.
A measurement that is of some value in the differential diagnosis of metabolic acidosis is the anion gap. This gap, which is something of a misnomer, refers to the difference between the concentration of cations other than Na+ and the concentration of anions other than Cl– and in the plasma. It consists for the most part of proteins in anionic form, HPO42–, SO42–, and organic acids; a normal value is about 12 mEq/L. It is increased when the plasma concentration of K+, Ca2+, or Mg+ is decreased; when the concentration of (or the charge on) plasma proteins is increased; or when organic anions such as lactate or foreign anions accumulate in blood. It is decreased when cations are increased or when plasma albumin is decreased. The anion gap is increased in metabolic acidosis due to ketoacidosis, lactic acidosis, and other forms of acidosis in which organic anions are increased.
Hypoxia is O2 deficiency at the tissue level. It is a more correct term than anoxia (lack of O2), since there is rarely no O2 at all left in the tissues.
Numerous classifications for hypoxia have been used, but the more traditional four-type system still has considerable utility if the definitions of the terms are kept clearly in mind. The four categories are (1) hypoxemia (sometimes termed hypoxic hypoxia), in which the PO2 of the arterial blood is reduced; (2) anemic hypoxia, in which the arterial PO2 is normal but the amount of hemoglobin available to carry O2 is reduced; (3) ischemic or stagnant hypoxia,in which the blood flow to a tissue is so low that adequate O2 is not delivered to it despite a normal PO2 and hemoglobin concentration; and (4) histotoxic hypoxia, in which the amount of O2 delivered to a tissue is adequate but, because of the action of a toxic agent, the tissue cells cannot make use of the O2 supplied to them. Some specific effects of hypoxia on cells and tissues are discussed in Clinical Box 35–3.
CLINICAL BOX 35–3
Effects of Hypoxia on Cells and Selected Tissues
Effects on Cells
Hypoxia causes the production of transcription factors (hypoxia-inducible factors; HIFs). These are made up of α and β subunits. In normally oxygenated tissues, the α sub-units are rapidly ubiquitinated and destroyed. However, in hypoxic cells, the α subunits dimerize with β subunits, and the dimers activate genes that produce several proteins including angiogenic factors and erythropoietin, among others.
Effects on the Brain
In hypoxymia and the other generalized forms of hypoxia, the brain is affected first. A sudden drop in the inspired PO2 to less than 20 mm Hg, which occurs, for example, when cabin pressure is suddenly lost in a plane flying above 16,000 m, causes loss of consciousness in 10–20 s and death in 4–5 min. Less severe hypoxia causes a variety of mental aberrations not unlike those produced by alcohol: impaired judgment, drowsiness, dulled pain sensibility, excitement, disorientation, loss of time sense, and headache. Other symptoms include anorexia, nausea, vomiting, tachycardia, and, when the hypoxia is severe, hypertension. The rate of ventilation is increased in proportion to the severity of the hypoxia of the carotid chemoreceptor cells.
Dyspnea is by definition difficult or labored breathing in which the subject is conscious of shortness of breath; hyperpnea is the general term for an increase in the rate or depth of breathing regardless of the patient’s subjective sensations. Tachypnea is rapid, shallow breathing. In general, a normal individual is not conscious of respiration until ventilation is doubled, and breathing is not uncomfortable until ventilation is tripled or quadrupled. Whether or not a given level of ventilation is uncomfortable also appears to depend on a variety of other factors. Hypercapnia and, to a lesser extent, hypoxia cause dyspnea. An additional factor is the effort involved in moving the air in and out of the lungs (the work of breathing).
By definition, hypoxemia is a condition of reduced arterial PO2. Hypoxemia is a problem in normal individuals at high altitudes and is a complication of pneumonia and a variety of other diseases of the respiratory system.
EFFECTS OF DECREASED BAROMETRIC PRESSURE
The composition of air stays the same, but the total barometric pressure falls with increasing altitude (Figure 35–10), and thus, the PO2 also falls. At 3000 m (∼10,000 ft) above sea level, the alveolar PO2 is about 60 mm Hg and there is enough hypoxic stimulation of the chemoreceptors under normal breathing to cause increased ventilation. As one ascends higher, the alveolar PO2 falls less rapidly and the alveolar PCO2 declines because of the hyperventilation. The resulting fall in arterial PCO2 produces respiratory alkalosis. A number of compensatory mechanisms operate over a period of time to increase altitude tolerance (acclimatization), but in unacclimatized subjects, mental symptoms such as irritability appear at about 3700 m. At 5500 m, the hypoxic symptoms are severe; and at altitudes above 6100 m (20,000 ft), consciousness is usually lost.
FIGURE 35–10 Composition of alveolar air in individuals breathing air (0–6100 m) and 100% O2 (6100–13,700 m). The minimal alveolar PO2 that an unacclimatized subject can tolerate without loss of consciousness is about 35–40 mm Hg. Note that with increasing altitude, the alveolar Pco2 drops because of the hyperventilation due to hypoxic stimulation of the carotid and aortic chemoreceptors. The fall in barometric pressure with increasing altitude is not linear, because air is compressible.
HYPOXIC SYMPTOMS AND BREATHING OXYGEN
Some of the effects of high altitude can be offset by breathing 100% O2. Under these conditions, the total atmospheric pressure becomes the limiting factor in altitude tolerance.
The partial pressure of water vapor in the alveolar air is constant at 47 mm Hg, and that of CO2 is normally 40 mm Hg, so that the lowest barometric pressure at which a normal alveolar PO2 of 100 mm Hg is possible is 187 mm Hg, the pressure at about 10,400 m (34,000 ft). At greater altitudes, the increased ventilation due to the decline in alveolar PO2 lowers the alveolar PCO2 somewhat, but the maximum alveolar PO2 that can be attained when breathing 100% O2 at the ambient barometric pressure of 100 mm Hg at 13,700 m is ∼40 mm Hg. At ∼14,000 m, consciousness is lost in spite of the administration of 100% O2. At 19,200 m, the barometric pressure is 47 mm Hg, and at or below this pressure the body fluids boil at body temperature. The point is largely academic, however, because any individual exposed to such a low pressure would be dead of hypoxia before the bubbles of body fluids could cause death.
Of course, an artificial atmosphere can be created around an individual; in a pressurized suit or cabin supplied with O2 and a system to remove CO2, it is possible to ascend to any altitude and to live in the vacuum of interplanetary space. Some delayed effects of high altitude are discussed in Clinical Box 35–4.
CLINICAL BOX 35–4
Delayed Effects of High Altitude
When they first arrive at a high altitude, many individuals develop transient “mountain sickness.” This syndrome develops 8–24 h after arrival at altitude and lasts 4–8 days. It is characterized by headache, irritability, insomnia, breathlessness, and nausea and vomiting. Its cause is unsettled, but it appears to be associated with cerebral edema. The low PO2 at high altitude causes arteriolar dilation, and if cerebral autoregulation does not compensate, there is an increase in capillary pressure that favors increased transudation of fluid into brain tissue.
Two more serious syndromes that are associated with high-altitude illness: high-altitude cerebral edema and high-altitude pulmonary edema. In high-altitude cerebral edema, the capillary leakage in mountain sickness progresses to frank brain swelling, with ataxia, disorientation, and in some cases coma and death due to herniation of the brain through the tentorium. High-altitude pulmonary edema is a patchy edema of the lungs that is related to the marked pulmonary hypertension that develops at high altitude. It has been argued that it occurs because not all pulmonary arteries have enough smooth muscle to constrict in response to hypoxia, and in the capillaries supplied by those arteries, the general rise in pulmonary arterial pressure causes a capillary pressure increase that disrupts their walls (stress failure).
All forms of high-altitude illness are benefited by descent to lower altitude and by treatment with the diuretic acetazolamide. This drug inhibits carbonic anhydrase, and results in stimulated respiration, increased PaCO2, and reduced formation of CSF. When cerebral edema is marked, large doses of glucocorticoids are often administered as well. Their mechanism of action is unsettled. In high-altitude pulmonary edema, prompt treatment with O2 is essential—and, if available, use of a hyperbaric chamber. Portable hyperbaric chambers are now available in a number of mountain areas. Nifedipine, a Ca2+ channel blocker that lowers pulmonary artery pressure, can also be useful.
Acclimatization to altitude is due to the operation of a variety of compensatory mechanisms. The respiratory alkalosis produced by the hyperventilation shifts the oxygen–hemoglobin dissociation curve to the left, but a concomitant increase in red blood cell 2,3-DPG tends to decrease the O2 affinity of hemoglobin. The net effect is a small increase in P50. The decrease in O2 affinity makes more O2 available to the tissues. However, the value of the increase in P50 is limited because when the arterial PO2 is markedly reduced, the decreased O2 affinity also interferes with O2 uptake by hemoglobin in the lungs.
The initial ventilatory response to increased altitude is relatively small, because the alkalosis tends to counteract the stimulating effect of hypoxia. However, ventilation steadily increases over the next 4 days (Figure 35–11)because the active transport of H+ into cerebrospinal fluid (CSF), or possibly a developing lactic acidosis in the brain, causes a fall in CSF pH that increases the response to hypoxia. After 4 days, the ventilatory response begins to decline slowly, but it takes years of residence at higher altitudes for it to decline to the initial level, if it is reached at all.
FIGURE 35–11 Effect of acclimatization on the ventilatory response at various altitudes. is the ventilatory equivalent, the ratio of expired minute volume to the O2 consumption . (Reproduced with permission from Lenfant C, Sullivan K: Adaptation to high altitude. N Engl J Med 1971;284:1298.)
Erythropoietin secretion increases promptly on ascent to high altitude and then falls somewhat over the following 4 days as the ventilatory response increases and the arterial PO2 rises. The increase in circulating red blood cells triggered by the erythropoietin begins in 2–3 days and is sustained as long as the individual remains at high altitude. Compensatory changes also occur in the tissues. The mitochondria, which are the site of oxidative reactions, increase in number, and myoglobin increases, which facilitates the movement of O2 into the tissues. The tissue content of cytochrome oxidase also increases.
The effectiveness of the acclimatization process is indicated by the fact that permanent human habitations exist in the Andes and Himalayas at elevations above 5500 m (18,000 ft). The natives who live in these villages are barrel-chested and markedly polycythemic. They have low alveolar PO2 values, but in most other ways they are remarkably normal.
DISEASES CAUSING HYPOXEMIA
Hypoxemia is the most common form of hypoxia seen clinically. The diseases that cause it can be roughly divided into those in which the gas exchange apparatus fails, those such as congenital heart disease in which large amounts of blood are shunted from the venous to the arterial side of the circulation, and those in which the respiratory pump fails. Lung failure occurs when conditions such as pulmonary fibrosis produce alveolar–capillary block, or there is ventilation–perfusion imbalance. Pump failure can be due to fatigue of the respiratory muscles in conditions in which the work of breathing is increased or to a variety of mechanical defects such as pneumothorax or bronchial obstruction that limit ventilation. It can also be caused by abnormalities of the neural mechanisms that control ventilation, such as depression of the respiratory neurons in the medulla by morphine and other drugs. Some specific causes of hypoxemia are discussed in the following text.
When a cardiovascular abnormality such as an interatrial septal defect permits large amounts of unoxygenated venous blood to bypass the pulmonary capillaries and dilute the oxygenated blood in the systemic arteries (“right-to-left shunt”), chronic hypoxemia and cyanosis (cyanotic congenital heart disease) result. Administration of 100% O2 raises the O2 content of alveolar air but has little effect on hypoxia due to venous-to-arterial shunts. This is because the deoxygenated venous blood does not have the opportunity to get to the lung to be oxygenated.
Patchy ventilation–perfusion imbalance is by far the most common cause of hypoxemia in clinical situations. In disease processes that prevent ventilation of some of the alveoli, the ventilation–blood flow ratios in different parts of the lung determine the extent to which systemic arterial PO2 declines. If nonventilated alveoli are perfused, the nonventilated but perfused portion of the lung is in effect a right-to-left shunt, dumping unoxygenated blood into the left side of the heart. Lesser degrees of ventilation–perfusion imbalance are more common. In the example illustrated in Figure 35–12, the balanced ventilation-perfusion example on the left illustrates a uniform distribution throughout gas exchange. However, when ventilation is not in balance with perfusion, O2 exchange is compromised. Note that the underventilated alveoli (B) have a low alveolar PO2, whereas the overventilated alveoli (A) have a high alveolar PO2 while both have the same blood flow. The unsaturation of the hemoglobin of the blood coming from B is not completely compensated by the slightly greater saturation of the blood coming from A, because hemoglobin is normally nearly saturated in the lungs and the higher alveolar PO2 adds only a little more O2 to the hemoglobin than it normally carries. Consequently, the arterial blood is unsaturated. The CO2 content of the arterial blood is generally normal in such situations, since extra loss of CO2 in overventilated regions can balance diminished loss in underventilated areas.
FIGURE 35–12 Comparison of ventilation/blood flow relationships in health and disease. Left: “Ideal” ventilation/blood flow relationship. Right: Nonuniform ventilation and uniform blood flow, uncompensated. A, alveolar ventilation; MV, respiratory minute volume. See text for details. (Reproduced with permission from Comroe JH Jr, et al: The Lung: Clinical Physiology and Pulmonary Function Tests, 2nd ed. Year Book, 1962.)
OTHER FORMS OF HYPOXIA
Hypoxia due to anemia is not severe at rest unless the hemoglobin deficiency is marked, because 2,3-DPG increases in the red blood cells. However, anemic patients may have considerable difficulty during exercise because of a limited ability to increase O2 delivery to the active tissues (Figure 35–13).
FIGURE 35–13 Effects of anemia and CO on hemoglobin binding of O2. Normal oxyhemoglobin (14 g/dL hemoglobin) dissociation curve compared with anemia (7 g/dL hemoglobin) and with oxyhemoglobin dissociation curves in CO poisoning (50% carboxy-hemoglobin). Note that the CO-poisoning curve is shifted to the left of the anemia curve. (Reproduced with permission from Leff AR, Schumacker PT: Respiratory Physiology: Basics and Applications. Saunders, 1993.)
CARBON MONOXIDE POISONING
Small amounts of carbon monoxide (CO) are formed in the body, and this gas may function as a chemical messenger in the brain and elsewhere. In larger amounts, it is poisonous. Outside the body, it is formed by incomplete combustion of carbon. It was used by the Greeks and Romans to execute criminals, and today it causes more deaths than any other gas. CO poisoning has become less common in the United States, since natural gas replaced other gases such as coal gas, which contain large amounts of CO. CO is, however, still readily available, as the exhaust of gasoline engines is 6% or more CO.
CO is toxic because it reacts with hemoglobin to form carbon monoxyhemoglobin (carboxyhemoglobin, COHb), and COHb does not take up O2 (Figure 35–13). CO poisoning is often listed as a form of anemic hypoxia because the amount of hemoglobin that can carry O2 is reduced, but the total hemoglobin content of the blood is unaffected by CO. The affinity of hemoglobin for CO is 210 times its affinity for O2, and COHb liberates CO very slowly. An additional difficulty is that when COHb is present, the dissociation curve of the remaining HbO2 shifts to the left, decreasing the amount of O2 released. This is why an anemic individual who has 50% of the normal amount of HbO2 may be able to perform moderate work, whereas an individual with HbO2 reduced to the same level because of the formation of COHb is seriously incapacitated.
Because of the affinity of CO for hemoglobin, progressive COHb formation occurs when the alveolar PCO is greater than 0.4 mm Hg. However, the amount of COHb formed depends on the duration of exposure to CO as well as the concentration of CO in the inspired air and the alveolar ventilation.
CO is also toxic to the cytochromes in the tissues, but the amount of CO required to poison the cytochromes is 1000 times the lethal dose; tissue toxicity thus plays no role in clinical CO poisoning.
The symptoms of CO poisoning are those of any type of hypoxia, especially headache and nausea, but there is little stimulation of respiration, since in the arterial blood, PO2 remains normal and the carotid and aortic chemoreceptors are not stimulated. The cherry–red color of COHb is visible in the skin, nail beds, and mucous membranes. Death results when about 70–80% of the circulating hemoglobin is converted to COHb. The symptoms produced by chronic exposure to sublethal concentrations of CO are those of progressive brain damage, including mental changes and, sometimes, a parkinsonism-like state.
Treatment of CO poisoning consists of immediate termination of the exposure and adequate ventilation, by artificial respiration if necessary. Ventilation with O2 is preferable to ventilation with fresh air, since O2 hastens the dissociation of COHb. Hyperbaric oxygenation (see below) is useful in this condition.
Ischemic hypoxia, or stagnant hypoxia, is due to slow circulation and is a problem in organs such as the kidneys and heart during shock. The liver and possibly the brain are damaged by ischemic hypoxia in congestive heart failure. The blood flow to the lung is normally very large, and it takes prolonged hypotension to produce significant damage. However, acute respiratory distress syndrome (ARDS) can develop when there is prolonged circulatory collapse.
Hypoxia due to inhibition of tissue oxidative processes is most commonly the result of cyanide poisoning. Cyanide inhibits cytochrome oxidase and possibly other enzymes. Methylene blue or nitrites are used to treat cyanide poisoning. They act by forming methemoglobin, which then reacts with cyanide to form cyanmethemoglobin, a nontoxic compound. The extent of treatment with these compounds is, of course, limited by the amount of methemoglobin that can be safely formed. Hyperbaric oxygenation may also be useful.
OXYGEN TREATMENT OF HYPOXIA
Administration of oxygen-rich gas mixtures is of very limited value in hypoperfusion, anemic, and histotoxic hypoxia because all that can be accomplished in this way is an increase in the amount of dissolved O2 in the arterial blood. This is also true in hypoxemia when it is due to shunting of unoxygenated venous blood past the lungs. In other forms of hypoxemia, O2 is of great benefit. Treatment regimens that deliver less than 100% O2 are of value both acutely and chronically, and administration of O2 24 h/d for 2 years in this fashion has been shown to significantly decrease the mortality of chronic obstructive pulmonary disease. O2 toxicity and therapy are discussed in Clinical Box 35–5.
CLINICAL BOX 35–5
Administration of Oxygen & Its Potential Toxicity
It is interesting that while O2 is necessary for life in aerobic organisms, it is also toxic. Indeed, 100% O2 has been demonstrated to exert toxic effects not only in animals but also in bacteria, fungi, cultured animal cells, and plants. The toxicity seems to be due to the production of reactive oxygen species including superoxide anion (O2–) and H2O2. When 80–100% O2 is administered to humans for periods of 8 h or more, the respiratory passages become irritated, causing substernal distress, nasal congestion, sore throat, and coughing.
Some infants treated with O2 for respiratory distress syndrome develop a chronic condition characterized by lung cysts and densities (bronchopulmonary dysplasia). This syndrome may be a manifestation of O2 toxicity. Another complication in these infants is retinopathy of prematurity (retrolental fibroplasia), the formation of opaque vascular tissue in the eyes, which can lead to serious visual defects. The retinal receptors mature from the center to the periphery of the retina, and they use considerable O2. This causes the retina to become vascularized in an orderly fashion. Oxygen treatment before maturation is complete provides the needed O2 to the photoreceptors, and consequently the normal vascular pattern fails to develop. Evidence indicates that this condition can be prevented or ameliorated by treatment with vitamin E, which exerts an anti-oxidant effect, and, in animals, by growth hormone inhibitors.
Administration of 100% O2 at increased pressure accelerates the onset of O2 toxicity, with the production not only of tracheobronchial irritation but also of muscle twitching, ringing in the ears, dizziness, convulsions, and coma. The speed with which these symptoms develop is proportional to the pressure at which the O2 is administered; for example, at 4 atm, symptoms develop in half the subjects in 30 min, whereas at 6 atm, convulsions develop in a few minutes.
On the other hand, exposure to 100% O2 at 2–3 atm can increase dissolved O2 in arterial blood to the point that arterial O2 tension is greater than 2000 mm Hg and tissue O2 tension is 400 mm Hg. If exposure is limited to 5 h or less at these pressures, O2 toxicity is not a problem. Therefore, hyperbaric O2 therapy in closed tanks is used to treat diseases in which improved oxygenation of tissues cannot be achieved in other ways. It is of demonstrated value in carbon monoxide poisoning, radiation-induced tissue injury, gas gangrene, very severe blood loss anemia, diabetic leg ulcers, and other wounds that are slow to heal, and rescue of skin flaps and grafts in which the circulation is marginal. It is also the primary treatment for decompression sickness and air embolism.
In hypercapnic patients in severe pulmonary failure, the CO2 level may be so high that it depresses rather than stimulates respiration. Some of these patients keep breathing only because the carotid and aortic chemoreceptors drive the respiratory center. If the hypoxic drive is withdrawn by administering O2, breathing may stop. During the resultant apnea, the arterial PO2 drops but breathing may not start again, as PCO2 further depresses the respiratory center. Therefore, O2 therapy in this situation must be started with care.
HYPERCAPNIA & HYPOCAPNIA
Retention of CO2 in the body (hypercapnia) initially stimulates respiration. Retention of larger amounts produces symptoms due to depression of the central nervous system: confusion, diminished sensory acuity, and, eventually, coma with respiratory depression and death. In patients with these symptoms, the PCO2 is markedly elevated and severe respiratory acidosis is present. Large amounts of are excreted, but more is reabsorbed, raising the plasma and partially compensating for the acidosis.
CO2 is so much more soluble than O2 that hypercapnia is rarely a problem in patients with pulmonary fibrosis. However, it does occur in ventilation–perfusion inequality and when for any reason alveolar ventilation is inadequate in the various forms of pump failure. It is exacerbated when CO2 production is increased. For example, in febrile patients there is a 13% increase in CO2 production for each 1°C rise in temperature, and a high carbohydrate intake increases CO2 production because of the increase in the respiratory quotient. Normally, alveolar ventilation increases and the extra CO2 is expired, but it accumulates when ventilation is compromised.
Hypocapnia is the result of hyperventilation. During voluntary hyperventilation, the arterial PCO2 falls from 40 to as low as 15 mm Hg while the alveolar PO2 rises to 120–140 mm Hg.
The more chronic effects of hypocapnia are seen in neurotic patients who chronically hyperventilate. Cerebral blood flow may be reduced 30% or more because of the direct constrictor effect of hypocapnia on the cerebral vessels. The cerebral ischemia causes light-headedness, dizziness, and paresthesias. Hypocapnia also increases cardiac output. It has a direct constrictor effect on many peripheral vessels, but it depresses the vasomotor center, so that the blood pressure is usually unchanged or only slightly elevated.
Other consequences of hypocapnia are due to the associated respiratory alkalosis, the blood pH being increased to 7.5 or 7.6. The plasma level is low, but reabsorption is decreased because of the inhibition of renal acid secretion by the low PCO2. The plasma total calcium level does not change, but the plasma Ca2+ level falls and hypocapnic individuals develop carpopedal spasm, a positive Chvostek sign, and other signs of tetany.
Partial pressure differences between air and blood for O2 and CO2 dictate a net flow of O2 into the blood and CO2 out of the blood in the pulmonary system.
The amount of O2 in the blood is determined by the amount dissolved (minor) and the amount bound (major) to hemoglobin. Each hemoglobin molecule contains four subunits that each can bind O2. Hemoglobin O2 binding is cooperative and also affected by pH, temperature, and the concentration of 2,3-diphosphoglycerate (2,3-DPG).
CO2 in blood is rapidly converted into H2CO3 due to the activity of carbonic anhydrase. CO2 also readily forms carbamino compounds with blood proteins (including hemoglobin). The rapid net loss of CO2 allows more CO2 to dissolve in blood.
The pH of plasma is 7.4. A decrease in plasma pH is termed acidosis and an increase of plasma pH is termed alkalosis. A short-term change in arterial PCO2 due to decreased ventilation results in respiratory acidosis. A short-term change in arterial PCO2 due to increased ventilation results in respiratory alkalosis. Metabolic acidosis occurs when strong acids are added to the blood, and metabolic alkalosis occurs when strong bases are added to (or strong acids are removed from) the blood.
Respiratory compensation to acidosis or alkalosis involves quick changes in ventilation. Such changes effectively change the PCO2 in the blood plasma. Renal compensation mechanisms are much slower and involve H+ secretion or reabsorption.
Hypoxia is a deficiency of O2 at the tissue level. Hypoxia has powerful consequences at the cellular, tissue, and organ level: It can alter cellular transcription factors and thus protein expression; it can quickly alter brain function and produce symptoms similar to alcohol (eg, dizziness, impaired mental function, drowsiness, headache); and it can affect ventilation. Long-term hypoxia results in cell and tissue death.
For all questions, select the single best answer unless otherwise directed.
1. Most of the CO2 transported in the blood is
A. dissolved in plasma.
B. in carbamino compounds formed from plasma proteins.
C. in carbamino compounds formed from hemoglobin.
D. bound to Cl–.
E. in .
2. Which of the following has the greatest effect on the ability of blood to transport oxygen?
A. Capacity of the blood to dissolve oxygen
B. Amount of hemoglobin in the blood
C. pH of plasma
D. CO2 content of red blood cells
E. Temperature of the blood
3. Which of the following is true of the system?
A. Reaction 2 is catalyzed by carbonic anhydrase.
B. Because of reaction 2, the pH of blood declines during hyperventilation.
C. Reaction 1 occurs in the red blood cell.
D. Reaction 1 occurs primarily in plasma.
E. The reactions move to the right when there is excess H+ in the tissues.
4. In comparing uncompensated respiratory acidosis and uncompensated metabolic acidosis which one of the following is true?
A. Plasma pH change is always greater in uncompensated respiratory acidosis compared to uncompensated metabolic acidosis.
B. There are no compensation mechanisms for respiratory acidosis, whereas there is respiratory compensation for metabolic acidosis.
C. Uncompensated respiratory acidosis involves changes in plasma , whereas plasma  is unchanged in uncompensated metabolic acidosis.
D. Uncompensated respiratory acidosis is associated with a change in PCO2, whereas in uncompensated metabolic acidosis PCO2 is constant.
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