Chapter 35: Gas Transport & pH

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 concentrations for O₂ and CO₂ (measured as partial pressures, or P_o2 and P_co2) change within each region of the lung, allowing for these gases to flow “downhill” or from higher partial pressures to lower partial pressures. For example, P_o2 is highest in the alveoli upon inspiration and lowest in the deoxygenated blood, whereas, P_co2 is exactly opposite. This allows for O₂ to cross the alveoli and re-oxygenate the blood in the pulmonary vasculature, while CO₂ leaves the bloodstream and enters the alveoli where it is expired. 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.

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 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.

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 35–1). 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.

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 (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.

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 35–2). 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.

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 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.

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.

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 H₂CO₃ because of the presence of carbonic anhydrase (Figure 35–4). The H₂CO₃ dissociates to H⁺ and HCO₃⁻, and the H⁺ is buffered, primarily by hemoglobin, while the HCO₃⁻ 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.

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.

CHLORIDE SHIFT

Because the rise in the HCO₃⁻ content of red cells is much greater than that in plasma as the blood passes through the capillaries, about 70% of the HCO₃⁻ formed in the red cells enters the plasma. The excess HCO₃⁻ leaves the red cells in exchange for Cl⁻ (Figure 35–4). 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 HCO₃⁻ or a Cl⁻ (Figure 35–4). 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.

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 35–5.

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 HCO₃⁻. 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 HCO₃⁻. 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 manner, 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/day). 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 35–6) illustrate the differences in H⁺ buffering capacity.

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. [HCO₃⁻] cannot be measured directly, but pH and Pco₂ can be measured with suitable accuracy with pH and Pco₂ glass electrodes, and [HCO₃⁻] 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 HCO₃⁻ is provided by the kidneys. When H⁺ is added to the blood, HCO₃⁻ declines as more H₂CO₃ is formed. If the extra H₂CO₃ were not converted to CO₂ and H₂O and the CO₂ excreted in the lungs, the H₂CO₃ concentration would rise. Without CO₂ removal to reduce H₂CO₃, sufficient H⁺ addition that would halve the plasma HCO₃⁻ 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 biologic buffer. First, the reaction CO₂ + H₂O H₂CO₃ 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 HCO₃⁻ into the plasma.

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 causes of acid–base disturbances are shown in Table 35–3.

RESPIRATORY ACIDOSIS

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 HCO₃⁻. The effective rise in plasma HCO₃⁻ means that a new equilibrium is reached at a lower pH. This can be indicated graphically on a plot of plasma HCO₃⁻ concentration versus pH (Figure 35–7). The pH change observed at any increase in Pco₂ during respiratory acidosis depends on the buffering capacity of the blood. The initial changes shown in Figure 35–7 are those that occur independently of any compensatory mechanism; that is, they are those of uncompensated respiratory acidosis.

RESPIRATORY ALKALOSIS

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 35–7) 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 35–7). 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 35–8). 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 35–7 and 35–8).

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 35–8). 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 35–8 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 HCO₃⁻. In contrast, the kidney responds to alkalosis by decreasing H⁺ secretion and by decreasing the retention of filtered HCO₃⁻.

Renal tubule cells in the kidney have active carbonic anhydrase and thus can produce H⁺ and HCO₃⁻ from CO₂. In response to acidosis, these cells secrete H⁺ into the tubular fluid in exchange for Na⁺ while the HCO₃⁻ is actively reabsorbed into the peritubular capillary; for each H⁺ secreted, one Na⁺ and one HCO₃⁻ 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 35–7. Conversely, in response to alkalosis, the kidney decreases H⁺ secretion and depresses HCO₃⁻ reabsorption. The result of this renal compensation for respiratory alkalosis is shown graphically in the shift from acute to chronic respiratory alkalosis in Figure 35–7. 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.

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.

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 35–9), 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 persons, 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.

HYPOXIC SYMPTOMS & 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.

ACCLIMATIZATION

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 35–10) 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.

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.

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.

VENOUS-TO-ARTERIAL SHUNTS

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.

VENTILATION-PERFUSION IMBALANCE

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 35–11, 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.

ANEMIC 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 35–12).

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 35–12). 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

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 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.

HISTOTOXIC HYPOXIA

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/day for 2 years in this manner has been shown to significantly decrease the mortality of chronic obstructive pulmonary disease. O₂ toxicity and therapy are discussed in Clinical Box 35–5.

HYPERCAPNIA

Retention of CO₂ in the body (hypercapnia) initially stimulates respiration. Retention of larger amounts produces such symptoms as confusion, diminished sensory acuity and, eventually, coma with respiratory depression and death due to depression of the central nervous system. In patients with these symptoms, the Pco₂ is markedly elevated and severe respiratory acidosis is present. Large amounts of HCO₃⁻ are excreted, but more HCO₃⁻ is reabsorbed, raising the plasma HCO₃⁻ 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

Hypocapnia is the result of hyperventilation. During voluntary hyperventilation, the arterial Pco₂ falls from 40 mm Hg 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 HCO₃⁻ level is low, but HCO₃⁻ 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 HCO₃⁻ 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.