Chapter 9: Alveolar O₂ and CO₂ Exchange, Physiological Shunt, and Acid-Base Balance

Once gases reach the alveolar parenchyma by ventilation, absorption into the blood or excretion from it occurs not by convection, but by molecular diffusion according to a physiological restatement of Ohm’s law (Fig. 9.1). Diffusion of any gas through the septal barrier and into the blood is proportional to the alveolar epithelial surface area (S_A) and the alveolar capillary endothelial surface area (S_C) comprising the membrane available for such exchange. Quantitative measurements on electron photomicrographs of normal lung have estimated S_A and S_C to each be 50-70 m². This symmetry of S_A and S_C dimensions is perhaps not surprising, given the importance placed earlier on good V̇_A/Q̇ matching. Alveolar diffusion of any gas is inversely proportional to septal barrier thickness, estimated as its harmonic mean (τ_S) to emphasize statistically the thinnest regions where diffusion is presumably favored.

Given these lung anatomical features that affect all gases, other factors will determine whether diffusional equilibrium is achieved between an alveolar airspace and the blood flowing through its capillaries. Again by analogy to Ohm’s law, each gas diffuses proportionally to the pressure gradient between its "source" (P₁, the higher value) and its "sink" (P₂, the lower value). For O₂, P₁ = P_Ao₂ (Chap. 8) and P₂ = P_V̄o₂ as measured by a pulmonary artery catheter, yielding a normal inwardly directed gradient of ~60 mm Hg on room air. That gradient is dramatically affected by both F_Io₂ and P_B insofar as those affect P_Io₂ and thus P_Ao₂. For CO₂, P₁ = P_V̄co₂, and P₂ = P_Aco₂ (= P_aco₂), for a normal outwardly directed gradient of 5-6 mm Hg and one that is less sensitive to F_Io₂ or P_B than that for Po₂. Indeed, data in Table 3.2 were used to make this point earlier of a tenfold larger gradient for O₂ despite that the flow of CO₂ outward and O₂ inward are nearly the same. How can this occur? Gases will diffuse at different rates, despite equal values for S_A, S_C, τ_S, and (P₁-P₂), because of differing coefficients of diffusivity (D), defined as the solubility of a gas in aqueous media divided by its mass-dependent rate of gaseous-free diffusion. The value of D for CO₂ is ~20 times that of O₂ in biological systems, implying that lung disorders will present more often with hypoxemia (low blood O₂ content) than with hypercarbia (high blood CO₂ content). One can also appreciate that alveolar diffusion of all gases will diminish in a disease like emphysema where S_A and S_C are decreased (Fig. 9.2). Likewise, alveolar diffusion decreases in those diseases for which τ_S is increased, for example during the edema of acute lung injury (Chap. 28) or after the development of fibrosis in some interstitial lung diseases that show a restrictive pattern by pulmonary function test (PFT) (Chap. 24).

Given this discussion, what time constraints exist on gas diffusion in the lung? This question can be answered by considering capillary transit times of erythrocytes in the lung in relation to the equilibration rate of alveolar gases with the interiors of those red blood cells (RBCs) (Fig. 9.3). An RBC spends ~0.8 seconds in an alveolar capillary at a resting Q̇ but less than 0.3 seconds when Q̇ approaches maximal values. The long RBC transit time at low Q̇ is usually sufficient for N₂O (an anesthetic gas), CO, CO₂, and O₂ to equilibrate across the alveolar-capillary barrier, that is, P₁ ≅ P₂ for these gases near the venular end of alveolar capillaries. By example, N₂O is very soluble in blood but does not bind to Hb. Thus, it equilibrates across the barrier regardless of the original (P_An₂o-P_c’n₂o) or transit time, so that its absorption is perfusion limited only by Q̇. If Q̇ increases, then N₂O uptake increases because more RBCs pass through the alveolar capillaries in the same interval of time. In contrast, CO binds to Hb in such large amounts that no RBC spends enough time in an alveolar capillary to equilibrate P_Aco with P_c’co. Thus, the absorption of CO is diffusion limited, and simply increasing Q̇ will not necessarily increase CO uptake. Rather, the alveolar uptake of CO and other diffusion limited gases will more likely increase if S_A and S_C increase, or if τ_s decreases.

Normally O₂ has an intermediate equilibration rate to those of N₂O or CO. In healthy individuals, O₂ is a perfusion-limited gas over a wide range of Q̇ (Fig. 9.3), and at sea level alveolar O₂ uptake usually is not considered to be the rate-limiting step to maximal O₂ consumption, V̇o_2max (Chap. 12). However, in diseased lungs with destroyed or fibrotic alveolar septa, O₂ becomes diffusion limited during moderate exercise, and potentially at rest despite long RBC transit times. Even in healthy individuals, O₂ becomes a diffusion-limited gas when P_Ao₂ is reduced by a low F_Io₂ or by the reduced P_B at high altitude (Chap. 13).

Based on its greater aqueous solubility, CO₂ diffuses into and out of tissues ~20 times faster than O₂ per mm Hg of pressure gradient. Consequently, there is usually ample capillary transit time for CO₂ to achieve equilibrium despite its much smaller partial pressure gradient versus O₂. However, under conditions of reduced RBC transit time or with thickening of the alveolar septal membranes, CO₂ transfer may be incomplete and result in hypercarbia.

The long equilibration time of inhaled CO is used clinically to estimate the single-breath lung diffusing capacity for CO (DL_CO). As detailed in Chap. 16, this pulmonary function test is most often conducted on patients who are suspected of having reduced S_A or S_C, or increased τ_s. Subjects begin the maneuver at their RV and inhale gas with a low F_Ico (usually ~0.003) up to their TLC. Once at TLC, the breath is held for 10 seconds and then exhaled completely. Concentrations of CO in the exhaled gas are measured to establish F_Ēco and F_Éco (= F_Aco), and thus P_Aco by Dalton’s law. These data yield the CO uptake rate (V̇co) plus the "P₁" from the equation in Fig. 9.1 that drove its absorption. "P₂" in that same equation, being the subject’s P_Ćco, is considered zero since inhaled CO never equilibrates with blood in the capillaries. The diffusivity coefficient D_CO is constant because the aqueous solubility and mass of CO are known. DL_CO is computed then as:

where carbon monoxide conductance, C_CO = [D_CO · (S_A + S_C)]/(2 · τ_s). Thus, the working equation for the DL_CO test becomes:

Since all terms on the right side of this equation are measured by the single-breath DL_CO procedure, the test yields a robust "lump sum" or aggregate estimate of a subject’s alveolar and capillary surface areas available for diffusion, as well as their alveolar barrier’s thickness as an impediment to that diffusion. The subject’s measured value for DL_CO then can be compared with expected normative values like other spirometric data to assess the severity of emphysema, edema, interstitial fibrosis, or other disease processes that impact S_A, S_C, or τ_S.

It should be emphasized that despite crossing the alveolar-capillary membrane, O₂ has yet to oxygenate the RBCs. Therefore, the lung’s overall diffusing capacity for O₂ consists of two linked components: its membrane diffusing capacity for O₂, DMo₂ representing the distance from alveolar airspace through the surfactant liquid, tissue, and plasma layers; and its erythrocytic diffusing capacity. As will be described in Chap. 16, this latter component depends on the blood transfer conductance coefficient for oxygen (Θo₂) between Hb and O₂, and on total pulmonary capillary blood volume, V_c. Perhaps surprisingly, the diffusive resistance of the membrane barrier (1/DMo₂) accounts for only about half of overall resistance to O₂ uptake in the lung, with the balance of that resistance being due to the erythrocytes themselves.

To this point, the Po₂ gradient in the body has encountered only one unavoidable reduction from the inspired P_Io₂, that occurring in conducting airways by Dalton’s law, as O₂ is displaced by CO₂ and H₂O vapor. Thus P_Ao₂ always is less than P_Io₂. The preceding discussion also implies that if O₂ is a perfusion-limited gas under most conditions, then the P_Ćo₂ of blood draining alveoli should equal P_Ao₂. However, as was seen in Chap. 8, a subject’s actual P_ao₂ as reported from blood gas analyses is always at least slightly less than P_Ao₂. Indeed, this (A − a) Po₂ difference can be quite large in some patients, implying that the higher P_Ćo₂ of blood draining their alveolar capillaries is diluted downstream with blood with a Po₂ nearer to that of mixed venous blood. This venous admixture, or contamination of well-oxygenated blood draining the alveoli by less oxygenated blood, comprises the essence of physiological shunt.

By analogy to comments regarding anatomical and physiological dead space (Chap. 8), there can exist anatomical and physiological shunts in the pulmonary or systemic circulations. As for dead space, physiological shunt always includes anatomical shunt, that is, blood flow through pulmonary arteries that never enters the respiratory parenchyma to permit alveolar gas exchange. Examples of anatomical shunts include a patent ductus arteriosus (PDA) and patent foramen ovale (PFO) that allow systemic venous blood to bypass the lungs entirely (Chap. 7). Importantly, physiological shunt includes that blood flow plus any mixed venous blood that passes through the septal capillaries in the respiratory parenchyma without gaining access to ventilated alveoli. Such physiological shunt was noted earlier in the low V̇_A/Q̇ ratios of patients with type B emphysema, as documented with the multiple inert gas technique (Chap. 8). In simplified form, the development of physiological shunt is shown in Fig. 9.4.

A working version of the shunt equation can be derived from Fig. 9.4, where Q̇_T equals total cardiac output, and Q̇_S is that portion of Q̇_T being shunted around alveolar capillaries, either anatomically or due to low V̇_A/Q̇ ratios. The blood O₂ concentrations needed to solve the shunt equation for Q̇_S include that of blood in alveolar capillaries (C_ĆO₂) with very high O₂ content, as well as blood in the systemic arteries (C_ao₂) and in the pulmonary artery (C_V̄o₂). One can report a patient’s physiological shunt (Q̇_S) either in absolute terms (L/min) or as a percent of Q̇_T. Deriving the shunt equation begins with the principle of mass balance for O₂ as expressed in the following equation:

Rearranging terms and making a sign change so that Q̇_S/Q̇_T is a positive value, yields the working version of the shunt equation that is solvable using a patient’s data:

In practice, shunt studies are done while subjects are breathing pure oxygen (F_Io₂ = 1.00). This minor intervention permits some simplifying assumptions about the amounts of HbO₂ versus dissolved O₂ needed in the calculation of total O₂ contents for each blood compartment. Shunt studies can be done on alert or sedated patients, provided that arterial and venous blood samples are available for determinations of P_ao₂ and P_V̄o₂, blood [Hb], and mixed venous % oxygenation or saturation, S_V̄o₂ (%). The calculated Q̇_S/Q̇_T is generally <10% in most healthy adults, but it may exceed 20% in disease conditions that are characterized by low V̇_A/Q̇ ratios as described in Chap. 8. Several examples of shunt calculation problems are included at the end of this chapter.

As detailed in Chap. 3, CO₂ is transported in blood as: dissolved CO₂ gas by Henry’s law; as HCO^–₃ from dissociated H₂CO₃ after CO₂ combines with H₂O (facilitated by carbonic anhydrase, CA); and as HbCO₂ from its reversible binding to Hb (Fig. 9.5). Recall that deoxy-Hb is a weaker acid than oxy-Hb and so binds H⁺ more readily (the Haldane effect), particularly in active tissues where H₂CO₃ formation predominates.

If the relationship is plotted between Pco₂ and total [CO₂] in a blood sample at equilibrium, a CO₂ dissociation curve is obtained (Fig. 9.6) that is analogous to such graphs for the O₂ content of whole blood (Chap. 3). Because such plots of Pco₂ versus [CO₂] include all three forms of CO₂, the resulting curves are not linear, owing to the saturable HbCO₂ component and also to the exhaustible supply of donor H⁺ from hemoglobin. Due to the Haldane effect, the [CO₂] for deoxygenated blood is higher than for oxygenated blood at all physiological values for Pco₂.

As shown in the inset to Fig. 9.6, the physiological range for CO₂ exchange is normally between P_aco₂ = 40 mm Hg and P_V̄co₂ = 45 mm Hg, which yields a net loss of about 5 mL CO₂/dL blood during each passage of blood through the lungs. Note that an essentially equivalent difference of 5 mL O₂/dL blood exists between arterial and venous bloods, although the required difference in P_ao₂ and P_V̄o₂ is closer to 50-60 mm Hg to achieve this same amount of gas exchange, and that is normally occurring on the upper shoulder of the O₂ dissociation curve. The transport and release of CO₂ by the respiratory system have profound effects on the body’s pH regulation and acid-base status. The following equation has been presented in the context of CO₂ transport, both for CO₂ uptake in metabolically active tissues, and for CO₂ excretion in the lungs:

The equation as written represents events in the tissues, while the right-to-left direction would describe the reaction in the lungs. Importantly, mass action considerations apply in both directions: increasing the concentration of either substrates or products will shift the equilibrium points accordingly in response to those changed conditions. The equilibrium between the weak acid H₂CO₃ and its dissociated ions, H⁺ and HCO^–₃, is described by the dissociation constant K_a:

Taking logarithms of both sides and then substituting for H₂CO₃ based on Henry’s law, yields the Henderson-Hasselbalch equation (see Chap. 17 for more detailed steps):

where 0.03 represents the solubility coefficient to convert P_aco₂ (in mm Hg) at 37°C into H₂CO₃ (in mM). In physiological systems, the value of pK_a for this first dissociation is 6.10 at 37°C, and an arterial pH of 7.40 is normally carefully regulated. Thus:

Given a typical P_aco₂ = 40 mm Hg, a normal resting [HCO₃⁻] is calculated to be:

Thus, to achieve a stable pH_a = 7.40 using the CO₂ buffer system requires maintaining an anion/acid ratio of approximately 20:1. Obviously, this 20:1 ratio can be satisfied by an infinite range of molarities for [HCO^–₃] and [H₂CO₃] (ie, P_aco₂). Several decades ago it was presumed that all mammals operate at P_aco₂ = 40 mm Hg. However smaller animals often function with a P_aco₂ of 25-30 mm Hg, and have [HCO^–₃] values that are appropriately lower, in the range of 18-20 mM. Nevertheless, at 37°C all mammals appear to protect a pH_a of ~7.40. Indeed, subsequent investigations confirmed that maintaining pH_a near 7.40 is far more important than is a particular value for total blood CO₂ content. Among healthy adults, total CO₂ is about 25.2 mM (= 24 mM HCO^–₃ + 1.2 mM H₂CO₃). However this total can vary widely, such that the measured [HCO^–₃] and total CO₂ content for individuals reflect either acute perturbations to their acid-base balance, or the chronic compensatory responses to such a perturbation (Chap. 17).

With the Henderson–Hasselbalch equation, knowing any two parameters among pH_a, P_aco₂, and HCO^–₃ fixes the third. Some years ago Davenport wrote The ABC of Acid-Base Chemistry that popularized the eponymous diagram in Fig. 9.7. It features an abscissa in pH units and an ordinate of [HCO^–₃]. Since knowing any pair of pH and [HCO^–₃] values determines P_aco₂, one can draw a family of Pco₂ isobars (lines of equal pressure) whose center point A shows that at 37°C, pHa = 7.40 if P_aco₂ = 40 mm Hg and [HCO^–₃] = 24 mM. The line CAB here is the CO₂ Blood Buffer Line and describes the effects on pH and [HCO^–₃] of blood titrated with acid in the form of H₂CO₃ and thus P_aco₂. A similar CO₂ Plasma Buffer Line would have a shallower slope since plasma contains fewer proteins and is thus a weaker buffer than whole blood.

There are four principal ways to perturb acid-base homeostasis within the CO₂-based buffer system, namely raising or lowering either P_aco₂ or [HCO^–₃]. Compensation usually involves altering the previously stable of the two (Fig. 9.8). Point A here and in Fig. 9.7 represents the normal, ideal balance among pH_a, P_aco₂, and [HCO^–₃]. If P_aco₂ abruptly increases toward a higher CO₂ isobar, this acute change in acid-base status to point B is termed respiratory acidosis. In the uncompensated phase of this response, P_aco₂ is too high, pH_a is too low, and blood [HCO^–₃] has not increased enough to reestablish a 20:1 ratio between [HCO^–₃] and [H₂CO₃]. Remembering that homeostatic mechanisms will first and foremost attempt to restore a normal pH_a, one can easily predict the appropriate response. Since respiratory impairment already exists (P_aco₂ is elevated), the appropriate compensation is to move along this new P_aco₂ isobar toward point D by retaining [HCO^–₃] in the kidneys and thereby regain a 20:1 ratio. Note that the uncompensated acidosis at point B does cause a slight increase in [HCO^–₃] by simple mass action. However, this effect is not sufficient to correct the acidosis unless P_aco₂ is allowed to increase very slowly from 40 to 60 mm Hg.

Acute respiratory acidosis may begin with food aspiration, heart attack, drug overdose, pneumothorax, head injury affecting ventilatory drive, etc. Chronic acidosis with some compensation via renal HCO^–₃ retention is common with V̇_A/Q̇ abnormalities due to obstructive disease. As the term implies, respiratory acidosis is mainly a lung disorder, whether it is acute and uncompensated, or chronic and partially or fully compensated.

In the opposite direction, an individual may abruptly increase V̇_A, causing P_aco₂ to fall below 40 mm Hg. Such respiratory alkalosis is most often due to hyperventilation during pain or anxiety (or accidentally during mechanical ventilation), or as a direct result of exposure to environmental hypoxia, as occurs at high altitude. In Fig. 9.8, respiratory alkalosis is seen acutely as moving from point A to point C toward a lower P_aco₂ isobar. Again in attempting to reestablish pH_a = 7.40, compensation will occur toward point F by promoting renal excretion of HCO^–₃. Again, such a respiratory disturbance could maintain the 20:1 ratio of [HCO^–₃]/[H₂CO₃] if it occurred slowly, since HCO^–₃ is eventually converted to H₂CO₃ by mass action. For example, ascent to altitude can be staged slowly enough to minimize such alkalotic increases in pH_a.

Numerous nonrespiratory diseases can affect pH_a, and their onset may be either acute or more chronic than respiratory acidosis and alkalosis. Excessive ingestion of antiacids or prolonged vomiting can induce metabolic alkalosis, shown in Fig. 9.8 as moving from point A to point E along a constant P_aco₂ isobar. Respiratory compensation occurs toward point D in the form of hypoventilation, again to restore the 20:1 ratio between anion and acid. This compensation increases total blood CO₂ content above that caused by the excessive [HCO^–₃] in the acute, uncompensated phase. Assuming patients survive any immediate crisis caused by this elevated pH_a, their hypoventilation can be reversed later to excrete the additional CO₂ content that compensation induced.

Metabolic acidosis is a serious perturbation caused primarily by the excessive production of organic acids that overwhelm the body’s supply of [HCO^–₃]. Diabetic ketoacidosis, septic shock, aspirin overdose, renal failure, and diarrhea are common causes. By observing movement from point A to point G in Fig. 9.8, the life-threatening nature of metabolic acidosis is apparent. Respiratory compensation from point G to point F requires lowering blood CO₂ content via hyperventilation, which consumes additional [HCO^–₃]. Thus, the 20:1 ratio for [HCO^–₃]/[H₂CO₃] is restored in such a manner that if the underlying cause of acid generation is not corrected, blood [HCO^–₃] stores are depleted, and irreversible acidosis and death ensue.

The numerous clinical variations of these acid-base disorders will be more extensively reviewed in Chap. 17, in the form of patient scenarios and their solutions.