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.
(a) Processes that absorb CO2 in active tissues are reversed in pulmonary capillaries during excretion of CO2 from mixed venous blood, even as oxygenation is occurring. Here, the roles of carbonic anhydrase (CA) within RBCs and on endothelial cells are emphasized. (b) About 91% of CO2 in mixed venous blood exists as HCO3−, with 5% as HbCO2 and 4% as dissolved CO2 gas. Only ~7% of CO2 in venous blood is excreted during one passage through the alveolar capillaries. Of that amount, ~80% is from HCO3− and ~9%-10% each from HbCO2 and dissolved CO2 pools. (a): From Fox, Human Physiology, 10th ed. 2008.
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.
CO2 dissociation curves for whole blood at different O2 saturations. Oxygenated blood carries less CO2 than deoxygenated blood at the same Pco2, but both transport far more CO2 than occurs as dissolved gas. The inset depicts differences between arterial and mixed venous blood. Modified from West, Respiratory Physiology; 2005.
As shown in the inset to Fig. 9.6, the physiological range for CO2 exchange is normally between Paco2 = 40 mm Hg and PV̄co2 = 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 Pao2 and PV̄o2 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:
CO2 + H2O ⇒ H2CO3 ⇔ H+ + HCO3−
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 Ka:
Ka = [H+] · [HCO–3]/[H2CO3]
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):
pHa = pKa + log [HCO–3] − log [H2CO3]
pHa = pKa + log [HCO–3] − log [(0.03) · (Paco2)]
where 0.03 represents the solubility coefficient to convert Paco2 (in mm Hg) at 37°C into H2CO3 (in mM). In physiological systems, the value of pKa 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 Paco2 = 40 mm Hg, a normal resting [HCO3−] is calculated to be:
Thus, to achieve a stable pHa = 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, Paco2). Several decades ago it was presumed that all mammals operate at Paco2 = 40 mm Hg. However smaller animals often function with a Paco2 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 pHa of ~7.40. Indeed, subsequent investigations confirmed that maintaining pHa 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 pHa, Paco2, 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 Paco2, 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 Paco2 = 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 Paco2. 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.
A Davenport diagram showing the basic relationships among blood HCO3−, pHa, and Paco2. Point A represents the normal values for healthy subjects at rest and with Paco2 = 40 mm Hg; the center line BAC illustrates the normal buffering capacity for whole blood. Modified from West, Respiratory Physiology; 2005.
There are four principal ways to perturb acid-base homeostasis within the CO2-based buffer system, namely raising or lowering either Paco2 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 pHa, Paco2, and [HCO–3]. If Paco2 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, Paco2 is too high, pHa 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 pHa, one can easily predict the appropriate response. Since respiratory impairment already exists (Paco2 is elevated), the appropriate compensation is to move along this new Paco2 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 Paco2 is allowed to increase very slowly from 40 to 60 mm Hg.
An expanded view of the physiological ranges encountered clinically for plasma HCO–3, pHa, and Paco2. Point A illustrates typical normal values at rest. The several paths to respiratory and metabolic disturbances are shown, and the typical compensatory responses to reestablish pHa. Modified from West, Respiratory Physiology; 2005.
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 V̇A/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 V̇A, causing Paco2 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 Paco2 isobar. Again in attempting to reestablish pHa = 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 pHa.
Numerous nonrespiratory diseases can affect pHa, 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 Paco2 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 pHa, 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.
CLINICAL CORRELATION 9.2
Why is arriving at point F in Fig. 9.8 via point G more dangerous than getting to point F via point C, as occurs in respiratory alkalosis? The answer relates to the causes that lead to lost pH equilibrium. The hyperventilation of uncompensated respiratory alkalosis is more easily corrected (by descending from altitude or reducing anxiety with sedation) than is the ketoacidosis of diabetes or the ischemia and lactate acidemia of septic shock.