Carbon Dioxide Hydration Reaction

The presence of CO₂ in the blood creates a special problem because CO₂ reacts with water (i.e., CO₂ is hydrated) to form carbonic acid (H₂CO₃). The blood must possess effective buffering mechanisms to prevent harmful increases in acidity as it transports CO₂. As the following reaction shows, when CO₂ diffuses from tissues into capillary blood, the CO₂ hydration reaction occurs:¹

Hydrolysis is a chemical reaction in which H₂O splits another molecule; the term is incorrect in reference to the reaction between H₂O and CO₂. Reaction 1 shows that CO₂ in the blood is associated with the formation of H₂CO₃ and the production of hydrogen ions (H⁺). A fundamental characteristic of an acid is the release of H⁺ into solution. Although CO₂ is technically not an acid, its immediate formation of H₂CO₃ in physiological fluids allows it to be treated as though it were an acid.

Hydration Reaction: Chemical Equilibrium (Le Chatelier’s Principle)

The CO₂ hydration reaction (reaction 1) can proceed in either direction (i.e., it is reversible). Chemical equilibrium exists when the reaction velocities to the left and right are equal. A state of equilibrium does not mean the concentrations of substances on both sides of the equation are equal, and it does not imply a static state of affairs. At equilibrium, the reaction continues to move in both directions at equal rates but in such a way that no net change occurs in the concentrations of constituents on either side of the reaction. This state is called dynamic equilibrium. The reaction between CO₂ and H₂O in plasma occurs only to a slight extent; in this state of the chemical equilibrium, CO₂ and H₂O molecules far outnumber H₂CO₃ molecules. Therefore, at equilibrium, the CO₂ hydration reaction is shifted to the left, as the following reaction shows:

The short arrows pointing to the right and the long arrows pointing to the left indicate that at equilibrium the reaction is left shifted. The numbers in parentheses indicate relative concentrations of the constituents.² At equilibrium, concentrations to the left of the arrows are greater than concentrations to the right of the arrows. Despite these concentration differences, the velocities of right-directed and left-directed reactions are identical at equilibrium.

According to Le Chatelier’s principle, if a system at equilibrium is placed under stress, it will react in such a way that counteracts the stress and creates a new equilibrium at a different point.³ For example, in reaction 2, if we add a certain amount of CO₂ molecules to the left side of the reaction, we disrupt the equilibrium and drive the reaction to the right until a new equilibrium is established. Similarly, removing CO₂ molecules from the left side “pulls” the reaction to the left. In other words, adding or subtracting CO₂ molecules drives the reaction either toward the H⁺ and HCO3− side or toward the CO₂ and H₂O side of the reaction.

Relationship between Dissolved Carbon Dioxide and Carbonic Acid Concentrations

All gases dissolve in water to some extent, as discussed in previous chapters. According to Henry’s law, the amount of CO₂ dissolving in plasma is proportional to the PCO₂ to which the plasma is exposed. In other words, CO₂ in the gaseous phase establishes equilibrium with CO₂ in the aqueous phase. In the lung, gaseous CO₂ in the alveoli establishes equilibrium with dissolved CO₂ in capillary blood plasma. The concentration of CO₂ in alveolar gas is expressed in terms of its partial pressure (mm Hg). The concentration of dissolved CO₂ in plasma is proportional to P_ACO₂ and is measured in millimoles per liter (mmol/L) rather than in milliliters per deciliter (mL/dL), as it is for oxygen content.

At 37° C, 0.03 mmol of CO₂ dissolves in 1 L of plasma for each mm Hg PCO₂; that is, mmol/L (CO₂) = 0.03 mmol/L/mm Hg × PCO₂. (The derivation of the conversion factor [0.03] to change PCO₂ to millimoles per liter of dissolved CO₂ is shown in Box 9-1.) Thus, if plasma PCO₂ is 40 mm Hg, the concentration of dissolved CO₂ in plasma is as follows: 40 mm Hg × 0.03 mmol/L/mm Hg = 1.2 mmol/L, which is the normal amount of dissolved CO₂ in arterial blood. Figure 9-1 summarizes the relationship between gaseous CO₂, dissolved CO₂, and H₂CO₃. The slow uncatalyzed reaction between CO₂ and H₂O theoretically requires about 400 molecules of dissolved CO₂ to produce 1 molecule of H₂CO₃.² In other words, an extremely small amount of H₂CO₃ in plasma is in equilibrium with a relatively large pool of dissolved CO₂. The reaction in Figure 9-1 shows that an increased alveolar PCO₂ increases plasma PCO₂, which increases the dissolved CO₂ and H₂CO₃ concentration (law of mass action). Conversely, a decrease in alveolar PCO₂ forces the hydration reaction to the left, decreasing the plasma H₂CO₃ concentration. Because it is in equilibrium with CO₂ gas, H₂CO₃ is called a volatile acid. Plasma PCO₂ is an important marker of the blood’s volatile acid content and the adequacy of alveolar ventilation.

BOX 9-1   Conversion Factors for Dissolved Carbon Dioxide: Millimoles per Liter and Milliliters per Deciliter

1. 1 mole CO₂ = 22.3 L at STP; 1 mmol CO₂ = 22.3 mL at STP

2. CO₂ sol coeff = 0.592 mL CO₂/mL plasma/760 mm Hg PCO₂

3. mL CO₂ dissolving per mL plasma per mm Hg PCO₂ is as follows: 0.592/760 mm Hg = 0.00078 mL CO₂/mL plasma/mm Hg

4. mL CO₂ dissolving per 100 mL plasma (mL/dL) = 0.078 mL

5. mL CO₂ dissolving per L (1000 mL) plasma per mm Hg PCO₂ is as follows:

0.00078× 1000 = 0.78 mL CO₂/L plasma/mm Hg

6. mmol CO₂ dissolving per L plasma per mm Hg PCO₂ is as follows: 0.78 mL CO₂/22.3 mL CO₂ per mmol = 0.03498 mmol CO₂/L/mm Hg

PCO2×0.03=mmol/LdissolvedCO2

7. Factor to convert mmol/L to mL/dL (from steps 4 and 6) = 0.078/0.03498 = 2.23:

mmol/LCO2×2.23=mL/dLCO2

mL/dLCO2/2.23=mmol/LCO2

STP, Standard temperature and pressure; sol coeff, soluble coefficient.

Although the concentration of dissolved CO₂ in plasma is not equal to the concentration of plasma H₂CO₃, its concentration is in direct proportion to the concentration of H₂CO₃; this makes it possible to treat CO₂ as if it were the acid instead of H₂CO₃. Because dissolved CO₂ and H₂CO₃ are indistinguishable from each other by chemical analysis,⁴ dissolved CO₂, which can be easily measured, is commonly substituted for the concentration of H₂CO₃ in clinical acid-base equations (see Chapter 10).

Role of Ventilation in Regulating Arterial Carbon Dioxide Pressure and Volatile Acid

Changes in alveolar PCO₂ ultimately change the plasma H₂CO₃ concentration (see Figure 9-1). (Chapter 4 discusses the reciprocal relationship between V˙A and PaCO₂.) Figure 9-2 shows the chemical events that occur during hypoventilation. In Figure 9-2, V˙A is halved, causing P_ACO₂ to double. Subsequently, PaCO₂ and dissolved CO₂ double, pushing the hydration reaction to the right. The doubling of CO₂ molecules on the left side of the reaction drives the reaction to the right to a new equilibrium point (Le Chatelier’s principle). Figure 9-2 shows that at equilibrium, the amount of H₂CO₃ molecules doubles, but the ratio of CO₂ to H₂CO₃ molecules stays the same.

At the outset of hypoventilation, the rate of CO₂ production momentarily exceeds the rate of alveolar CO₂ elimination, causing alveolar and blood CO₂ levels to increase. However, CO₂ levels cannot continually increase; instead, a new equilibrium point (i.e., a new steady state) is reached at which CO₂ production and elimination rates are again equal, but at higher P_ACO₂ and PaCO₂ levels. In Figure 9-1, a normal V˙A of 4 L per minute maintains a P_ACO₂ of 40 mm Hg and eliminates 200 mL of CO₂