Carbon Dioxide: Storage, Transport, and CO2 Dissociation Curve

Introduction

• CO₂ is an essential byproduct generated intracellularly by the process of cellular metabolism, particularly within the citric acid cycle.¹
• The primary physiological function of the respiratory system is not merely to provide oxygen (O₂) but equally to eliminate the CO₂ produced by peripheral tissues.
• Beyond its role as a metabolic waste product, CO₂ serves crucial regulatory functions within the human body:
  • The stringent maintenance of blood pH equilibrium
  • The modulation of respiratory drive
  • The allosteric regulation of Hb’s affinity for O₂ (the Bohr effect).¹

CO₂ Storage and Transport

CO₂ Storage

• A typical adult produces approximately 200 mL/min of CO₂ at a resting (basal) rate, which is slightly less than the basal O₂ consumption of 250 mL/min. However, during strenuous exercise, CO₂ production can dramatically increase to as much as 4000 mL/min.²
• The human body holds a large reserve of approximately 120 L of CO₂ in adults.
• CO₂ is stored mainly as dissolved CO₂ and HCO₃^–.³
• Establishing a new CO₂ equilibrium following a production/elimination imbalance is a slow process, requiring 20 to 30 minutes. This is significantly longer than the 4 to 5 minutes needed for O₂.
• CO₂ is distributed across three compartments based on their equilibration speed:
  • Rapid equilibrating
  • Intermediate equilibrating
  • Slow equilibrating³

CO₂ Transport^2,3

• CO₂ is transported in the circulation in three forms:

1. As HCO₃^{– 2}

• Most CO₂ is transported in the blood as HCO₃^–.
• The enzyme CA catalyses the reaction between CO₂ and water (H₂O) to form carbonic acid (H₂CO₃), which then rapidly dissociates into HCO₃^– and H⁺.

• CA is abundant in the cytoplasm of RBCs but absent in the plasma, meaning this conversion only happens inside the RBCs.
• CO₂ and H₂O can freely diffuse into the RBC, but the reaction products (H⁺ and HCO₃^–) cannot cross the membrane.
• To prevent the buildup of these products, which would stop the reaction (being an equilibrium reaction), two continuous processes occur: (Table 2)
  • Chloride shift (or Hamburger effect)
  • Binding of H⁺ to histidine residues

• The net effect of both processes is that for every CO₂ molecule produced by the tissues, a Cl^– ion is added to the RBC, whereas the H⁺ is bound and HCO₃^– is moved to the extracellular fluid, maintaining electrical neutrality.²
• The reverse process occurs in the pulmonary capillaries.
  • HCO₃^– diffuses back into the RBC, and chloride diffuses out.
  • CA converts HCO₃^– back into CO₂ and H₂O.

2. Bound to Hb and Other Proteins as Carbamino Compounds.²

• Carbaminohaemoglobin (HbCO₂) is a compound formed when CO₂ binds directly to the Hb molecule.
• CO₂ does not bind to the iron, but rather to a terminal amine group (-NH₂) within the globin chains (specifically, side chains of arginine and lysine).
• The reaction for the formation of HbCO₂ is:

• Deoxyhemoglobin (Hb that has released its O₂) forms carbamino compounds more readily than does oxyhemoglobin. This difference is key to the Haldane effect.
• HbCO₂ should not be confused with carboxyhemoglobin, which is formed when deadly carbon monoxide binds to the Hb.
• The Bohr and Haldane effects are reciprocal modulators that work synergistically: the release of O₂ in the tissues enhances CO₂ uptake, and the subsequent uptake of CO₂ facilitates further O₂ unloading, optimizing gas exchange across the circulation. The key differences between the two are shown below.

• The efficient transfer of O₂ and CO₂ across the placenta is critical for fetal development and survival. This gas exchange is significantly enhanced by two interrelated physiological phenomena: the double Bohr effect and the double Haldane effect.⁵

3. Dissolved in Plasma

• A small fraction of CO₂ is transported directly dissolved in the plasma.
• According to Henry’s law, the amount dissolved is proportional to the partial pressure of CO₂ (PCO₂).

• This method of transport makes a relatively greater overall contribution to total CO₂ carriage than dissolved O₂ does to O₂ carriage because CO₂ is about 20 times more soluble in blood than O₂, with a solubility coefficient of 0.031 mmol/L/mm Hg (0.067 mL/dL/mm Hg) at 37°.³

CO₂ Dissociation Curve

• The CO₂ dissociation curve illustrates the relationship between the PCO₂ and the total CO₂ concentration carried in the blood, and how that CO₂ is distributed among its three transport forms.

Axes and Components

• X-axis: Represents the PCO₂ in mmHg. This is the driving force for CO₂ exchange.
• Y-axes: Represent the total amount of CO₂ carried in blood in millimoles per liter.
• The curve: The overall curve shows that the total CO₂ content of the blood increases significantly with increasing PCO₂. Unlike the O₂ dissociation curve, the CO₂ curve is relatively linear over the physiological range of PCO₂.
• The curve is divided vertically to show the three primary ways CO₂ is transported:
  • HCO₃^–: This is the largest fraction (light purple area in Figure 2). This form accounts for approximately 80-90% of total CO₂ transport.
  • Carbaminohemoglobin: This is the small dark purple and grey area at the top of the curve (Figure 2). It represents CO₂ bound directly to Hb as carbaminohemoglobin, accounting for 5-10% of total transport.
  • Dissolved CO₂ gas: This is the small red area at the bottom of the curve (Figure 2). It represents CO₂ physically dissolved in the blood plasma, accounting for about 5-10% of total transport.
• The most striking feature is the presence of two distinct lines, which demonstrates the Haldane effect:
  • Upper curve: Venous blood
    • This curve represents deoxygenated blood
    • It shows that for any given PCO₂, deoxygenated blood has a higher CO₂ concentration because deoxyhaemoglobin is a much better carrier of CO₂.
    • Venous Point: Represents blood returning to the lungs from the tissues (deoxygenated, higher PCO₂, higher total CO₂ content). Approximate PCO₂ = 45 mHg
• Lower curve: Arterial blood
  • This curve represents oxygenated blood.
  • It shows that oxyhemoglobin has a reduced capacity to carry CO₂, resulting in a lower curve.
  • Arterial point: Represents blood leaving the lungs (fully oxygenated, lower PCO₂, lower total CO₂ content). Approximate PCO₂ value = 40 mmHg
  • The vertical distance between the arterial and venous points represents the CO₂ exchanged and transported from the tissues to the lungs.