8.2 O2/CO2 Transport & Regulation of Respiration

O₂ and CO₂ Transport & Regulation of Respiration

Quick Answer: Oxygen travels bound to hemoglobin (the vast majority) or dissolved in plasma; a sigmoidal dissociation curve captures how saturation depends on partial pressure, and it shifts with pH, CO₂, temperature, and 2,3-BPG. Carbon dioxide travels chiefly as bicarbonate, formed inside red cells by carbonic anhydrase. Breathing is regulated by central chemoreceptors on the medulla (responding to CSF H⁺ from CO₂) and peripheral chemoreceptors in the carotid/aortic bodies (responding to low PaO₂).

Hemoglobin and the O₂ Dissociation Curve

Each hemoglobin (Hb) tetramer carries four heme groups, each binding one O₂. The binding is cooperative — binding of the first O₂ increases affinity for the next — which produces the characteristic sigmoidal curve.

Key points on the curve:

• PaO₂ = 100 mmHg (systemic arterial blood): saturation ≈ 97%
• PaO₂ = 60 mmHg: saturation ≈ 90% — the curve is flat above 60 mmHg, so moderate hypoxemia is well tolerated
• PvO₂ = 40 mmHg (mixed venous blood): saturation ≈ 75%
• P50 (PaO₂ at 50% saturation) ≈ 27 mmHg — a useful index of Hb affinity

The flat shoulder above ~60 mmHg is a safety buffer: a fall in PaO₂ from 100 to 60 barely changes saturation. Below 60 mmHg the curve is steep, so small drops in PaO₂ cause large falls in saturation — the rationale for targeting PaO₂ above 60 mmHg in respiratory failure.

Bohr and Haldane Effects

The Bohr effect: increased H⁺ (lower pH), increased CO₂, increased temperature, and increased 2,3-bisphosphoglycerate (2,3-BPG) shift the curve to the right, reducing Hb affinity and releasing more O₂ to actively metabolizing tissue (muscle, exercising tissue, high-altitude acclimatization). The opposite shifts it left — fetal hemoglobin has lower 2,3-BPG affinity and a left-shifted curve, favoring O₂ loading from maternal blood.

The Haldane effect: deoxygenated Hb binds CO₂ and H⁺ more readily than oxygenated Hb. In the tissues, O₂ unloading promotes CO₂ uptake; in the lungs, O₂ loading promotes CO₂ unloading. The Bohr and Haldane effects are complementary and together double the gas transport efficiency of a single circulatory pass.

CO₂ Transport

Carbon dioxide is carried in three forms:

1. Bicarbonate (HCO₃⁻) — ~70%. In the RBC, carbonic anhydrase catalyzes CO₂ + H₂O ⇌ H₂CO₃ ⇌ H⁺ + HCO₃⁻. The HCO₃⁻ exits via the chloride-bicarbonate exchanger (the "chloride shift"). In the lungs the reaction reverses and CO₂ is exhaled.
2. Carbaminohemoglobin — ~20–23%. CO₂ binds to the terminal amino groups of Hb.
3. Dissolved CO₂ — ~7–10%. CO₂ is far more soluble than O₂.

Regulation of Respiration

The respiratory center in the medulla (dorsal respiratory group, ventral respiratory group) and the pons (pneumotaxic and apneustic centers) generate the rhythmic pattern.

Central chemoreceptors lie on the ventral surface of the medulla. They are bathed in CSF, which is poorly buffered, so they sense H⁺ generated when CO₂ crosses the blood-brain barrier and hydrates to carbonic acid. CO₂ is the dominant long-term drive to breathe under normal conditions. A rise in PaCO₂ of just a few mmHg markedly increases ventilation.

Peripheral chemoreceptors sit in the carotid bodies (at the bifurcation of the common carotids, via CN IX) and the aortic bodies (arch of the aorta, via CN X). They respond to:

• Decreased PaO₂ — the strongest stimulant kicks in below ~60 mmHg, the shoulder of the O₂-Hb curve where saturation begins to fall steeply.
• Increased H⁺ (acidosis) — independent of CO₂, e.g., lactic acid, ketoacidosis.
• Increased PaCO₂ — faster than central receptors but less dominant quantitatively.

A practical example: a patient with COPD who chronically retains CO₂ becomes less responsive to the central CO₂ drive; their ventilation increasingly depends on the hypoxic drive from peripheral chemoreceptors. Giving high-flow O₂ can blunt that drive and worsen hypercapnia — the rationale for controlled O₂ therapy in COPD exacerbations.

Irritant receptors in the epithelium, stretch receptors (Hering-Breuer reflex), and Juxtacapillary (J) receptors in the alveolar interstitium round out the sensory network, mediating cough, bronchoconstriction, and the sensation of dyspnea in pulmonary edema.

Integrating the Loop

At the tissues: high Pco₂, low pH, high temperature → Bohr right shift → O₂ release; deoxy-Hb binds CO₂ (Haldane). At the lungs: high Po₂ → Hb loads O₂, curve left-shifts locally, CO₂ is released. Central chemoreceptors titrate ventilation to hold PaCO₂ near 40 mmHg; peripheral receptors guard against hypoxemia. This integrated feedback is a common PA-CAT Physiology item frame.

Quantifying the Curve: P50, Shifts, and O2 Content

The P50 — the PaO2 at which hemoglobin is 50% saturated — is the single best index of Hb affinity, and PA-CAT items use it as the diagnostic handle for a shift. Normal P50 is ~27 mmHg at pH 7.40, 37 °C. A right shift raises P50 (lower affinity, more unloading) and is produced by increased H+, CO2, temperature, and 2,3-BPG — the milieu of exercising muscle. A left shift lowers P50 (higher affinity) and is produced by decreased H+/CO2/temp, decreased 2,3-BPG, HbF, and carbon monoxide. The payoff is asymmetric: at the venous point (PaO2 40 mmHg) a right shift can drop saturation from 75% toward 60%, delivering an extra ~1.5 mL O2/dL to tissue with no change in arterial saturation, whereas a left shift impairs unloading and is why CO poisoning and severe alkalosis cause tissue hypoxia despite a normal-looking PaO2.

O2 content is what the blood actually carries, and it is the quantity the examiner asks you to compare. The equation is CaO2 = 1.34 × Hb × SaO2 + 0.003 × PaO2 (mL O2/dL): the dissolved term is negligible, so content tracks hemoglobin and saturation. A PA-CAT-style trap contrasts three patients with the same PaO2 of 100 mmHg: (1) a right-shifted curve from fever/acidosis — SaO2 is near normal at the arterial point but more O2 unloads at tissue, so content is normal and delivery improves; (2) anemia — PaO2 and SaO2 are both normal, but with Hb of 7 g/dL the content is roughly half (1.34 × 7 × 0.97 ≈ 9 mL/dL), so the deficit is carrying capacity, not saturation; (3) carbon monoxide poisoning — CO binds Hb with ~240× the affinity of O2, so pulse-ox SaO2 reads falsely high (it cannot distinguish CO-Hb from Oxy-Hb), the curve is left-shifted, and true O2 content is low. The discriminating labs are CO-oximetry (shows carboxyhemoglobin), PaO2 (normal in CO and anemia), and Hb (low only in anemia).

The chloride-bicarbonate exchanger (band 3, AE1) makes bulk CO2 transport possible. Inside the RBC, carbonic anhydrase rapidly converts CO2 + H2O to H+ + HCO3−; if HCO3− accumulated, the reaction would halt. Band 3 exports HCO3− in electroneutral exchange for Cl− moving in — the chloride shift — keeping intracellular HCO3− low so hydration continues. In the lungs the exchanger reverses: HCO3− re-enters, carbonic anhydrase regenerates CO2, and CO2 diffuses out. The H+ released is buffered by deoxyhemoglobin, coupling the Haldane effect to the band 3 shuttle. Plasma Cl− therefore falls slightly in systemic capillaries as Cl− moves into RBCs, a classic PA-CAT biochemical clue.