Respiratory Physiology: Gas Exchange & the Oxygen–Hemoglobin Curve
A Step 1 tour of pulmonary gas exchange — Fick's law, diffusion vs perfusion limitation, and the A–a gradient — anchored to the sigmoidal oxygen–hemoglobin dissociation curve, its right/left shifts, and the classic dyshemoglobinemias (CO, methemoglobin, HbF).
The alveolar–capillary interface
Gas exchange occurs across the alveolar–capillary membrane (roughly 0.5 µm thick) by simple diffusion down partial-pressure gradients — no active transport. Alveolar O2 (~100 mmHg) diffuses into deoxygenated pulmonary capillary blood (~40 mmHg), while CO2 diffuses out (venous ~45 → alveolar ~40 mmHg). Once dissolved, O2 is carried almost entirely bound to hemoglobin; only a trivial fraction stays dissolved. How readily Hb loads O2 in the lung and releases it in tissue is dictated by the O2–hemoglobin dissociation curve, the central concept of this lesson.
- Fick's law: diffusion rate ∝ (area × ΔP) / thickness, and ∝ solubility / √MW. CO2 diffuses ~20× faster than O2 (far more soluble).
- Perfusion-limited gases (O2 normally, CO2, N2O): equilibrate early along the capillary — transfer rises only with more blood flow.
- Diffusion-limited gases (CO always — Hb binds it so avidly its capillary partial pressure stays ~0, so transfer never stops; O2 in emphysema, fibrosis, strenuous exercise): fail to equilibrate along the capillary.
- Thickened membrane (fibrosis, edema) ↓ diffusion via ↑ thickness; emphysema ↓ diffusion via ↓ surface area.
- Alveolar gas equation: PAO2 = 150 − PaCO2/0.8 (room air, sea level). A–a gradient = PAO2 − PaO2, normally ~5–15 mmHg, ↑ with age.
- ↑ A–a gradient: shunt, V/Q mismatch, diffusion defect. Normal A–a gradient with hypoxemia: high altitude and hypoventilation.
Why the curve is sigmoidal
The O2–Hb curve is sigmoidal because O2 binding is cooperative: binding of the first O2 nudges hemoglobin from the low-affinity T (taut) state toward the high-affinity R (relaxed) state, so affinity rises as saturation rises. The steep middle lets tissues extract lots of O2 for a small fall in PO2; the flat top keeps SaO2 high even when alveolar PO2 drops modestly. P50 — the PO2 at 50% saturation (normally ~26–27 mmHg) — indexes affinity: a right shift raises P50 (lower affinity, better tissue unloading), a left shift lowers P50 (higher affinity, poorer unloading). Myoglobin, monomeric and non-cooperative, has a hyperbolic curve lying far to the left (holds O2 tightly until very low PO2).
- O2 content: CaO2 = (1.34 × Hb × SaO2) + (0.003 × PaO2). Hb-bound O2 dominates; dissolved O2 is negligible.
- Anemia: ↓ O2 content but normal PaO2 and normal SaO2 (each remaining Hb is fully saturated).
- O2 delivery = CaO2 × cardiac output.
- Bohr effect: in active tissue, ↑ CO2 / ↑ H+ right-shift the curve → more O2 unloaded.
- Haldane effect: in the lung, O2 binding promotes CO2 release (oxygenated Hb holds less CO2/H+).
- CO2 transport: ~70% as HCO3− (carbonic anhydrase + chloride shift), ~20–23% carbaminohemoglobin, ~7% dissolved.
Right shift = ↓ affinity = more O2 released to tissues → "CADET, face Right!"
- C — ↑ CO2
- A — ↑ Acid (↓ pH)
- D — ↑ 2,3-DPG (2,3-BPG)
- E — Exercise
- T — ↑ Temperature
The opposites (↓ CO2, ↑ pH/alkalosis, ↓ 2,3-BPG, ↓ temperature) plus HbF, carbon monoxide, and methemoglobin shift the curve left.
Left shift vs right shift
| Feature | Left shift (↑ affinity) | Right shift (↓ affinity) |
|---|---|---|
| P50 | ↓ (lower) | ↑ (higher) |
| Tissue O2 unloading | Impaired | Enhanced |
| pH | ↑ (alkalosis) | ↓ (acidosis) |
| PCO2 | ↓ | ↑ |
| 2,3-BPG | ↓ | ↑ |
| Temperature | ↓ | ↑ |
| Classic causes | HbF, CO, methemoglobin | Exercise, chronic high altitude (↑ 2,3-BPG) |
Dyshemoglobins at a glance
| Feature | Carboxyhemoglobin (CO) | Methemoglobin (Fe³⁺) | Fetal Hb (HbF) |
|---|---|---|---|
| Mechanism | CO binds Hb ~200–250× O2 affinity | Iron oxidized Fe²⁺→Fe³⁺, can't bind O2 | α2γ2; γ chains bind 2,3-BPG poorly |
| Curve effect | Left shift + ↓ O2 content | Left shift (functional anemia) | Left shift (physiologic) |
| PaO2 | Normal | Normal | — |
| Pulse oximetry | Falsely normal/high | Fixed ~85% | — |
| Triggers | Smoke/fire, faulty heater | Dapsone, nitrites, benzocaine/local anesthetics | Normal fetus (pulls O2 from maternal HbA) |
| Treatment | 100% O2 (± hyperbaric) | Methylene blue (ascorbic acid if G6PD) | — |
- CO poisoning: winter, faulty furnace or house fire, a whole household with headache, nausea, confusion; normal PaO2 with a falsely normal pulse ox (need co-oximetry). "Cherry-red" skin is a late/postmortem clue. Next step: 100% O2, hyperbaric if severe/pregnant.
- Methemoglobinemia: cyanosis unresponsive to O2, "chocolate-brown" blood, and a saturation gap (pulse ox ~85% while PaO2 normal); classic after dapsone, topical benzocaine/lidocaine, or nitrites. Treat with methylene blue.
- Cyanide (not a dyshemoglobin): inhibits cytochrome c oxidase (complex IV) → cells can't use O2, ↑ venous O2, anion-gap lactic acidosis; from nitroprusside or industrial fires. Treat with hydroxocobalamin ± sodium thiosulfate.
- High altitude: low inspired PO2 → hypoxemia with a normal A–a gradient; chronic compensation ↑ 2,3-BPG (right shift) and ↑ EPO.
Practice Physiology now
Board-style questions, spaced-repetition flashcards, and a Socratic AI tutor — free to start.