Step 1 · Respiratory

Gas Exchange & Oxygen Transport

Name: Gas Exchange & Oxygen Transport
Creator: Veli Bakalov, MD

V/Q, the A-a gradient, and how hemoglobin loads and unloads O2

Respiratory·Physiology·4 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Apex V/Q is about 3 (dead-space-like, high PO2, favored by reactivation TB); base V/Q is about 0.6 (shunt-like), because perfusion rises toward the base more than ventilation.
V/Q = 0 is shunt (airway obstruction) and V/Q = ∞ is dead space (pulmonary embolism); 100% O2 corrects V/Q mismatch and diffusion limitation but not a true shunt.
Alveolar gas equation at sea level: PAO2 ≈ 150 − PaCO2/0.8; normal A–a gradient is 5–15 mmHg and rises with age (about age/4 + 4).
Hypoxemia with a normal A–a gradient = high altitude or hypoventilation; widened = V/Q mismatch, right-to-left shunt, or diffusion limitation.
The oxyhemoglobin curve is sigmoid from cooperative T→R binding (P50 ~27 mmHg); myoglobin's is hyperbolic.
Right shift (CADET: CO2, acid, 2,3-BPG, exercise, temperature) raises P50 and unloads O2; left shift = HbF, CO, methemoglobin, alkalosis, hypothermia.
CO binds Hb ~200–250× more avidly than O2, left-shifts the curve, lowers O2 content, and gives a falsely normal pulse oximeter; confirm with co-oximetry, treat with 100% or hyperbaric O2.
O2 content = 1.34 × Hb × SaO2 + 0.003 × PaO2; anemia lowers content with normal PaO2 and SaO2; cyanide causes histotoxic hypoxia by blocking complex IV.
CO2 travels ~70% as bicarbonate (carbonic anhydrase, chloride shift); the Bohr effect unloads O2 in tissue and the Haldane effect releases CO2 in the lung.

Ventilation–perfusion matching

Apex vs base. In the upright lung both ventilation and perfusion are greater at the base, but perfusion increases more. V/Q is therefore high at the apex (about 3.0: wasted ventilation, dead-space-like, higher PO2) and low at the base (about 0.6: wasted perfusion, shunt-like).

Reactivation TB favors the apex, where the high PO2 suits the obligate aerobe Mycobacterium tuberculosis. Pancoast tumors also sit at the apex, but by definition (superior sulcus location), not because of oxygen tension.

The two extremes. V/Q = 0 is a shunt: perfused but not ventilated, as with airway obstruction. V/Q = ∞ is dead space: ventilated but not perfused, as with pulmonary embolism. Supplemental 100% O2 corrects hypoxemia from V/Q mismatch and diffusion limitation but not from a true shunt, because shunted blood never meets the enriched alveolar gas.

Hypoxic vasoconstriction. Low alveolar PO2 constricts pulmonary arterioles — the opposite of systemic vessels — diverting blood toward better-ventilated units. When hypoxia is diffuse and chronic, as in COPD, the same reflex drives pulmonary hypertension.

The A–a gradient and causes of hypoxemia

Alveolar gas equation. PAO2 = FiO2 × (Patm − PH2O) − PaCO2/R. At sea level on room air, 0.21 × (760 − 47) ≈ 150 and R ≈ 0.8, so PAO2 ≈ 150 − PaCO2/0.8, about 100 mmHg when PaCO2 is 40.

A–a gradient. PAO2 − PaO2 is normally 5–15 mmHg and rises with age (upper limit roughly age/4 + 4). A normal gradient means O2 transfer across the lung is intact and the problem lies in how much O2 reaches the alveolus.

Mechanisms of hypoxemia

Mechanism	Example	A–a gradient	100% O2
Low inspired PO2	High altitude	Normal	Corrects
Hypoventilation	Opioid overdose (PaCO2 rises)	Normal	Corrects
V/Q mismatch	COPD, pneumonia, pulmonary embolism	Widened	Corrects
Diffusion limitation	Pulmonary fibrosis	Widened	Corrects
Right-to-left shunt	Airway obstruction, intracardiac shunt	Widened	Does not correct

Perfusion vs diffusion limitation. Normally O2 and CO2 equilibrate early along the capillary, so their transfer is perfusion-limited; CO is diffusion-limited, which is why it is used to measure diffusing capacity (DLCO). In fibrosis or emphysema, O2 transfer can become diffusion-limited, especially during exercise, when capillary transit time shortens.

The oxyhemoglobin dissociation curve

Sigmoid shape. Positive cooperativity makes the curve sigmoidal: each O2 that binds shifts hemoglobin from the taut (T) toward the relaxed (R) state, raising affinity for the next. P50 (50% saturation) is about 27 mmHg. The flat upper portion keeps saturation high despite modest falls in alveolar PO2, and the steep middle portion releases large amounts of O2 for small drops in tissue PO2. Myoglobin, a single chain, has a hyperbolic curve with higher affinity and no cooperativity.

Curve shifts

Feature	Right shift	Left shift
Affinity and P50	↓ affinity, ↑ P50	↑ affinity, ↓ P50
Net effect	Unloads O2 to tissues	Holds on to O2
Causes	↑ CO2, acid (↓ pH), ↑ 2,3-BPG, exercise, ↑ temperature (CADET face Right)	Fetal Hb, carbon monoxide, methemoglobin, alkalosis, hypothermia, ↓ 2,3-BPG
Classic setting	Exercising muscle	Fetal circulation

Bohr effect. In metabolically active tissue, high CO2 and H+ right-shift the curve so hemoglobin unloads O2 where it is needed.

Fetal hemoglobin. HbF (α2γ2) binds 2,3-BPG poorly, so it stays left-shifted and pulls O2 from maternal HbA across the placenta.

Oxygen content and tissue hypoxia

O2 content. CaO2 = (1.34 × Hb × SaO2) + (0.003 × PaO2). Hemoglobin-bound O2 dominates and dissolved O2 is tiny, so anemia lowers content while PaO2 and SaO2 stay normal.

Definitions. Hypoxemia is a low PaO2. Hypoxia is inadequate O2 delivery to, or use by, tissue. Ischemia is loss of blood flow from impeded arterial inflow or reduced venous drainage. Hypoxia may be hypoxemic, anemic (low Hb or CO), stagnant or circulatory (low flow), or histotoxic (cyanide blocks cytochrome c oxidase, complex IV).

Tissue hypoxia with a normal PaO2

Condition	Pulse oximetry	True O2 content	Key features
Anemia	Normal	↓	Low Hb; PaO2 and SaO2 normal
Carbon monoxide	Falsely normal	↓	Binds Hb ~200–250× more avidly than O2; left shift; headache; diagnose by co-oximetry; treat with 100% or hyperbaric O2
Methemoglobinemia	Reads about 85%	↓	Ferric (Fe3+) heme cannot carry O2; left shift; chocolate-colored blood; oxidant drugs such as dapsone or benzocaine
Cyanide	Normal	Normal	Blocks complex IV so tissues cannot use O2: high venous O2, lactic acidosis

CO2 transport and the Haldane effect

CO2 enters the RBCDiffuses in from tissue.
Carbonic anhydraseCO2 + H2O → H2CO3.
DissociationH2CO3 → H+ + HCO3−; deoxyhemoglobin buffers the H+.
Chloride shiftHCO3− leaves in exchange for Cl− (Hamburger shift); the process reverses in the lung.

Forms of CO2. About 70% travels as bicarbonate, about 23% as carbaminohemoglobin (bound to globin amino groups), and about 7% dissolved.

Haldane effect. In the lung, oxygenation of hemoglobin lowers its affinity for CO2 and H+, promoting CO2 release; in tissues, deoxygenated hemoglobin carries more. The Bohr (tissue) and Haldane (lung) effects are reciprocal, together optimizing O2 delivery and CO2 removal.