In one breath
Air reaches the alveoli by bulk flow, but it crosses the 0.2–0.5 µ alveolar-capillary membrane by diffusion, each gas moving down its own partial-pressure gradient (about 60 mmHg for O₂, only 6 mmHg for CO₂). Fick’s law sets the rate: more with a larger area, a steeper gradient and a more diffusible gas, less with a thicker membrane. CO₂ diffuses about 20 times more readily than O₂, so a thickened or waterlogged membrane causes hypoxemia long before it raises PCO₂. O₂ and N₂O uptake is limited by blood flow, while CO uptake is limited by diffusion, which is why CO is used to measure the lung’s diffusing capacity.
Builds on: Alveolar ventilation · Leads to: Oxygen transport · Carbon dioxide transport · Tests of gas exchange and pulmonary circulation · Hypoxia
Bulk flow, then diffusion
- Air travels from the nostrils down to the alveoli by bulk flow. The push is the difference between barometric pressure (at the mouth) and alveolar pressure.
- Between alveolar air and capillary blood, gases move by diffusion across the alveolar-capillary membrane, each down its own partial-pressure gradient. O₂ enters the blood, for example, because its partial pressure is higher in the alveoli than in the capillaries.
- How much of a gas the blood takes up depends on three things, which are the three sections below:
- the diffusion properties of the membrane;
- the partial-pressure gradient of the gas;
- the pulmonary capillary blood flow.
- History: the French chemist Antoine Laurent de Lavoisier (1743–1794) first showed the part O₂ plays in combustion and in lung gas exchange, and he disproved Stahl’s phlogiston theory. Working with Pierre Simon de Laplace, he used a calorimeter of their own design to measure the respiratory quotient. The French Revolution sent him to the guillotine.
The alveolar-capillary membrane
- Also called the respiratory membrane: the blood-gas interface between alveolar gas and pulmonary capillary blood.
- It is extremely thin. Its main parts are the alveolar epithelium, a film of interstitial fluid and the capillary endothelium.
- As blood flows through the capillaries and air ventilates the alveoli, O₂ and CO₂ diffuse across it.
Its layers
Between alveolar air and capillary blood there are six layers. An O₂ molecule going all the way to Hb (or back out) crosses ten.
The membrane itself, from the alveolar side:
- surfactant lining the alveolus
- alveolar epithelial cells
- their basement membrane
- a thin film of interstitial fluid
- the capillary basement membrane
- capillary endothelial cells
Then in the blood:
- plasma
- the red cell membrane
- the fluid inside the red cell
- the Hb molecule
- Thickness: 0.2–0.5 µ. This thinness is what lets gases cross so easily.
- Worth knowing, though not in your pages: the total area of the membrane in an adult is about 70 m².
Draw it: the respiratory membrane
- Draw an alveolus on the left and a capillary with one red cell on the right.
- Between them, draw six thin bands from left to right: surfactant, alveolar epithelium, epithelial basement membrane, interstitial fluid, endothelial basement membrane, capillary endothelium.
- Inside the capillary, label plasma, the red cell membrane, the red cell’s fluid and Hb.
- Arrows: O₂ from alveolus to Hb; CO₂ the other way.
- Write “0.2–0.5 µ” across the six bands.
Factors affecting diffusion
Your book lists six:
| Factor | Effect on diffusion | Example |
|---|---|---|
| Partial-pressure gradient | ↑ with a steeper gradient | see below |
| Diffusing capacity | ↑ with higher capacity | see below |
| Surface area | ↑ with more area | ↓ emphysema; ↑ exercise |
| Solubility | ↑ with more solubility | CO₂ crosses easily |
| Thickness | ↓ as it thickens | double it, halve diffusion |
| Molecular weight | smaller is faster | see the warning |
- In exercise the area grows because more capillaries open.
- Fick’s law, below, ties these together.
Molecular weight: it is the square root
In its list of six factors your book says diffusion is inversely proportional to molecular weight. Its own diffusion-coefficient paragraph, a page later, has it right: inversely proportional to the square root of molecular weight. Write the square root in the exam. Worth knowing, though not in your pages: this is Graham’s law.
Clinical significance
- In health the membrane is too thin to hold up exchange. In disease it can, and your book calls this the alveolar-capillary obstruction syndrome. Worth knowing, though not in your pages: most books call it alveolar-capillary block.
- Two kinds of defect cause it:
- a thickened membrane: diffuse interstitial fibrosis, asbestosis;
- a wider gap between alveolus and capillary, from interstitial edema: heart failure.
- O₂ diffusion falls, but CO₂ diffusion does not. Both gases dissolve well in lipid, but CO₂ is 20 times more soluble in water, so extra fluid barely slows it.
- The result is hypoxemia without much change in PCO₂.
Applied: diffusion defects
The same idea explains why a diffusion problem lowers PaO₂ but rarely raises PaCO₂. Ch114 lists the conditions that lower the diffusing capacity, and exercise as the one that raises it (Tests of gas exchange and pulmonary circulation). The hypoxemia is one type of respiratory hypoxia (Hypoxia).
Partial-pressure gradients
Diffusion gradient
- The diffusion gradient is the difference in a gas’s partial pressure across the membrane. The steeper it is, the faster the gas diffuses.
| Gas | Gradient across the membrane |
|---|---|
| O₂ | about 60 mmHg |
| CO₂ (venous − alveolar) | about 6 mmHg |
A slip in your book
Your book arrives at the 60 mmHg O₂ gradient as alveolar PO₂ “160” minus arterial PO₂ “100”. But 160 is roughly the PO₂ of inspired air, and arterial blood has already equilibrated with the alveoli. The gradient is alveolar PO₂ (100) − PO₂ of the venous blood entering the capillaries (40) = 60 mmHg, which is what the book’s own Table 105.1 gives. CO₂ works the same way: 46 − 40 = 6 mmHg.
- Gases dissolved in a liquid such as plasma still exert a partial pressure.
- Henry’s law: at a given temperature, the amount of a gas that dissolves in a liquid is proportional to its partial pressure and its solubility.
- Fick’s law: the volume of gas diffusing across a membrane per minute is
- directly proportional to the surface area, the diffusion coefficient of the gas and the partial-pressure difference;
- inversely proportional to the membrane thickness.
- In short: rate ∝ (area × diffusion coefficient × pressure difference) ÷ thickness.
Partial pressures along the way
Your book’s Table 105.1, rearranged (all in mmHg):
| Site | PO₂ | PCO₂ |
|---|---|---|
| Inspired air | 158 | 0.3 |
| Alveolar air | 100 | 40 |
| Arterial blood | 95 | 40 |
| Venous blood | 40 | 46 |
| Expired air | 116 | 32 |
| Site | PN₂ | PH₂O |
|---|---|---|
| Inspired air | 596 | 5.7 |
| Expired air | 565 | 47 |
| Alveolar air and blood | 573 | 47 |
- The table repeats the venous values for “capillary blood”: read it as the blood arriving at the pulmonary capillaries.
- Worth knowing, though not in your pages:
- expired air lies between inspired and alveolar values because it is alveolar air mixed with dead-space air (Dead space);
- 47 mmHg is the pressure of water vapour in air saturated at body temperature, which is why every value after inspired air is 47;
- arterial PO₂ sits a little below alveolar PO₂ because of the normal physiological shunt (Ventilation–perfusion ratio).
Diffusion coefficient
- A gas’s diffusion coefficient is directly proportional to its solubility and inversely proportional to the square root of its molecular weight.
- So a very soluble gas, or a small molecule, diffuses fast.
- CO₂’s coefficient in water is about 20 times that of O₂. It is the larger molecule, but its much higher solubility wins.
Capillary blood flow
- Blood flow through the pulmonary capillaries strongly affects O₂ uptake.
- Transit time, the time a red cell spends in a pulmonary capillary, is about 0.75 s at rest. In that time the blood’s gas tensions equilibrate with the alveolar ones.
- A higher cardiac output speeds the flow and shortens the transit time.
Flow-limited and diffusion-limited uptake
| Gas | Reaches alveolar tension in | Uptake is |
|---|---|---|
| N₂O | 0.1 s | flow-limited |
| CO | never, within 0.75 s | diffusion-limited |
| O₂ | about 0.3 s (a third of the time) | flow-limited |
- N₂O, an anaesthetic gas, crosses easily and equilibrates within 0.1 s. After that, the blood can take up more only if more blood arrives, so its uptake is set entirely by blood flow: flow-limited.
- CO also crosses easily, but it binds Hb so avidly that its partial pressure in the blood stays low. The gradient never disappears within the transit time, so the amount taken up is set by diffusion, not by flow: diffusion-limited.
- O₂ equilibrates within about a third of the transit time, which leaves a wide safety margin for end-capillary PO₂ to match alveolar PO₂.
- In severe exercise the transit time shortens, but there is still time to oxygenate the blood fully.
- O₂ binds Hb less avidly than CO does, and it equilibrates fast, so O₂ uptake is flow-limited.
- Worth knowing, though not in your pages:
- a third of 0.75 s is 0.25 s, the figure most books quote; your book rounds it to 0.3 s;
- N₂O equilibrates so quickly because it does not bind Hb;
- O₂ uptake can become diffusion-limited when the membrane is thickened, or during exercise at high altitude, where the alveolar PO₂ is low.
Draw it: uptake along the capillary
- Axes: time in the capillary, 0 to 0.75 s, on x; partial pressure in the capillary blood on y, with the alveolar value marked as a dashed line near the top.
- N₂O: a curve that shoots up and meets the dashed line by 0.1 s (flow-limited).
- O₂: a curve that starts at 40 mmHg and meets the alveolar 100 mmHg about a third of the way along (flow-limited, with a safety margin).
- CO: a line that barely leaves the x-axis (diffusion-limited).
Diffusing capacity (DC)
- Definition: the rate at which a gas is transferred in the lungs per unit of partial-pressure gradient, in mL/min per mmHg.
- Worth knowing, though not in your pages: the DC for O₂ is about 21 mL/min/mmHg at rest and about 65 in heavy exercise (Guyton). Ch114 of your book says CO₂’s diffusing capacity is 20 times O₂’s, which is why diffusion problems seldom cause CO₂ retention.
Measuring it with CO
CO is the gas of choice, for three reasons:
- its uptake is diffusion-limited, not flow-limited;
- venous blood contains essentially no CO;
- Hb binds CO about 210 times more strongly than O₂, which keeps the PCO in the capillaries at practically zero.
- DC = V̇CO ÷ PACO, where V̇CO is the CO taken up (mL/min) and PACO is the alveolar partial pressure of CO. Since the capillary PCO is near zero, PACO is the whole gradient.
- The most common method is the single-breath test.
- Worth knowing, though not in your pages: the subject takes one breath containing a little CO (about 0.3%), holds it for about 10 s, and the CO that disappears is measured.
Factors affecting DC
- DC depends on the membrane, and also on the blood that receives the gas:
- hemoglobin (the hematocrit);
- the pulmonary capillary blood volume.
- A fall in either lowers DC. Worth knowing, though not in your pages: anemia is the everyday example.
- The membrane factors above (area, thickness) change DC too; see the lists in Tests of gas exchange and pulmonary circulation.
Exam-answer skeleton: "Describe the respiratory membrane and the factors that affect diffusion of gases across it" (long essay)
- Bulk flow down the airways vs diffusion across the membrane; the three factors in uptake.
- The membrane: definition, main parts, the six layers (ten to Hb), 0.2–0.5 µ (draw it).
- The six factors affecting diffusion, with Fick’s law as the summary.
- Partial-pressure gradients: O₂ about 60 mmHg, CO₂ about 6 mmHg, with the table of partial pressures; Henry’s law.
- The diffusion coefficient: solubility and √MW; why CO₂ diffuses 20 times faster.
- Capillary blood flow: transit time 0.75 s; flow-limited (N₂O, O₂) vs diffusion-limited (CO) uptake.
- Diffusing capacity: definition, why CO measures it, the formula, factors.
- Applied: alveolar-capillary block, with hypoxemia but a near-normal PCO₂.
Asked in exams
- The respiratory membrane and diffusion across it: Dec 2015, 10 marks · Aug 2016, 2 marks · Jul 2018, 10 marks · Apr 2021, 2 marks
- Partial pressures of the gases in air and blood: May 2022, MCQ · Aug 2024, MCQ · Oct 2024, MCQ