From atmosphere to cell
The physiological oxygen cascade
What you should already have
None beyond general physiology — this is where the module starts.
About 55 minutes
Plus the time it takes to redraw this lesson’s figures from memory, which is the fastest way to find out what you have not understood.
Where this shows up
This lesson answers why a patient on high-flow oxygen can still be hypoxaemic. Shunt and V/Q mismatch look alike at the bedside and behave completely differently when oxygen is added, and the difference between them is the difference between a treatment that works and one that does not.
Learning outcomes
By the end of this lesson you should be able to:
- Draw the oxygen cascade from inspired to mitochondrial, stating the assumptions every value in it depends on.
- Apply the alveolar gas equation with every symbol defined and units stated, and say what each term contributes.
- Separate the two distinct falls in PO₂ between alveolus and arterial blood, and explain why only one of them is a diffusion problem.
- Calculate and interpret the A–a gradient, and state what widens it.
- Explain ventilation–perfusion matching, and distinguish shunt from dead space by their effect on arterial gases.
- Predict why a shunt responds poorly to supplemental oxygen while V/Q mismatch responds well.
Together these settle 3 syllabus objectives: The oxygen cascade; Alveolar–capillary oxygen transfer and the A–a gradient and Ventilation–perfusion matching, shunt and dead space. Tick them on the Physiology objective list once you can do all of the above without notes.
The stages, and why the pressure falls at each
| Stage | PO₂ | Mechanism of the fall |
|---|---|---|
| Dry atmosphere | 159–160 mmHg (21 kPa) | 0.2093 × 760. The starting point |
| Humidified tracheal gas | 150 mmHg (19.9 kPa) | Water vapour added by the upper airway occupies 47 mmHg of the total, diluting every other gas: 0.2093 × (760 − 47) |
| Alveolar gas | 100 mmHg (13.3 kPa) | Oxygen removed and carbon dioxide added. The alveolar gas equation subtracts PaCO₂/R — a further 50 mmHg. The largest single step |
| Pulmonary end-capillary | ≈ 100 mmHg | Essentially no fall: equilibration is complete within a third of the transit time |
| Systemic arterial | 90–95 mmHg (12–12.6 kPa) | Venous admixture — bronchial and Thebesian drainage plus V/Q inequality. This is the A–a gradient |
| Systemic capillary | ≈ 40–50 mmHg | Oxygen diffuses into tissue down its gradient as blood flows along the capillary |
| Mixed venous | 40 mmHg (5.3 kPa) | The pooled result of extraction, normally about 25% of delivered oxygen |
| Mitochondrion | 4–20 mmHg (0.5–3 kPa) | Diffusion through cytoplasm. Oxidative phosphorylation continues to the Pasteur point, ≈1–2 mmHg, below which metabolism becomes anaerobic |
The assumptions the numbers rest on
These come before the numbers. Every value in the cascade is conditional on them, and a cascade quoted without them is a sequence of figures that happens to be true of one particular subject breathing one particular gas at one particular altitude.
| Quantity | Value | What changes it |
|---|---|---|
| Barometric pressure | 760 mmHg (101.3 kPa) | Altitude, hyperbaric therapy |
| FiO₂ | 0.2093 | Supplemental oxygen, hypoxic gas mixture |
| Saturated vapour pressure | 47 mmHg (6.3 kPa) at 37 °C | Body temperature only — not barometric pressure |
| PaCO₂ | 40 mmHg (5.3 kPa) | Ventilation |
| Respiratory quotient | 0.8 | Diet: ≈1.0 on carbohydrate, ≈0.7 on fat |
Oxygen cascade: atmosphere to mitochondria
Adult · air · sea level · 37 °C · R = 0.8
Hover over a step or select a stage to open its equation and explanation.
Dry atmosphere
21.2 kPa · 159 mmHgPdryO₂ = PB × FiO₂ = 101.3 kPa × 0.2093 = 21.2 kPa.This is the starting partial pressure in dry air at sea level. FiO₂ remains about 20.93%, while barometric pressure falls with altitude.
Label the y-axis PO₂ with units and state the assumed PB and FiO₂.
Check the oxygen source, delivered FiO₂ and ambient pressure before attributing a low downstream PO₂ to lung disease.
Alveolus to arterial blood
Oxygen transfer and the A–a gradient
The two falls, and which one matters
| First fall | Second fall | |
|---|---|---|
| Where | Across the alveolar–capillary membrane | After the exchange units, in the pulmonary veins and left heart |
| Mechanism | Diffusion down a partial pressure gradient | Venous admixture — blood that never took part in gas exchange mixing with blood that did |
| Size in a normal lung at rest | Effectively zero — end-capillary PO₂ all but equals alveolar PO₂ | Almost the whole of the normal gradient |
| Becomes important when | Transit time is short or the membrane is thickened — and rarely on its own | Always. It is the default explanation for a widened gradient |
1 · The driving pressure: the alveolar gas equation
Alveolar PO₂ cannot be measured, so it is calculated. Each term is a distinct route by which the alveolar pressure can fall, which is what makes the equation clinically useful rather than merely examinable.
| Term | Meaning and normal value | How it causes hypoxaemia |
|---|---|---|
| FiO₂ | Fraction of inspired oxygen; 0.21 in air | Hypoxic gas mixture, oxygen supply failure |
| P B | Barometric pressure; 760 mmHg (101.3 kPa) at sea level | Altitude — PAO₂ falls although FiO₂ is unchanged |
| P H₂O | Saturated vapour pressure; 47 mmHg (6.3 kPa) at 37 °C | Takes a larger share of the total as barometric pressure falls |
| PaCO₂ | Arterial carbon dioxide; 40 mmHg (5.3 kPa), standing in for alveolar CO₂ | Hypoventilation — carbon dioxide displaces oxygen from the alveolus, giving hypoxaemia with a normal gradient |
| R | Respiratory quotient, CO₂ produced ÷ O₂ consumed; 0.8 | Not itself a cause, but alters the calculated value and so the gradient |
2 · Across the membrane: Fick’s law of diffusion
| Term | Value in the adult lung | Altered by |
|---|---|---|
| A — surface area | 50–80 m² | Emphysema, lobectomy, consolidation, collapse |
| T — barrier thickness | 0.2–0.5 µm, about one fiftieth of a red cell | Increased by pulmonary oedema and fibrosis |
| ΔP — pressure gradient | ≈60 mmHg at the start of the capillary (alveolar 100 against mixed venous 40) | Low alveolar PO₂, or a raised mixed venous PO₂ |
| D — diffusion coefficient | ∝ solubility, ∝ 1/√molecular weight (Graham’s law); CO₂ is ≈20× more diffusible than O₂ | Fixed for a given gas — but the ratio explains why diffusion impairment causes hypoxaemia long before hypercapnia |
3 · Perfusion limitation against diffusion limitation
A red cell spends about 0.75 seconds in the pulmonary capillary at rest, and equilibration with alveolar gas is complete in roughly 0.25 seconds — a third of the way along. That threefold reserve is why normal oxygen transfer is perfusion-limited: the only way to move more oxygen is to bring more blood, not to allow more time.
| Feature | Perfusion-limited | Diffusion-limited |
|---|---|---|
| Capillary equilibrium | Reached at about one third of transit | Not reached by the capillary end |
| More uptake requires | More blood flow | More area, less thickness, or more time |
| Gas examples | O₂ and CO₂ normally; N₂O | Carbon monoxide always |
| When O₂ becomes limited | — | Exercise (transit falls towards 0.25 s), altitude, thickened membrane — usually in combination |
4 · Where the normal gradient actually comes from
| Component | Mechanism | Contribution |
|---|---|---|
| Regional V/Q inequality | Apical units relatively over-ventilated, basal units over-perfused; high-V/Q units cannot compensate because they sit on the ODC plateau | The larger share |
| Bronchial venous drainage | Deoxygenated blood drains into the pulmonary veins, after gas exchange | True anatomical shunt |
| Thebesian veins | Drain part of the coronary circulation directly into the left heart chambers | True anatomical shunt |
| Together | Physiological shunt of about 2–5% of cardiac output | Normal gradient 5–10 mmHg on air |
5 · Using the gradient to find the cause of hypoxaemia
This is the clinical point of the calculation. There are five causes; the gradient separates the first two from the rest, and the response to oxygen separates shunt from the others.
| Cause | A–a gradient | Responds to O₂? | Example |
|---|---|---|---|
| Low inspired PO₂ | Normal | Yes | Altitude, hypoxic gas mixture |
| Hypoventilation | Normal | Yes | Opioid, residual block, obesity hypoventilation — PaCO₂ is raised |
| V/Q mismatch | Widened | Yes | The commonest cause: asthma, atelectasis, embolism, most lung disease |
| Shunt (V/Q = 0) | Widened | Poorly — the discriminator | Consolidation, intracardiac right-to-left |
| Diffusion limitation | Widened | Yes | Fibrosis, oedema; rarely the sole cause at rest |
Regional lung physiology
Ventilation, perfusion and their ratio
Ventilation, perfusion and V̇A/Q̇ in one graph
Normal upright lung · distribution per unit lung volume
At the marked third-rib level, V̇A, Q̇ and V̇A/Q̇ converge at 1.
Ventilation and perfusion both increase from apex to base. Perfusion changes more steeply, so V̇A/Q̇ rises toward the apex. At approximately the third-rib level, V̇A equals Q̇ and the local ratio is 1.
Basal units have relatively lower PAO₂ and higher PACO₂; apical units have higher PAO₂ and lower PACO₂. More total gas exchange still occurs basally because blood flow is greater.
High V̇A/Q̇ is not dead space unless perfusion reaches zero. Low V̇A/Q̇ is not true shunt unless ventilation reaches zero.
Positive-pressure ventilation or low pulmonary arterial pressure may increase apical dead space. Atelectasis, consolidation and airway obstruction produce low-V̇A/Q̇ or shunt-like units.
1 · Why ventilation increases towards the base
The lung has weight and is suspended in the thorax, so intrapleural pressure is most negative at the apex — about −10 cmH₂O — and least negative at the base, about −2.5 cmH₂O. Transpulmonary pressure is correspondingly larger at the apex, so apical alveoli sit already well expanded, high on the pressure–volume curve where compliance is low. Basal alveoli start smaller, on the steep part of the curve where compliance is high.
2 · Why perfusion increases more steeply still
Pulmonary arterial pressure is low — around 25/8 mmHg, mean 15 mmHg — equivalent to a column of blood about 20 cm high. In an upright adult lung of some 30 cm, that is simply not enough to perfuse top and bottom equally. A hydrostatic gradient of roughly 1 cmH₂O per cm of height therefore dominates regional flow, and because pulmonary vessels are thin-walled and collapsible the effect is amplified by recruitment and distension rather than being merely additive.
| Zone | Pressures | What determines flow | Comment |
|---|---|---|---|
| Zone 1 | P A > P a > P v | No flow — capillaries collapsed | Alveolar dead space. Absent in the normal upright lung; created by haemorrhage, hypotension or high PEEP |
| Zone 2 | P a > P A > P v | Arterial minus alveolar pressure | The Starling resistor. Flow rises down the zone as arterial pressure rises; venous pressure is irrelevant |
| Zone 3 | P a > P v > P A | Arterial minus venous pressure | Conventional flow. Further increase down the zone is by capillary distension |
| Zone 4 | Interstitial > venous | Extra-alveolar vessel compression | At the extreme base, and larger at low lung volumes or with interstitial oedema — flow falls again |
3 · The regional consequences
Both ventilation and perfusion increase from apex to base, but perfusion increases more steeply. The ratio therefore falls down the lung, passing through 1 at about the level of the third rib.
| Apex | Base | |
|---|---|---|
| Ventilation | Low | High |
| Perfusion | Very low | High |
| V̇/Q̇ ratio | ≈ 3.3 | ≈ 0.6 |
| Alveolar PO₂ | ≈ 132 mmHg (17.6 kPa) | ≈ 89 mmHg (11.9 kPa) |
| Alveolar PCO₂ | ≈ 28 mmHg (3.7 kPa) | ≈ 42 mmHg (5.6 kPa) |
| Alveolar size | Larger | Smaller |
| Compliance | Lower | Higher |
| End-capillary pH | Higher | Lower |
| Clinical association | Favours reactivation of tuberculosis — high PO₂, poor lymphatic drainage | Where atelectasis and airway closure appear first under anaesthesia |
4 · The two extremes: dead space and shunt
Every lung unit sits on a continuum bounded by two limiting cases. Naming both ends, and the equation that quantifies each, turns a descriptive answer into an analytical one.
| Alveolar dead space | True shunt | |
|---|---|---|
| V̇/Q̇ | Infinite — ventilation without perfusion | Zero — perfusion without ventilation |
| Gas composition | Approaches inspired gas: PO₂ 150, PCO₂ 0 | Approaches mixed venous blood: PO₂ 40, PCO₂ 46 |
| Typical cause | Pulmonary embolism, low cardiac output, excessive PEEP | Consolidation, collapse, intracardiac right-to-left shunt |
| Effect of 100% oxygen | PaCO₂ still rises if severe | PaO₂ rises very little — the diagnostic feature |
| Quantified by | Bohr equation | Shunt equation |
Normal VD/VT is 0.2–0.35. The equation works because carbon dioxide in mixed expired gas is diluted by dead space gas containing none, so the shortfall between arterial and mixed expired PCO₂ measures the diluting fraction directly. Using end-tidal PCO₂ instead gives the anatomical dead space (the Fowler method); using arterial PCO₂ gives the physiological dead space, which includes the alveolar component.
Normal physiological shunt is 2–5% of cardiac output, rising to about 10% under general anaesthesia. End-capillary content cannot be sampled, so it is assumed equal to the content calculated from ideal alveolar PO₂ — which is why the measurement is conventionally made on 100% oxygen, when every non-shunt unit is fully saturated and the assumption becomes safe.
5 · Why V/Q inequality causes hypoxaemia but not hypercapnia
This is the most commonly examined idea in the topic, and it turns entirely on the difference in shape between the two dissociation curves.
| Oxygen | Carbon dioxide | |
|---|---|---|
| Shape of its dissociation curve | Sigmoid, with a flat plateau above 60 mmHg | Steep and near-linear across the physiological range |
| What a high-V/Q unit can do | Raising PO₂ from 100 to 130 mmHg adds almost no content — it is already on the plateau | Blows off proportionally more CO₂, so it genuinely compensates |
| Result of mixing | Net fall in content, and therefore in PaO₂ | Net normal, or low, PaCO₂ |
| Effect of the chemoreceptors | Increased ventilation cannot correct it, for the reason above | Any rise in PaCO₂ increases ventilation, which corrects it |
6 · Hypoxic pulmonary vasoconstriction
The lung has its own local mechanism for limiting mismatch. Alveolar hypoxia constricts the pulmonary arterioles supplying that region — the opposite of the systemic response — diverting flow towards better-ventilated lung.
| Detail | |
|---|---|
| Stimulus | Alveolar rather than arterial PO₂; the response is roughly proportional to PAO₂ cubed and is most sensitive around 60 mmHg (8 kPa) |
| Mechanism | Hypoxia inhibits voltage-gated potassium channels in pulmonary artery smooth muscle → depolarisation → voltage-gated calcium entry → contraction |
| Time course | Begins within seconds, maximal at about 15 minutes, with a slower sustained second phase |
| Purpose | Reduces shunt fraction; in the fetus it maintains high pulmonary vascular resistance so blood bypasses the unventilated lung |
| Attenuated by | Volatile agents (dose-dependent), nitrates, calcium channel blockers, nitric oxide, hypocapnia, alkalosis, high pulmonary artery pressure, sepsis, excessive cardiac output |
| Preserved by | Intravenous agents including propofol — one argument for total intravenous anaesthesia during one-lung ventilation |
7 · What anaesthesia does to all of this
Every element above changes the moment the patient is anaesthetised, and the physiology is expected to be carried into the theatre.
| Change | Mechanism | Consequence |
|---|---|---|
| FRC falls | ≈15–20% on induction, more supine, from loss of tone and cephalad diaphragmatic displacement | Once FRC falls below closing capacity, dependent airways close during tidal breathing |
| Atelectasis | Appears in dependent lung within minutes in most patients; absorption atelectasis added by a high FiO₂ | Those units become low-V̇/Q̇ or true shunt |
| Shunt rises | From about 2–5% to around 10% | The main reason PaO₂ falls under anaesthesia |
| Positive pressure ventilation | Redistributes ventilation towards non-dependent lung while gravity keeps perfusion dependent | Worsens the match. PEEP corrects by recruitment, but excessive PEEP creates zone 1 and adds dead space |
| Volatile agents | Blunt hypoxic pulmonary vasoconstriction in a dose-dependent way | Removes the compensation the lung would otherwise apply |
| One-lung ventilation | The non-dependent lung is perfused but not ventilated | A large shunt until hypoxic vasoconstriction and surgical compression reduce it — the extreme case of everything above |