Appearance
8.4 — Gas Exchange and Transport
Only about 1.5 percent of the oxygen in your blood is dissolved in the plasma. The other 98.5 percent is bound to haemoglobin, and without it your blood could carry roughly a seventieth of the oxygen it does — a cardiac output of 5 litres a minute would deliver nowhere near enough to keep you alive.
Haemoglobin is what makes an animal of our size possible, and the shape of its oxygen-binding curve is one of the most elegant pieces of chemistry in the body.
Partial pressures
Gases move by diffusion, down gradients of partial pressure — the pressure a gas would exert if it alone occupied the space.
Air is 21 percent oxygen. At sea level, atmospheric pressure is 760 mmHg (about 101 kPa), so:
P_{O_2} = 0.21 \times 760 = 160\ \text{mmHg}
By the time it reaches the alveoli it is about 100 mmHg, and the drop happens for two reasons: the air is humidified, and water vapour takes up part of the pressure; and alveolar air is continuously mixed with the residual air already there.
| Location | pO₂ (mmHg) | pCO₂ (mmHg) |
|---|---|---|
| Atmosphere | 160 | 0.3 |
| Alveoli | 100 | 40 |
| Blood arriving at the lung | 40 | 46 |
| Blood leaving the lung | 100 | 40 |
| Tissues | 40 or less | 46 or more |
Read the gradients. Oxygen goes from 100 in the alveolus to 40 in arriving blood — a driving gradient of 60 mmHg. Carbon dioxide goes from 46 to 40 — a gradient of only 6.
And yet the same amount of carbon dioxide crosses. The reason is solubility: carbon dioxide is about 20 times more soluble in the membrane than oxygen, so it needs only a fraction of the gradient.
This has a real clinical consequence. In diseases that thicken the barrier or reduce its area, oxygen transfer fails first while carbon dioxide clearance is preserved, because CO₂ has so much margin. So early lung disease shows low oxygen with normal or even low carbon dioxide — the low CO₂ because the person breathes faster in response to the low oxygen. A rising carbon dioxide is therefore a late and ominous sign, meaning ventilation itself is now failing.
The exchange
Blood spends about 0.75 seconds in a pulmonary capillary at rest, and equilibration with alveolar gas is complete in about 0.25 seconds. So there is a threefold safety margin.
That margin is why you can exercise. At maximal exercise, cardiac output rises and transit time falls to about 0.25 seconds — exactly the time needed. Healthy lungs still fully oxygenate the blood. But in disease, where the barrier is thickened and equilibration takes longer, the margin is consumed and the person becomes hypoxic on exertion while appearing normal at rest. This is why exercise desaturation is tested for, and why a normal resting oxygen level does not exclude significant lung disease.
Ventilation–perfusion matching. For efficient exchange, air and blood must arrive at the same places in the same proportions. The overall ratio is about 0.8, and it varies by region: the top of an upright lung is relatively over-ventilated and under-perfused, the base the reverse, because gravity affects blood more than air.
Two extreme failures:
Shunt — perfused but not ventilated. Blood passes through without picking up oxygen. Pneumonia and collapse do this, and the crucial feature is that giving more oxygen barely helps, because the affected blood never meets any air at all.
Dead space — ventilated but not perfused. A pulmonary embolus does this.
And the lung actively minimises mismatch by hypoxic pulmonary vasoconstriction (Chapter 7.5), diverting blood away from poorly ventilated regions.
Carrying oxygen
Each haemoglobin molecule binds four oxygen molecules, one per iron atom. Fully saturated blood carries about 1.34 ml of oxygen per gram of haemoglobin. With 150 g/L of haemoglobin:
150 \times 1.34 \approx 200\ \text{ml of oxygen per litre of blood}
Against about 3 ml per litre dissolved. That is the seventyfold difference.
The dissociation curve
The curve is S-shaped, and the shape is the point.
Why S-shaped: cooperative binding. When one oxygen binds a haemoglobin subunit, that subunit changes shape slightly, and the change is transmitted to the others — making them bind oxygen more readily. So the first oxygen is hard to bind, the second easier, the third easier still, the fourth easiest.
And it works in reverse when unloading: releasing one makes the rest release more easily.
Now read what each part of the curve does.
The flat upper portion, above about 60 mmHg, means saturation stays above 90 percent even when alveolar oxygen falls substantially. This is an enormous safety margin. A person at moderate altitude, or with moderate lung disease, still saturates well. It is also why giving supplementary oxygen to someone already at 97 percent achieves almost nothing — there is nowhere for the curve to go.
The steep middle portion, between about 20 and 60 mmHg, is where the tissues operate. A small fall in tissue partial pressure releases a large amount of oxygen. Between 40 mmHg (resting tissue) and 20 mmHg (exercising tissue), saturation falls from 75 percent to about 35 percent — so more than half the remaining oxygen is delivered for a modest change in gradient.
At rest, tissues extract only about 25 percent of the oxygen delivered. So venous blood is still 75 percent saturated, which is a large reserve available immediately when demand rises.
What shifts the curve
A right shift means oxygen is released more readily — the same partial pressure gives lower saturation, so more oxygen is delivered to the tissue.
Four things shift it right, and every one of them signals a tissue that needs oxygen:
- Increased carbon dioxide
- Decreased pH (acidity) — the Bohr effect
- Increased temperature
- Increased 2,3-BPG, a molecule red cells produce that binds haemoglobin and reduces its oxygen affinity
Look at that list against a working muscle. It is producing carbon dioxide, producing acid, and generating heat. All three shift the curve right, precisely where and when more oxygen is wanted. The signal that a tissue needs oxygen is the same signal that makes haemoglobin let go of it. No sensor, no control system — the chemistry does it.
And in the lungs, where CO₂ is being unloaded and pH rises, the curve shifts back left, helping haemoglobin pick oxygen up. The same molecule behaves oppositely at the two ends of its journey because the local conditions differ.
2,3-BPG explains three separate things.
Altitude adaptation — 2,3-BPG rises within a day or two at altitude, shifting the curve right and improving tissue delivery.
Anaemia and chronic hypoxia — the same adaptation.
And stored blood loses its 2,3-BPG. After a couple of weeks in a blood bank, stored red cells hold onto oxygen too tightly and deliver it poorly. Levels regenerate over about 24 hours after transfusion, which matters in massive transfusion.
Fetal haemoglobin sits to the left of the adult curve, because it binds 2,3-BPG poorly. Higher affinity means it pulls oxygen from maternal blood across the placenta (Chapter 7.9).
And carbon monoxide is the same curve weaponised. It binds haemoglobin about 200 to 250 times more tightly than oxygen, so even small concentrations occupy a large fraction of binding sites. Worse, it shifts the curve for the remaining sites to the left, so whatever oxygen is still bound is released less readily. Reduced carrying capacity and impaired unloading together.
And this is why a pulse oximeter is dangerously misleading in carbon monoxide poisoning. It cannot distinguish carboxyhaemoglobin from oxyhaemoglobin, so it reads normal or high while the person is suffocating. Diagnosis needs a specific blood measurement, and treatment is high-flow oxygen — which reduces carbon monoxide's half-life in blood from about 4 to 5 hours on room air to around 60 to 90 minutes. Chapter 23.6.
Carrying carbon dioxide
Three forms, and the proportions matter.
Dissolved — about 7 percent. More than oxygen, because CO₂ is far more soluble.
Bound to haemoglobin — about 23 percent. It binds the protein chains rather than the iron, so it does not compete with oxygen directly.
As bicarbonate — about 70 percent. This is the main route.
Inside the red cell:
\mathrm{CO_2} + \mathrm{H_2O} \;\rightleftharpoons\; \mathrm{H_2CO_3} \;\rightleftharpoons\; \mathrm{H^+} + \mathrm{HCO_3^-}
Carbon dioxide plus water gives carbonic acid, which splits into a hydrogen ion and a bicarbonate ion.
The first step is catalysed by carbonic anhydrase, one of the fastest enzymes known — around a million reactions per second (Chapter 1.3). Without it the reaction is far too slow to be useful, and you could not clear CO₂ fast enough to survive.
The bicarbonate then leaves the red cell in exchange for a chloride ion — the "chloride shift" — and travels in the plasma. In the lungs the whole sequence runs backwards, and CO₂ is released into the alveoli.
The hydrogen ions produced are mopped up by haemoglobin, which is a good buffer. And deoxygenated haemoglobin buffers better than oxygenated haemoglobin — the Haldane effect — so blood that has just given up its oxygen is better at carrying CO₂ away. Again, the two functions assist each other automatically.
Carbonic anhydrase inhibitors such as acetazolamide are used for glaucoma, for altitude sickness and as a mild diuretic, and every one of those uses comes from interfering with this reaction somewhere in the body.
Reading a blood gas
A useful shortcut, since these numbers appear in every hospital record.
Normal arterial values: pH 7.35–7.45, pCO₂ 4.7–6.0 kPa (35–45 mmHg), pO₂ 11–13 kPa (80–100 mmHg), bicarbonate 22–26 mmol/L.
Type 1 respiratory failure — low oxygen, normal or low CO₂. A gas exchange problem: pneumonia, pulmonary oedema, embolism, fibrosis. The person is breathing adequately; the lung is failing to transfer oxygen.
Type 2 respiratory failure — low oxygen with high CO₂. A ventilation problem: severe COPD, respiratory muscle weakness, opioid overdose, exhaustion. The person is not moving enough air.
The distinction determines the treatment. Type 1 needs oxygen and treatment of the cause. Type 2 needs the ventilation supported — non-invasive ventilation or intubation — because giving oxygen alone corrects the number without fixing the problem.
And there is a specific caution in chronic type 2 respiratory failure that deserves to be stated accurately, because it is widely half-understood. In some people with long-standing COPD, high-concentration oxygen worsens carbon dioxide retention. The old explanation — that their breathing is driven only by low oxygen and removing that stops them breathing — is largely wrong. The main mechanisms are that oxygen abolishes hypoxic pulmonary vasoconstriction, worsening ventilation–perfusion matching, and the Haldane effect, since oxygenated haemoglobin carries less CO₂.
The practical rule is what matters: in known COPD, target an oxygen saturation of 88 to 92 percent rather than 94 to 98 percent. And the rule must never be used as a reason to withhold oxygen from someone who is severely hypoxic — hypoxia kills within minutes and CO₂ retention takes hours. Give oxygen, then adjust.
Pulse oximetry
A clip on the finger shining red and infrared light through it. Oxygenated and deoxygenated haemoglobin absorb the two wavelengths differently, so the ratio gives the saturation. The device isolates the pulsatile component so it measures arterial rather than venous or tissue absorption.
It is one of the most valuable monitoring devices ever invented and it has clear limitations, all of which follow from how it works:
- Carbon monoxide — falsely high, as above.
- Poor peripheral circulation, cold hands, shock — unreliable or no reading.
- Nail polish and some dyes — interference.
- Severe anaemia — saturation can be 100 percent while oxygen content is dangerously low, because saturation is a percentage of whatever haemoglobin is present.
- Skin pigmentation — several studies have found oximeters overestimate saturation in people with darker skin, meaning hypoxia is missed more often. This became a recognised safety issue during the COVID-19 pandemic and has led to calls for redesign and recalibration.
And the general point behind all of these: saturation is not the same as oxygen delivery. Delivery depends on saturation, haemoglobin concentration and cardiac output together, and a normal number on one of the three says nothing about the other two.
What the next page fixes
Breathing is automatic, and yet you can override it at will. Chapter 8.5 covers what controls it — where the rhythm is generated, what is actually being measured, and why the answer is carbon dioxide rather than oxygen.