Types of Hypoxia — Hypoxic, Anaemic, Stagnant and Histotoxic Hypoxia with PaO2, SaO2 and Oxygen Content

Hypoxia means oxygen is insufficient at the tissue level to maintain normal function. StatPearls names two primary mechanisms: low blood flow to the tissue or low oxygen content in the blood, the latter being hypoxaemia. Hypoxaemia is therefore a cause of hypoxia, not a synonym: a patient can be severely hypoxic with a perfectly normal arterial PaO2 (for example in cyanide poisoning or shock).

The classical four-way classification asks one question at each step of the oxygen cascade: is oxygen entering the blood (hypoxic), is the blood able to carry it (anaemic), is the blood reaching the tissue (stagnant), and can the cell use it (histotoxic)? StatPearls lists the same categories under differential diagnosis: hypoxaemic, circulatory, anaemic and histotoxic.

Only in hypoxic hypoxia do all three arterial measurements fall together. In the other three types the lungs oxygenate normally, so PaO2 is normal — the single most useful fact for exam questions. The giveaway for histotoxic hypoxia is the venous side: because tissues cannot extract oxygen, venous oxygen saturation stays high (StatPearls: 'arterialisation of venous blood', central venous saturation above 90%).

Arterial oxygen content is CaO2 = (1.34 × Hb × SaO2) + (0.003 × PaO2), where Hb is in g/dL, SaO2 is a fraction and PaO2 is in mmHg. StatPearls gives 1.34 mL of O2 per gram of haemoglobin (1.39 in ideal stoichiometry) and 0.003 mL of dissolved oxygen per dL per mmHg. Normal oxygen bound to haemoglobin is roughly 20 mL O2/dL, compared with only about 0.3 mL/dL dissolved in plasma.

So the haemoglobin term dominates. Halve the haemoglobin and the content roughly halves while PaO2 and SaO2 do not change — that is anaemic hypoxia. Equally, it is the dissolved oxygen tension (PaO2), not the total content, that drives haemoglobin saturation, which is why a normal PaO2 gives a normal SaO2 in anaemia.

For the shape of the curve and the effect of shifts, see oxygen-haemoglobin dissociation curve.

StatPearls groups the causes of low arterial oxygen into five mechanisms. Each is a favourite exam item because the A–a gradient and the response to oxygen differ:

In anaemic hypoxia the oxygen-carrying capacity of blood falls because haemoglobin is low in amount (anaemia, haemorrhage) or unable to carry oxygen (carbon monoxide, methaemoglobinaemia). The lungs and the circulation are normal, so PaO2 is normal.

• Carbon monoxide: binds haemoglobin to form carboxyhaemoglobin with 200 to 250 times the affinity of oxygen. It reduces carrying capacity and shifts the curve to the left, so the remaining oxygen is released poorly. StatPearls notes haemoglobin concentration and measured PO2 can look normal while oxygen content is markedly reduced.
• Carbon monoxide also inhibits cytochrome c oxidase, so CO poisoning has a histotoxic component as well.
• Methaemoglobinaemia: iron oxidised to the ferric state cannot carry oxygen; cyanosis may appear at methaemoglobin levels as low as 10%, with 'chocolate brown blood' from about 15%; treatment is methylene blue.
• Carboxyhaemoglobin is below 3% in non-smokers; smokers may reach 10%, and a level above 10% suggests additional exposure.

In stagnant hypoxia the blood is well oxygenated but not delivered fast enough: cardiac output falls (heart failure, cardiogenic or hypovolaemic shock) or flow to one tissue is blocked (arterial occlusion, embolus). StatPearls describes circulatory hypoxia as inadequate delivery due to pump failure. PaO2, SaO2 and arterial content are all normal.

• Because blood spends longer in the capillary, tissues extract a larger fraction of the oxygen delivered, so venous oxygen content is lower than normal — the opposite of histotoxic hypoxia.
• Hypoxia can be generalised (shock, heart failure) or localised (limb ischaemia, stroke, myocardial infarction).
• Raising PaO2 with oxygen therapy helps little, because the fault is delivery, not oxygenation. The treatment is to restore flow: fluids, inotropes, revascularisation.

In histotoxic hypoxia (dysoxia) oxygen arrives normally, but cells cannot use it. The classic cause is cyanide, which binds copper and iron in the electron transport chain and inhibits cytochrome c oxidase (complex IV), halting oxidative phosphorylation and ATP production. Anaerobic metabolism takes over, producing profound lactic acidosis.

• Sources: bitter almonds, apricot pits and flax seeds, and prolonged sodium nitroprusside infusion (contains cyano groups).
• Clues: normal PaO2 and SaO2, severe lactic acidosis (a lactate of 8 mmol/L or more is sensitive and specific for toxic cyanide levels), and venous blood that looks arterial (central venous saturation above 90%).
• Antidote: hydroxocobalamin binds cyanide to form cyanocobalamin and is preferred for its mild side-effect profile; sodium nitrite and sodium thiosulfate are additional antidotes. Thiosulfate acts through rhodanese, which converts cyanide to thiocyanate.
• Similar mechanism: hydrogen sulphide and carbon monoxide also inhibit cytochrome c oxidase.

Related reading: ABG interpretation for PaO2, SaO2 and the A–a gradient, and regulation of respiration for how peripheral chemoreceptors respond to low PaO2 for the respiratory drive that low PaO2 produces.