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[Physiology](https://durgical.com/en/physiology/) · [Respiratory](https://durgical.com/en/physiology/#s-resp)

# The causes of hypoxemia

- Mechanism
- Exam priority: high

There are only a few ways to end up with too little oxygen in the blood. The A–a gradient and the response to oxygen tell you which.

Updated 2026-11-01

Also called: Mechanisms of hypoxemia, Hypoxemia vs. hypoxia

## Key points

- Normal A–a gradient: low inspired PO₂ (altitude) or hypoventilation (high PaCO₂).
- Wide A–a gradient: V/Q mismatch (the most common), shunt or diffusion impairment.
- Shunt barely responds to 100% O₂; V/Q mismatch does respond.
- Diffusion impairment worsens with exercise (shorter capillary transit time).
- Anemia and CO cause hypoxia with a normal PaO₂: PaO₂ measures dissolved O₂, not content.

## What it is

Hypoxemia is a low PaO₂; hypoxia is too little oxygen in the tissues, which can happen with a normal PaO₂ (anemia, CO, cyanide, low cardiac output). There are five mechanisms of hypoxemia: low inspired PO₂, hypoventilation, diffusion impairment, V/Q mismatch and shunt. The first two have a normal A–a gradient.

## How it works, step by step

- Calculate PAO₂ with the local barometric pressure and compare it with PaO₂.
- If the gradient is normal, look at PaCO₂: high means hypoventilation; normal or low with a low PB means altitude.
- If the gradient is wide, think about the O₂ response: a big rise in PaO₂ means V/Q or diffusion; almost none means shunt.
- On 100% O₂, low-V/Q alveoli fill with O₂ over time; shunt units never receive air.

### Oxygen–hemoglobin dissociation curve

**P50** 27.7 mmHg **Arterial blood** 97 % **Mixed venous blood** 73 % **O₂ given up to the tissues** 24 %

Right shift (P50 27.7 mmHg): Hb has less affinity and gives up more O₂ in the tissues. Acid, CO₂, heat and 2,3-BPG cause it.

- Current curve
- Normal curve (pH 7.40 · 37 °C)
- Arterial blood (PO₂ 100)
- Mixed venous blood (PO₂ 40)
- O₂ given up to the tissues

At altitude PaO₂ falls, but saturation holds on the flat part of the curve.

## The five mechanisms

| Mechanism | A–a gradient | Improves with O₂ | Example |
| --- | --- | --- | --- |
| Low inspired PO₂ | Normal | Yes | Altitude (Bogotá, páramo) |
| Hypoventilation | Normal | Yes | Opioids, neuromuscular disease |
| [Diffusion impairment](https://durgical.com/en/conditions/interstitial-lung-disease/) | Wide | Yes | Interstitial fibrosis (especially on exercise) |
| [V/Q mismatch](https://durgical.com/en/conditions/chronic-obstructive-pulmonary-disease/) | Wide | Yes | COPD, asthma, pulmonary embolism |
| [Shunt](https://durgical.com/en/conditions/acute-respiratory-distress-syndrome/) | Wide | Little | ARDS, lobar pneumonia, right-to-left cardiac shunt |

## Clinical notes

- ARDS: large shunt with O₂-refractory hypoxemia; alveoli must be recruited.
- COPD: V/Q mismatch dominates; in advanced disease hypoventilation with hypercapnia is added.
- CO poisoning: tissue hypoxia with a normal PaO₂ and a misleadingly normal pulse oximeter.

## Memory aid

Two 'clean' causes (altitude, breathing too little) keep the gradient normal; three 'lung' causes (V/Q, shunt, diffusion) widen it.

## Test yourself

Think of the answer, then tap the question to see it.

## Hypoxemia barely improves on 100% O₂. Which mechanism dominates?

Shunt: blood crosses unventilated regions and is never exposed to the added O₂.

## Opioid overdose: PaCO₂ 70 mmHg, low PaO₂. What will the A–a gradient be?

Normal: hypoventilation explains the hypoxemia (more alveolar CO₂ displaces O₂), with no exchange defect.

## Why does a patient with pulmonary fibrosis desaturate when walking but not at rest?

Exercise raises cardiac output and shortens red cell transit through the capillary; across a thickened membrane there is no longer time to equilibrate.

## Why doesn't severe anemia lower PaO₂?

PaO₂ reflects dissolved O₂, set by alveolar exchange; what falls in anemia is the O₂ content bound to hemoglobin.

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## Related topics

- [The alveolar gas equation and the A–a gradient](https://durgical.com/en/physiology/the-alveolar-gas-equation-and-the-a-a-gradient/)
- [Ventilation–perfusion matching and West zones](https://durgical.com/en/physiology/ventilation-perfusion-matching-and-west-zones/)
- [Diffusion across the respiratory membrane and DLCO](https://durgical.com/en/physiology/diffusion-across-the-respiratory-membrane-and-dlco/)
- [Oxygenation: SpO₂, PaO₂, cyanosis and oxygen therapy](https://durgical.com/en/physiology/oxygenation-spo-pao-cyanosis-and-oxygen-therapy/)
- [Hypoxemic and hypercapnic respiratory failure](https://durgical.com/en/physiology/hypoxemic-and-hypercapnic-respiratory-failure/)
- [High altitude and acclimatization](https://durgical.com/en/physiology/high-altitude-and-acclimatization/)

## Related conditions

- [Pulmonary embolism](https://durgical.com/en/conditions/pulmonary-embolism/)
- [Acute respiratory distress syndrome (ARDS)](https://durgical.com/en/conditions/acute-respiratory-distress-syndrome/)
- [Chronic obstructive pulmonary disease (COPD)](https://durgical.com/en/conditions/chronic-obstructive-pulmonary-disease/)
- [Community-acquired pneumonia](https://durgical.com/en/conditions/community-acquired-pneumonia/)
- [Interstitial lung disease](https://durgical.com/en/conditions/interstitial-lung-disease/)
- [Carbon monoxide poisoning](https://durgical.com/en/conditions/carbon-monoxide-poisoning/)

## In Pharmacology

- [Opioids and antagonists](https://durgical.com/en/pharmacology/classes/opioids-and-antagonists/)

[← All of physiology](https://durgical.com/en/physiology/)

Educational physiology content; not a diagnostic or treatment guide and no substitute for a health professional's advice. Values are approximate references. No doses are given.

Sources: [22.4 Gas Exchange](https://openstax.org/books/anatomy-and-physiology-2e/pages/22-4-gas-exchange) (OpenStax (Rice University), 2022); [Acute Respiratory Distress Syndrome](https://www.ncbi.nlm.nih.gov/books/NBK436002/) (StatPearls (NCBI Bookshelf), 2024); [Interstitial Lung Disease](https://www.ncbi.nlm.nih.gov/books/NBK541084/) (StatPearls (NCBI Bookshelf), 2024); Hall JE. Guyton and Hall Textbook of Medical Physiology, 13th ed. (ch. 43). Reference book used to check facts; its text and figures are not reproduced (Elsevier, 2016).

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