Accurately assessing and managing oxygenation disturbances is critical to optimal patient outcomes. The alveolar to arterial (A-a) oxygen gradient, which is the difference between the amount of the oxygen in the alveoli (the alveolar oxygen tension [PAO₂]) and the amount of oxygen dissolved in the plasma (PaO₂), is an important measure to help narrow the cause of hypoxemia. It describes the overall efficiency of oxygen uptake from alveolar gas to pulmonary capillary blood.

A-a Gradient Calculation

The formula to calculate the A-a gradient is:
 
The PaO₂ is measured by arterial blood gas, while the PAO₂ is calculated using the alveolar gas equation: In this equation, FiO₂ is the fraction of inspired oxygen (0.21 at room air), Patm is the atmospheric pressure (760 mm Hg at sea level), PH₂O is the partial pressure of water (47 mmHg at 37⁰C), PaCO₂ is the arterial carbon dioxide tension, and R is the respiratory quotient (approximately 0.8 at steady state, but varies according to the relative utilization of carbohydrate, protein, and fat.)

In addition, the A-a gradient varies with age and can be estimated from the following equation:  

Important Notes about the A-a Gradient

• In patients who are healthy, there is generally a small difference between PAO₂ and PaO₂ because PAO₂ is approximately 100 mm Hg and PaO₂ is about 95 mm Hg.
• Proper determination of the A-a gradient requires exact measurement of FiO₂, most easily done when a patient is breathing room air or receiving mechanical ventilation. The FiO₂ of patients receiving supplemental oxygen by nasal cannula or mask can be estimated, but this does limit the usefulness of the A-a gradient. 
• The A-a gradient increases with higher FiO₂. When a patient receives a high FiO₂, both PAO₂ and PaO₂ increase. However, the PAO₂ increases disproportionately, causing the A-a gradient to increase.

Clinical Implications related to the A-a Gradient

Measuring the A-a gradient helps narrow the cause of hypoxemia as either extrapulmonary (outside of the lungs) or intrapulmonary (inside of the lungs); in other words, to distinguish hypercapnic respiratory failure due to global hypoventilation (extrapulmonary respiratory failure) from respiratory failure due to abnormal gas exchange from intrinsic lung disease. An A-a gradient within the normal range (< 20 mm Hg) in the setting of an elevated PaCO₂ is highly suggestive of global hypoventilation, whereas a widened gradient (> 20 mm Hg) suggests that underlying lung disease may be contributing to the measured hypercapnia.

Let’s consider two patients…

Case #1

A young, healthy patient comes in with drug overdose and a respiratory rate of 8 breaths/minute. Their arterial blood gas (ABG) on room air reveals a respiratory acidosis with hypoxemia 7.31/55/65/24/88%. Assuming the Patm, PH₂O, and R are constant, we calculate the A-a gradient:

A-a oxygen gradient = [(FiO₂ x [Patm - PH₂O]) - (PaCO₂ ÷ R)] - PaO₂
A-a gradient = [(0.21) x (760-47) – (55 ÷ 0.8)] – 65
A-a gradient = [(149.73) – (68.75)] – 65
A-a gradient = 80.98 – 65
A-a gradient = 15.98

Since the A-a gradient is < 20 mm Hg, we conclude that their hypoxemia is caused by hypoventilation due to central nervous system depression; their alveolar oxygenation and arterial oxygenation are both decreased, so the gradient between the two remains within normal limits. Use of the appropriate reversal agent is indicated to arouse them and stimulate respiration; intubation and mechanical ventilation are indicated if reversal is not possible or is ineffective.  

Case #2

A patient with pneumonia on mechanical ventilation is developing worsening hypoxemia. Their FiO₂ on the ventilator is increased to 80% and the ABG reveals a respiratory acidosis with hypoxemia: 7.31/55/65/24/88%. Again, assuming the Patm, PH₂O, and R are constant, we calculate the A-a gradient:

A-a oxygen gradient = [(FiO₂ x [Patm - PH₂O]) - (PaCO₂ ÷ R)] - PaO₂
A-a gradient = [(0.80) x (760-47) – (55 ÷ 0.8)] – 65
A-a gradient = [(570.4) – (68.75)] – 65
A-a gradient = 501.65 – 65
A-a gradient = 436.65

In this patient, the increased A-a gradient (> 20 mm Hg) is due to pneumonia creating a physical barrier within the alveoli, limiting the transfer of oxygen into the capillaries. The alveolar oxygenation is normal, however the arterial oxygenation is decreased, so the gradient between the two is widened. This is an example of an intrapulmonary cause of hypoxemia. For this patient, treatment of their pneumonia will be critical to improving arterial oxygenation, while supportive pulmonary hygiene measures are provided.

It’s good to be familiar with this measurement and to feel comfortable recognizing what a normal or elevated A-a gradient indicate. Also, there are tools and calculators for calculating the A-a gradient to help!

References:

Hantzidiamantis, P. & Amaro, E. (2023, June 5). Physiology, Alveolar to Arterial Oxygen Gradient . StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK545153/

Kopman, D. & Schwartztein, R. (2024, April 1). The evaluation, diagnosis, and treatment of the adult patient with acute hypercapnic respiratory failure. UpToDate.  https://www.uptodate.com/contents/the-evaluation-diagnosis-and-treatment-of-the-adult-patient-with-acute-hypercapnic-respiratory-failure

Theodore, A. (2023, August 15). Measures of oxygenation and mechanisms of hypoxemia. UpToDate. https://www.uptodate.com/contents/measures-of-oxygenation-and-mechanisms-of-hypoxemia

 

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