Introduction

The A-a gradient, or the alveolar-arterial gradient, measures the difference between the oxygen concentration in the alveoli and arterial system. The A-a gradient has important clinical utility as it can help narrow the differential diagnosis for hypoxemia. The A-a gradient calculation is as follows:

•  A-a Gradient = PAO2 – PaO2.

With PAO2 representing alveolar oxygen pressure and PaO2 representing arterial oxygen pressure. The arterial oxygen pressure (PaO2) can be directly assessed with an arterial blood gas test (ABG) or estimated with a venous blood gas test (VBG). The alveolar oxygen pressure (PAO2) is not easily measured directly; instead, it is estimated using the alveolar gas equation:

• PAO2 = (Patm – PH2O) FiO2 – PaCO2/RQ

(Please see the article on the alveolar gas equation for more information.)

 In a perfect system, no A-a gradient would exist: oxygen would diffuse and equalize across the capillary membrane, and the pressures in the arterial system and alveoli would be equal (resulting in an A-a gradient of zero). However, there is a physiologic V/Q mismatch in the lungs due to heterogeneity in apical vs. basilar perfusion and ventilation. This mismatch is, in part, responsible for the slight difference in oxygen tension between the alveoli and arterial blood. So there exists a physiologic A-a gradient that changes based on a patient's age. The expected A-a gradient can be estimated with the following equation:

• A-a gradient = (Age + 10) / 4 

The value calculated for a patient's A-a gradient can assess if their hypoxia is due to the dysfunction of the alveolar-capillary unit, for which it will elevate, or due to another reason, in which the A-a gradient will be at or lower than the calculated value using the above equation.[1]

Issues of Concern

The A-a gradient is calculated using the alveolar oxygen tension estimated from the alveolar gas equation (PAO2 = (Patm - PH2O) FiO2 - PaCO2/RQ). The alveolar gas equation is valid only in the setting of steady-state conditions.[1]

Cellular Level

The alveoli are the lung's functional units. The alveolar wall is composed mainly of cells called pneumocytes. There are two known types of pneumocytes; type I and type II. Type I pneumocytes, making up 90% to 95% of the alveolar wall, are efficient gas exchangers due to their thin, plate-like structure, with the trade-off being their inability to replicate and susceptibility to toxic injury. Type II pneumocytes comprise most of the remaining cells in the alveoli Type II pneumocytes secrete pulmonary surfactant, which is an important factor in lowering surface tension in the alveoli and thus preventing atelectasis. Moreover, they are mitotically active cells and replace the easily damaged type I pneumocytes.[2]

Organ Systems Involved

To understand the A-a gradient, it is first important to understand the interplay between the vascular system and the lungs. The heart serves as the body's pumping system, pushing oxygen-rich blood to peripheral tissues and pulling oxygen-poor blood back toward the heart. Let us imagine a single red blood cell as it travels through the body. We will start in the left ventricle. At this point in the circuit, the RBC is highly oxygenated after traversing through the pulmonary capillaries. The heart contracts pushing the cell through the aorta and into the body's arterial system. From there, the cell will travel to the capillary beds of peripheral tissues, be it the kidney, liver, muscle, skin, brain, or any other tissue that receives blood. The capillaries are thin-walled, allowing for gasses to diffuse across their membranes. In peripheral tissues, oxygen will leave the RBC, transverse the capillary wall, and be taken up by a cell. There it will serve a vital role in cellular respiration. The RBC, now deoxygenated, will continue to be pushed through the body and return to the heart via the venous system. It will travel through the right side of the heart and eventually is conducted through the pulmonary arterial system. It again arrives at thin-walled capillaries where gas exchange occurs with adjacent alveoli. However, now the oxygen diffuses from the alveoli, across the capillaries, and into the de-oxygenated RBC. The newly oxygenated RBC travels through the pulmonary venous system and empties into the left atrium and finally back to the starting point, the left ventricle.[3][4]

Function

The function of the A-a gradient is to help determine the source of hypoxemia. The measurement helps narrow the etiology of hypoxemia as either extrapulmonary (outside of the lungs) or intrapulmonary (inside the lungs).[1]

Clinical Significance

The A-a gradient has clinical utility in patients with hypoxemia of undetermined etiology. The A-a gradient can be broken down categorically as either elevated or normal. Causes of hypoxemia will fall into either category. To better understand which etiologies of hypoxemia fall in either category, I will use a simple analogy. Think of the oxygen's journey through the body like a river. The respiratory system will serve as the first part of the river. Then imagine a waterfall from that point leading to the second part of the river. The waterfall represents the alveolar and capillary walls, and the second part of the river represents the arterial system. The river empties into a lake, which can represent end-organ perfusion.

When a patient is hypoxemic, there is a pathologically low partial pressure of oxygen in their body resulting in tissue hypoxia leading to cell injury and eventually cell death and necrosis. Using our analogy, decreasing the flow through the river will ultimately result in the lake drying out, this can represent the phenomenon of hypoxemia. The A-a gradient helps to determine where there is flow obstruction.[1]

For example, consider hypoventilation. Patients can exhibit hypoventilation for various reasons; some include CNS depression, neuromuscular diseases such as myasthenia gravis, poor chest elasticity, as seen in kyphoscoliosis, or patients with vertebral fractures, and many others. Patients with poor ventilation lack oxygen tension throughout their arterial system in addition to the respiratory system. Thus, the river will have decreased flow throughout both parts. Since both the "A" and the "a" decrease in concert, the gradient between the two will remain within normal limits (even though both values will decrease). Thus patients with hypoxemia due to hypoventilation will have an A-a gradient within normal limits.[5]

Now let us consider pneumonia. Patients with pneumonia have a physical barrier within the alveoli, limiting the diffusion of oxygen into the capillaries.[6] However, these patients can ventilate (unlike the patient with hypoventilation), which will result in a well-oxygenated respiratory tract (A) with poor diffusion of oxygen across the alveolar-capillary unit and thus lower oxygen levels in the arterial blood (a). In this case, the obstruction would occur at the waterfall in our example, limiting the flow of water only through the second part of the river.  Thus patients with hypoxemia due to pneumonia will have an inappropriately elevated A-a gradient (due to normal "A" and low "a").[5]

Applying this analogy to different causes of hypoxemia should help determine whether to expect an elevated or normal A-a gradient. As a general rule of thumb, any pathology of the alveolar-capillary unit will result in a high A-a gradient.[7][8][9][10]