• The alveolar–arterial gradient and ratio provide a useful, objective means to determine how effectively oxygen from the alveolus moves into the pulmonary circulation. It aids with:
  • Identifying increases in venous admixtures, even in the presence of increased inspired oxygen concentrations
  • Monitoring improvement or worsening of the venous admixture
  • Assessing effectiveness of treatment and interventions
  • Differentiating between causes of hypoxia (impaired uptake vs. decreased alveolar oxygen availability)

• Definitions:
  • PAO₂ = alveolar PO₂. It is determined by the alveolar gas equation and is calculated as follows: PAO₂ = [FiO₂ × (P_atm – P_H2O) – (PaCO₂/0.8)]; measured in units of mm Hg.
  • PaO₂ = arterial PO₂. It is determined by direct arterial blood gas values and is measured in units of mm Hg. Small amounts of oxygen are dissolved in the plasma, which are in equilibrium with the oxygen bound to hemoglobin. Thus, a decrease in arterial oxygen content would reflect a decrease in hemoglobin binding and decreased oxygen saturation.
• A-a gradient: The difference between the alveolar and arterial partial pressure of oxygen
  • Normal adult values in nonsmokers are <15 mm Hg on room air (FiO₂ = 0.21) (1). for example, a patient with a PAO₂ = 100 mm Hg and a PaO₂ = 93 mm Hg has an A-a gradient of 7.
  • Higher FIO₂ values result in an increased A-a gradient. for every 10% increase in FiO₂, the A-a gradient increases by 5–7 mm Hg. This effect is caused by the loss of regional hypoxic vasoconstriction in the lungs (2).
• Advancing age: Results in a steady rise in the A-a gradient (3); PaO₂ predicted = 109 – (0.4 × age in years). for example, a 60-year-old breathing room air would have an average A-a gradient of 14 mm Hg. In comparison, someone below the age of 40 would have a gradient of 7 mm Hg (3).
• A-a gradient: The arterial oxygen concentration divided by the alveolar oxygen concentration. This value is useful in predicting the change in PaO₂ when the FIO₂ also changes since it is relatively unaffected by varying oxygen levels (4).
  • The normal a/A PO₂ ratio is 0.74–0.77 when breathing room air (FIO₂ = 0.21). It only increases to 0.80–0.82 when breathing 100% oxygen (5).
• Physiologic shunting and normal venous admixture
  • The thebesian veins drain venous blood from all 4 walls of the myocardium (mostly right atrium) and empty into the left atrium.
  • Deep bronchial veins drain venous blood from the bronchi and roots of the lungs and empty into the pulmonary veins (deoxygenated blood that returns to the left atrium).
  • Venous blood from these areas does not enter the pulmonary circulation; instead, it returns to the systemic circulation without becoming oxygenated. This accounts for a total of 2–5% of cardiac output, and the mixing of oxygenated and deoxygenated blood is known as venous admixture.
  • This normal venous admixture accounts for the 10–15 mm Hg A-a gradient and the 0.74–0.77 a/A ratio that is considered normal.
• Hypoxic pulmonary vasoconstriction describes a physiologic phenomenon in which the pulmonary arterioles constrict in the presence of low oxygen tension in the alveoli (e.g., atelectasis).
  • This vessel constriction results in re-directing blood flow to well-oxygenated lung units and away from poorly oxygenated lung units to ultimately improve ventilation-perfusion (V/Q) matching.
  • When a patient is given supplemental oxygen, more alveoli become well-oxygenated; however, it also, in turn, decreases hypoxic vasoconstriction.
  • This increase in V/Q mismatch leads to more deoxygenated blood entering the systemic circulatory system and in turn increases the A-a gradient.

• Alveolus
  • Air sac that is lined with a thin membrane consisting of epithelium with collagen and elastin
  • Gas exchange occurs across this membrane where gases move down a concentration gradient between alveolus and pulmonary capillary.
• Pulmonary circulation
  • Consists of blood vessels that carry deoxygenated blood to the site of gas exchange
• Pulmonary capillaries
  • Consists of a single layer of squamous epithelium surrounded by a basement membrane
  • Gases must diffuse across these layers to enter circulation.

• Hypoxia with increased A-a gradient and a/A ratio: Results from an increase in the venous admixture secondary to blood passing through the lung without being properly oxygenated (in addition to the physiologic admixture). Examples of this include:
  • V/Q mismatch: Discrepancy between the alveolar ventilation and capillary perfusion
  • Pulmonary shunt: Perfusion of the alveolar unit without ventilation, due to pathologic processes. Atelectasis describes alveolar deflation or fluid collection of the alveolar unit. Deflation can result from airway obstruction, mucus or blood plugging, inadequate tidal volumes due to pain, or positioning changes; other causes include endobronchial intubation, pneumothorax, collapse of emphysematous blebs, and one lung ventilation (6). Fluid collection can result from pulmonary edema, pneumonia, or adult respiratory distress syndrome (ARDS).
  • Intracardiac shunt: Venous blood is diverted from the pulmonary circulation directly into the systemic circulation. Examples include atrial or septal defects, pulmonary atrioventricular (AV) malformations, and cyanotic congenital heart disease.
  • Diffusion defects: Observed when the alveolar oxygen and carbon dioxide tensions are normal, but oxygen uptake by the alveolar capillaries is abnormal or impaired. Examples include pulmonary fibrosis, interstitial lung inflammation, and interstitial edema.
• Hypoxia with normal A-a gradient or a/A ratio: Can be seen in situations where the alveolar oxygen (or carbon dioxide) is affected, but oxygen uptake by the capillaries is not impaired. The decreased arterial oxygen concentration reflects the decreased alveolar concentration.
  • Hypoxic delivery: Anesthesia machine or ventilator malfunction, or high altitude
  • Hypoventilation: Respiratory depression from drugs, stroke in the pontine area, respiratory muscle fatigue (such as myasthenia gravis), or obesity–hypoventilation syndrome. The increase in carbon dioxide decreases the oxygen partial pressure (concentration) within the alveoli.

• Assessing the A-a gradient or ratio can:
  • Differentiate between hypoxia secondary to low alveolar oxygen tension or due to increase in venous admixture from underlying pathology
  • Provide an objective means to trend venous admixtures and, hence, assess pulmonary processes
  • Assess the effectiveness of treatment and interventions such as positive end expiratory pressures (PEEP)
  • The A-a gradient is directly proportional to shunt while being inversely proportional to the mixed venous oxygen tension.
  • Pulse oximetry only provides an assessment of hemoglobin binding. As oxygen saturation reaches the high 90’s, it can no longer be a reliable marker for arterial oxygen content. Therefore, pulse oximetry cannot aid with assessing the severity of the A-a gradient in a given disease state. for example, patients A and B both have ARDS. Patient A is on 50% FiO₂; his PAO₂ is 350 mm Hg and his PaO₂ is 120 mm Hg resulting in an A-a gradient of 230 mm Hg and SpO₂ of 99%. Patient B also has ARDS and is on 50% FiO₂; his PAO₂ is 350 mm Hg and his PaO₂ is 320 mm Hg resulting in an A-a gradient of 30 and SpO₂ of 99%. Therefore, it is not possible to assess the status of the underlying pathology with higher supplemental oxygen based on oxygen saturation alone; one must obtain a blood gas and calculate the A-a gradient.
  • Assessing a/A ratio: In patients receiving higher or changing FiO₂, the ratio can provide a more consistent value that allows for comparison. Additionally, it has been shown to be more reliable than the A-a gradient in hemodynamically stable patients (7).
  • Perioperative conditions: The functional residual capacity (FRC) is decreased by several factors that ultimately increase the venous admixture, A-a gradient, and a/A ratio.
    • General anesthesia
    • Positioning (supine, prone or steep Trendelenburg position)
    • Surgical procedure (laparoscopy, abdominal retractors)
    • Patient (obesity, pregnancy, ascites) (8)
• Maneuvers and techniques to improve lung oxygenation can be assessed objectively by calculating the A-a gradient or a/A ratio.
  • Pulmonary edema may be treated by optimizing preload (diuresis, venodilators) and afterload (vasodilators) to increase inotropy.
  • Ventilator adjustments such as PEEP, adjusting rate, volume, I:E ratios, and lung recruitment maneuvers
  • Surgical maneuvers such as decreasing the insufflation pressures during laparoscopy or retractor tension
  • Positioning changes: Elevating the head of the bed can shift the abdominal contents away from the diaphragm and allow for increased lung expansion.

• A-a gradient = PAO₂ – PaO₂
• a/A ratio = PaO₂/PAO₂
• PAO₂ = [FiO₂ × (P_atm – P_H2O) – (PaCO₂/0.8)]
• On room air (21%) at sea level, a simplified version: A-a gradient = [(150 – 5)/4(PCO₂)] – PaO₂
• Normal A-a gradient ~ (age +10)/4

• Functional Residual Capacity
• Mixed Venous Oxygen Saturation
• Oxygen Carrying Capacity
• Pulmonary Ventilation Perfusion Matching
• One Lung Ventilation
• Hypoxia, Intraoperatively
• Pao2

Sharanya Nama , MD

Michael Mangione , MD