Oxygenation and mechanisms of hypoxemia

Hypoxemia refers to insufficient oxygenation. It can be caused by 5 mechanisms: hypoventilation, ventilation-perfusion mismatch, right-to-left shunt, diffusion impairment, or reduced inspired oxygen tension.

Hypoventilation — Both arterial (PaCO2) and alveolar (PACO2) carbon dioxide tension increase during hypoventilation, which causes the alveolar oxygen tension (PAO2) to decrease. As a result, diffusion of oxygen from the alveolus to the pulmonary capillary declines. The net effect is hypoxemia.

Hypoxemia due to pure hypoventilation can be identified by two characteristics. First, it readily corrects with a small increase if the fraction of inspired oxygen (FiO2). Second, the A-a gradient is usually normal. An exception exists when the hypoventilation is prolonged because atelectasis can occur, which will increase the A-a gradient. Abnormalities that cause pure hypoventilation include:

• CNS depression, such as drug overdose, structural CNS lesions, or ischemic CNS lesions that impact the respiratory center
• Obesity hypoventilation (Pickwickian) syndrome
• Impaired neural conduction, such as amyotrophic lateral sclerosis, Guillain-Barré syndrome, high cervical spine injury, phrenic nerve paralysis, or aminoglycoside blockade
• Muscular weakness, such as myasthenia gravis, idiopathic diaphragmatic paralysis, polymyositis, muscular dystrophy, or severe hypothyroidism
• Poor chest wall elasticity, such as a flail chest or kyphoscoliosis

V/Q mismatch — Ventilation-perfusion (V/Q) mismatch refers to an imbalance of blood flow and ventilation. It causes the composition of alveolar gas to vary among lung regions:

• Lung regions with low ventilation compared to perfusion will have a low alveolar oxygen content and high CO2 content
• Lung regions with high ventilation compared to perfusion will have a low CO2 content and high oxygen content

In the normal lung, there is V/Q mismatch because both perfusion and ventilation are heterogeneous. Specifically, perfusion is greater in basilar than apical regions, while ventilation is greater in apical than basilar regions. V/Q mismatch is responsible for the normal A-a gradient.

In the diseased lung, V/Q mismatch increases because heterogeneity of both ventilation and perfusion worsen. The net effect is hypoxemia. Hypoxemia due to V/Q mismatch can be corrected with low to moderate flow supplemental oxygen and is characterized by an increased A-a gradient. Common causes of hypoxemia due to V/Q mismatch include obstructive lung diseases, pulmonary vascular diseases, and interstitial diseases.

Right-to-left shunt — A right-to-left shunt exists when blood passes from the right to the left side of the heart without being oxygenated. There are two types of right-to-left shunts:

• Anatomic shunts exist when the alveoli are bypassed. Examples include intracardiac shunts, pulmonary arteriovenous malformations (AVMs), and hepatopulmonary syndrome.
• Physiologic shunts exist when non-ventilated alveoli are perfused. Examples include atelectasis and diseases with alveolar filling (eg, pneumonia, acute respiratory distress syndrome).

Right-to-left shunts cause extreme V/Q mismatch, with a V/Q ratio of zero in some lung regions. The net effect is hypoxemia, which is difficult to correct with supplemental oxygen.

The degree of shunt can be quantified from the shunt equation:

Qs/Qt = (CcO2 - CaO2) ÷ (CcO2 - CvO2)

where Qs/Qt is the shunt fraction, CcO2 is the end-capillary oxygen content, CaO2 is the arterial oxygen content, and CvO2 is the mixed venous oxygen content. CaO2 and CvO2 are calculated from arterial and mixed venous blood gas measurements, respectively. CcO2 is estimated from the PAO2.

Diffusion limitation — Diffusion limitation exists when the movement of oxygen from the alveolus to the pulmonary capillary is impaired. It is usually a consequence of alveolar and/or interstitial inflammation and fibrosis, such as that due to interstitial lung disease. In such diseases, diffusion limitation usually coexists with V/Q mismatch, which makes the relative contribution of each to the patient's hypoxemia uncertain.

Diffusion limitation is characterized exercise-induced or -exacerbated hypoxemia. This is illustrated by the following:

• During rest, blood traverses the lung relatively slowly. Thus, there is usually sufficient time for oxygenation to occur even if diffusion limitation exists.
• During exercise, cardiac output increases and blood traverses the lung more quickly. As a result, there is less time for oxygenation.

• - In the healthy individuals, several compensatory mechanisms occur. Pulmonary capillaries dilate, which increases the surface area available for gas exchange by perfusing additional regions of lung. PAO2 also increases, which promotes oxygen diffusion by increasing the oxygen gradient from the alveolus to the artery. The net effect is that full oxygenation is sustained.
• - In patients with diffusion limitation, there is insufficient time for oxygenation to occur. In addition, most such patients have parenchymal destruction, which renders it impossible to recruit additional surface area for gas exchange. The net effect is measurable hypoxemia.

Reduced inspired oxygen tension — The inspired oxygen tension (PiO2) is a component of the alveolar gas equation that was described above. It can be determined by the equation:

PiO2 = FiO2 x (Patm - PH2O)

where FiO2 is the fraction of inspired oxygen (0.21 at room air), Patm is the atmospheric pressure (760 mmHg at sea level), and PH2O is the partial pressure of water (47 mmHg at 37 degrees C).

Reduction of the PiO2 will decrease the PAO2. This impairs oxygen diffusion by decreasing the oxygen gradient from the alveolus to the artery. The net effect is hypoxemia. A reduced PiO2 is most commonly associated with high altitude.