What is the physiology of gas exchange in the lungs?

Physiology of Gas Exchange in the Lungs

Gas exchange in the lungs occurs through four integrated processes: pulmonary ventilation (air movement), pulmonary diffusion (O₂ and CO₂ exchange between alveoli and blood), blood transport of gases, and capillary gas exchange at tissues—with the first two processes constituting external respiration that is essential for maintaining life. 1

The Four Core Processes of Gas Exchange

The American Heart Association defines the complete gas exchange system through these sequential steps 1:

• Pulmonary ventilation moves air into and out of the lungs, bringing fresh oxygen to the alveoli while removing carbon dioxide 1
• Pulmonary diffusion facilitates the passive exchange of O₂ and CO₂ between alveolar gas and pulmonary capillary blood based on partial pressure gradients 1, 2
• Blood transport carries oxygen bound to hemoglobin and carbon dioxide in dissolved and buffered forms through the circulation 1
• Capillary gas exchange delivers oxygen to working tissues and removes metabolic CO₂ at the tissue level 1

Alveolar Gas Exchange Mechanics

Gas exchange occurs in the alveoli where oxygen diffuses from inspired air into blood while carbon dioxide moves in the opposite direction, driven entirely by partial pressure gradients. 2, 3

Key Physiological Principles:

• Only the portion of tidal volume reaching the alveoli participates in gas exchange; air remaining in conducting airways constitutes dead space (VD) 1
• Alveolar partial pressures of O₂ and CO₂ are determined by inspiratory gas composition and alveolar ventilation rates 2
• During exercise, respiratory passages dilate, increasing dead space, but tidal volume increases proportionally to maintain adequate alveolar ventilation 1
• Normal oxygen saturation (SaO₂) in healthy adults ranges from 95-98% at sea level, representing near-maximal hemoglobin saturation 1

Ventilation-Perfusion Matching

The efficiency of gas exchange critically depends on matching ventilation (V̇A) to perfusion (Q̇) in each lung unit—mismatching is the most common cause of hypoxemia in clinical practice. 1, 4, 3

Normal V̇A/Q̇ Relationships:

• Proper ventilation-perfusion matching ensures that blood flow increases proportionally with ventilation during exercise 1
• The lung actively diverts blood flow away from poorly ventilated regions to optimize gas exchange 1
• Cardiac output must increase appropriately to match ventilation so necessary gas exchange can occur 1

Pathological V̇A/Q̇ Mismatch:

• Shunt and low V̇A/Q̇ regions worsen arterial oxygenation and are the most frequent causes of hypoxemia 2, 4
• High V̇A/Q̇ regions and alveolar dead space reduce CO₂ elimination efficiency, requiring increased minute ventilation 4, 3
• In pulmonary disease, higher than normal dead space limits exercise because fewer healthy lung tissues are available for gas exchange 1
• Chronic heart failure causes impaired cardiac output response, leading to ventilation-perfusion mismatching where ventilation increases disproportionately to metabolic needs 1

Oxygen Transport and Hemoglobin Saturation

Oxygen is transported primarily bound to hemoglobin (with negligible amounts dissolved in plasma), and the oxygen saturation (SO₂) represents the percentage of hemoglobin's oxygen-carrying capacity being utilized. 1

Clinical Oxygen Thresholds:

• The brain is most sensitive to hypoxia, with impaired mental function occurring below approximately 80% saturation 1
• Most experts recommend keeping SaO₂ above 90% for acutely ill patients, with a desirable target range of 94-98% 1
• Supplemental oxygen provides minimal benefit to healthy individuals (increasing saturation only from ~97% to 99-100%) because hemoglobin is already near-maximally saturated 1
• Carotid body receptors sense falling PaO₂ and stimulate increased ventilation to restore oxygen levels 1

Gas Exchange Efficiency Indices

Alveolar-Arterial Oxygen Gradient (P(a-a)O₂):

• Normal P(a-a)O₂ is less than 10 mmHg at rest but may increase to more than 20 mmHg during exercise in healthy individuals 1
• Values greater than 35 mmHg indicate possible gas exchange abnormality; values exceeding 50 mmHg indicate likely pulmonary pathology 1
• The gradient increases during exercise due to V̇A/Q̇ mismatching, O₂ diffusion limitation, and low mixed venous oxygen 1

Physiologic Dead Space-to-Tidal Volume Ratio (VD/VT):

• VD/VT represents the fraction of each breath "wasted" on ventilating anatomic dead space and unperfused alveoli 1
• Increased VD/VT reflects ventilation-perfusion mismatching or shunt, requiring increased minute ventilation to maintain normal PaCO₂ 1
• This measurement is highly dependent on breathing pattern—rapid shallow breathing increases VD/VT even without V̇A/Q̇ abnormalities 1

Six Mechanisms of Hypoxemia

Understanding the specific cause of hypoxemia is essential because therapeutic interventions must target the underlying physiological mechanism. 3

The six distinct causes are 3:

1. Inspiratory hypoxia (low inspired O₂)
2. Hypoventilation (inadequate alveolar ventilation)
3. Ventilation-perfusion inequality (most common in lung disease)
4. Diffusion limitation (impaired gas transfer across alveolar-capillary membrane)
5. Shunting (blood bypassing ventilated alveoli—responds poorly to supplemental oxygen)
6. Reduced mixed venous oxygenation (increased tissue O₂ extraction)

Critical Clinical Distinction:

• Hypoxemia from shunt responds poorly to supplemental oxygen, unlike other causes 4, 3
• This distinction is crucial for determining appropriate oxygen therapy strategies 4

Compensatory Mechanisms

The body employs three primary tactics to compensate for gas exchange disturbances: greater O₂ extraction from blood, increased ventilation, and increased cardiac output. 3

• During exercise, cardiac output may increase up to 6 times resting levels, with redistribution away from splanchnic/renal circulation to skeletal muscles 1
• Pulmonary blood flow increases through both elevated cardiac output and pulmonary vasodilation 1
• Greater O₂ extraction at tissues results in widening of the arteriovenous oxygen difference 1
• The degree to which ventilation is abnormally heightened during exercise directly relates to disease severity and is a strong prognostic marker 1

Common Clinical Pitfalls

• Do not use end-tidal PCO₂ (PetCO₂) as a substitute for arterial PCO₂ (PaCO₂) in patients with lung disease—PetCO₂ can actually exceed PaCO₂ during exercise in normal individuals 1
• In critically ill patients with shock or hypotension, arterio-venous differences may be greater than normal, making venous blood gas less reliable 5
• For patients requiring precise oxygenation assessment or those with respiratory failure, arterial samples are preferred over venous samples 5
• Proper blood gas sample handling is crucial—air bubbles, delayed analysis, or improper storage significantly affect results 5