Physiology: Respiratory Physiology

Respiratory physiology explains how the lungs move air, how gases cross from alveoli to blood, and how the body maintains stable levels of oxygen and carbon dioxide. Its clinical importance is immediate: shortness of breath, hypoxemia, and acid base disorders are all expressions of the same core system, stretching from the mechanics of ventilation to blood gas regulation.

The goals of the respiratory system

At a practical level, the respiratory system must accomplish three things:

1. Provide adequate alveolar ventilation to bring oxygen in and remove carbon dioxide.
2. Enable efficient gas exchange across the alveolar capillary membrane.
3. Coordinate pulmonary blood flow with ventilation so that ventilation perfusion (V/Q) matching is maintained.

Because carbon dioxide is tied directly to blood acidity through the bicarbonate buffer system, respiration also plays a central role in acid base balance.

Ventilation: moving air into and out of the lungs

Mechanics and pressures

Airflow occurs because of pressure gradients. During inspiration, contraction of the diaphragm and external intercostals expands the thoracic cavity, lowering intrapleural pressure and thereby lowering alveolar pressure below atmospheric pressure. Air flows inward until pressures equalize. Expiration at rest is largely passive, driven by elastic recoil.

Two mechanical properties shape the effort required to breathe:

• Compliance: how easily the lungs expand. High compliance means the lungs inflate easily but may recoil poorly; low compliance means stiff lungs and increased work of breathing.
• Airway resistance: primarily determined by airway radius, especially in medium sized bronchi. Resistance increases with bronchoconstriction, mucus, or airway edema.

Clinically, obstructive diseases increase resistance and make expiration difficult. Restrictive diseases reduce compliance and make inspiration energetically costly.

Dead space and alveolar ventilation

Not all inspired air participates in gas exchange. Anatomic dead space includes conducting airways, while physiologic dead space also includes alveoli that are ventilated but poorly perfused.

The key variable for gas exchange is alveolar ventilation: the volume of fresh air reaching alveoli per minute. It can be conceptualized as:

• Minute ventilation minus dead space ventilation.

Shallow rapid breathing can produce a high minute ventilation but low alveolar ventilation because dead space occupies a larger fraction of each breath. This distinction matters in conditions like pulmonary embolism, where physiologic dead space rises and effective ventilation falls.

Gas exchange: diffusion across the alveolar capillary membrane

Diffusion and the alveolar environment

Oxygen and carbon dioxide move down partial pressure gradients across the alveolar epithelium, interstitium, and capillary endothelium. Oxygen moves from alveolus to blood; carbon dioxide moves from blood to alveolus.

Diffusion depends on:

• Surface area available for exchange.
• Thickness of the membrane.
• Diffusivity of the gas and the pressure gradient driving movement.

Emphysema reduces surface area, while interstitial fibrosis increases diffusion distance. Either can impair oxygenation, particularly during exercise when capillary transit time is shorter.

Alveolar oxygen and the alveolar gas equation

Alveolar oxygen tension is determined by inspired oxygen, atmospheric pressure, water vapor, and how much oxygen is removed relative to carbon dioxide added. Clinically, the relationship is often summarized by the alveolar gas equation:

$$P_{A{O}_2}=P_{I{O}_2}-\frac{P_{aC{O}_2}}{R}$$

where $R$ is the respiratory quotient, reflecting metabolic fuel use. This equation anchors interpretation of hypoxemia and the alveolar arterial oxygen gradient, helping distinguish low inspired oxygen or hypoventilation from V/Q mismatch or shunt.

Ventilation perfusion (V/Q) matching: the core of oxygenation

Why matching matters

Even with normal ventilation and a healthy diffusion barrier, gas exchange can fail if airflow and blood flow are not properly aligned. V/Q matching describes how well alveolar ventilation matches pulmonary perfusion at the level of individual lung units.

• Low V/Q: perfusion exceeds ventilation. Alveoli behave more like shunt units, lowering arterial oxygen.
• High V/Q: ventilation exceeds perfusion. This increases physiologic dead space and wastes ventilation.

A true right to left shunt occurs when blood bypasses ventilated alveoli entirely, as in alveolar collapse, severe pneumonia, or certain cardiac defects. Shunt tends to respond poorly to supplemental oxygen compared with V/Q mismatch.

Gravity and regional differences

In an upright person, both ventilation and perfusion increase from lung apex to base, but perfusion increases more steeply due to gravity. As a result:

• The apex tends to have higher V/Q (more ventilation relative to blood flow).
• The base tends to have lower V/Q.

This gradient is physiologic, yet it becomes clinically important when disease selectively affects certain regions or when overall perfusion is compromised.

Hypoxic pulmonary vasoconstriction

Unlike systemic vessels, pulmonary arterioles constrict in response to low alveolar oxygen. This reflex redirects blood away from poorly ventilated regions to better ventilated areas, improving V/Q matching. However, when hypoxia is widespread, such as at high altitude or in diffuse lung disease, the same mechanism can raise pulmonary arterial pressure and strain the right heart.

Oxygen transport: from alveolus to tissue

Hemoglobin binding and oxygen content

Most oxygen is carried bound to hemoglobin; a smaller amount is dissolved in plasma. The clinically relevant quantity is arterial oxygen content, which depends heavily on hemoglobin concentration and saturation, not just partial pressure.

This is why a patient with severe anemia can have a normal $P_{a{O}_2}$ but reduced oxygen delivery, and why carbon monoxide poisoning can produce tissue hypoxia despite deceptively acceptable $P_{a{O}_2}$.

The oxygen hemoglobin dissociation curve

Hemoglobin’s affinity for oxygen is not fixed. The sigmoid shape of the dissociation curve allows near full saturation in the lungs and substantial unloading in tissues.

Factors that shift the curve:

• Right shift: increased CO2, increased H+, increased temperature, increased 2,3 BPG. This promotes oxygen unloading in metabolically active tissues.
• Left shift: the opposite conditions. This increases loading but can impair unloading.

A practical example is fever and lactic acidosis in sepsis, which tend to shift the curve rightward and facilitate tissue oxygen delivery, while hypothermia can shift left and make tissues relatively oxygen starved at a given saturation.

Carbon dioxide transport and ventilation control

Carbon dioxide is carried in three main forms:

• Dissolved CO2.
• Carbamino compounds bound to proteins, including hemoglobin.
• Bicarbonate, formed via carbonic anhydrase within red blood cells.

Because CO2 is highly diffusible, diffusion limitation is rarely the primary problem. Instead, CO2 retention typically reflects inadequate alveolar ventilation, such as from central hypoventilation, neuromuscular weakness, severe airway obstruction, or increased dead space.

Ventilation is regulated by central and peripheral chemoreceptors. Central chemoreceptors respond primarily to changes in CSF pH driven by CO2, making carbon dioxide a dominant driver of minute to minute ventilation. Peripheral chemoreceptors in the carotid and aortic bodies respond to low arterial oxygen, high CO2, and low pH. Clinically, chronic hypercapnia can blunt central responsiveness, increasing reliance on hypoxic drive in some patients with longstanding lung disease.

Acid base physiology: the respiratory component

Respiration controls $P_{aC{O}_2}$, which is linked to pH through the bicarbonate buffer relationship:

$$pH\propto \frac{[HC{O}_3^{-}]}{P_{aC{O}_2}}$$

• Respiratory acidosis results from hypoventilation and CO2 retention.
• Respiratory alkalosis results from hyperventilation and excessive CO2 removal.

Compensation is renal, not pulmonary: the kidneys adjust bicarbonate over hours to days. Understanding this division is essential when interpreting arterial blood gases. A patient with acute opioid induced hypoventilation will show rising $P_{aC{O}_2}$ and falling pH with minimal immediate bicarbonate change, while chronic hypoventilation will show elevated bicarbonate as the kidneys retain base.

Clinical applications: tying physiology to bedside decisions

Respiratory physiology becomes most useful when it guides interpretation of common scenarios:

• Hypoxemia: consider the major mechanisms, including low inspired oxygen, hypoventilation, diffusion limitation, V/Q mismatch, and shunt. V/Q mismatch is common in asthma, COPD, and pulmonary edema; shunt becomes prominent in lobar pneumonia or atelectasis.
• Dyspnea with normal oxygenation: increased work of breathing from high resistance or low compliance can cause severe distress even before gas exchange fails.
• Hypercapnia: think ventilation first. Rising CO2 often signals inadequate alveolar ventilation due to muscle fatigue, suppressed respiratory drive, or increased dead space.
• Response to oxygen therapy: improvement suggests V/Q mismatch or low inspired oxygen; poor response raises concern for shunt or severe alveolar collapse.

Respiratory physiology is not abstract. It is a framework that links lung mechanics, gas exchange, and blood gas regulation to real clinical patterns, allowing symptoms and arterial blood gases to be interpreted as consequences of a few core principles.