Respiratory physiology

The main function of the respiratory system is gas exchange (O₂ and CO₂). Ventilation is the movement of air through the respiratory tract into (inspiration) and out of (expiration) the respiratory zone (lungs). The physiologic dead space is the volume of inspired air that does not participate in gas exchange. Perfusion of the pulmonary capillaries is closely regulated to match ventilation in order to maximize gas exchange. The ventilation-perfusion ratio is higher in the apex of the lung than at its base. The Euler-Liljestrand mechanism regulates the perfusion of nonventilated alveoli: if a lung section is perfused but not ventilated, there will be a drop in the oxygen concentration in the blood, resulting in hypoxic vasoconstriction. Diseases that affect the perfusion (e.g., pulmonary embolism) or ventilation (e.g., foreign body aspiration) can cause a V/Q mismatch. Gas exchange occurs via simple diffusion across the blood-air barrier. The gases diffuse across the barrier following pressure gradients. In the capillaries, oxygen binds to hemoglobin in erythrocytes or dissolves into the plasma (oxygenation). CO₂ diffuses into the alveoli and is exhaled. Central regulation of respiration is provided by the respiratory center located in the reticular formation of the medulla oblongata and pons. Inspiration is an active process driven by the respiratory musculature while expiration is passive at rest, driven by the elastic properties of lung tissue.

Ventilation

• Definition: movement of air through the respiratory tract into (inspiration) and out of (expiration) the respiratory zone (lungs) to facilitate gas exchange (O₂ and CO₂)
• Process
  • Inspiration of air into the conducting zone of the respiratory tree (anatomic dead space): nose → pharynx → larynx → trachea → bronchi → bronchioles → terminal bronchioles
    • Inspiratory muscles (mainly external intercostal muscles and the diaphragm) elevate the ribs and sternum and increase the intrathoracic volume.
    • Intrathoracic pressure becomes even more negative to fill the lungs with air.
  • Air reaches the respiratory zone of the respiratory tree (site of gas exchange): respiratory bronchioles → alveolar ducts → alveoli
  • Expiration of air out of the lungs
    • Expiration is primarily a passive process (i.e. passive elastic recoil of the lungs) but expiratory muscles (e.g., intercostal muscles, subcostal muscles) can assist.
    • Intrathoracic pressure becomes positive to expel the air (passive elastic recoil of the lungs).
  • See “Chest wall dynamics” for details.

Parameters of ventilation

• Respiratory rate (RR): number of breaths per minute
• Tidal volume (V_T): the volume of air that is inspired or expired in a single breath
• Minute ventilation (V_E)
  • Volume of air that a person breathes per minute
  • V_E = V_T x RR
• Physiologic dead space (V_D): volume of inspired air that does not participate in gas exchange
  • V_D is the sum of the anatomic dead space and the alveolar dead space.
    • Anatomic dead space: the volume of air in the conducting zone, e.g., mouth, trachea (approx. ⅓ of the resting tidal volume)
    • Alveolar dead space: the sum of the volumes of alveoli that do not participate in gas exchange (mainly apex of the lungs); These alveoli are ventilated but not perfused.
  • Bohr equation determines the physiologic dead space: V_D = V_T x (PaCO₂ - PeCO₂)/(PaCO₂)
  • In a healthy lung, V_D equals the anatomic dead space (normal value: approx. 150 mL/breath).
• Alveolar ventilation (V_A)
  • Volume of gas that reaches the alveoli each minute
  • V_A = (V_T - V_D) x RR

V_D is greater than anatomic dead space in diseases with a V/Q mismatch (e.g., pulmonary embolism).

Normal and pathologic ventilation

If alveolar ventilation increases (i.e., hyperventilation), more CO₂ is exhaled and the PaCO₂ decreases. If alveolar ventilation decreases (i.e. hypoventilation), PaCO₂ increases.

Lung volumes

Lung volumes depend on age, height, and sex. The values that are listed below are for a healthy young adult.

Residual volume cannot be measured by spirometry. Use full-body plethysmography or a gas dilution test.

References:^[1]

Definitions

• Mean pulmonary arterial pressure (mPAP): normal 10–14 mmHg
• Pulmonary capillary pressure: ∼ 8 mmHg
• Pulmonary vascular resistance (PVR): the resistance offered by the pulmonary circulatory system that must be overcome to create blood flow
  • PVR = P_{pulm artery} - P_{L atrium}/Q
    • P_{pulm artery} = pulmonary artery pressure
    • P_{L atrium} = left atrial pressure (pulmonary capillary wedge pressure)
    • Q = cardiac ouptut
  • ΔP = Q × R; therefore: R = ΔP/Q
  • R = 8ηl/πr⁴
    • R = resistance
    • η = blood viscosity
    • l = vessel length
    • r = vessel radius

Pulmonary blood flow

• Pulmonary circulation
  • In healthy individuals the resistance is low and the compliance is high.
  • Blood flow is equivalent to cardiac output (∼ 5 L/min).
• Distribution of blood flow: depends on the position of the body and is precisely regulated in relation to the ventilation to optimize gas exchange
  • Standing and sitting position: due to gravity, circulation is highest in the lung base
  • Supine position: nearly equal distribution of the blood throughout the lung

Regulation of pulmonary blood flow

• The pulmonary circulation can be regulated to match the ventilation of the alveoli in order to optimize gas exchange.
• Ventilation-perfusion ratio (V/Q ratio): the volumetric ratio of air that reaches the alveoli (ventilation) to alveolar blood supply (perfusion) per minute
  • Ideal V/Q ratio = 1
  • Average V/Q ratio = 0.8
    • At the apex = 3 (V > Q)
    • At the base = 0.6 (Q > V)
  • In an upright position, the lung bases are better ventilated and perfused than the apices .
• If a lung section is perfused but not ventilated, there is a drop in the oxygen concentration in the blood → hypoxic vasoconstriction (Euler-Liljestrand mechanism) → blood shift from poorly ventilated to better ventilated areas
  • In order to keep the ventilation-perfusion ratio constant, the vessels of the lungs react to hypoxia with vasoconstriction.
  • In contrast, hypoxia in other organs causes vasodilation to increase perfusion.

The apical lung segments have higher O₂ partial pressures because the perfusion in these lung segments is lower than the ventilation and thus less O₂ diffuses from the alveoli into the bloodstream. Some microorganisms (e.g, M. tuberculosis) favor apical lung segments due to the higher O₂ content.

During exercise, the increased cardiac output from the right ventricle increases pulmonary circulatory pressure, which then opens apical blood vessels that were initially collapsed. This allows for perfusion in that region, thereby reducing dead space (V/Q ratio ≈ 1).

Ventilation-perfusion mismatch (V/Q mismatch)

• Description
  • An imbalance between total lung ventilation (airflow; V) and total lung perfusion (blood flow; Q)
  • Characterized by an increased A-a gradient
  • Occurs when either ventilation or perfusion or both change in a way that the two parameters no longer match
  • Most common cause of hypoxemia
• Increased V/Q ratio (dead space): ventilation of poorly perfused alveoli (if Q = 0 → V/Q ratio = ∞)
  • Causes include:
    • Blood flow obstruction (e.g., pulmonary embolism, cardiovascular shock)
    • Exercise (cardiac output increases, leading to vasodilation of apical capillaries)
  • PaO₂ can be improved by 100% O₂.
• Decreased V/Q ratio (shunt): perfusion of poorly ventilated alveoli (if V = 0 → V/Q ratio = 0)
  • Causes include:
    • Airway obstruction (e.g., foreign body aspiration)
    • Pneumonia, atelectasis, cystic fibrosis, pulmonary edema
  • PaO₂ cannot be improved by 100% O₂.

Administering 100% O₂ improves PaO₂ in patients with increased V/Q ratio due to pulmonary embolism (i.e. increased physiological dead space due to blood flow obstruction). It does not improve PaO₂ in patients with airway obstruction, e.g., due to foreign body aspiration.

References:^[1]

The main function of the lung is gas exchange (O₂ and CO₂), which occurs via simple diffusion across the blood-air barrier. The gases diffuse across the barrier following pressure gradients, meaning no energy is required for this process. In the capillaries, oxygen binds to hemoglobin in erythrocytes or dissolves into the plasma (oxygenation). CO₂ diffuses into the alveoli and is exhaled.

Diffusion (gas exchange)

• Diffusion: V_gas = A x D_k x (P1 – P2)/Δ_x
  • A = surface area of blood-air barrier
  • Dk = diffusion coefficient of the gas
  • P1–P2 = partial pressure gradient
  • Δx = alveolar wall thickness
• Factors that affect diffusion
  • Air composition
  • Solubility of gases (e.g., CO₂ > O₂ > N₂)
  • Partial pressure gradient: difference in partial pressures of gases between blood and inhaled air
    • Partial pressure: the pressure of a single gas in a mixture of gases
    • Gas moves from an area where its partial pressure is higher to an area where its partial pressure is lower.
    • The partial pressure gradient determines the rate of diffusion.
  • Alveolar-capillary membrane surface area
    • Normal: ∼ 100 m²
    • Decreased in emphysema
  • Thickness of alveolar-capillary membrane
    • Normal: 0.6 μm
    • Increased in pulmonary fibrosis; hypoxia usually occurs before hypercapnia
• Diffusion capacity
  • May be used to assess gas exchange across the blood-air barrier (e.g., in intraparenchymal lung diseases)
  • See “Diffusion capacity” for details.
• Diffusion capacity of the lung for carbon monoxide: measures the amount of CO transferred from the lungs to the blood

Decreased diffusion capacity can occur when the surface area of the blood-air barrier is reduced (e.g., emphysema), the diffusion distance is increased (e.g., interstitial lung disease, pulmonary fibrosis, pulmonary edema), or the capacity to transport gases in blood is reduced (e.g., anemia).

Partial pressures

Inspired air contains more O₂, less CO₂, and less water vapor than expired air.

Alveolar-arterial gradient (A-a gradient)

• Definition: the difference between the partial pressure of oxygen in the alveoli (A) and the arterial (a) partial pressure of oxygen (normal: 75–100 mm Hg)
• Formulas
  • A-a gradient = PAO₂ - PaO₂
    • PaO₂ is measured by arterial blood gas, while PAO₂ is calculated using the alveolar gas equation.
    • Estimated as age/4 + 4 (e.g., for an individual < 60 years of age, the gradient should be < 19)
  • Alveolar gas equation: PAO₂ = PiO₂ - (PaCO₂/R)
    • PiO₂ = partial pressure of O₂ in inspired air (∼ 150 mm Hg at sea level)
    • PAO₂ = alveolar Po₂
    • PaCO₂ = arterial Pco₂
    • R = respiratory quotient (CO₂ produced/O₂ consumed), typically 0.8
• Use
  • A measure of oxygenation (assesses the functionality of the blood-air barrier)
  • Can help determine causes of hypoxemia as intrapulmonary or extrapulmonary (e.g., pulmonary embolism vs. congestive heart failure)
• Normal ranges
  • 5–10 mm Hg for a young person breathing room air at sea level
  • 15–20 mm Hg in healthy older adult
• Causes of increased A-a gradient
  • Age
  • Higher concentration of inhaled oxygen (e.g., goes up to 50–60 mm Hg with 100% O₂ in a few minutes)
  • Right-to-left shunting
  • Fluid in alveoli: e.g., CHF, ARDS, pneumonia
  • V/Q mismatch (due to increased dead space or shunting): e.g., pulmonary embolism, pneumothorax, atelectasis, obstructive lung disease, pneumonia, pulmonary edema
  • Alveolar hypoventilation: interstitial lung disease, lung fibrosis (usually manifests with ↑ CO₂)

An increased A-a gradient may occur in hypoxemia due to shunting, ventilation-perfusion mismatch, or impaired gas diffusion across the alveoli due to fibrosis or edema. The A-a gradient remains normal with hypoventilation due to CNS and neuromuscular disorders (no diffusion defect) and in high altitude (despite a lower fraction of inhaled O₂).

Types of gas exchange

• Perfusion-limited gas exchange: Gas exchange is limited by the rate of blood flow through the pulmonary capillaries.
  • Gases (e.g., O₂, CO₂, N₂O) can diffuse freely across the blood-air barrier.
  • The concentration of gases in the plasma will become equal to the concentration in the alveoli before the blood reaches the end of the capillary.
  • An increase in blood flow causes an increase in gas exchange .
  • Occurrence: under normal conditions (i.e., at rest)
• Diffusion-limited gas exchange: Gas exchange is limited by the diffusion rate of the gas (e.g., O₂, CO) across the blood-air barrier.
  • The gas concentration in the plasma will not be in equilibrium at the end of the capillary.
  • Occurrence
    • Strenuous exercise
    • In certain pathological conditions that affect the blood-air barrier (e.g., emphysema, lung fibrosis)

At rest, gas exchange is perfusion-limited, meaning it is limited by the rate of blood flow through the pulmonary capillaries; during strenuous exercise and in certain pathological conditions that affect the blood-air barrier (e.g., emphysema), gas exchange is limited by the diffusion rate of the gas across the blood-air barrier.

References:^[1]

Lung compliance

• Definition: the ability of the lungs to distend under pressure
• Measurement: change in volume of the lung per unit change in pressure (C = ΔV/ΔP)
• Increased in: emphysema (lungs fill easier), aging
• Decreased in: conditions associated with increased lung stiffness (e.g., pulmonary fibrosis, pulmonary edema, pneumoconioses, ARDS)

Surfactant reduces the surface tension in the alveoli and thus increases the compliance of the lungs.

In old age, lung compliance increases due to loss of elastic recoil, while chest wall compliance decreases because the chest wall stiffens.

Chest wall dynamics

• Resting expiratory position (functional residual capacity)
  • Thorax pulls outward and lungs pull inward (due to the passive elastic recoil of the lungs).
  • Alveolar and airway pressure = atmospheric pressure (state zero)
    • Atmospheric pressure (zero state) = point of functional residual capacity
    • When FRC is at zero, the pulmonary vascular resistance is also at its lowest.
  • Intrapleural pressure is negative (to keep the lungs expanded and prevent atelectasis).
• Inspiration
  • Intrathoracic pressure becomes even more negative to fill the lungs with air.
  • Inspiratory muscles: mainly external intercostal muscles and the diaphragm (elevate ribs and sternum)
• Expiration
  • Intrathoracic pressure becomes positive to expel the air (passive elastic recoil of the lungs).
  • Expiratory muscles: mainly internal intercostal muscles, innermost intercostal muscles, and subcostal muscles

References:^[1][3]

• Definition: opposition to airflow through the upper and lower airways caused by the forces of friction during inspiration and expiration (normal: 2–3 cm H₂O/L/s) ^[4]
• Depends on:
  • Diameter of the airways: The smaller the diameter, the greater the resistance.
  • Velocity of airflow (laminar flow < turbulent flow)
  • Viscosity of the gas breathed
    • Viscosity creates friction.
    • The higher the viscosity, the higher the resistance.
  • Number of parallel pathways
    • Resistance reduces at each generation of branching.
    • Resistance in large and medium-sized airways is greater than in small airways.
• Increased in: forced expiration, obstructive lung diseases (e.g., asthma, COPD)
• Decreased in: exercise

Airway resistance is lowest in the small airways due to a large number of parallel bronchioles, while the highest airway resistance is in the larger airways (trachea, bronchi).

• Definition: the energy used to overcome elastic recoil and airway resistance by the respiratory muscles for respiration (expressed in J/L) ^[5]
  • Elastic recoil
    • Increases with ↑ inspiratory volume
    • Influenced by, e.g., pulmonary airway elasticity and surface tension of alveoli
  • Airway resistance
    • Increases with ↑ lung compression (e.g., due to ↑ intraabdominal pressure, pleural disease, mediastinal mass), ↑ flow rate (e.g., due to ↑ respiratory rate), and ↓ airway diameter (e.g., due to bronchospasm)
    • Influenced by, e.g., tissue resistance (e.g., chest wall/lung resistance) and airway resistance
• Formula ^[5]
  • In physics, work (W) is defined as the product of force (F) and distance (d) and is measured in joules: W = F × d
  • In respiratory physiology, W is more specifically defined as the product of pressure (P) and volume (V): W = P × V
• Normal value: ∼ 0.35 J/L (in a healthy person at rest) ^[6]
• Regulation ^[5]
  • Optimization of respiratory rate (RR)
    • ↑ RR → ↓ elastic WOB
    • ↓ RR → ↓ resistive WOB
  • Optimization of tidal volume (VT)
    • ↑ VT → ↓ resistive WOB
    • ↓ VT → ↑ resistive WOB
• Changes in WOB due to respiratory condition ^[5]
  • Restrictive diseases: ↑ RR and ↓ VT (to overcome elastic recoil)
  • Obstructive diseases: ↓ RR and ↑ VT (to overcome airway resistance)

Respiratory center

Regulation of respiration takes place centrally in the respiratory center located in the reticular formation of the medulla oblongata and pons.

Medullary center

• Function: creates rhythmic innervation of the respiratory muscles and is influenced by various respiratory stimuli
• Dorsal respiratory group
  • Responsible for inspiration
  • Input: peripheral chemoreceptors and mechanoreceptors (via the vagus and glossopharyngeal nerve)
  • Output: phrenic nerve
• Ventral respiratory group
  • Responsible for expiration
  • Expiration is usually passive, only becoming active during physical exercise.

Pontine center ^[7]

• Function: modifies the activity of the medullary center
• Apneustic center
  • Controls the intensity of breathing
  • Promotes deep gasping inspiration (apneusis) by stimulation of the dorsal respiratory group and inhibition of the pneumotaxic center
• Pneumotaxic center
  • Controls the respiratory rate and pattern of breathing
  • Limits or delays inspiration

Regulation

• Respiratory stimuli
  • ↑ pCO₂: strongest respiratory drive under normal conditions
  • ↓ pO₂
    • Strongest respiratory drive in chronic hypercapnia (e.g., in COPD)
    • The respiratory center develops a tolerance for increased pCO_2..
  • ↓ pH
  • Nonspecific stimuli: fever, pain, norepinephrine
• Receptors
  • Central chemoreceptors in the medulla oblongata: detect ↑ pCO₂ and ↓ pH
  • Peripheral chemoreceptors in aorta and carotids (carotid body) via CN IX and CN X: detect ↓ pO₂ (< 60 mmHg), ↑ pCO₂, and ↓ pH
  • Mechanoreceptors in the airways and respiratory muscles
• Responses
  • Hering-Breuer inflation reflex
    • Inhibits inspiration to prevent overinflation of the lungs and alveolar damage
    • Mediated by pulmonary stretch receptors and vagal afferents
  • Diving reflex: immersion of the head triggers peripheral vasoconstriction, redirection of blood to the heart and brain, and slowed pulse rate, which optimizes respiration
  • Spinal cord responses: recruitment of additional respiratory muscles (e.g., to compensate hypoventilation) via stimulation of motor neurons by the respiratory center
  • Upper airway responses (e.g., coughing, sneezing)

A chronically elevated pCO₂ ≥ 70 mmHg (e.g., in COPD) inhibits the respiratory center instead of stimulating it.

Hyperventilation can reduce the PaCO₂ and thus the respiratory drive; this technique is used, for example, by divers before a dive.

Oxygen deprivation

Pathological breathing patterns

References:^[1][3]

Respiratory adaptation to exercise

• ↑ O₂ consumption and ↑ CO₂ production lead to ↑ depth and rate of ventilation (hyperventilation).
  • ↑ Venous CO₂ and ↓ venous O₂
  • PaCO₂ and PaO₂ remain normal despite hyperventilation.
• ↑ HR and ↑ SV → ↑ cardiac output → ↑ pulmonary blood flow
• ↓ Arterial pH (due to lactic acidosis)
• Rightward shift of the oxygen dissociation curve
• Oxygen diffusion becomes diffusion-limited (in resting state it is perfusion-limited).
• ↑ V/Q ratio (from base to apex) → V/Q ratio is more evenly distributed throughout the lung during exercise than at rest

Respiratory adaptation to high altitude

Decreased atmospheric oxygen (PiO₂) at high altitudes triggers various adaptation mechanisms; in the respiratory system. Insufficient adaptation to the high altitude results in altitude sickness.

• ↓ PaO₂ → ↑ ventilation rate (stimulated by hypoxemia) → ↓ PaCO₂ and ↑ arterial pH (respiratory alkalosis)
• ↑ Renal HCO₃^- excretion (to compensate for respiratory alkalosis)
• ↑ Pulmonary vascular resistance (Euler-Liljestrand reflex): chronic hypoxia → pulmonary vasoconstriction → pulmonary hypertension → right ventricular hypertrophy
• ↑ Hb and hematocrit (due to chronic hypoxia triggering ↑ erythropoietin levels)
• ↑ 2,3-BPG concentration → ↓ Hb affinity to O₂ → rightward shift of the oxygen dissociation curve
• ↑ Number of mitochondria in cells

Respiratory adaptation in the elderly population

• ↓ Chest wall compliance
• ↑ Lung compliance
• ↓ PaO₂ and ↑ A-a gradient
• ↑ V/Q mismatch
• ↓ FVC
• ↑ Susceptibility to aspiration and infections
• See “Aging changes in the respiratory system” for details.

References:^[3]