Respiratory Physiology

Every minute of your life, without a single conscious command, roughly six litres of air move in and out of your lungs, and about 250 mL of oxygen crosses from air into blood while 200 mL of carbon dioxide travels the other way. Respiratory physiology is the study of how this exchange is engineered — how muscles generate the pressures that pull air in, how the delicate alveolar membrane lets gases diffuse, how blood carries far more oxygen than it could ever dissolve, and how the brainstem tunes the whole system breath by breath. Understanding it is the difference between memorising blood-gas numbers and actually knowing why a patient with pneumonia is hypoxic, why an asthmatic wheezes on the way out, and why a heroin overdose stops the breathing before it stops the heart.

This page walks through the four pillars — ventilation, gas exchange, gas transport, and control of breathing — with the clinical reasoning that makes them stick.

Learning Objectives

• Explain the mechanics of ventilation: pressures, compliance, resistance, and the work of breathing.
• Distinguish anatomic dead space, alveolar ventilation, and minute ventilation, and calculate them.
• Describe alveolar gas exchange using the concepts of diffusion, ventilation–perfusion (V/Q) matching, and the alveolar gas equation.
• Explain how oxygen and carbon dioxide are transported in blood, including the oxygen–haemoglobin dissociation curve and its shifts.
• Outline the neural and chemical control of breathing and how central and peripheral chemoreceptors respond.
• Apply these principles to interpret hypoxia, hypercapnia, and common respiratory diseases.

Quick Answer

Breathing has two phases driven by pressure gradients: the diaphragm and external intercostals contract to enlarge the thorax, dropping alveolar pressure below atmospheric so air flows in; relaxation and elastic recoil push it out. Fresh air reaching the alveoli (alveolar ventilation) meets pulmonary capillary blood across a membrane less than one micrometre thick, where oxygen and carbon dioxide diffuse down partial-pressure gradients. Efficient exchange requires matching ventilation to perfusion (V/Q). Oxygen is carried mostly bound to haemoglobin (about 98.5%), described by the sigmoid oxygen dissociation curve; carbon dioxide travels mainly as bicarbonate. Breathing is controlled by respiratory centres in the medulla and pons, driven chiefly by central chemoreceptors sensing CO₂ (via pH of cerebrospinal fluid) and, in emergencies, by peripheral chemoreceptors sensing low oxygen. Failure of any step produces hypoxaemia or hypercapnia.

Where It Came From

For most of history, air was thought to be a single elemental substance, and breathing was believed to cool the "innate heat" of the heart — an idea traceable to Galen. The real problem was that no one knew what in air sustained life or why breathing was essential; a candle and a mouse both died in a sealed jar, but the cause was mysterious.

The breakthrough came in the 1770s. Joseph Priestley isolated a gas in 1774 that made a flame burn more brightly and kept a mouse alive longer; he called it "dephlogisticated air," interpreting it through the flawed phlogiston theory. Carl Wilhelm Scheele independently discovered the same gas. It fell to Antoine Lavoisier to grasp the meaning. Through meticulous quantitative experiments in the late 1770s and 1780s, Lavoisier showed that combustion and respiration were the same chemical process — the consumption of this gas, which he named oxygène ("acid-former"), combined with a fuel to release heat and produce "fixed air" (carbon dioxide) and water. He and Pierre-Simon Laplace measured the heat and CO₂ produced by a guinea pig and showed respiration was a slow combustion occurring within the living body. This overturned centuries of dogma: breathing was not cooling but a controlled burning that powers life.

The physiological details followed over two centuries: John Dalton's law of partial pressures, Christian Bohr and the dissociation curve and the Bohr effect (early 1900s), Haldane's work on CO₂ carriage and the chemical control of breathing, and August and Marie Krogh on capillary diffusion. But it began with Lavoisier answering the ancient question: why must we breathe?

Ventilation: The Mechanics of Moving Air

Air moves because of pressure differences, and the body generates those differences by changing the volume of the thorax.

Inspiration is active. The diaphragm contracts and descends; the external intercostals lift and expand the rib cage. Thoracic volume increases, so intrapleural pressure becomes more negative (from about −5 cm H₂O to −8 cm H₂O), the lungs expand, alveolar pressure drops about 1 cm H₂O below atmospheric, and air flows in. Expiration at rest is passive — the muscles relax and the elastic recoil of the stretched lungs and chest wall does the work. Forced expiration (coughing, exercise) recruits the internal intercostals and abdominal muscles.

Two mechanical properties govern how hard this is:

• Compliance (ΔVolume / ΔPressure): how stretchy the lung is. Fibrosis stiffens the lung (low compliance, hard to inflate); emphysema destroys elastic tissue (high compliance, easy to inflate but hard to empty).
• Airway resistance: dominated by medium bronchi. Bronchoconstriction (asthma) raises resistance, especially on expiration when airways narrow.

Surfactant, produced by type II pneumocytes, is essential. By lowering alveolar surface tension it reduces the pressure needed to keep small alveoli open (Laplace's law: pressure ∝ tension / radius) and prevents small alveoli from collapsing into large ones. Its absence in premature infants causes neonatal respiratory distress syndrome.

Dead Space and Alveolar Ventilation

Not all inhaled air reaches the alveoli. The conducting airways — trachea to terminal bronchioles — hold about 150 mL of anatomic dead space where no exchange occurs. This matters enormously:

Worked example. A person breathes a tidal volume of 500 mL, 12 times per minute.

• Minute ventilation = 500 × 12 = 6,000 mL/min.
• Alveolar ventilation = (500 − 150) × 12 = 4,200 mL/min.

Now compare rapid shallow breathing: tidal volume 250 mL at 24 breaths/min.

• Minute ventilation = 250 × 24 = 6,000 mL/min — identical!
• Alveolar ventilation = (250 − 150) × 24 = 2,400 mL/min — far worse.

The lesson: because dead space is subtracted from every breath, deep slow breathing is far more efficient than fast shallow breathing at the same minute ventilation. This is why a panicking, shallow-breathing patient can be hypercapnic despite a high respiratory rate.

Gas Exchange: Across the Alveolar Membrane

At the alveolus, oxygen must cross alveolar epithelium, a fused basement membrane, and capillary endothelium — a barrier under 1 micrometre thick spread over roughly 70 m² of surface. Diffusion follows Fick's law: rate is proportional to surface area and the partial-pressure gradient, and inversely proportional to thickness. CO₂ diffuses about 20 times faster than O₂ because it is far more soluble, which is why gas-exchange problems typically cause hypoxaemia before hypercapnia.

Typical partial pressures (mmHg):

Site	PO₂	PCO₂
Inspired (humidified) air	150	0
Alveolar gas	100	40
Deoxygenated blood entering lung	40	46
Arterial blood leaving lung	95–100	40

The alveolar gas equation estimates alveolar PO₂: PAO₂ = PIO₂ − (PaCO₂ / R), roughly 150 − (40 / 0.8) ≈ 100 mmHg at sea level. The difference between this and measured arterial PO₂ (the A–a gradient, normally under about 15 mmHg) is a key diagnostic: a normal gradient with hypoxia points to hypoventilation or altitude; a widened gradient points to a problem in the lung itself.

Ventilation–Perfusion (V/Q) Matching

Gas exchange is only as good as the pairing of air and blood. The ideal V/Q ratio is about 0.8 overall.

• High V/Q (dead space effect): ventilation without perfusion, e.g. pulmonary embolism — air reaches alveoli but no blood arrives to take up oxygen.
• Low V/Q (shunt effect): perfusion without ventilation, e.g. pneumonia or pulmonary oedema filling alveoli — blood passes but is not oxygenated.

A pure shunt is the classic reason hypoxaemia fails to correct fully with 100% oxygen — the shunted blood never contacts oxygen at all. The lung defends itself with hypoxic pulmonary vasoconstriction: poorly ventilated regions constrict their vessels to divert blood to better-ventilated areas — the opposite of the systemic circulation's response to low oxygen.

Oxygen and Carbon Dioxide Transport

Carrying Oxygen

Oxygen barely dissolves in plasma (only about 0.3 mL per 100 mL). Life depends on haemoglobin, which carries about 20 mL per 100 mL — roughly 98.5% of the total. Each gram of haemoglobin binds up to 1.34 mL O₂ when fully saturated.

The oxygen–haemoglobin dissociation curve relating saturation to PO₂ is sigmoid, and its shape is functionally brilliant:

• The flat upper plateau (PO₂ above ~60 mmHg) means saturation stays high even if arterial PO₂ falls somewhat — a safety margin at altitude or with mild lung disease.
• The steep middle portion means that in tissues, where PO₂ is 20–40 mmHg, small pressure drops unload large amounts of oxygen.

The curve shifts right (haemoglobin releases oxygen more readily) with increased CO₂, increased H⁺ (lower pH), increased temperature, and increased 2,3-BPG — exactly the conditions of hard-working tissue. This is the Bohr effect: metabolically active tissue automatically gets more oxygen delivered. A left shift (alkalosis, hypothermia, stored blood, fetal haemoglobin) holds oxygen more tightly.

Carrying Carbon Dioxide

CO₂ is transported three ways:

1. As bicarbonate (~70%) — CO₂ enters red cells, carbonic anhydrase converts it to H⁺ and HCO₃⁻; bicarbonate exits in exchange for chloride (the chloride shift).
2. Bound to haemoglobin as carbamino compounds (~23%).
3. Dissolved in plasma (~7%).

The Haldane effect completes the elegant coupling: deoxygenated haemoglobin binds CO₂ and H⁺ more readily, so in the tissues (where oxygen leaves) CO₂ loading is enhanced, and in the lungs (where oxygen binds) CO₂ is released. This system also makes the lungs a major regulator of blood pH.

Control of Breathing

Breathing is unusual: automatic yet overridable. The rhythm is generated in the medulla oblongata (the dorsal and ventral respiratory groups, including the pre-Bötzinger complex pacemaker), fine-tuned by the pons (pneumotaxic and apneustic centres). The cortex can seize temporary control (speaking, breath-holding), but chemical drives eventually win.

Central chemoreceptors in the medulla are the dominant minute-to-minute driver. They do not sense CO₂ directly — they sense the H⁺ produced when CO₂ crosses the blood–brain barrier into cerebrospinal fluid and forms carbonic acid. A rise in arterial PCO₂ is thus the most powerful normal stimulus to breathe.

Peripheral chemoreceptors in the carotid and aortic bodies respond mainly to a fall in arterial PO₂, but only strongly when PO₂ drops below about 60 mmHg — they are the emergency backup for hypoxia. They also respond to CO₂ and pH.

Clinical vignette. A patient with severe chronic COPD is chronically hypercapnic; over time the central chemoreceptors adapt to the high CO₂ (bicarbonate buffers the CSF), and their remaining respiratory drive relies more on the hypoxic stimulus. Giving high-flow oxygen carelessly can, in a minority, blunt this drive and worsen CO₂ retention — hence the practice of controlled, titrated oxygen in COPD. (The dominant mechanism is actually worsened V/Q matching and the Haldane effect, but the teaching point stands: oxygen in COPD needs care and monitoring.)

Real-World Applications

• Interpreting arterial blood gases: the A–a gradient distinguishes lung disease from hypoventilation; the pattern of PaCO₂ and pH separates respiratory from metabolic problems.
• Mechanical ventilation: clinicians manipulate tidal volume and rate (alveolar ventilation controls CO₂) and FiO₂ and PEEP (oxygenation) using exactly these principles.
• Altitude and aviation: low inspired PO₂ explains altitude hypoxia; the curve's plateau explains why acclimatisation is possible.
• Pulse oximetry: reads haemoglobin saturation — but because of the curve's plateau, a drop from 100 to 95 mmHg PO₂ barely moves the reading, so oximetry can lag behind a falling PaO₂.
• Anaesthesia and overdose: opioids suppress the medullary response to CO₂, causing hypoventilation — the usual cause of death in overdose.

Common Mistakes

1. "You breathe because your body needs oxygen." Under normal conditions the primary drive is rising CO₂ / falling pH, sensed centrally — not low oxygen. Oxygen becomes the main driver only in significant hypoxaemia. Correction: CO₂ is the everyday master switch.
2. "Most oxygen is dissolved in blood." Only about 1.5% is dissolved; 98.5% rides on haemoglobin. This is why anaemia can cause tissue hypoxia even with a perfectly normal PaO₂ and saturation. Correction: content depends on haemoglobin, not just partial pressure.
3. "A normal pulse oximetry reading means gas exchange is fine." Because of the plateau of the dissociation curve, saturation can stay near-normal while PaO₂ is falling, and oximetry says nothing about CO₂. Correction: check an arterial gas when in doubt.
4. "Rapid breathing always means good ventilation." Fast shallow breaths waste air on dead space; alveolar ventilation can fall even as respiratory rate rises. Correction: depth matters as much as rate.
5. "In the lungs, low oxygen dilates vessels like everywhere else." The pulmonary circulation does the opposite — hypoxic vasoconstriction — to redirect blood to ventilated regions.

Comparison and Connections

Concept	Ventilation	Perfusion	Diffusion
What it means	Air reaching alveoli	Blood reaching capillaries	Gas crossing the membrane
Fails in	Airway obstruction, hypoventilation	Pulmonary embolism	Fibrosis, oedema
Effect	Low V/Q if perfusion normal	High V/Q (dead space)	Impaired transfer, wide A–a

Feature	Central chemoreceptors	Peripheral chemoreceptors
Location	Medulla	Carotid and aortic bodies
Main stimulus	H⁺ from CO₂ in CSF	Low PaO₂ (below ~60 mmHg)
Role	Everyday control	Emergency hypoxic drive
Speed	Slower	Fast

The Bohr effect (H⁺/CO₂ shifts the O₂ curve) and the Haldane effect (O₂ status shifts CO₂ carriage) are two sides of the same molecular coupling in haemoglobin — worth learning together rather than as separate facts.

Practice Questions

Recall

Q: What are the two chief forms in which carbon dioxide is transported in blood, and which is dominant? A: Bicarbonate (about 70%, the dominant form, via carbonic anhydrase and the chloride shift) and carbamino compounds bound to haemoglobin (about 23%); about 7% is dissolved.

Understanding

Q: Why does a right shift of the oxygen dissociation curve benefit exercising muscle? A: Exercising muscle produces CO₂, H⁺, and heat, all of which shift the curve right. At any given tissue PO₂ this lowers haemoglobin's affinity so more oxygen is released exactly where and when it is needed — the Bohr effect.

Application

Q: A patient breathes tidal volume 400 mL at 20 breaths/min; dead space is 150 mL. Calculate minute and alveolar ventilation, and comment. A: Minute ventilation = 400 × 20 = 8,000 mL/min. Alveolar ventilation = (400 − 150) × 20 = 5,000 mL/min. The relatively small tidal volume means dead space claims a large fraction of each breath; slower, deeper breathing would improve alveolar ventilation efficiency.

Analysis

Q: A patient is hypoxaemic. On 100% oxygen the PaO₂ rises only slightly. What is the likely mechanism and why does oxygen not fully correct it? A: A right-to-left shunt (e.g. consolidated pneumonia, pulmonary oedema, or a cardiac shunt). Shunted blood bypasses ventilated alveoli entirely, so supplemental oxygen never reaches it; the un-oxygenated blood dilutes the well-oxygenated blood downstream. This is distinct from a simple diffusion or V/Q-mismatch problem, which usually responds well to oxygen.

FAQ

Why do we yawn and sigh? Periodic deep breaths (sighs) re-expand alveoli that have partially collapsed during quiet breathing, recruiting surfactant and preventing atelectasis. Yawning likely serves similar arousal and alveolar-recruitment functions, though its full purpose is still debated.

If CO₂ drives breathing, why do breath-hold divers hyperventilate first? Hyperventilation blows off CO₂, lowering the drive to breathe and letting them hold longer. It is dangerous: oxygen can fall to fainting levels before CO₂ rises enough to force a breath — "shallow water blackout."

Why can someone with anaemia have a normal oxygen saturation but still be short of oxygen? Saturation and PaO₂ describe how full the haemoglobin is and the pressure of dissolved oxygen — not how much haemoglobin exists. With half the normal haemoglobin, oxygen content (and delivery) is halved even at 100% saturation.

What actually happens at high altitude? Barometric pressure falls, so inspired PO₂ falls, so alveolar and arterial PO₂ fall. Peripheral chemoreceptors drive hyperventilation (which lowers CO₂ and causes respiratory alkalosis), and over days the kidneys excrete bicarbonate and the body makes more red cells and 2,3-BPG to compensate.

Why does holding your breath eventually become impossible? Rising CO₂ (and falling pH), plus falling oxygen, stimulate the chemoreceptors ever more strongly until the drive overrides cortical control. The break point is set mainly by CO₂, which is why pre-hyperventilating extends it.

Is expiration ever active? At rest, no — it is passive elastic recoil. During exercise, coughing, or airway obstruction, the internal intercostals and abdominal muscles contract to force air out more quickly and completely.

Quick Revision

• Inspiration is active (diaphragm + external intercostals); resting expiration is passive elastic recoil.
• Alveolar ventilation = (tidal volume − dead space) × rate; deep slow breathing beats fast shallow.
• Surfactant lowers surface tension and prevents alveolar collapse (Laplace's law).
• Gas exchange follows Fick's law; CO₂ diffuses ~20× faster than O₂.
• Ideal V/Q ≈ 0.8; high V/Q = dead space (PE), low V/Q = shunt (pneumonia); shunt resists 100% O₂.
• ~98.5% of O₂ is carried on haemoglobin; the dissociation curve is sigmoid.
• Right shift (↑CO₂, ↑H⁺, ↑temp, ↑2,3-BPG) unloads O₂ to tissues — the Bohr effect.
• CO₂ carried mainly as bicarbonate (~70%); Haldane effect couples O₂ and CO₂ carriage.
• Central chemoreceptors sense CSF H⁺ from CO₂ (main drive); peripheral sense low PaO₂ (below ~60 mmHg).
• Lavoisier showed respiration is a controlled combustion consuming oxygen — the foundation of the whole field.

Related Topics

Prerequisites

• Pulmonology Overview
• Cardiovascular physiology and circulation — see Cardiology
• General physiology principles — see Physiology

Related Topics

• Acid–base balance and blood-gas interpretation — see Nephrology
• Haemoglobin structure and oxygen carriage — see Hematology

Next Topics

• Obstructive and restrictive lung disease
• Respiratory failure and mechanical ventilation
• Pulmonary function testing (spirometry)