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PY6.1-13 | Respiratory Physiology — Part 3

Oxygen Transport in Blood (PY6.8)

Oxygen is carried in blood in two forms:

Figure: Oxygen Transport in Blood (PY6.8)

1. Dissolved O₂ — only 1.5% of total oxygen. Dissolved O₂ is proportional to PO₂ (Henry's Law: 0.003 mL O₂/dL per mmHg PO₂). At PaO₂ = 100 mmHg: dissolved = 0.3 mL O₂/dL. This is far too little for tissue needs (~5 mL O₂/dL required at rest).

2. Bound to haemoglobin — 98.5% of total oxygen. Each haemoglobin molecule has 4 haem groups, each binding one O₂. Fully saturated: 1 g Hb carries 1.34 mL O₂. With normal Hb of 15 g/dL: O₂ capacity = 15 × 1.34 = 20.1 mL/dL.

The Oxyhaemoglobin Dissociation Curve (ODC):
This is THE most important graph in respiratory physiology. It plots % Hb saturation (SaO₂) against PO₂.

• Shape: Sigmoid (S-shaped) — due to cooperative binding (each O₂ molecule makes the next bind more easily)
• Flat upper portion (PO₂ 60–100 mmHg): Hb is 90–100% saturated. Even if PO₂ drops from 100 to 60 mmHg, saturation only drops from 98% to 90%. This is a safety buffer — moderate drops in PO₂ barely affect O₂ content.
• Steep middle portion (PO₂ 20–60 mmHg): Small drops in PO₂ cause large drops in saturation. This is where O₂ is unloaded to tissues.
• P50 = PO₂ at which Hb is 50% saturated = 26.7 mmHg

Shifts of the ODC (Bohr Effect):

Right shift (decreased O₂ affinity → easier O₂ unloading at tissues):
• ↑ Temperature (exercising muscle is hot)
• ↑ PCO₂ (exercising muscle produces CO₂)
• ↑ H⁺ (↓ pH) — acidosis
• ↑ 2,3-DPG (produced by RBCs during chronic hypoxia/anaemia)

Mnemonic: "CADET, face Right" — CO₂, Acid, 2,3-DPG, Exercise, Temperature → right shift.

Left shift (increased O₂ affinity → O₂ binds tighter, harder to unload):
• ↓ Temperature, ↓ PCO₂, ↓ H⁺ (alkalosis), ↓ 2,3-DPG
• Carbon monoxide (CO) — binds Hb with 250× affinity of O₂ → left shifts the remaining Hb → O₂ can't be unloaded → tissue hypoxia even with normal PaO₂
• Fetal haemoglobin (HbF) — has higher O₂ affinity than adult HbA (left-shifted), which helps the fetus extract O₂ from maternal blood across the placenta

Carbon Dioxide Transport (PY6.9)

CO₂ is transported from tissues to lungs in three forms:

Figure: Carbon Dioxide Transport (PY6.9)

1. Dissolved CO₂ — 7–10% of total. CO₂ is 20× more soluble than O₂ in plasma.

2. Bicarbonate (HCO₃⁻) — 60–70% (the major form). The reaction:

CO₂ + H₂O ⇌ H₂CO₃ ⇌ H⁺ + HCO₃⁻

This reaction is slow in plasma but extremely fast inside red blood cells because of the enzyme carbonic anhydrase (CA). So:
• CO₂ enters the RBC → CA converts it to H₂CO₃ → H₂CO₃ dissociates to H⁺ + HCO₃⁻
• HCO₃⁻ exits the RBC into plasma (via the band 3 protein) in exchange for Cl⁻ entering the RBC — this is the chloride shift (Hamburger phenomenon)
• The H⁺ is buffered by deoxyhaemoglobin (which is a better buffer than oxyhaemoglobin — this is why venous blood can carry more CO₂ without acidosis)

3. Carbaminohaemoglobin — 20–30%. CO₂ binds directly to the amino groups (–NH₂) of the globin chains (NOT to the haem group):

Hb–NH₂ + CO₂ → Hb–NHCOOH (carbamino compound)

Deoxyhaemoglobin binds more CO₂ than oxyhaemoglobin — so CO₂ loading occurs preferentially in the tissues (where Hb is deoxygenated).

The Haldane Effect: Deoxygenated blood carries MORE CO₂ than oxygenated blood (at the same PCO₂). This is the mirror of the Bohr effect:
• Bohr effect: ↑CO₂ → ↓O₂ affinity (helps O₂ unloading at tissues)
• Haldane effect: ↓O₂ → ↑CO₂ carrying capacity (helps CO₂ loading at tissues)

Both effects work together: at the tissues, CO₂ is produced → Bohr effect releases O₂ → deoxygenated Hb → Haldane effect loads more CO₂. At the lungs, O₂ is picked up → Haldane effect releases CO₂ → CO₂ exhaled.

Ventilation-Perfusion Matching (PY6.10)

For efficient gas exchange, ventilation (V) and perfusion (Q) must be matched at each alveolus. The ideal V/Q ratio is 0.8 (alveolar ventilation ~4.2 L/min, cardiac output ~5.25 L/min).

Figure: Ventilation-Perfusion Matching (PY6.10)

Regional differences in the upright lung:
Due to gravity, both ventilation and perfusion increase from apex to base — but perfusion increases MORE than ventilation:

• Apex: V/Q ≈ 3.3 (relatively over-ventilated, under-perfused)
→ High PAO₂ (~130 mmHg), low PACO₂ (~28 mmHg)
→ This is where TB likes to settle — high O₂ favours Mycobacterium tuberculosis

• Base: V/Q ≈ 0.6 (relatively under-ventilated, over-perfused)
→ Lower PAO₂ (~89 mmHg), higher PACO₂ (~42 mmHg)

V/Q mismatch — two extremes:

1. Dead space (V/Q → ∞): Ventilation without perfusion. Example: pulmonary embolism blocking blood flow. The alveolus is ventilated but no gas exchange occurs.

1. Shunt (V/Q → 0): Perfusion without ventilation. Example: pneumonia filling alveoli with fluid, or atelectasis (collapsed alveoli). Blood passes through without picking up O₂ → deoxygenated blood enters the arterial system → hypoxaemia that does NOT respond to supplemental O₂ (because O₂ can't reach the blocked alveoli).

Hypoxic pulmonary vasoconstriction (HPV): A unique feature of the pulmonary circulation (opposite of systemic vessels). When an alveolus becomes hypoxic (low PAO₂), the local pulmonary arteriole constricts — diverting blood AWAY from the poorly ventilated region toward better-ventilated alveoli. This is a protective mechanism to optimise V/Q matching.

Contrast with systemic circulation: Systemic arterioles DILATE in response to tissue hypoxia (to deliver more O₂). Pulmonary arterioles do the opposite — they constrict to REDIRECT blood, not deliver more.

Neural Regulation of Breathing (PY6.11)

Breathing is generated and regulated by centres in the brainstem, with inputs from higher centres and peripheral reflexes.

Brainstem respiratory centres:

1. Medullary centres (the rhythm generators):
• Dorsal Respiratory Group (DRG) — in the nucleus tractus solitarius (NTS). Primarily inspiratory neurons. They fire rhythmically, sending impulses via the phrenic nerve (diaphragm) and intercostal nerves (external intercostals). This is the basic rhythm generator for quiet breathing.
• Ventral Respiratory Group (VRG) — in the nucleus ambiguus and retroambiguus. Contains BOTH inspiratory and expiratory neurons. Mostly inactive during quiet breathing — recruited during forced breathing (exercise, coughing).

2. Pontine centres (fine-tuning):
• Pneumotaxic centre (nucleus parabrachialis medialis) — sends inhibitory signals to the DRG, limiting the duration of inspiration. A strong pneumotaxic signal = shorter inspiration = higher respiratory rate. If destroyed: prolonged inspiratory gasps (apneusis).
• Apneustic centre (lower pons) — sends excitatory signals to the DRG, prolonging inspiration. Normally kept in check by the pneumotaxic centre and vagal input.

Key reflexes:
• Hering-Breuer inflation reflex: Stretch receptors in the bronchial smooth muscle detect lung inflation → send signals via the vagus nerve → inhibit the DRG → terminate inspiration. This prevents over-inflation. (Mainly active during large tidal volumes, not quiet breathing in adults.)
• Hering-Breuer deflation reflex: Activated by lung deflation → stimulates inspiration. Important in neonates.

Higher centre control:
• Voluntary control (cerebral cortex) — you CAN hold your breath or hyperventilate deliberately, but only to a point. Rising CO₂ eventually overrides cortical control.
• Limbic system — emotional breathing (sighing, gasping with fear)
• Hypothalamus — temperature regulation affects breathing rate

Chemical Regulation of Breathing (PY6.12)

Chemical control of breathing is the body's way of matching ventilation to metabolic demand. Three stimuli are monitored: CO₂ (the most powerful), H⁺ (pH), and O₂.

Central chemoreceptors (on the ventrolateral surface of the medulla):
• Respond to H⁺ in the CSF (cerebrospinal fluid)
• CO₂ crosses the blood-brain barrier freely → reacts with H₂O → H₂CO₃ → H⁺ + HCO₃⁻ → the H⁺ stimulates the central chemoreceptors
• CO₂ is the primary driver of ventilation through this mechanism
• Responsible for ~80% of the chemical drive to breathe
• In chronic CO₂ retention (COPD), central chemoreceptors gradually reset to tolerate high CO₂ → the hypoxic drive (peripheral chemoreceptors) becomes the main stimulus → giving high-flow O₂ can abolish this drive → hypoventilation → CO₂ narcosis

Peripheral chemoreceptors:
• Carotid bodies (at the bifurcation of the common carotid, innervated by the glossopharyngeal nerve CN IX) — the MAIN peripheral chemoreceptors
• Aortic bodies (in the aortic arch, innervated by the vagus nerve CN X) — minor role
• Respond to: ↓PaO₂ (primary), ↑PaCO₂, and ↑H⁺ (↓pH)
• O₂ response: significant stimulation occurs only when PaO₂ drops below 60 mmHg — this correlates with the steep portion of the ODC where saturation begins to fall rapidly
• They respond to PaO₂ (dissolved O₂), NOT to O₂ content — so anaemia (low Hb but normal PaO₂) does NOT stimulate the peripheral chemoreceptors

Response hierarchy:
1. CO₂ is the most potent stimulus under normal conditions — a rise of just 2 mmHg PaCO₂ can double ventilation
2. O₂ becomes the dominant driver only in chronic CO₂ retention or when PaO₂ < 60 mmHg
3. pH (metabolic acidosis) can independently stimulate ventilation — this is Kussmaul breathing (deep, rapid) in diabetic ketoacidosis