L13 Respiratory Physiology 6 Gas transport

Overview

This lecture has two parts. The first covers how CO2 is carried in the blood and how disturbances of ventilation or gas exchange produce hypoxaemia and CO2/pH abnormalities, including how the lungs and kidneys compensate for acid-base disturbances. The second covers control of breathing: the central controller, chemical and non-chemical sensors, and how ventilation is driven to keep PaO2 and PaCO2 within tight limits.

CO2 transport in blood

CO2 is carried in three forms:

• Dissolved in plasma (10%) - CO2 is about 20 times more soluble than O2.
• As bicarbonate (70%).
• As carbamino compounds bound to blood proteins (20%), the most important being carbamino-haemoglobin.

In the tissue capillary, CO2 diffuses from the body cell into plasma as dissolved CO2, then into the red blood cell (RBC). Inside the RBC:

• Carbonic anhydrase catalyses $C{O}_2+H_{2}O\rightleftharpoons H_{2}C{O}_3\rightleftharpoons H^{+}+HC{O}_3^{-}$.
• HCO3- leaves the RBC for plasma in exchange for Cl- (the chloride shift).
• CO2 also combines with the terminal amine groups of blood proteins, principally the globin of haemoglobin: $Hb\cdot N{H}_2+C{O}_2\rightleftharpoons Hb\cdot NH\cdot COOH$ (carbamino-haemoglobin).
• O2 diffuses from plasma into the RBC and binds Hb, while H+ and H2O move in the reverse direction.

Haldane effect: deoxygenation of blood increases its capacity to carry CO2 - when Hb loses O2 it is better able to buffer H+ and bind CO2 as carbamino compound.

The Bohr and Haldane effects together

The Bohr and Haldane effects act reciprocally at the lungs and at the tissues:

• At the lungs: Haldane - Hb oxygenation facilitates CO2 unloading; Bohr - falling CO2 facilitates O2 loading.
• At the tissues: Bohr - rising CO2 facilitates O2 unloading; Haldane - unoxygenated Hb facilitates CO2 loading.

Causes of hypoxaemia and CO2-driven pH problems

Arterial hypoxaemia (reduced PaO2) means tissues cannot get adequate O2. Five mechanisms cause it:

1. Reduced barometric pressure (PB) or FIO2.
2. Hypoventilation.
3. Impaired diffusion.
4. Shunt.
5. Ventilation-perfusion (V/Q) mismatch.

Mechanisms 3-5 (impaired diffusion, shunt, V/Q mismatch) are grouped together as “gas exchange problems”, distinct from the reduced-inspired-O2 and hypoventilation causes.

CO2 problems arise through altered ventilation: hypoventilation causes hypercapnia (raised PCO2); hyperventilation causes hypocapnia (lowered PCO2). Hypoxaemia impairs metabolism/function; hyper/hypocapnia causes pH abnormalities.

Acid-base balance and compensation

The body produces about 13,000 mmol CO2/day (10 mmol/min) - potentially 13,000 mmol of acid via $C{O}_2+H_{2}O\rightleftharpoons H_{2}C{O}_3\rightleftharpoons H^{+}+HC{O}_3^{-}$. This is normally not a problem because CO2 is removed via the lungs, but this requires continuous ventilation.

• Hypoventilation: CO2 is not removed and accumulates, shifting the equation right, producing excess H+ - respiratory acidosis.
• Hyperventilation: excess CO2 is removed, shifting the equation left, decreasing H+ - respiratory alkalosis.

Compensation is an integrated lung/kidney response:

• Respiratory control acts on CO2; renal control acts on HCO3- levels.
• Renal compensation of respiratory acidosis/alkalosis, and respiratory compensation of metabolic acidosis/alkalosis.

Respiratory acidosis (e.g. hypoventilation, excess CO2 -> excess H+): kidneys compensate by excreting more H+ and synthesising more HCO3-.

Metabolic acidosis example - diabetic ketoacidosis: low insulin drives fat metabolism and ketoacid production, causing excess H+. Lungs compensate by exhaling more CO2 (shifting the equation left, reducing H+). Kidneys also enhance compensation by: decreasing GFR to reduce the filtered load of HCO3-, decreasing HCO3- filtered, and increasing H+ secretion (via H2PO4- and NH4+ buffers, which generates more HCO3-) - and by any other mechanism that removes H+ or increases HCO3-.

Overview of breathing control

The overall circuit runs: external ventilation -> pulmonary gas exchange -> transport -> internal/systemic tissue gas exchange -> cellular respiration. Respiratory control centres in the brain receive input from O2, CO2 and pH sensors and send motor output to the respiratory muscles.

PaO2 and PaCO2 must be kept within close limits for metabolic and biochemical stability (e.g. pH), even though O2 demand and CO2 production vary, because ventilation is tightly controlled.

Control of breathing has three basic elements:

1. Central control (brainstem respiratory centre) - sets the pattern/rhythm of breathing and coordinates sensors and effectors to maintain respiratory homeostasis.
2. Sensors (central/peripheral) - gather chemical and physical information.
3. Effectors (respiratory muscles) - adjust ventilation.

The respiratory centre receives neural and humoral (chemical) inputs from peripheral and central receptors, in a closed loop: sensors -> central controller -> effectors, with feedback from the effectors’ output back to the sensors.

In the fuller circuit, the motor cortex feeds into the brainstem respiratory centres (dorsal and ventral respiratory groups flanking a central rhythm generator), which drive inspiratory and expiratory neurons. Chemoreceptors feed into the dorsal/ventral groups, and lung stretch/irritant receptors also feed in. The inspiratory/expiratory neurons drive the respiratory muscles -> lung inflation -> ventilation, which sets arterial PCO2, pH and PO2; this arterial signal feeds back to the chemoreceptors, and lung inflation feeds back to the stretch/irritant receptors - two closed feedback loops.

Central controller: brainstem respiratory centres

Normal automatic breathing originates from brainstem impulses; the cortex can override these centres for voluntary control. Afferent inputs to the brainstem come from: the cerebral cortex, limbic system and hypothalamus (chemical control); CO2 (via CSF H+), O2 and H+ via the carotid and aortic bodies (chemical control); and, for non-chemical control, proprioceptive afferents, afferents for sneezing/coughing/swallowing/yawning, vagal inflation and deflation receptors, and baroreceptors (arterial, ventricular, atrial, pulmonary).

The periodic nature of inspiration and expiration is controlled by neurons in the pons and medulla, in three main groups:

1. Medullary respiratory centre (beneath the 4th ventricle): the Pre-Bötzinger complex (rhythm generator/“pacemaker”); the dorsal respiratory group (inspiration); the ventral respiratory group (mainly expiration). How the intrinsic rhythmicity of respiration arises is uncertain.
2. Apneustic centre (pons) - possible inspiratory cut-off.
3. Pneumotaxic centre (pons) - possible fine-tuning.

Key points: the respiratory centres are in the medulla/pons, are responsible for generating rhythmicity, receive input from chemoreceptors, lung and other receptors and the cortex, and their major output is via the phrenic nerves.

Chemical sensors: central and peripheral chemoreceptors

Central chemoreceptors (CCR, brainstem) sense brain tissue PCO2 slowly; peripheral chemoreceptors (PCR, carotid bodies) sense arterial PCO2 and PO2 fast. Both feed into the respiratory controller, which drives minute ventilation ($V_E=V_T\times f$), which sets arterial PCO2 and PO2, closing the loop back to CCR and PCR. Reference values: PaO2 = 100 Torr, PaCO2 = 40 Torr.

Central chemoreceptors: located near the ventral surface of the medulla; sensitive to PCO2 but not PO2 of blood; respond to the change in pH of the ECF/CSF as CO2 diffuses out of the cerebral capillaries. Mechanism: central chemoreceptors are bathed in brain ECF, which CO2 crosses the blood-brain barrier into easily, reaching the CSF; the CO2 lowers CSF pH, which stimulates the chemoreceptor.

Peripheral chemoreceptors: located in the carotid bodies (at the carotid artery bifurcation) and the aortic bodies (near the heart); respond to decreased arterial PO2, and to increased PCO2 and H+; respond rapidly; account for roughly 90%+ of the ventilatory O2 response and roughly 20-30% of the ventilatory CO2 response.

Ventilatory responses to CO2 and hypoxia

Response to CO2:

1. PaCO2 is the most important stimulus to ventilation under most conditions, normally held within +/-3 mmHg.
2. Most of the stimulus comes from the central chemoreceptors, though peripheral chemoreceptors also contribute and respond faster.
3. The response to PCO2 is reduced by sleep, increasing age, and genetic factors.
4. The response is magnified if PaO2 is lowered.

Minute ventilation rises steeply and roughly linearly as alveolar PCO2 rises from about 38 to 50 mmHg (roughly 6-7 L/min up to roughly 30 L/min). A study (Nielsen & Smith, 1952) plotting ventilation against PACO2 at several fixed PAO2 levels (from strongly hypoxic to hyperoxic) shows a linear CO2 response at each O2 level, with the slope steeper and ventilation higher at a given PACO2 under hypoxia - i.e. hypoxia sensitises the carotid body to CO2.

Response to hypoxia:

1. Only the peripheral chemoreceptors are involved.
2. There is negligible control during normoxic conditions.
3. Augmented by hypercapnia.
4. Hypoxic control becomes important at high altitude, and in long-term hypercapnia caused by chronic lung disease (“CO2 retainers”).

Hypercapnia augments the ventilatory response to peripheral chemoreceptor stimulation, such that ventilation is stimulated at PaO2 levels above 60 mmHg. On a ventilation-vs-PAO2 graph, ventilation rises steeply as PAO2 falls below about 60 mmHg for all PACO2 levels tested, and for any given PAO2 ventilation is progressively higher at higher PACO2 (49 > 44 > 37 mmHg) - hypercapnia shifts the hypoxic ventilatory response curve up/left.

Chronic CO2 retention (“CO2 retainers”)

In chronic hypoventilation (e.g. chronic bronchitis/emphysema), CO2 retention and the resulting acidosis drive increased HCO3- retention to normalise blood and brain pH, which "resets" the central chemoreceptor H+ stimulus to near-normal despite persistently high CO2. Hypoventilation (from increased work of breathing) and V/Q mismatch make these patients hypoxic, and hypoxia can become their main drive to ventilate rather than CO2/pH. The lecture poses, without answering in the slides, what would happen if such a patient were given a high-O2 mix.

Non-chemical control of breathing

Receptors located in the airways and lungs affect respiration through afferent connections via the vagus nerve to the respiratory centres:

• Lung receptors: slowly adapting stretch receptors; rapidly adapting stretch receptors; juxtacapillary receptors.
• Other receptors: nose/upper airway, joint/muscle, arterial baroreceptors, pain and temperature.

Self-test

1. Describe the three forms in which CO2 is transported in the blood, with their approximate proportions.
2. Describe the steps by which CO2 is converted to bicarbonate inside the red blood cell, including the roles of carbonic anhydrase and the chloride shift.
3. Define the Haldane effect and explain why deoxygenation of haemoglobin increases its capacity to carry CO2.
4. Distinguish how the Bohr and Haldane effects act together at the lungs versus at the tissues.
5. List the five mechanisms that can cause arterial hypoxaemia, and identify which three are grouped together as “gas exchange problems”.
6. Distinguish hypoventilation from hyperventilation in terms of their effect on PaCO2.
7. Using the CO2/bicarbonate equilibrium, explain why hypoventilation causes respiratory acidosis and hyperventilation causes respiratory alkalosis.
8. Describe how the kidneys compensate for a respiratory acidosis.
9. Using diabetic ketoacidosis as an example, describe how the lungs and kidneys compensate for a metabolic acidosis.
10. List the three basic elements of the control-of-breathing system and state the role of each.
11. Name the three main centres/neuron groups in the medulla and pons responsible for the rhythmicity of breathing, and state each one’s proposed function.
12. Distinguish central chemoreceptors from peripheral chemoreceptors in terms of location, the stimulus each responds to, and speed of response.
13. Describe the mechanism by which central chemoreceptors detect a rise in PCO2.
14. Describe the four features of the ventilatory response to CO2.
15. Describe the four features of the ventilatory response to hypoxia.
16. Explain why chronic CO2 retainers come to depend on hypoxia rather than CO2/pH as their main ventilatory drive.
17. List the lung receptors involved in non-chemical control of breathing, and name one other receptor type also involved.
18. Integrative: trace a CO2 molecule from its production in a tissue cell to its elimination by ventilation, naming the blood transport form(s) it may take, the chemoreceptor(s) that detect the resulting change in PCO2, and the effector response this produces.

Answers

Reveal answers

1. Dissolved in plasma (10%, CO2 being ~20x more soluble than O2), as bicarbonate (70%), and as carbamino compounds bound to blood proteins, chiefly carbamino-haemoglobin (20%).
2. CO2 diffuses into the RBC, where carbonic anhydrase catalyses $C{O}_2+H_{2}O\rightleftharpoons H_{2}C{O}_3\rightleftharpoons H^{+}+HC{O}_3^{-}$; the resulting HCO3- leaves the RBC for plasma in exchange for Cl- entering the RBC (the chloride shift).
3. The Haldane effect: deoxygenation of blood increases its CO2-carrying capacity, because deoxygenated Hb buffers H+ and binds CO2 as carbamino compound more readily than oxygenated Hb.
4. At the lungs, Hb oxygenation facilitates CO2 unloading (Haldane) while falling CO2 facilitates O2 loading (Bohr); at the tissues, rising CO2 facilitates O2 unloading (Bohr) while unoxygenated Hb facilitates CO2 loading (Haldane) - the two effects reinforce gas exchange in each direction.
5. Reduced PB or FIO2, hypoventilation, impaired diffusion, shunt, and V/Q mismatch; the last three (impaired diffusion, shunt, V/Q mismatch) are grouped as “gas exchange problems”.
6. Hypoventilation raises PaCO2 (hypercapnia); hyperventilation lowers PaCO2 (hypocapnia).
7. Hypoventilation lets CO2 accumulate, shifting $C{O}_2+H_{2}O\rightleftharpoons H_{2}C{O}_3\rightleftharpoons H^{+}+HC{O}_3^{-}$ right and producing excess H+ (respiratory acidosis); hyperventilation removes excess CO2, shifting the equation left and decreasing H+ (respiratory alkalosis).
8. The kidneys excrete more H+ and synthesise more HCO3-.
9. In DKA, low insulin drives fat metabolism and ketoacid production, raising H+ (metabolic acidosis). The lungs compensate by exhaling more CO2, shifting the equilibrium left and lowering H+. The kidneys additionally compensate by decreasing GFR (reducing filtered HCO3- load), decreasing filtered HCO3-, and increasing H+ secretion via H2PO4-/NH4+ buffers, which generates more HCO3-.
10. Central control (brainstem respiratory centre) sets the rhythm/pattern and coordinates sensors and effectors; sensors (central/peripheral) gather chemical/physical information; effectors (respiratory muscles) adjust ventilation.
11. The Pre-Bötzinger complex (rhythm generator/pacemaker) and the dorsal respiratory group (inspiration) and ventral respiratory group (mainly expiration) in the medulla; the apneustic centre in the pons (possible inspiratory cut-off); the pneumotaxic centre in the pons (possible fine-tuning).
12. Central chemoreceptors are near the ventral medulla, sense PCO2 (via CSF pH) but not PO2, and respond slowly (to brain tissue PCO2); peripheral chemoreceptors are in the carotid and aortic bodies, respond to falling PO2 and rising PCO2/H+, and respond rapidly.
13. CO2 diffuses easily across the blood-brain barrier into brain ECF and the CSF, lowering CSF pH, which stimulates the chemoreceptor.
14. PaCO2 is the most important ventilatory stimulus under most conditions (controlled to +/-3 mmHg); most of the response comes from central chemoreceptors, with peripheral chemoreceptors contributing faster; the response is reduced by sleep, age and genetic factors; the response is magnified when PaO2 is lowered.
15. Only peripheral chemoreceptors are involved; there is negligible control during normoxia; the response is augmented by hypercapnia; hypoxic control becomes important at high altitude and in chronic CO2 retainers.
16. Chronic hypoventilation causes CO2 retention and acidosis, driving increased HCO3- retention that normalises blood/brain pH and “resets” the central chemoreceptor H+ stimulus toward normal; meanwhile hypoventilation and V/Q mismatch make the patient hypoxic, so hypoxia (sensed by peripheral chemoreceptors) becomes the main drive to ventilate instead of CO2/pH.
17. Slowly adapting stretch receptors, rapidly adapting stretch receptors, and juxtacapillary receptors; also arterial baroreceptors (or nose/upper airway, or joint/muscle, or pain/temperature receptors).
18. CO2 produced in a tissue cell diffuses into plasma and the RBC, where it is carried dissolved, as bicarbonate, or as carbamino-Hb; on reaching the lungs it is released and raises alveolar/arterial PCO2, which is sensed by the central chemoreceptors (via CSF pH, slowly) and the peripheral chemoreceptors (directly, rapidly); these drive the respiratory controller to increase minute ventilation via the inspiratory/expiratory neurons and respiratory muscles, increasing CO2 elimination.