L14 Respiratory Physiology 7 Central control

Overview

This lecture covers the causes and classification of arterial hypoxaemia, then works through how O2 and CO2 are actually carried in the blood. It starts with the five mechanisms that can lower PaO2 and how these map onto Type I and Type II respiratory failure, then gives an overview diagram of the O2/CO2 transport pathway from external respiration through transport to internal respiration. The bulk of the lecture is then O2 carriage (dissolved vs Hb-bound, the oxyhaemoglobin dissociation curve and its clinical shape, O2 capacity/content calculations), the clinical states that reduce O2 delivery (anaemia, carbon monoxide poisoning, cyanosis), and finally CO2 transport and the Haldane effect.

Mechanisms of arterial hypoxaemia and respiratory failure

Arterial hypoxaemia (a fall in PaO2) means the body cannot deliver adequate O2 to cells. Along the O2 transport pathway, PO2 falls in a stepwise cascade from atmosphere (~150 mmHg) to inspired air (~150) to alveolar gas (~100) to pulmonary capillary (~100) to arterial blood (~95-100) to tissues (~50) to mitochondria (~0).

There are five mechanisms of arterial hypoxaemia:

• Reduced PB (barometric pressure) or FIO2 - e.g. at altitude. Worked example: on Mt Everest (~8000 m, PB ~279 mmHg), an ABG showed PaO2 27 mmHg, PaCO2 9 mmHg (R = 0.8).
• Hypoventilation
• Impaired diffusion - a true diffusion limitation; worse with exercise; responsive to added O2
• Shunt - anatomical (e.g. cardiac) or from pneumonia; unresponsive to added O2
• Ventilation-perfusion (V/Q) mismatch - the commonest gas exchange abnormality; responsive to added O2

Mechanisms 3-5 (impaired diffusion, shunt, V/Q mismatch) are grouped together as “gas exchange problems” and all increase the alveolar-arterial (A-a) O2 gradient, distinguishing them from reduced PB/FIO2 and hypoventilation.

Hypoventilation is shown on a graph of alveolar PO2/PCO2 against alveolar ventilation: as ventilation falls below the normal point (~4.2 L/min, PO2 ~98 mmHg, PCO2 ~40 mmHg), PO2 falls and PCO2 rises. Causes of hypoventilation:

• High work of breathing (reduced compliance; increased airways resistance)
• Damage to the chest wall, or fatigue/paralysis of the respiratory muscles
• Respiratory depressants (e.g. morphine, barbiturates)
• Sleep

Key points on hypoventilation: it always increases PaCO2, and it decreases PaO2 unless additional O2 is inspired. The hypoxaemia of hypoventilation is reversible by giving supplemental O2: less air is entering the alveoli, but if that air is enriched in O2, the amount of O2 delivered to the alveoli (and available for transfer to blood) is increased.

Respiratory failure is defined as PaO2 < 60 mmHg or PaCO2 > 55 mmHg, and is classified as:

• Type I - PaO2 low, PaCO2 normal: a gas exchange problem (V/Q mismatch, shunt), e.g. pneumonia
• Type II - PaO2 low, PaCO2 high: ventilatory failure, e.g. chronic bronchitis, emphysema

The two types may co-exist.

Overview of the O2/CO2 transport pathway

The overall pathway runs: external respiration (pulmonary ventilation and gas exchange at the alveoli, O2 in/CO2 out) -> transport (pulmonary circulation -> heart -> systemic circulation) -> internal respiration (gas exchange at body tissues/cells, O2 in/CO2 out). Regulation of breathing appears in this diagram only as a small branch, showing respiratory control centres in the brainstem receiving input from O2, CO2 and pH sensors and sending motor output to the respiratory muscles; the transcript does not develop this branch as standalone content.

O2 carriage in the blood

O2 is carried in blood in two forms: dissolved, and combined with haemoglobin (Hb).

Dissolved O2 is poorly soluble: only 0.03 ml dissolved O2 per litre of blood per mmHg PO2. Arterial blood at PO2 100 mmHg therefore contains only 3 ml/L of dissolved O2, making dissolved O2 a very ineffective transport mechanism on its own - Hb is needed to carry clinically useful amounts of O2.

O2 combines reversibly with Hb to form oxyhaemoglobin: O2 + Hb <-> HbO2. Binding depends on PO2 in a non-linear (sigmoidal) relationship, giving the oxyhaemoglobin dissociation curve. O2 saturation of Hb is the percentage of available binding sites that have O2 attached. On the curve, arterial blood (point a) sits at PO2 ~95 mmHg / 97% saturation, and mixed venous blood (v̄) sits at PO2 ~40 mmHg / 70% saturation, with P50 (the PO2 at 50% saturation) around 25-28 mmHg.

The sigmoid shape has two functional advantages:

• The upper, flat part of the curve (around the normal arterial PO2 of ~95 mmHg) means moderate changes in PO2 have only small effects on % saturation and hence on the O2 carried by arterial blood - this buffers O2 loading against fluctuations in alveolar PO2.
• The steep lower part of the curve means small changes in PO2 produce large changes in saturation, which both helps unload O2 to the tissues and allows large amounts of O2 to be loaded onto Hb in the lungs.

O2 capacity and content. O2 capacity is the maximal amount of O2 that can combine with Hb, i.e. when Hb is 100% saturated. One gram of Hb can combine with 1.34 ml O2, and normal blood has ~150 g Hb/litre, so O2 capacity = 1.34 x 150 = 200 ml O2/litre of blood.

O2 content (the amount of O2 actually being carried) = O2 capacity x saturation, plus the small dissolved component:
$O_{2}content(ml/L)=1.34\times Hb\times \frac{Sat}{100}+0.03\times P{O}_2$
where Hb is haemoglobin concentration (g/L), Sat is % Hb saturation, and PO2 is in mmHg.

Worked example (arterial blood, Hb 150 g/L, saturation 98%, PO2 100 mmHg):
$1.34\times 150\times \frac{98}{100}+0.03\times 100=197+3=200ml{O}_2/L$

Shifts of the oxyhaemoglobin dissociation curve

A leftward shift of the curve means increased Hb affinity for O2, favouring more loading of O2 in the lungs. A rightward shift means decreased affinity, favouring more unloading of O2 in the tissues.

The Bohr effect describes a rightward shift of the curve caused by an increase in: H+ concentration, PCO2, temperature, and 2,3-diphosphoglycerate (2,3-DPG) in red blood cells. A leftward shift is caused by decreases in the same four variables. A memory aid given in the lecture: exercising muscle is acidic, hypercapnic and hot, and benefits from the increased O2 unloading that the rightward shift produces.

2,3-DPG is a by-product of glycolysis; red blood cells contain no mitochondria and rely on glycolysis for metabolism. 2,3-DPG increases with intense exercise training, at altitude, and with severe lung disease or anaemia. Raised 2,3-DPG shifts the curve rightward, allowing more O2 to be released from Hb at a given PO2 (increased unloading), helping deliver O2 to tissues.

Clinical states of reduced O2 delivery

Anaemia: the saturation curve itself is unchanged, but because total Hb is reduced, O2 content is reduced (e.g. Hb 100 g/L: 1.34 x 100 x 0.98 = 131 ml O2/L, versus 200 ml/L normal). Because the arterial-venous (a-v̄) O2 content difference is smaller than normal, anaemia causes exercise problems.

Carbon monoxide (CO) poisoning: CO combines with Hb to form carboxyhaemoglobin (COHb), blocking O2 binding sites. CO has about 250 times the affinity of O2 for Hb, so small amounts of CO can tie up a large proportion of blood Hb, making it unavailable for O2 carriage and reducing O2 content. CO also shifts the O2 dissociation curve to the left, making it more difficult to unload the remaining bound O2 to the tissues.

Cyanosis: a blue-purple discolouration, most obvious in the skin, nail beds and mucosal membranes, caused by low SaO2 (poorly oxygenated blood). It is detectable when there is at least 50 g/L of deoxyhaemoglobin present (detectability also depends on skin pigmentation, illumination, and adequate capillary perfusion).

• Central cyanosis (blue mouth and tongue) is due to poor oxygenation.
• Peripheral cyanosis occurs when the lungs are healthy but circulation is poor.

CO2 transport and the Haldane effect

CO2 is transported in the blood in three forms:

• Dissolved in plasma (10%) - CO2 is about 20 times more soluble than O2.
• As bicarbonate (70%).
• Combined with proteins as carbamino compounds (20%).

In the systemic capillaries: CO2 diffuses from tissue into plasma (dissolved), then into the red blood cell (dissolved), where carbonic anhydrase (CA) catalyses $C{O}_2+H_{2}O\rightleftharpoons H_{2}C{O}_3\rightleftharpoons H^{+}+HC{O}_3^{-}$. HCO3- then leaves the red cell for plasma in exchange for Cl- entering the cell (the chloride shift). The H+ generated binds haemoglobin, forming reduced (deoxy-) Hb and releasing O2. Some CO2 also binds Hb directly to form carbamino-Hb: $Hb.N{H}_2+C{O}_2\rightleftharpoons Hb.NH.COOH$. The most important protein for carbamino compound formation is the globin of Hb.

The Haldane effect describes how deoxygenation of blood increases its capacity to carry CO2. Putting the Bohr and Haldane effects together across lungs and tissues:

• In the lungs: oxygenation of Hb facilitates CO2 unloading (Haldane), while the resulting decrease in CO2 facilitates further O2 loading (Bohr).
• In the tissues: increased CO2 facilitates O2 unloading (Bohr), while deoxygenation of Hb facilitates CO2 loading (Haldane).

Self-test

1. List the five mechanisms of arterial hypoxaemia, and state which three are grouped as “gas exchange problems” and why they are grouped together.
2. Describe the effect of hypoventilation on PaO2 and PaCO2, and explain why the hypoxaemia of hypoventilation is reversible by giving supplemental O2.
3. List four causes of hypoventilation.
4. Distinguish Type I from Type II respiratory failure, including the PaO2/PaCO2 pattern and an example cause of each.
5. Explain why dissolved O2 alone is an ineffective transport mechanism, using the transcript’s figures.
6. Describe the shape of the oxyhaemoglobin dissociation curve and explain the functional advantage of (a) its upper flat portion and (b) its steep lower portion.
7. Define O2 capacity and calculate it for blood with 150 g Hb/litre.
8. Calculate the O2 content of blood with Hb 150 g/L, saturation 98%, PO2 100 mmHg, showing the dissolved and Hb-bound contributions separately.
9. Describe the Bohr effect: which four factors shift the oxyhaemoglobin dissociation curve to the right, and what is the physiological benefit of this shift during exercise?
10. Explain how 2,3-DPG is produced and how it affects O2 delivery to tissues.
11. Explain why O2 content, but not O2 saturation, is reduced in anaemia, and what consequence this has for exercise.
12. Explain how carbon monoxide reduces O2 delivery to tissues, describing both of its effects on the oxyhaemoglobin dissociation curve/content.
13. Distinguish central from peripheral cyanosis, and state the deoxyhaemoglobin threshold at which cyanosis becomes detectable.
14. List the three forms in which CO2 is transported in the blood, with their approximate proportions.
15. Describe the steps by which CO2 taken up in a systemic capillary is converted to bicarbonate, including the role of carbonic anhydrase and the chloride shift.
16. Describe the Haldane effect and explain how it and the Bohr effect act together in the lungs versus in the tissues.

Answers

Reveal answers

1. Reduced PB or FIO2, hypoventilation, impaired diffusion, shunt, and V/Q mismatch. Impaired diffusion, shunt and V/Q mismatch are grouped as “gas exchange problems” because they all increase the alveolar-arterial (A-a) O2 gradient.
2. Hypoventilation always increases PaCO2, and decreases PaO2 unless extra O2 is given. It is reversible with supplemental O2 because although less air is entering the alveoli, if that air is enriched in O2 the amount of O2 delivered to the alveoli (and available for transfer to blood) increases.
3. Any four of: high work of breathing (reduced compliance, increased airways resistance); damage to the chest wall or fatigue/paralysis of respiratory muscles; respiratory depressants (e.g. morphine, barbiturates); sleep.
4. Type I: PaO2 low, PaCO2 normal, due to a gas exchange problem (V/Q mismatch or shunt), e.g. pneumonia. Type II: PaO2 low, PaCO2 high, due to ventilatory failure, e.g. chronic bronchitis or emphysema. The two may co-exist.
5. Dissolved O2 contributes only 0.03 ml O2/litre of blood per mmHg PO2, so arterial blood at PO2 100 mmHg carries only 3 ml/L dissolved O2 - far too little for adequate transport, so Hb-bound O2 is needed.
6. The curve is sigmoidal. The upper flat portion (around the normal arterial PO2 of ~95 mmHg) means moderate PO2 changes have little effect on % saturation, protecting O2 loading against fluctuation. The steep lower portion means small PO2 changes cause large saturation changes, aiding O2 unloading at the tissues and rapid loading onto Hb in the lungs.
7. O2 capacity is the maximal O2 that can combine with Hb when it is 100% saturated. With 150 g Hb/L and 1.34 ml O2/g Hb: capacity = 1.34 x 150 = 200 ml O2/litre.
8. Hb-bound: 1.34 x 150 x (98/100) = 197 ml/L. Dissolved: 0.03 x 100 = 3 ml/L. Total O2 content = 200 ml/L.
9. The curve shifts right with increased H+, increased PCO2, increased temperature, and increased 2,3-DPG. This rightward shift decreases Hb-O2 affinity, increasing O2 unloading to the (acidic, hypercapnic, hot) exercising tissue.
10. 2,3-DPG is a by-product of glycolysis, which red blood cells rely on because they lack mitochondria. It rises with intense exercise training, altitude, and severe lung disease or anaemia, and shifts the dissociation curve rightward, releasing more O2 from Hb at a given PO2 (increased unloading).
11. In anaemia the saturation curve is unchanged (Hb that is present still binds O2 normally), but with less total Hb the O2 content is reduced (e.g. Hb 100 g/L gives ~131 ml O2/L versus 200 ml/L normal). The smaller a-v̄ O2 content difference causes exercise problems.
12. CO binds Hb (as carboxyhaemoglobin) with ~250x the affinity of O2, tying up a large proportion of Hb and reducing O2 content even at low CO levels. It also shifts the dissociation curve to the left, making it harder for the O2 that is still bound to be unloaded to tissues.
13. Central cyanosis (blue mouth/tongue) results from poor oxygenation; peripheral cyanosis occurs when the lungs are healthy but circulation is poor. Cyanosis becomes detectable at ≥50 g/L of deoxyhaemoglobin.
14. Dissolved in plasma (10%), as bicarbonate (70%), and as carbamino compounds bound to protein (20%).
15. CO2 diffuses from tissue into plasma then into the red blood cell (both dissolved); carbonic anhydrase catalyses CO2 + H2O <-> H2CO3 <-> H+ + HCO3-; HCO3- leaves the red cell for plasma in exchange for Cl- entering the cell (chloride shift); the H+ produced binds Hb, forming deoxy-Hb and releasing O2.
16. The Haldane effect is that deoxygenation of Hb increases its capacity to carry CO2. In the lungs, Hb oxygenation facilitates CO2 unloading (Haldane) while the fall in CO2 facilitates further O2 loading (Bohr). In the tissues, rising CO2 facilitates O2 unloading (Bohr) while Hb deoxygenation facilitates CO2 loading (Haldane).