Intrapleural pressure is about −4 cmH₂O at the end of quiet expiration (Fig. 64). Contraction of the inspiratory muscles increases the outward force exerted by the diaphragm and chest wall on the parietal pleura and causes the intrapleural pressure to fall to about −9 cmH₂O. This raises the distending pressure acting across the walls of the alveoli (i.e., the difference between the intra-alveolar and intrapleural pressures, Fig. 61B) and so causes the lung to expand. A small, negative intra-alveolar pressure is generated by the expansion of the alveolar walls and this draws air in from the atmosphere. (This is analogous to drawing fluid into a syringe by pulling outwards on the plunger.) In forced inspiration, maximal contraction of the inspiratory muscles is reinforced by use of the accessory inspiratory muscles in the neck, which elevate the sternum and upper ribs as well. This leads to the generation of much more negative intrapleural pressures (e.g., −30 cmH₂O) and more rapid airflow.

Fig. 64 The relationship between (a) lung volume, (b) intrapleural pressure and (c) intra-alveolar pressure during quiet breathing.

During passive expiration, the elastic recoil of the stretched lungs produces a positive intra-alveolar pressure which drives air out (Fig. 64). Active contraction of abdominal and internal intercostal muscles during forced expiration generates strongly positive intrapleural pressures (e.g. +20 cmH₂O) which deflate the lungs more rapidly.

Work of breathing

Three elements contribute to this work.

• Compliance work is necessary to expand the lungs against elastic and surface tension forces.

• Airways resistance to airflow has to be overcome. This is usually very low but may be markedly increased in certain pulmonary diseases.

• Tissue resistance results from frictional forces which oppose the movement of one layer of pulmonary and pleural tissue past another during chest expansion.

Under normal conditions, the relative magnitudes of these components are:

Compliance work >> Airways resistance > Tissue resistance.

Work is usually only performed during inspiration. During rapid ventilation, however, increased airways resistance and tissue resistance effects necessitate energy expenditure during expiration as well and this raises the work of breathing in heavy exercise. Respiratory disease may have similar effects at rest, e.g., if the airways resistance is increased.

4.2 Pulmonary function tests

Measurements of lung function are of great clinical significance because they allow respiratory disease to be classified pathophysiologically, its severity to be assessed and the benefits of therapy to be monitored objectively. Appropriate interpretation of these tests requires a knowledge of the normal pulmonary function test values which provide a benchmark for comparison.

Lung volumes

The volume of gas which can be moved in and out of the lungs during breathing is highly dependent on age, sex, body build and level of fitness, making it difficult to quote a single normal value for most of these measures.

Ventilatory volumes

The gas movement during ventilation can be recorded using a device called a spirometer (Fig. 65). This measures functionally important changes in lung volume.

• Tidal volume is the amplitude of the oscillation in lung volume during quiet respiration. It is usually about 400–500 ml.

• Inspiratory reserve volume (IRV) is the maximum volume of air which can be inspired in excess of normal inspiration. It is about 30% lower in females than males.

• Expiratory reserve volume (ERV) is the maximum volume of air which can be expired in excess of normal expiration. It is lower in females than males.

Fig. 65 Spirometer trace showing changes in lung volume during ventilation. Tidal volume is typical for quiet respiration. IRV, inspiratory reserve volume; ERV, expiratory reserve volume; FRC, functional residual capacity. As FRC and residual volume cannot be determined directly by spirometry, an indicator gas dilution method has to be used to determine the FRC to convert these measurements to total lung volumes.

Residual volume

Not all the gas can be expired from the lungs and the volume remaining after maximal expiration is called the residual volume. This cannot be measured directly using a spirometer but can be estimated from separate measures of the functional residual capacity (FRC, see below) and the expiratory reserve volume.

This gives a value in the region of 1–2 L, but this tends to increase with age.

Lung capacities

• Total lung capacity represents the sum of all the ventilatory volumes plus the residual volume (Fig. 65).

• Vital capacity is the sum of the ventilatory volumes, i.e., it is the volume of gas that is expelled from the lungs from peak inspiration to peak expiration. Values of 5 L in men and 3.5 L in women would be fairly typical, but vital capacity depends on body build, being larger in tall thin individuals as opposed to more obese subjects, decreases with age and is increased in athletically fit individuals. Body position is also important since, when lying down, the abdominal contents are forced against the diaphragm, restricting its movement (splinting the diaphragm) and thus reducing the vital capacity.

• Functional residual capacity is the volume of gas left in the lungs at the end of quiet expiration; this can be estimated using a variation of the indicator dilution technique (Section 1.1). A known amount of the inert gas helium is equilibrated with the gas in the lungs. Since helium is insoluble in water and, therefore, does not diffuse out of the alveoli, the final concentration achieved can be used to calculate the functional residual capacity, which is typically about 3 L. This means that the normal tidal volume of incoming air (about 450 ml) is mixed with a 6–7 times larger volume of residual gas in the lungs, greatly reducing the breath-to-breath changes in alveolar O₂ and CO₂ concentrations during quiet respiration.

• Inspiratory capacity equals tidal volume plus inspiratory reserve volume.

Ventilation rates and minute volumes

The respiratory minute volume is the amount of new air being brought into the lungs each minute and can be calculated from the respiratory rate (about 12–15 min⁻¹) and the tidal volume (450 ml).

(Eq. 19)

Dead space and alveolar ventilation rate

Not all the inspired air will actually reach the areas where gas exchange with the pulmonary circulation can take place. The volume which has to be ventilated but which does not participate in gas exchange is called the dead space. The anatomical dead space includes all the airways down to bronchiolar level. The air which enters these during inspiration is immediately expelled again at the beginning of the next expiration without contributing to pulmonary oxygenation. In some areas of the lung, there may also be alveoli which are ventilated but receive very little pulmonary perfusion. These regions cannot contribute to gas exchange either, and when their volume is included, we refer to the resulting total as the physiological dead space. It is this measurement which is of functional significance. Normally the dead space is about 150 ml.

The purpose of ventilation is to regulate alveolar gas concentrations. The rate at which the gas in the alveoli is renewed is determined by the alveolar ventilation rate where:

(Eq. 20)

It can be seen from this that any increase in the dead space automatically increases the respiratory minute volume necessary to achieve a given rate of alveolar ventilation. This is important in disease states which increase the physiological dead space. Also, in patients requiring artificial ventilation, a considerable volume of tubing is used to connect the airways to the ventilator itself. This adds to the dead space of the system and the tidal volume delivered by the machine has to be increased appropriately to ensure adequate alveolar ventilation.

Forced vital capacity and forced expiratory volume

In clinical practice, these measurements are often used to classify respiratory disease as either restrictive or obstructive in type. The patient is asked to take a maximal inspiration and then to breathe out as rapidly and fully as possible into a specialized spirometer which plots the expired volume against time in seconds (Fig. 66). Two measurements are commonly made from this.

Fig. 66 Measurement of forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV₁) from a forced expiration following maximal inspiration.

Forced vital capacity (FVC) is the total volume of expired gas. This is similar to the vital capacity but is measured during forced expiration. The FVC is reduced in restrictive lung diseases. These may arise from conditions which limit the compliance of the lungs, e.g., lung fibrosis, or from a reduction in available lung volume caused by removal or collapse of part of the lung.

Forced expiratory volume (FEV) is the volume of gas expelled in a given time; if this is measured for the first second it is called the forced expiratory volume in 1 second (FEV₁). This is limited by the speed with which gas can be forced through the airways and is decreased in obstructive lung disease. Since the actual magnitude of FEV₁ is always reduced in parallel with any reduction in FVC, even in the absence of obstruction, it is the ratio of FEV₁/FVC which is most useful diagnostically. This ratio should normally exceed 0.75 (75%) in healthy individuals but often falls below 0.5 (50%) when there is increased airways resistance, e.g., in asthma.

Peak expiratory flow rate (PEFR)

This is a simple test of ventilatory function which is widely used in clinical practice. The patient is simply asked to blow air out of their fully inflated lungs as rapidly as they can and the peak flow rate achieved is recorded with a flow meter. Normal values are again very dependent on age, sex and build but are of the order of 400 L min⁻¹. This may fall dramatically in cases of obstructive airways disease.

Box 13 Clinical note: Obstructive airways disease

Obstructive airways disease is a pathophysiological diagnosis characterized by reductions in FEV₁/FVC and PEFR. It is seen in two main groups of patients, asthmatics and those with chronic obstructive pulmonary disease (COPD). Asthma is characterized by wheezing episodes caused by an acute increase in airways resistance. There is an association with allergic conditions such as hay fever and atopic eczema and attacks may be triggered by a variety of stimuli including inhaled dust and antigens. Between episodes lung function is often normal, especially in young patients. In COPD, however, airways resistance is persistently elevated but function deteriorates further during chest infections. COPD is often caused by smoking and atmospheric pollution and is associated with chronic bronchitis (cough with spit) and emphysema (destruction of alveolar tissue). Despite these differences, both asthma and COPD may be treated with adrenergic agonists which mimic sympathetic nervous activity and cause relaxation of bronchial smooth muscle.

4.3 Gas exchange in the lungs and tissues

The movement of O₂ and CO₂ in and out of the capillaries both in the lungs and in the peripheral tissues depends on gas diffusion. This is affected by three main factors.

Pressure gradients drive gas movements. The relevant SI unit of pressure is the kPa (1000 N m⁻²), although mmHg is also often used in respiratory physiology (1 mmHg = 0.133 kPa). Differences in total pressure lead to bulk flow of a gas mixture, e.g., air flows from regions of high pressure to regions of low pressure. At the interface between two gas mixtures, however, the tendency for any individual gas to diffuse from one region to another is determined by differences in the partial pressure for that gas, i.e., diffusion is driven by partial pressure gradients.

Partial pressure is defined as the pressure a gas would exert if it alone occupied the total volume available to the mixture of gases. It is determined both by the concentration of a gas, expressed as a fraction of the total mixture, and the total pressure of the mixture. For example, if we consider a mixture of gases at a total pressure of 1 kPa, and if 20% of the mixture is O₂, then the partial pressure of oxygen () can be calculated as follows:

(Eq. 21)

We could double the partial pressure of O₂ to 0.4 kPa either by increasing its concentration to 40%, or by doubling the total pressure of the mixture to 2 kPa. It is also important to note that the partial pressures of all the gases in a gas mixture must always add up to the total pressure of the mixture.

The diffusion coefficient for each gas is a measure of the ease with which it can diffuse through the aqueous body fluids, and is determined by its solubility in water and its molecular weight.

(Eq. 22)

Even though CO₂ has a higher molecular weight, it diffuses about 20 times more easily than O₂ since it is much more soluble in water. Both gases are highly lipid soluble and so pass easily through cell membranes.

Tissue properties

The physical properties of the tissues at the site of exchange, particularly the surface area over which diffusion can occur and the diffusion distances between one compartment and the other, also influence the total rate of gas exchange. The lungs are well adapted for gas diffusion, with a very large alveolar surface area and a very thin layer of fluid and tissue separating alveolar gas from pulmonary blood.

Gas exchange in the lungs

Gas exchange depends on the partial pressure gradients between alveolar air and pulmonary arterial blood for O₂ and CO₂. Effective gas exchange also requires easy diffusion between alveoli and blood and an appropriate balance between ventilation and perfusion within the lungs.

Alveolar gases

Room air is chiefly a mixture of N₂ and O₂, with variable amounts of water vapour and a tiny percentage of CO₂ (Table 5). Although the average total pressure in the alveoli is equal to that in the atmosphere, alveolar air differs from the air we breathe (the inspirate) in a number of ways. Firstly, it has a higher water vapour pressure, since the inspired gases become fully saturated as they pass through the airways. The partial pressure of water vapour in the alveoli always equals the saturated water vapour pressure at 37°C (6.3 kPa; 47 mmHg), irrespective of the total alveolar pressure. Since water molecules have been added to the inspirate, the concentrations of all the other gases in the mix are reduced by dilution (Table 5). This decreases their partial pressures, as illustrated by the changes in gas pressure which result from simply humidifying previously dry room air (Table 6).

Table 5 Concentrations of the gases in dry room air, air completely humidified at 37°C and alveolar air

Table 6 Partial pressures of the gases in dry room air, air completely humidified at 37°C and alveolar air

The other major differences between alveolar gas and room air reflect constant removal of O₂ by diffusion into the pulmonary blood and constant addition of CO₂ from the same source. This reduces the and elevates the as compared with humidified air (Table 6). The actual values achieved depend on the balance between the rate of ventilation and the rates of O₂ consumption and CO₂ production by the body. If ventilation were to increase without any change in gas use or production, alveolar air would become more like humidified air, with a rise in and a fall in . This limits the maximum possible alveolar to about 20 kPa (150 mmHg), i.e., the value in saturated room air (Table 6), at least while breathing air at normal atmospheric pressure. Higher partial pressures can only be achieved by breathing an oxygen-enriched gas mixture or by increasing the total pressures of the inspirate.

Normally, of course, ventilation is homeostatically regulated so that alveolar and remain relatively constant (Section 5). As previously explained, the large functional residual capacity during quiet respiration also acts as a buffer against large changes in alveolar gas pressures during each respiratory cycle, since the incoming tidal volume is diluted in a much larger volume of residual pulmonary gas (Section 4.2).

Pulmonary blood gases

Gas diffusion gradients in the lung are determined by the differences between the partial pressures within the alveoli and those within the pulmonary capillaries. The partial pressures of O₂ and CO₂ in pulmonary arterial blood entering these capillaries are determined by the levels in systemic venous blood from peripheral tissues. Venous blood is mixed in the right ventricle, giving a in the pulmonary arteries of 5.3 kPa (40 mmHg) and a of 6 kPa (45 mmHg). Since the in the alveoli is 13.7 kPa (103 mmHg), O₂ diffuses into the pulmonary blood. Carbon dioxide, also driven by a partial pressure gradient (Fig. 67), diffuses in the opposite direction, from the capillaries ( = 6 kPa, or 45 mmHg) into the alveoli ( = 5.3 kPa, or 40 mmHg). Gas diffusion across the combined alveolar and capillary wall system is rapid, so that pulmonary blood normally equilibrates with alveolar gases before leaving the pulmonary capillary. Thus, the gas pressures in pulmonary venous blood equal those in the alveoli under physiological conditions (Fig. 67).

Fig. 67 Gas exchange in the lungs and tissues. Diffusion of O₂ and CO₂ from high to low pressure occurs until capillary blood equilibrates with the gases in the alveoli or in the interstitial fluid of peripheral tissues.

The in systemic arterial blood is somewhat lower than that in the pulmonary veins because of mixing with deoxygenated blood from the bronchial veins. Bronchial blood vessels provide the nutritive needs of the bronchial system, losing O₂ and gaining CO₂ as they do so, and do not take part in alveolar gas exchange. Bronchial venous blood drains into the left atrium and reduces systemic arterial to about 13 kPa (98 mmHg). Thus, the bronchial circulation acts as a shunt, bypassing pulmonary oxygenation.

The diffusion processes described above lead to a change in the gas content of pulmonary blood, as determined by the dissociation curves for O₂ and CO₂ transport in blood (Section 4.4). Oxygen content normally rises from 15 to 20 ml O₂ 100 ml⁻¹ blood. At the same time CO₂ levels drop from about 52 to 48 ml CO₂ 100 ml⁻¹ blood. The ratio of CO₂ release (4 ml CO₂ 100 ml⁻¹ blood) to O₂ uptake (5 ml O₂ 100 ml⁻¹ blood) is called the respiratory exchange ratio, which has a value of 0.8 in this case. This ratio is also, though not strictly correctly, referred to as the respiratory quotient. Under steady state conditions the respiratory exchange ratio is determined by the substrates being metabolized by the body and 0.8 is fairly typical for someone on a mixed, Western-style diet (Section 4.7).

Pulmonary diffusion

Pulmonary gases must diffuse through several structures between the alveoli and the capillary blood (Fig. 68). A layer of alveolar fluid lies over the epithelium, which sits on a basement membrane. This may actually fuse with the basement membrane of the capillary endothelium so that the total thickness of the diffusion barrier can be as little as 0.2 μm. Coupled with the large alveolar surface area (about 70 m²), this short diffusion distance makes the lungs very efficient gas exchange units, i.e., they have a high diffusion capacity. If the thickness of the diffusion barrier is increased, e.g., because of an increase in alveolar fluid during pulmonary oedema, or the available alveolar area is decreased, e.g., in emphysema, which involves alveolar destruction, gas exchange will be impaired as a result of the reduced diffusion capacity. This may cause abnormalities in the systemic arterial blood gas levels, even when alveolar ventilation is perfectly adequate.

Fig. 68 The alveolar wall through which pulmonary diffusion must occur. The basement membrane of the respiratory epithelium and the capillary endothelium have fused. A surfactant-secreting type II pneumocyte is also shown.

Ventilation : perfusion ratio

Normal gas exchange requires both that alveoli are adequately ventilated and that they are perfused with pulmonary blood at an appropriate rate. One way of quantifying this relationship is to measure the alveolar ventilation : perfusion ratio, .

(Eq. 23)

This may deviate from normal, a situation which is referred to as ventilation–perfusion mismatch. If an area of the lung is perfused but inadequately ventilated, will obviously be reduced. As a result, the alveolar falls and the rises since less ‘fresh’ air is brought into the alveoli than normal. In the most extreme case, where (perfusion with no ventilation), alveolar gas pressures will become equal to those in pulmonary arterial blood (Fig. 69). Blood passing through such a region will be inadequately oxygenated and this will reduce the final in the systemic arterial blood. Thus, areas with a decreased increase the physiological shunting of blood. This is a major factor contributing to the abnormal blood gases seen in many respiratory diseases.

Fig. 69 Changes in the alveolar gas concentrations with changing ratio. As increases, increases and decreases. Three specific points on the curve are indicated. When (i.e., perfusion with no ventilation), alveolar (5.3 kPa) and (6 kPa) equilibrate to the values in pulmonary arterial blood. When (i.e., ventilation with no perfusion), alveolar (20 kPa) and (0 kPa) become equal to the values in humidified air. The intermediate point plots the alveolar (13.7 kPa) and (5.3 kPa) when is normal.

Where alveoli are ventilated but not properly perfused, will be increased. Such regions contribute less than they should to pulmonary gas exchange so they add to the physiological dead space. In the absence of gas diffusion in and out of the pulmonary blood, alveolar rises and falls. In the most extreme case, where pulmonary flow equals zero (i.e., ), the alveolar gas pressures become equal to those in humidified room air (Table 6; Fig. 69). This can occur in regions of the lung affected by a pulmonary embolus, a travelling blood clot which completely obstructs one of the pulmonary arteries.

For the lungs as a whole under normal conditions, the mean value for = 4 L min⁻¹ (alveolar ventilation rate) ÷ 5 L min⁻¹ (pulmonary blood flow) = 0.8. The local value of varies with posture. The upper regions of the lung are more poorly ventilated and more poorly perfused than the bases. When standing, however, the increase in ventilation between the apex and the base of the lung is much smaller than the parallel increase in perfusion, so that decreases as one moves towards the base. At the apices of the lungs is about 3.0 (contributing to the physiological dead space), but this falls to about 0.6 at the bases (which contribute to the physiological shunt).

Measurement of pulmonary gas exchange

The efficiency of gas exchange in the lungs is often measured in terms of the transfer factor for carbon monoxide (T_CO). This is added to the inspired air at very low concentrations (CO is poisonous; Section 4.4). The increase in arterial CO content over a short period of time is then measured to provide a value for the rate of CO absorption. Since haemoglobin has an extremely high CO affinity, essentially all the absorbed CO becomes attached to the haemoglobin leaving none in the plasma. This means that the pulmonary arterial PCO can be assumed to be zero, so that the diffusion gradient driving CO absorption equals the alveolar PCO, which is measured. From this the transfer factor for CO can be calculated.

(Eq. 24)

The transfer factors for O₂ and CO₂, though different from that for CO, will be proportional to T_CO, which can, therefore, be used clinically to assess whether pulmonary gas exchange is impaired. Defects may arise because of impaired diffusion across the alveolar walls themselves but are more commonly caused by a ventilation–perfusion mismatch.

Gas exchange in peripheral tissues

The pressure gradients driving peripheral gas exchange are normally dictated by and levels within a given tissue, since systemic arterial blood gas pressures are kept constant, with a of about 13 kPa (98 mmHg) and a of 5.3 kPa (40 mmHg). Tissue gas pressures may vary widely from organ to organ and time to time, depending on the balance between blood flow and local metabolic activity, which consumes O₂ and produces CO₂. Average values are about 5.3 kPa (40 mmHg) for and 6 kPa (45 mmHg) for , so the pressure gradients favour O₂ diffusion from the blood into the interstitium, while CO₂ diffuses in the opposite direction. Systemic capillary blood equilibrates with the interstitial fluid so that systemic venous gas tensions equal those in the interstitium (Fig. 67). On average, resting body tissues take up O₂ at a rate of about 5 ml 100 ml⁻¹ blood flow, and release CO₂ at about 4 ml 100 ml⁻¹ blood.

4.4 Gas transport in blood

Both O₂ and CO₂ are transported between the lungs and the tissues in the blood. The mechanisms involved will be considered separately for each gas.

Oxygen transport

Haemoglobin

The vast majority of the O₂ in blood is transported within red cells and is bound to haemoglobin, with only a negligible additional amount dissolved in the plasma. One haemoglobin molecule consists of four polypeptide chains (the globin elements), each of which is attached to a pigmented haem group made up of a protoporphyrin ring surrounding a ferrous ion (Fe²⁺). Oxygen can bind reversibly with these haem elements, forming oxyhaemoglobin, so a single molecule of haemoglobin can carry up to four O₂ molecules.

Various factors may reduce the O₂-carrying capacity of blood. Simplest, and most common, is a reduction in the concentration of haemoglobin, a condition known as anaemia. This may arise in various ways, although nutritional deficiencies and chronic blood loss are probably the commonest causes in Western society (Section 2.3). The O₂-carrying capacity of the blood is proportional to the haemoglobin concentration, and this explains the main symptoms of anaemia, which include weakness, tiredness and reduced exercise tolerance. The normal haemoglobin concentration is about 15 g dl⁻¹ in males and 13 g dl⁻¹ in females (1 dl = 0.1 L = 100 ml). Since each gram of haemoglobin can carry 1.34 ml of O₂, this equates to O₂ capacities of 20 and 17.5 ml 100 ml⁻¹ blood, respectively.

Some conditions reduce the ability of the haemoglobin molecules to carry O₂ (reduce their O₂ affinity). For example, if the Fe²⁺ is converted to Fe³⁺, then the O₂-binding capability is greatly reduced. Certain drugs can oxidize haemoglobin in this way, forming methaemoglobin. Carbon monoxide can also interfere with O₂ transport since it binds very tightly to haemoglobin, leading to a build-up of carboxy-haemoglobin. Little unbound haemoglobin is left for O₂ transport.

Oxygen dissociation curve

This sigmoid, or S-shaped curve describes the relationship between the partial pressure of O₂ and the concentration of O₂ in blood (Fig. 70A). As is raised from zero to 2 kPa the O₂ content of the blood also rises, slowly at first and then more rapidly. The shape of this initial part of the curve reflects the fact that there are four O₂ binding sites on each haemoglobin molecule. When one site attaches to O₂, the O₂-binding ability of the other sites is increased and so the rate of rise of O₂ concentration also increases. This phenomenon is known as cooperativity, since the separate haemoglobin subunits cooperate in their function. As the is increased further, more and more O₂ is carried in the blood until all the available sites on haemoglobin are occupied (saturation); the curve reaches a plateau at a of around 16 kPa (120 mmHg). Further increases in have little effect on O₂ transport.

Fig. 70 Oxygen dissociation curves. (A) Oxygen content for a normal blood sample ([Hb] = 15 g dl⁻¹), and for an anaemic sample ([Hb] = 7.5 g dl⁻¹). (B) Oxygen saturation curve showing O₂ content as a percentage of the maximum in each sample. This is independent of [Hb].

The quantity of O₂ carried depends on the haemoglobin concentration, so that a 50% reduction in haemoglobin (from 15 to 7.5 g dl⁻¹) also reduces the oxygen content at the plateau (the O₂-carrying capacity) by half (Fig. 70A). It is important to appreciate, however, that this only alters the height of the dissociation curve; its shape is not affected by the haemoglobin concentration. Plotting the O₂ concentrations in the normal and anaemic samples as percentages of their own maximum values, i.e., in terms of the O₂ saturation of the blood, produces identical curves (Fig. 70B). Any change in this saturation curve indicates a change in the O₂-carrying properties of the haemoglobin itself, rather than a change in haemoglobin concentration.