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Respiratory function tests 

Respiratory function tests
Chapter:
Respiratory function tests
Author(s):

G.J. Gibson

DOI:
10.1093/med/9780199204854.003.180301_update_001

July 30, 2015: This chapter has been re-evaluated and remains up-to-date. No changes have been necessary.

Update:

Chapter reviewed by author in December 2012—minor alterations made.

Updated on 30 May 2013. The previous version of this content can be found here.
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Essentials

Respiratory function tests are used in diagnosis, assessment and prognosis and in monitoring the effects of treatment of various respiratory conditions. Their use as a diagnostic tool is in recognizing patterns of abnormality which characterize particular types of disease; more often they are used to quantify the severity of functional disturbance or to locate the likely anatomical site(s) of disease (airways, alveoli, or chest wall).

The commonly applied tests are most conveniently classified as (1) tests of respiratory mechanics, (2) carbon monoxide uptake, (3) arterial blood gases and acid–base balance, and (4) exercise.

Tests of respiratory mechanics

Spirometers record the volume of air that is displaced from the lungs in tidal breathing or with forced inspiratory and expiratory manoeuvres. This allows measurement of the tidal volume (VT), inspiratory capacity (IC), forced expiratory volume in 1 s (FEV1) and vital capacity (VC). Residual volume (RV) remains in the lungs after full expiration. Total lung capacity (TLC) represents the volume of air in the lungs after full inspiration—the sum of VC and RV.

RV cannot be measured by spirometric methods: inert gas dilution and whole-body plethysmography are the two main clinical methods used for the measurement of absolute lung volume.

Forced expiratory tests are simple to perform, do not require complex equipment, and are relatively independent of the effort applied by the patient.

The characteristic feature of diffuse airway obstruction is slowing of the rate of expiration, so that the ratio of FEV1 to FVC (or FEV1 to VC) is reduced, which defines an ‘obstructive’ ventilatory defect. In the alternative ‘restrictive’ pattern of ventilatory function TLC is reduced and both FEV1 and VC are reduced in approximate proportion.

Measurement of FEV1 and VC is not sensitive to localized narrowing of the central airway: air flow during forced expiration and inspiration should be examined as maximum flow–volume curves if this is suspected.

Measurements of respiratory muscle function are indicated in evaluation of patients with various neuromuscular diseases.

Carbon monoxide uptake

Carbon monoxide (CO) diffusing capacity (DLco) or transfer factor (TLco) is widely used as a simple test of the integrity of the alveolar capillary membrane and the overall gas exchanging function of the lungs.

Arterial blood gases and acid–base balance

The primary measurements made by modern blood gas analysers are the arterial partial pressures of oxygen (PaO2) and carbon dioxide (PaCo2), and hydrogen ion concentration [H+] or pH.

A reduction in PaO2 can occur by various mechanisms, but in disease the commonest is mismatching of alveolar ventilation (.VA) and perfusion ( .Q).

Respiratory failure is defined in terms of the arterial blood gas tensions as a reduction in PaO2 below 8 kPa (60 mmHg) at sea level, either without (‘type I’) or with (‘type II’, ‘ventilatory failure’) CO2 retention.

The ratio of PaO2/FIo2 is widely used in assessment of patients with severe problems of oxygenation: in acute lung injury a value greater than 300 (PaO2 in mmHg, FIo2 as a fraction) indicates relatively mild hypoxaemia, whilst a value of less than 100 represents very severe disturbance of gas exchange.

Abnormal acid–base disturbances are traditionally classified as one of four types: respiratory acidosis and respiratory alkalosis—where the primary disturbance is reduced or increased CO2 excretion respectively—and metabolic acidosis and metabolic alkalosis—where the primary disturbance is increased or decreased [H+] respectively. A mixed picture is frequently seen.

The likely cause(s) of metabolic acidosis are usefully classified in terms of the ‘anion gap’, which is calculated simply by subtracting the concentrations of the most abundant anions in blood (chloride and bicarbonate) from the most abundant cations (sodium and potassium).

Exercise

Exercise tests can be useful in evaluating the symptom of breathlessness, in the assessment of disability, and in determining the likely factors limiting performance.

Introduction

Respiratory function tests are used in diagnosis, assessment and prognosis and in monitoring the effects of treatment of various respiratory conditions. In the diagnosis of specific diseases, respiratory function tests —like functional tests of other organs—inevitably have limitations. Their use as a diagnostic tool is in recognizing patterns of abnormality which characterize particular types of disease. More often they are used to quantify the severity of functional disturbance or to locate the likely anatomical site(s) of disease (airways, alveoli, or chest wall). The commonly applied tests are most conveniently classified as (1) tests of respiratory mechanics, (2) carbon monoxide uptake, (3) arterial blood gases and acid–base balance, and (4) exercise. Measurements made during sleep are described elsewhere (see Chapter 18.5.2).

Tests of respiratory mechanics

Mechanics of breathing

The volume of air in the lungs at the end of tidal expiration at rest (functional residual capacity—FRC) represents the ‘neutral’ volume of the thorax, i.e. the volume pertaining when the respiratory muscles are inactive (as also during anaesthesia with muscle paralysis). Expansion of the lungs above FRC is achieved by contraction of the inspiratory muscles (predominantly the diaphragm), while normal resting tidal expiration is essentially passive, with the driving force provided by elastic recoil of the lungs. The main expiratory muscles are those of the abdominal wall; their contraction increases abdominal pressure which is transmitted to the thorax. In health these muscles become active when ventilation is increased markedly, as on exercise, or during coughing, when a high intrathoracic pressure aids the clearance of airway secretions.

Measurements of ventilation

Measurements of tidal breathing (tidal volume, respiratory frequency) are rarely made in the resting awake subject, other than recording respiratory rate as part of clinical examination. Measurement of ventilation is, however, of importance in patients receiving ventilatory support (such as in intensive care units), during detailed exercise testing, and during sleep investigations. During exercise testing, ventilation is usually obtained by electrical integration of airflow measured at the mouth, but this approach is impracticable for prolonged monitoring (such as during sleep) and the application of a mouthpiece and nose clip may itself disturb the pattern of resting breathing. Less intrusive methods of varying complexity are available, based on measuring external movement of the chest wall (ribcage and abdomen). Most are at best semiquantitative. They include the traditional mercury/rubber tube stethograph (measuring chest circumference), magnetometers (diameter) and the inductance plethysmograph (cross-sectional area). To obtain an estimate of ventilation, measurements of both ribcage and abdominal motion are required, together with an appropriate calibration procedure using a spirometer. The most recent and most complex technique of optoplethysmography uses a number of small reflectors on the chest and abdomen, illuminated by infrared light, with the reflected signals captured and processed electronically to allow three-dimensional reconstruction of dynamic chest wall volume, e.g. during exercise testing.

Elastic properties of the lungs

In principle the mechanical function of the respiratory system can be characterized by the compliance (‘stiffness’) of the lungs and chest wall and the resistance of the airway. In practice, however, none of these is commonly measured directly in clinical testing. For measurement of pulmonary compliance the pressure required to distend the lungs is obtained by recording oesophageal pressure, which equates to pleural pressure. In clinical investigation, the elastic properties of the lungs are usually inferred from measurements of lung volumes, because lungs which are unusually stiff and poorly compliant (as in pulmonary fibrosis) are usually shrunken and reduced in volume, while lungs with abnormally high compliance (as in emphysema) are easily distensible and are associated with increased total lung capacity. The traditional subdivisions of lung volume are illustrated in Fig. 18.3.1.1 and the changes seen in disease in Fig. 18.3.1.2.

Fig. 18.3.1.1 Subdivisions of lung volume illustrated by spirometric recording of volume against time during tidal breathing for three breaths, followed by maximal inspiration and then maximal forced expiration, before returning to tidal breathing in a normal subject. FEV1, forced expiratory volume in 1 s; FRC, functional residual capacity; IC, inspiratory capacity; RV, residual volume; TLC, total lung capacity; VC, vital capacity; VT, tidal volume. Note that TLC = FRC + IC = VC + RV.

Fig. 18.3.1.1
Subdivisions of lung volume illustrated by spirometric recording of volume against time during tidal breathing for three breaths, followed by maximal inspiration and then maximal forced expiration, before returning to tidal breathing in a normal subject. FEV1, forced expiratory volume in 1 s; FRC, functional residual capacity; IC, inspiratory capacity; RV, residual volume; TLC, total lung capacity; VC, vital capacity; VT, tidal volume. Note that TLC = FRC + IC = VC + RV.

Fig. 18.3.1.2 Pattern of lung volumes in disease. Overall height of bars represents total lung capacity (TLC) as % predicted; shaded areas show relative sizes of residual volume (RV); horizontal solid line shows functional residual capacity (FRC); vital capacity (VC) is represented by open bars. Dotted lines refer to normal TLC, FRC, and RV.

Fig. 18.3.1.2
Pattern of lung volumes in disease. Overall height of bars represents total lung capacity (TLC) as % predicted; shaded areas show relative sizes of residual volume (RV); horizontal solid line shows functional residual capacity (FRC); vital capacity (VC) is represented by open bars. Dotted lines refer to normal TLC, FRC, and RV.

Airway resistance

Direct measurement of airway resistance requires estimation of the pressure difference along the airway, between the alveoli and mouth. The various techniques available for estimating alveolar pressure include oesophageal pressure monitoring, body plethysmography, and transient interruption of airflow. With the latter (interruption) method, mouth pressure during transient occlusion is assumed to equal the alveolar pressure immediately prior to occlusion. As this requires little cooperation from the subject it is used more often in paediatric than adult practice. The plethysmographic method can be combined with measurement of lung volumes (see below). It requires the subject to make gentle panting efforts both with and without an occlusion at the mouth, while seated in a body plethysmograph.

Airway resistance varies with lung volume, falling as volume increases due to an expanding effect of more negative pleural pressure and the increased tension in the lung tissue surrounding the intrapulmonary airways. Resistance (RAW) is often expressed as its reciprocal, conductance (GAW), which in turn can be divided by the lung volume at which it is measured (specific airway conductance, SGAW) to allow for variations in volume. Resistance is dominated by the narrowest part of the airway, which in the normal subject is the upper airway (trachea and larynx). Although more peripheral airways are smaller individually, the great increase in their number with sequential branching creates a much larger overall cross-sectional area. Since chronic airway disease usually has its greatest impact on peripheral airways, plethysmographic measurements of airway resistance are not sensitive to the earlier stages of disease.

An alternative method for evaluating airway resistance is by forced oscillation, which involves superimposition of a small oscillating pressure at the mouth during tidal breathing; the resulting pressure and flow information is used to calculate airway resistance.

In practice airway function is more commonly assessed by tests based on forced expiration (see below).

Measurements of lung volume

A spirometer records only the air which can be displaced from the lungs and not their absolute volume, because the unmeasured residual volume (RV) remains in the lungs after full expiration. The maximum volume expired after a full inspiration (or inspired after a full expiration) is known as the vital capacity (VC), and the total lung capacity (TLC) represents the volume of air in the lungs after full inspiration—the sum of VC and RV (Fig. 18.3.1.1). Two main clinical methods are used for measurement of absolute lung volume—inert gas dilution and whole-body plethysmography.

Inert gas dilution

The subject breathes a gas mixture containing an inert marker gas, usually helium, from a closed circuit. The helium equilibrates gradually with the gas in the lungs so that its concentration falls progressively and stabilizes once mixing is complete. In a healthy individual this occurs in 5 to 10 min, but in patients with diffuse airway disease, such as asthma or chronic obstructive pulmonary disease, the test gas is very unevenly distributed, equilibration is much slower, the endpoint is less definite and, consequently, lung volume is likely to be underestimated. The lung volume which is measured is that in the lungs when the subject was connected to the circuit (usually FRC). After disconnection from the rebreathing circuit the subject inspires fully and the volume inspired (inspiratory capacity, IC) added to FRC gives TLC (Fig. 18.3.1.1). Uneven distribution of the inspired gas and poor mixing in the lungs result in underestimation of lung volumes in patients with moderate or severe airway disease.

Whole-body plethysmography

The subject sits within a large airtight rigid chamber and makes gentle breathing efforts against a shutter, which closes the airway at the mouth. According to Boyle’s law (pressure × volume = a constant), as intrathoracic pressure falls during an inspiratory effort, the air in the lungs is rarefied and lung volume increases by a small amount. This, in turn, causes the pressure in the plethysmograph to increase. The converse occurs during expiratory efforts and the thoracic gas volume can be calculated from the pressure changes recorded. Total lung capacity and residual volume are then derived by full inspiration and expiration immediately on opening the shutter. This method measures the volume of any air spaces within or without the lung that share pressure changes during breathing efforts, hence poorly ventilated areas of lung (or even those totally unventilated, such as a bulla) are included.

Abnormalities of lung volumes

An increase in TLC occurs in most patients with symptomatic diffuse airway obstruction. A large increase is characteristic of emphysema, but is not specific for this condition. Increases are also seen in asthma, even in relative remission. A pathological reduction in TLC occurs in several conditions (Table 18.3.1.1), not only lung diseases such as pulmonary fibrosis, but also extrapulmonary conditions affecting the pleura, thoracic skeleton, or respiratory muscles, conditions which—along with severe obesity—all potentially impede full lung expansion (Fig. 18.3.1.2).

Table 18.3.1.1 Common causes of reduced total lung capacity

Intrapulmonary

  • Surgical resection of lobes/lung

  • Pulmonary collapse

  • Consolidation

  • Pulmonary oedema

  • Interstitial fibrosis

Extrapulmonary

  • Pleural effusion

  • Pleural thickening

  • Pneumothorax

  • Ribcage deformity, e.g. scoliosis

  • Respiratory muscle weakness

  • Gross obesity

Patients with airway disease develop marked increases in RV and FRC, and the latter (or more strictly, the end expiratory lung volume) increases further on exercise, a phenomenon known as dynamic hyperinflation. This is a useful adaptation for such patients in that breathing over a higher tidal volume range allows ventilation to increase on exertion. However, maintaining higher lung volumes requires more work by the inspiratory muscles, and hyperinflation contributes significantly to the dyspnoea which such patients develop on exertion. The extent of dynamic hyperinflation can be assessed by measuring inspiratory capacity during exercise by having the subject inspire periodically to full inflation and then return to tidal breathing.

Tests of forced expiration

Spirometry

The strengths of forced expiratory tests include the simplicity of both the manoeuvre and equipment required, and also the relative independence of the measurements of the effort applied by the patient. Forced expiratory tests are effort-dependent to the extent that a preceding full inspiration is required, but during forced expiration the larger intrathoracic airways are subject to dynamic compression by the surrounding pleural pressure. The net result is that, provided a modest effort is applied, increasing the effort merely compresses the airway further and produces no increase in flow. This effort independence is more marked as forced expiration proceeds, and is also more marked in patients with airway obstruction than in healthy subjects.

Maximum expiratory flow is most dependent on effort at higher lung volumes (i.e. closer to full inflation). As peak expiratory flow (PEF) is attained very rapidly at the start of forced expiration, it is therefore more effort-dependent than the forced expiratory volume in 1 s (FEV1), which effectively integrates flow over a large proportion of the expired volume. PEF is measurable with a simple peak flow meter and is used by patients, particularly those with asthma, to monitor respiratory function at home.

The most commonly used index of mechanical function of the lungs is the 1 s forced expiratory volume (FEV1)—the volume expired forcefully in 1 s following complete inspiration (Fig. 18.3.1.1). This is usually obtained together with the forced vital capacity (FVC), the maximum volume expired during a forced expiration. In healthy subjects the FVC is effectively the same as VC, but in patients with airway disease the FVC is often appreciably less than the true (‘relaxed’) VC obtained if the subject is encouraged to expire completely without excessive initial effort.

The characteristic feature of diffuse airway obstruction is slowing of the rate of expiration so that the ratio of FEV1 to FVC (or FEV1 to VC) is reduced. This defines an ‘obstructive’ ventilatory defect. In the alternative ‘restrictive’ pattern of ventilatory function, both FEV1 and FVC are reduced in approximate proportion but, strictly, a restrictive defect implies that TLC is reduced so cannot be diagnosed confidently by spirometry alone.

Although in patients with diffuse airway obstruction the FVC and VC are reduced—at least in those with symptomatic disease—the reduction is proportionally less than that in FEV1. The ratio of FEV1 to (F)VC indicates the presence of airway obstruction but it is a poor guide to severity, which is better assessed by comparing the FEV1 alone with its predicted value. An obstructive spirometric pattern is seen in asthma, chronic obstructive pulmonary disease, and widespread bronchiectasis, while a restrictive ventilatory pattern is seen in numerous conditions (Table 18.3.1.1).

A further feature of diffuse airway obstruction is an increase in RV and in the ratio RV/TLC, but the latter is less specific than a reduced FEV1/VC ratio as it also occurs in some patients with cardiac disease or respiratory muscle weakness. With dual pathology, combined obstructive (low FEV1/VC) and restrictive (low TLC) defects are often found. Sometimes TLC may be within the normal range due to opposing influences with, for example, lung fibrosis tending to reduce it and airway obstruction to increase it.

Maximum flow–volume curves

Measurement of FEV1 and VC is the best way of identifying the diffuse airway narrowing of chronic obstructive pulmonary disease or asthma, but is less sensitive to localized narrowing of the central airway. If the latter is suspected, it is particularly helpful to visualize air flow obtained during forced expiration (and also inspiration) as maximum flow–volume curves, which relate instantaneous flow to volume expired and inspired (Fig. 18.3.1.3).

Fig. 18.3.1.3 Schematic maximum expiratory and inspiratory flow–volume curves in: (a) normal young adult; (b) normal older adult; (c) patient with pulmonary fibrosis and reduced FVC; (d) patient with moderately severe chronic obstructive pulmonary disease showing overall reduction in maximal flow but particularly in V˙E max, at lower lung volumes; (e) patient with subglottic (extrathoracic) tracheal stenosis showing markedly reduced V˙I max at all volumes and reduced V˙E max at higher volumes; (f) patient with central intrathoracic (carinal) tracheal narrowing showing similar plateau of flow to (e) but greater reduction of V˙E max than of V˙I max.

Fig. 18.3.1.3
Schematic maximum expiratory and inspiratory flow–volume curves in: (a) normal young adult; (b) normal older adult; (c) patient with pulmonary fibrosis and reduced FVC; (d) patient with moderately severe chronic obstructive pulmonary disease showing overall reduction in maximal flow but particularly in E max, at lower lung volumes; (e) patient with subglottic (extrathoracic) tracheal stenosis showing markedly reduced I max at all volumes and reduced E max at higher volumes; (f) patient with central intrathoracic (carinal) tracheal narrowing showing similar plateau of flow to (e) but greater reduction of E max than of I max.

Expiration

The expiratory curve has a characteristic shape, with an early peak equivalent to the PEF obtained with a peak flow meter. Maximum expiratory flow then declines progressively as volume is expired. In young healthy subjects (Fig. 18.3.1.3a), the descending limb of the curve approximates a straight line, whilst in older normal subjects (Fig. 18.3.1.3b), maximum expiratory flow is less, particularly at lower lung volumes, and the curve becomes concave to the volume axis. In patients with diffuse intrathoracic airway obstruction (such as chronic obstructive pulmonary disease or asthma) the pattern is qualitatively similar to that of ageing, but greatly exaggerated, with expiratory flow reduced more markedly as lung volume declines (Fig. 18.3.1.3d). The shape of the flow–volume curve does not distinguish between different causes of diffuse airway narrowing and so cannot allow the distinction of asthma from chronic obstructive pulmonary disease or emphysema. In principle, measurements of maximum expiratory flow in the latter part of forced expiration should be more sensitive to milder degrees of airway narrowing. In practice, however, use of indices such as maximum flow after 75% of the FVC has been expired (FEF75) has proved disappointing because the very wide normal range seriously reduces its discriminating power. Another widely used measurement is the average maximum flow over the middle two quarters of expiration (FEF25–75, formerly known as maximum mid-expiratory flow—MMEF). Again, however, the value of this index is seriously compromised by its wide variation in the healthy population and also by its dependence on VC, such that reductions are seen with both obstructive and restrictive ventilatory defects.

The ‘plateau’ of maximum expiratory flow seen with upper airway obstruction has implications for the shape of the more commonly recorded forced expiratory spirogram. Since, on the spirogram (volume vs time) flow is represented by the gradient of the curve, a plateau on the flow–volume curve implies a ‘straight’ (rectilinear) spirogram over the same volume range. Such an appearance should therefore raise the possibility of narrowing of the central airway rather than the more common diffuse airway obstruction seen with asthma and chronic obstructive pulmonary disease (Fig. 18.3.1.4).

Fig. 18.3.1.4 Schematic spirograms of two patients with airway obstruction and similar FEV1. (a) Diffuse intrathoracic airway narrowing (chronic obstructive pulmonary disease or asthma). Note that forced expiration is continuing after 6 s. (b) Upper airway narrowing with ‘straight’ spirogram which corresponds to plateau of flow in earlier part of expiration in Fig. 18.3.1.3e.

Fig. 18.3.1.4
Schematic spirograms of two patients with airway obstruction and similar FEV1. (a) Diffuse intrathoracic airway narrowing (chronic obstructive pulmonary disease or asthma). Note that forced expiration is continuing after 6 s. (b) Upper airway narrowing with ‘straight’ spirogram which corresponds to plateau of flow in earlier part of expiration in Fig. 18.3.1.3e.

Inspiration

The maximum inspiratory flow–volume curve has a more symmetrical appearance than the expiratory curve. In patients with diffuse airway narrowing there is an overall reduction in maximum inspiratory flow, but little change in shape (Fig. 18.3.1.3d). In patients with a restrictive ventilatory defect caused, for example, by pulmonary fibrosis, the volume displaced (FVC) is reduced but absolute flows are little affected (Fig. 18.3.1.3c).

Characteristic features are seen in patients with localized narrowing of the central airway, with the pattern depending on whether the narrowing is extra- or intrathoracic. Extrathoracic narrowing (Fig. 18.3.1.3e), such as occurs with subglottic tracheal stenosis or upper tracheal tumours, has a relatively greater effect on inspiratory than expiratory flow (which corresponds to the predominantly inspiratory timing of the stridor of upper airway narrowing). Maximum expiratory flow is also affected, but unlike chronic obstructive pulmonary disease or asthma the effects are most marked at higher lung volumes, often producing a virtual ‘plateau’ of expiratory flow in the first part of forced expiration. If the central airway is narrowed within the thorax (e.g. lower trachea or carina) a similar plateau of expiratory flow, often with a small initial peak, may be seen, but maximum inspiratory flow is relatively less affected (Fig. 18.3.1.3f).

These patterns can be quantified in terms of various ratios, such as that of maximum expiratory to inspiratory flow at 50% of VC, or the ratio of PEF (markedly reduced with upper airway obstruction) to FEV1 (proportionally less reduced). Such derived indices should be interpreted in light of the overall shape of the curves.

Respiratory muscle function

Forcible static inspiratory and expiratory efforts against a closed airway allow measurement of maximum expiratory and inspiratory pressures (PE max, PI max). In general, the expiratory (predominantly abdominal) muscles perform most effectively at high lung volumes and the inspiratory muscles (predominantly the diaphragm) at lower volumes. PE max is therefore usually measured after full inspiration and PI max at FRC or RV. Unfortunately, the normal ranges for these tests are wide and some patients find difficulty in performing the manoeuvres, which are by definition completely effort-dependent. Alternatively, inspiratory muscle strength can be assessed during a forceful sniff, with the pressure measured in the nose via an occluded nostril. Many (though not all) patients find this easier than performing maximum static inspiratory manoeuvres, so that the maximal sniff technique may give more reproducible results. Many laboratories ask patients to perform both and report the numerically greater result.

These measurements all assess the global strength of the inspiratory or expiratory muscles. More specific information on diaphragmatic function requires measurement of transdiaphragmatic pressure using pressure-sensing devices in both oesophagus and stomach—a specialized investigation available in only a few centres. A simple indirect index of disproportionate diaphragmatic weakness or paralysis is a large (>25%) reduction in VC in the supine compared with the erect posture. However, isolated bilateral diaphragmatic paralysis or severe weakness is very uncommon and most patients with respiratory muscle weakness have disease affecting all the muscles. Causes include not only primary neuromuscular diseases such as myopathies, muscular dystrophies, motor neuron disease, and myasthenia gravis, but also drug treatment (corticosteroids), several endocrine and connective tissue disorders, and cachexia from whatever cause. Respiratory muscle weakness is often an important factor preventing weaning from assisted ventilation.

Measurements of respiratory muscle function are indicated in evaluation of patients with various neuromuscular diseases. They are also helpful in confirming or excluding muscle problems in those with otherwise unexplained dyspnoea and in patients with a restrictive ventilatory defect in whom the cause of the lung volume reduction is not apparent on clinical and radiographic grounds. Interpretation may be complicated in patients with airway obstruction (such as chronic obstructive pulmonary disease or asthma) because the associated hyperinflation of the lungs itself impairs inspiratory muscle function. Maximum expiratory pressure is not affected by hyperinflation, however, and can be used as a guide to the presence of true muscle weakness in this situation.

Carbon monoxide uptake

Carbon monoxide (CO) diffusing capacity (DLco) or transfer factor (TLco) is widely used as a simple test of the integrity of the alveolar capillary membrane and the overall gas exchanging function of the lungs. It has good sensitivity but poor specificity, as impairment can result from several pathological processes (Table 18.3.1.2).

Table 18.3.1.2 Common causes of reduced carbon monoxide diffusing capacity (transfer factor, TLco)

Pulmonary diseases

  • COPD/emphysemaa

  • Asthma (with severe airway obstruction)

  • Pneumonectomy

  • Pulmonary fibrosisa

  • Sarcoidosis

  • Pulmonary vascular diseasea

Cardiac diseases

  • Pulmonary oedemaa

  • Mitral valve diseasea

  • Congenital right to left shuntsa

Systemic diseases

  • Anaemiaa

  • Renal failurea

  • Hepatic cirrhosisa

  • Rheumatoid disease

  • Systemic sclerosisa

  • Systemic lupusa

COPD, chronic obstructive pulmonary disease.

a Kco usually also reduced.

In the commonest method, the subject inspires fully a gas mixture containing a very low concentration of CO and the rate of uptake of gas is measured during breath holding for 10 s. The most important determining factor in most conditions is the effective surface area of alveoli available for gas exchange. Consequently DLco is reduced, for example, after resection of lung, but also with widespread emphysema, in which normal-sized alveoli are replaced by much larger air spaces, with a consequently greatly diminished area. DLco is also reduced when there is loss of the ‘effective’ alveolar volume (VA) in which the test gas is distributed. The latter is measured simultaneously from the dilution of helium which is also included in the inspired gas. The ‘effective’ VA is reduced if there is maldistribution of ventilation as this causes some alveoli to receive little or none of the inspired gas. Other factors affecting the DLco include the haemoglobin concentration and disease involving the pulmonary capillaries.

The transfer coefficient (Kco), which is obtained along with DLco, represents the uptake of CO per litre of ‘effective’ alveolar volume, that is, Kco = DLco/VA. Kco is typically normal or increased after lung resection, when both DLco and VA are reduced. It is usually normal (or sometimes mildly increased) in asthma, where any reduction in DLco is due only to maldistribution of ventilation secondary to airway narrowing. By contrast, DLco is reduced in widespread emphysema not only due to maldistribution of inspired gas, but also because even in the relatively better ventilated parts of the lung the gas exchanging surface area is diminished, hence Kco is also reduced. Some of the diseases associated with low DLco and Kco are listed in Table 18.3.1.2.

In some conditions Kco and, less commonly, DLco may be high (Table 18.3.1.3). Both increase with an increase in red blood cells in the lungs due to increased capillary blood volume, alveolar haemorrhage, or polycythaemia. Kco is also increased if, at full inflation, the density of pulmonary capillaries per unit alveolar volume is greater than normal. This occurs most commonly in patients with extrapulmonary volume restriction (e.g. muscle weakness), when the density of pulmonary capillaries is unusually high in relation to the (restricted) TLC at which the measurement is made.

Table 18.3.1.3 Conditions producing increased carbon monoxide diffusing capacity

DLco

Kco

Asthma

Sometimes

+

Pneumonectomy

+

Extrapulmonary restriction

Pleural disease

+

Ribcage deformity

+

Respiratory muscle weakness

+

Obesity

+

Left-to right-shunts

+

+

Polycythaemia

+

+

Lung haemorrhage

+a

+a

a May be an increase from an initially reduced value (e.g. Goodpasture’s syndrome).

Interpretation of respiratory function tests

Reference values

The results of respiratory function tests should be compared with reference values obtained in an appropriate healthy population. The major factors determining the results of most tests in the normal population are sex, age, body size (usually defined by height) and ethnicity. A variety of sources of reference values is available (see ‘Further reading’) and, increasingly, prediction equations are being developed for countries and ethnic groups hitherto poorly represented. Choice of the most appropriate equation(s) for a local population or a specific individual may not be straightforward; the problems are discussed extensively in the references quoted. The counsel of perfection is to compare results with those obtained in a large number of the local healthy population of the same ethnicity, but often this is not possible. An alternative is to use whichever equation(s) give results similar to those obtained in healthy subjects studied by the same operator or in the same laboratory. Good recent reference equations relevant to residents of North America are available (at least for spirometric and related measurements) from the third National Health and Nutrition Examination Survey (NHANES III). No equivalent large data sets are available in Europe and many laboratories still use the ‘summary equations’ derived by combining the results of many different series and published by the European Respiratory Society (ERS) in 1993, although these are no longer endorsed officially by the ERS in their latest (2005) recommendations.

Normal or abnormal?

After standardizing for the variables mentioned above, most lung function measurements are distributed normally in the healthy population. Classification of ‘normal’ or ‘abnormal’ is best done in terms of the number of standardized residuals by which a given measurement deviates from the mean predicted value (z score). With this approach a z score ranging from –2 to +2 encompasses 95% of a normally distributed population and –1.645 to +1.645 encompasses 90%. In general, when evaluating the results of respiratory function tests, the need is to identify a unidirectional abnormality, e.g. a low, rather than high, FEV1. It is therefore conventional to regard z values outside the 90% confidence intervals as ‘abnormal’. Thus, a z value more negative than –1.645 represents the lower 5th percentile of the normal range, i.e. only 1 in 20 of the healthy population would be expected to have a result below this value. The choice of this level is of course a compromise between sensitivity and specificity and should not be regarded as an absolute ‘cut-off’ which will accurately classify every individual.

The test results should be examined for internal consistency and interpreted in the light of the clinical and radiographic information available. A number of characteristic patterns of abnormality of spirometry, lung volumes, and CO diffusing capacity are recognized (Table 18.3.1.4).

Table 18.3.1.4 Common patterns of abnormal lung volumes and carbon monoxide diffusing capacity

Condition

FEV1

VC

FEV1/VC

RV

TLC

DLco

Kco

COPD/emphysema

↓↓

↑↑

↓↓

Asthma

↓↓

↑↑

→ or ↑

Interstitial lung disease

↓↓

↓ or →

Extrapulmonary volume restriction

↑ or →

Pulmonary vascular disease

↓↓

↓↓

Combined pathology (e.g. COPD + interstitial fibrosis)

↓↓

↑ or →

→ or ↓

↓↓

↓↓

COPD, chronic obstructive pulmonary disease.

→, normal; ↓, moderately reduced; ↓↓, markedly reduced.

Arterial blood gases

The primary measurements made by modern blood gas analysers are the arterial partial pressures of oxygen (PaO2) and carbon dioxide (PaCO2), and hydrogen ion concentration [H+] or pH. The alternative, commonly used, method of assessing oxygenation is by pulse oximetry, which estimates arterial oxygen saturation (SaO2). An oximeter has the advantage of allowing continuous monitoring, but it provides no information on PaCO2. Easy to use transcutaneous electrodes for estimating PaCO2 are becoming more widely available, but experience is limited to date.

Haemoglobin–oxygen dissociation curve

The general relation between the oxygen partial pressure in blood and haemoglobin saturation is defined by the oxygen–haemoglobin dissociation curve (Fig. 18.3.1.5). Its position is influenced by the prevailing pH, temperature, and Pco2, as well as by the concentration of 2,3-diphosphoglycerate (2,3-DPG) in red cells. Approximate values for normal arterial and resting mixed venous Po2 and saturation are shown in Fig. 18.3.1.5. A clinically useful ‘landmark’ is a saturation of 90% which, with a normally positioned curve, represents a Po2 of approximately 8 kPa (60 mmHg). Also shown in Fig. 18.3.1.5 is the P50, i.e. the Po2 at a saturation of 50%, which for normal adult haemoglobin is approximately 3.5 kPa (27 mmHg). This is measured in vitro and used to characterize abnormal haemoglobin molecules associated with increased (low P50) or decreased (high P50) affinity for oxygen.

Fig. 18.3.1.5 Normal haemoglobin–oxygen dissociation curve relating saturation to Po2. Point a represents normal arterial values (Po2 90 mmHg, 12 kPa; SaO2 98%) and v¯ normal resting mixed venous values (Pv¯o2 40 mmHg, 5.3 kPa; SaO2 75%). Also shown are the Po2 (c.60 mmHg, 8 kPa) corresponding to 90% saturation (point b) and the P50 (point c), i.e. Po2 corresponding to 50% saturation (c.27 mmHg, 3.5 kPa).

Fig. 18.3.1.5
Normal haemoglobin–oxygen dissociation curve relating saturation to Po2. Point a represents normal arterial values (Po2 90 mmHg, 12 kPa; SaO2 98%) and v¯ normal resting mixed venous values (Po2 40 mmHg, 5.3 kPa; SaO2 75%). Also shown are the Po2 (c.60 mmHg, 8 kPa) corresponding to 90% saturation (point b) and the P50 (point c), i.e. Po2 corresponding to 50% saturation (c.27 mmHg, 3.5 kPa).

Ventilation–perfusion mismatching

A reduction in PaO2 can occur by various mechanisms (Table 18.3.1.5). In disease, the commonest is mismatching of alveolar ventilation (A) and perfusion (). Even in healthy lungs, distribution of both ventilation and perfusion is uneven, due mainly to gravity. In disease, these relatively small effects are outweighed by unevenly distributed pathological changes affecting the distribution of ventilation or perfusion or both. Alveoli with greater than average A/ have higher than average local Po2 and lower Pco2, i.e. closer to those of inspired air. Conversely, alveoli with lower than average A/ have lower Po2 and higher Pco2, i.e. closer to the values in mixed venous (pulmonary arterial) blood. Within a single alveolus, complete equilibration of local gas tensions usually occurs, but in different pulmonary capillaries the gas tensions essentially reflect those of the alveoli which they subtend. For CO2 the effects of high A/ and low A/ areas on the final arterial Pco2 approximately cancel out, so that the arterial Pco2 is close to the average value in all the capillaries draining the alveoli. With oxygen, however, blood draining alveoli with high A/ (and therefore relatively high local Po2) cannot compensate for the areas with low A/ (and low Po2). This arises mainly because of the shape of the oxygen dissociation curve: the relatively flat upper part of the curve implies that increasing Po2 adds very little to oxygen saturation or concentration (content). Consequently, mixed pulmonary venous (and therefore systemic arterial) blood has an appreciably lower Po2 than would be found in mixed alveolar air.

Table 18.3.1.5 Mechanisms of arterial hypoxaemia

Mechanism

Cause

Low inspired Po2

Altitude (including air travel)

Hypoventilation

Neuromuscular diseases

Drugs depressing ventilatory drive

A/ mismatching

All pulmonary diseases

Anatomical shunt

Intracardiac right-to-left shunt

Pulmonary arteriovenous malformations

Limitation of oxygen diffusion

Pulmonary fibrosis (on exercise)

An approximate assessment of the overall effects of A/ mismatching on arterial oxygenation and PaO2 is given by calculation of the alveolar to arterial oxygen pressure gradient (P(A – a)o2 = PAo2PaO2). This requires estimation of the average alveolar Po2 (PAO2), which depends on the inspired Po2 (PIo2) and the average alveolar Pco2 (PACO2). For the reasons discussed above, alveolar and arterial Pco2 (unlike Po2) are virtually the same and the alveolar Po2 is given approximately by: (Equation 18.3.1.1)

PAo2=PIo2Paco2/0.8

The PIo2 breathing room air at sea level (moistened and warmed to body temperature) is approximately 20 kPa (150 mmHg). In normal young subjects the upper limit for P(A – a)o2 is about 2 kPa (15 mmHg). It increases with age and in healthy subjects aged 60 to 70 years may be as high as 4.7 kPa (35 mmHg). Unfortunately, interpretation of the P(A – a)o2 is complicated by the fact that its relation to the severity of A/ mismatching is not constant. For a given degree of A/ mismatching, the P(A – a)o2 increases as the alveolar Po2 increases. It therefore increases if the inspired oxygen is increased or if PaCO2 falls (see Equation 18.3.1.1).

Alternative indices which relate more predictably to the severity of A/Q· mismatching are the ratios of arterial to alveolar Po2 (a/A Po2), and of arterial Po2 to the inspired oxygen fractional concentration (PaO2/FIo2). The former is normally greater than 0.75 and changes little as FIo2 increases, whereas the more traditional P(A – a)o2 difference increases. The ratio of PaO2/FIo2 is widely used in assessment of patients with severe problems of oxygenation. For example, in acute lung injury a value greater than 300 (PaO2 in mmHg, FIo2 as a fraction) indicates relatively mild hypoxaemia, whilst a value of less than 100 represents very severe disturbance of gas exchange.

Estimation of ‘anatomical’ shunt

The dependence of P(A – a)o2 on inspired oxygen is exemplified by the effects of breathing pure oxygen. This is sometimes used as a test for the presence of anatomical right to left shunting, since the effects of A/ mismatching on PaO2 are effectively eliminated by breathing pure oxygen: even in diseased lungs, nitrogen is gradually ‘washed out’ of all the alveoli and the only remaining cause of arterial hypoxaemia is the anatomical shunt via channels which bypass the lungs, or through the capillaries supplying any alveoli that are totally unventilated. Although prolonged breathing of 100% oxygen encourages alveolar atelectasis which would exaggerate the shunt, in practice the technique is often helpful in investigating the causes of hypoxaemia. The usually quoted normal upper limit for the ‘anatomical’ shunt measured in this way is 5% of the cardiac output. In terms of the PaO2, a value greater than 500 mmHg (>73 kPa) is usually achieved.

Respiratory failure

Respiratory failure is defined in terms of the arterial blood gas tensions as a reduction in PaO2 below 8 kPa (60 mmHg) at sea level, either without (‘type I’) or with (‘type II’) CO2 retention. Hypercapnic (type II) respiratory failure is also known as ventilatory failure. The causes of type I respiratory failure are legion and include virtually all diseases which can affect the alveoli or the airways, either primarily or secondarily (e.g. cardiac failure). Hypercapnic (type II) respiratory failure is most commonly due to severe chronic airway disease. Less often it results from reduced ventilation as, for example, with severe respiratory muscle weakness or scoliosis. The mechanisms of elevation of PaCO2 in type II respiratory failure are twofold. Sustained ‘pure’ hypoventilation—reduction in overall ventilation resulting in hypercapnia—is rare. It is seen with inadequate performance of the respiratory ‘bellows’, e.g. in neuromuscular disease, or because of reduced drive to breathe in the unconscious subject. Much more commonly, as in chronic airway disease, the ‘effective’ alveolar ventilation is reduced as a consequence of mismatching of ventilation and perfusion. In this situation there is often a considerable amount of ineffectual or wasted ventilation (‘physiological dead space’) and consequently in such patients the total ventilation is often greater than normal, even in the presence of hypercapnia.

Acid–base balance

The carriage of CO2 by the blood and its excretion by the lungs constitute one of the two homeostatic mechanisms for regulating the acid–base status of the body. Because of the ease with which CO2 excretion can normally be increased, the lungs are able to adjust acid–base balance much more rapidly than the kidneys.

The carbonic acid association/dissociation equation is: Equation (18.3.1.2)

CO2+H2OH2Co3H++HCO3-

This defines the chemical relation between the three variables, Pco2, hydrogen ion concentration [H+], and bicarbonate concentration [HCO3]. If two are measured, the third is readily calculated. Hydrogen ion concentration is usually expressed as pH, its negative logarithm (to the base 10). This has the dubious advantage of expressing a very small numerical value as a more easily accessible number, but the pH scale is deceptive as it obscures the fact that the hydrogen ion concentration in blood and the changes seen in disease are exquisitely small in comparison to other commonly measured ions. Thus, a normal arterial pH of 7.4 represents [H+] of 40 × 10–9 mol/litre (i.e. approximately 1 millionth the concentration of other ions, which are usually expressed in units of 10–3 mol/litre). Doubling [H+] to 80 × 10–9 mol/litre or halving it to 20 × 10–9 mol/litre are equivalent to reducing pH to 7.1 or increasing it to 7.7 respectively (since the log10 of 2 is c.0.3, and pH is the negative log10 of [H+], 0.3 is simply subtracted from, or added to, the normal value of 7.4 if [H+] is multiplied or divided by 2).

Abnormal acid–base disturbances are traditionally classified in terms of these variables as four types (Table 18.3.1.6 and Fig. 18.3.1.6), but combined disturbances are frequently seen. The commoner causes of each are given in Table 18.3.1.7.

Table 18.3.1.6 Types of acid–base disturbance

Arterial

[H+]

pH

PaCO2

[HCO3]

Respiratory acidosis:

Acute

↑↑

↓↓

Chronic

↑↑

Respiratory alkalosis

Metabolic acidosis

Metabolic alkalosis

↑ or →

→, normal; ↓, moderately reduced; ↓↓, markedly reduced; ↑, moderately increased; ↑↑, markedly increased.

Fig. 18.3.1.6 Relations of pH and [H+] to Pco2 in acid–base disorders. Bands indicate the expected ranges in uncomplicated respiratory (acute and chronic) and metabolic disorders. Isopleths represent corresponding estimates of arterial [HCO3–] (× 10–3mol/litre). Values outside these bands indicate intermediate or combined disturbances. For example: patient a with an acute exacerbation of chronic obstructive pulmonary disease has an ‘acute-on-chronic’ respiratory acidosis (PaCO2 10.6 kPa, pH 7.24, [H+] 58 × 10–9mol/litre, [HCO3–] 34 × 10–3mol/litre); patient b with both respiratory and circulatory failure has a combined respiratory and metabolic acidosis (PaCO2 8 kPa, pH 7.04, [H+] 95 × 10–9mol/litre [HCO3–] 15 × 10–3mol/litre).

Fig. 18.3.1.6
Relations of pH and [H+] to Pco2 in acid–base disorders. Bands indicate the expected ranges in uncomplicated respiratory (acute and chronic) and metabolic disorders. Isopleths represent corresponding estimates of arterial [HCO3] (× 10–3mol/litre). Values outside these bands indicate intermediate or combined disturbances. For example: patient a with an acute exacerbation of chronic obstructive pulmonary disease has an ‘acute-on-chronic’ respiratory acidosis (PaCO2 10.6 kPa, pH 7.24, [H+] 58 × 10–9mol/litre, [HCO3] 34 × 10–3mol/litre); patient b with both respiratory and circulatory failure has a combined respiratory and metabolic acidosis (PaCO2 8 kPa, pH 7.04, [H+] 95 × 10–9mol/litre [HCO3] 15 × 10–3mol/litre).

Table 18.3.1.7 Commoner causes of acid–base disturbance

Disturbance and site of disease

Cause

Respiratory acidosis

Cerebral

  • Drugs (sedatives, hypnotics, anaesthetics)

  • Raised intracranial pressure

  • Primary alveolar hypoventilation (very rare)

Spinal cord

Trauma

Motor neurons

Motor neuron disease, poliomyelitis

Peripheral nerves

Guillain–Barré syndrome, etc.

Motor endplate

Myasthenia gravis, neuromuscular blocking agents

Respiratory muscles

Myopathies, dystrophies etc.

Ribcage

Scoliosis, trauma, thoracoplasty

Lung parenchyma

ARDS, pulmonary oedema (severe), interstitial fibrosis (very advanced)

Airways

COPD, asthma (severe), upper airway obstruction (very severe)

Respiratory alkalosis

Cerebral

Anxiety, central neurogenic hyperventilation (very rare), drugs (aspirin)

Pulmonary

Pulmonary fibrosis etc., pneumonia, pulmonary embolism, asthma, pulmonary oedema

Iatrogenic

Mechanical overventilation

Metabolic acidosis

Increased anion gap

Ketoacidosis, uraemia, lactic acidosis, drugs (aspirin), poisons (ethylene glycol)

Normal anion gap

Renal tubular acidosis, severe diarrhoea

Metabolic alkalosis

Severe vomiting

Pyloric stenosis, etc.

Iatrogenic

Diuretics, corticosteroids, bicarbonate infusion

ARDS, acute respiratory distress syndrome; COPD, chronic obstructive pulmonary disease.

Respiratory acidosis and alkalosis

In respiratory acidosis the prime event is accumulation of CO2 due to inadequate or ineffective ventilation. This causes the equilibrium of Equation 18.3.1.2 to shift to the right, generating hydrogen and bicarbonate ions. The immediate increase in bicarbonate concentration is dictated by this chemical relationship and not by the physiological response, which occurs later. The vast majority of hydrogen ions produced are buffered by proteins and the increase in [HCO3] (measured in 10–3 mol/litre) is actually very much greater than the measured increase in hydrogen ion concentration (10–9 mol/litre). Conventionally the effects of acute respiratory acidosis are distinguished from the chronic respiratory acidosis, which results after several hours or days. This follows renal retention of even more bicarbonate, which in turn tends to correct the pH towards normal (Table 18.3.1.6).

In respiratory alkalosis the primary event is increased CO2 excretion resulting from hyperventilation, so that both [HCO3] and [H+] fall (pH rises), but, again, most of the change in [H+] is buffered.

Metabolic acidosis and alkalosis

In metabolic acidosis [H+] rises (pH falls) and [HCO3] falls. The physiological response is so rapid that acute and chronic phases are not distinguishable. Any tendency for PaCO2 to rise (equilibrium of Equation 18.3.1.2 shifted to the left) is more than offset by the increased drive to breathe resulting from production of acid, and the measured effect is a reduction in PaCO2. The likely cause(s) of metabolic acidosis are usefully classified in terms of the ‘anion gap’, which is calculated simply by subtracting the concentrations of the most abundant anions in blood (chloride and bicarbonate) from the most abundant cations (sodium and potassium). The difference represents other anions (mostly protein and inorganic phosphate) normally present in blood. An increase above the normal anion gap therefore implies an excess of other anions associated with metabolic acidosis (e.g. lactate, ketoacids).

In metabolic alkalosis there is an increase in [HCO3] and a reduction in [H+] (pH increases). The measured result is somewhat variable due to opposing influences: any increase in PaCO2 tends to stimulate breathing, but the reduced acidity tends to inhibit it. In subjects with healthy lungs, the net effect is often maintenance of PaCO2 in the high normal range, unless the alkalosis is profound (e.g. as seen with vomiting due to pyloric stenosis and severe depletion of acid). However, in patients with chronic airway disease and pre-existing or incipient hypercapnia, an increase in PaCO2 occurs more readily. This is particularly relevant to patients with chronic obstructive pulmonary disease receiving treatment with diuretics and corticosteroids, both of which tend to produce a metabolic alkalosis.

Other acid–base indices

Several other indices of acid–base status have their advocates. Standard bicarbonate, base excess and deficit, and total buffer base are often derived when blood gases are measured by automated equipment. They are obtained by titration of the blood in vitro to specified standard values of pH and/or Pco2. They are open to the objection that the results differ from those which would be obtained if the same titration could be performed in vivo, where the extracellular fluid, and not just the blood, participates in buffering. Indices such as standard bicarbonate and base excess are used mainly to distinguish ‘respiratory’ and ‘metabolic’ components of an acid–base disturbance, but in this context the ‘metabolic’ component includes renal compensation for a primary respiratory disturbance. Consequently, in a respiratory acidosis, an increased standard bicarbonate indicates some degree of chronicity. Conversely, the severity of acidaemia in a hypercapnic patient is a useful practical index of the ‘acute’ component of an acute-on-chronic respiratory acidosis and is widely used, for example, when deciding on the need for noninvasive ventilation.

Another simple and frequently available index of acid–base status is the venous ‘bicarbonate’ (strictly total CO2 content), which is often obtained routinely when electrolytes are measured. A raised value is seen with primary metabolic alkalosis, but in patients with respiratory disease it may also be a useful clue to unsuspected ventilatory failure.

‘Strong ion’ approach

The analysis of acid–base balance presented above is oversimplified. A more comprehensive (but more complex) approach based on the principles of physical chemistry was proposed by Stewart and subsequently developed by others. This focuses on the factors that independently determine [H+], reducing the emphasis on [HCO3], which is shown to be itself a dependent variable. According to this analysis, the independent variables controlling acid–base balance are three: the Pco2, the ‘strong ion difference’ (SID), and the total weak acid concentration (a weak acid is one which is partly dissociated rather than completely ionized). SID is the difference between the charge of the strong (completely dissociated) cations and anions in plasma, which in effect boils down to [Na+] + [K+] – [Cl]. A higher value of SID reduces acidity (higher pH). The weak acids in blood are predominantly proteins, particularly albumin, with a small contribution from inorganic phosphate.

This approach defines six rather than four primary acid–base disorders. Respiratory disturbances remain as before, but metabolic acidosis and alkalosis can each be either of two types, resulting from increases or decreases either in SID or total weak acid concentration. Decreasing SID or increasing [weak acid] produces acidosis, while increasing SID or decreasing [weak acid] produces alkalosis.

In practice the strong ion approach is of most value in understanding complex metabolic disturbances, as commonly occur in patients receiving intensive care. In particular it highlights the important role of albumin concentration: since albumin is a weak acid, a reduction in its concentration has an alkalinizing effect, such that a metabolic acidosis resulting from a reduction in SID may be underestimated or concealed in patients with hypoalbuminaemia. Again, it is well recognized that infusion of large volumes of normal saline can result in an acidosis: in terms of the strong ion theory this is readily explicable as due to a reduction in plasma SID as plasma [Cl] increases relatively more than [Na+]. An important determinant of SID is renal function, in particular the regulatory effect of the kidneys on plasma chloride concentration. Thus, in ‘renal compensation’ for a respiratory acidosis, the strong ion approach emphasizes increased excretion of chloride (rather than retention of bicarbonate); this increases plasma SID and therefore reduces acidaemia.

Exercise testing

Exercise tests can be useful in evaluating the symptom of breathlessness, in the assessment of disability, and in determining the likely factors limiting performance.

In healthy subjects during progressive exercise, ventilation and cardiac output increase with oxygen consumption. Oxygen uptake (o2) increases with work rate, but at higher levels of exercise anaerobic respiration increases with generation of lactic acid. Initially, CO2 production is proportional to oxygen consumption until increasing anaerobic metabolism results in disproportionate production of CO2. Measurement of an ‘anaerobic threshold’ during progressive exercise is favoured by some investigators, but the criteria used for its identification are not universally agreed.

In a healthy subject, the maximum oxygen consumption (maximum aerobic capacity) is determined by the ability of the circulation to supply oxygen to exercising muscle, rather than by the maximum ventilation which can be achieved. In patients with lung disease, however, the maximum attainable ventilation is reduced, approximately in proportion to the abnormality of pulmonary mechanics. This may then determine exercise capacity, although circulatory factors and deconditioning also contribute in many patients and dominate in some.

Exercise tests vary considerably in complexity and in the number and types of measurements made. Simple self-paced tests of walking distance, most commonly in 6 min, aim to mimic the real life situation and are widely used for global assessment of disability. However, such tests are insensitive to mild disease and there is a significant learning effect, as well as dependence on motivation and encouragement. An alternative simple test is the shuttle walk test in which the subject increases his walking speed each minute; this gives more reproducible results than the 6-min walk and is more akin to laboratory-based tests of maximum performance.

More formal testing involves controlled exercise on a bicycle ergometer or treadmill. Usually the workload is increased progressively by a constant amount, with periods of 1 to 3 min at each level. Measurements include heart rate, ventilation, gas exchange (o2 and co2), and oxygen saturation by pulse oximetry. The level of breathlessness at each workload in an incremental test can be assessed using simple self-rating scales (visual analogue scale or Borg scale). The subject exercises at increasing loads until no longer able to continue because of discomfort, or until stopped by the investigator. The maximum oxygen consumption (symptom limited o2 max) is a useful indicator of overall exercise capacity. Comparison of the maximum ventilation and heart rate at the end of progressive exercise with those predicted from spirometric measurements and age, respectively, gives some indication of the likely factor(s) limiting performance. If, for example, a patient achieves the predicted maximum heart rate during a progressive test (as is seen in normal subjects), it is reasonable to conclude that the limit to further exercise is set by the cardiovascular system. In most respiratory diseases, patients cease exercise with a lower heart rate, as more often the limit is set by the maximum ventilation achievable. Arterial oxygen desaturation is seen in some (but not all) patients with advanced chronic obstructive pulmonary disease, and also in those with interstitial lung disease and pulmonary vascular disease; this can be helpful in predicting patients likely to benefit from the use of ambulatory oxygen.

The identification of exercise-induced asthma has rather different requirements. During exercise, most subjects with asthma show bronchodilatation; in those who develop exercise-induced asthma, bronchoconstriction develops after exercise. Of course many patients with asthma become unduly breathless during exercise, but in most this is due to the increased work of breathing associated with a degree of pre-exercise airway obstruction or to deconditioning, rather than to exercise-induced bronchoconstriction. The intensity of exercise necessary to provoke asthma is relatively high and, for this reason, exercise-induced asthma is relevant mainly to children and young adults. Optimally it is demonstrated after exercising for at least 5 min at a constant rate, chosen to increase ventilation to around 50% maximal or to increase heart rate to around 80% maximal. FEV1 or peak flow should be measured beforehand and for up to 30 min afterwards.

Miscellaneous tests

Analysis of expired air has traditionally been limited to oxygen and carbon dioxide, but recently attention has turned to other gases which are present in very low concentrations. The concentration of exhaled carbon monoxide has been used for some years as a guide to its inhalation and as a valuable method for confirming non-smoking claims. The measurement can now be made very simply with a portable analyser. Breath carbon monoxide is also increased in nonsmoking subjects with asthma, where it appears to be released as a result of airway inflammation. In similar fashion, expired nitric oxide concentration is increased as a consequence of airway inflammation and it has been proposed as a non-invasive way of assessing airway inflammation and its treatment, particularly in those with asthma. Care needs to be taken to avoid contamination of expired air from the bronchial tree with that from the nose and nasal sinuses, which contain higher concentrations of NO.

Further reading

American Thoracic Society/European Respiratory Society (2002). ATS/ERS statement on respiratory muscle testing. Am J Respir Crit Care Med, 166, 518–624.Find this resource:

    Gibson GJ (2009). Clinical Tests of Respiratory Function, 3rd edition. Hodder Arnold, London.Find this resource:

      Hughes JMB (2009). Physiology and Practice of Pulmonary Function. Association for Respiratory Technology and Physiology, Boldmere, UK.Find this resource:

        Kharitonov S, Alving K, Barnes PJ (1997). ERS Task Force Report: Exhaled and nasal nitric oxide measurements: recommendations. Eur Respir J, 10, 1683–93.Find this resource:

          MacIntyre N, et al. (2005). Standardisation of the single breath determination of carbon monoxide uptake in the lung. Eur Respir J, 26, 720–5.Find this resource:

            Miller MR, et al. (2005). General considerations for lung function testing. Eur Respir J, 26, 153–61.Find this resource:

              Miller MR, et al. (2005). Standardisation of spirometry. Eur Respir J, 26, 319–38.Find this resource:

                Pellegrino R, et al (2005). Interpretative strategies for lung function tests. Eur Respir J, 26, 948–68.Find this resource:

                  Roca J, Whipp BJ (eds) (1997). Clinical exercise testing. Eur Respir Monogr, 2(6).Find this resource:

                    Sirker AA, et al. (2002). Acid–base physiology: the ‘traditional’ and the ‘modern’ approaches. Anaesthesia, 57, 348–56.Find this resource:

                      Wanger J, et al. (2005). Standardisation of the measurement of lung volumes. Eur Respir J, 26, 511–22.Find this resource:

                        West JB, Wagner PD (1997). Ventilation–perfusion relationships. In: Crystal RG, West JB (eds) The lung: scientific foundations, 2nd edition, pp. 1693–709. Lippincott-Raven, Philadelphia.Find this resource:

                          Sources of normal reference values

                          Cerveri I, et al. (1995). Reference values of arterial oxygen tension in middle-aged and elderly. Am J Respir Crit Care Med, 152, 934–41.Find this resource:

                            Cotes JE, Chinn DJ, Miller MR (2006). Lung function, 6th edition. Blackwell, Oxford.Find this resource:

                              European Respiratory Society (1993). Standardised lung function testing. Eur Respir J, 6(Suppl 16).Find this resource:

                                Hankinson JL, Odenkrantz JR, Fedan KB (1999). Spirometric reference values from a sample of the general U.S. population. Am J Respir Crit Care Med, 159, 179–87.Find this resource:

                                  Jones NL, Summers E, Killian KJ (1989). Influence of age and stature on exercise capacity during incremental cycle ergometry in men and women. Am Rev Respir Dis, 140, 1373–80.Find this resource: