Investigations

Pulmonary function: the basics

J M B Hughes

Abbreviations used in pulmonary function tests

Mechanics FEV1 FVC VC TLC FRC IC RV ERV PEF FEF75

Abstract
The basics of pulmonary function testing in hospital laboratories are spirometry (FEV1, FVC, FEV1/FVC) and the carbon monoxide transfer fac tor (TLCO) and its components (KCO [TLCO/VA] and VA). A low FEV1/FVC ratio indicates intrapulmonary airflow obstruction. Distinction between intrapulmonary and extrapulmonary (upper airway) obstruction is given by maximal inspiratory and expiratory flowvolume curves. Other tests of lung mechanics are measurements of absolute lung volumes (TLC, FRC, RV) and maximal inspiratory and expiratory pressures against an ob struction at the mouth. Spirometry, lung volumes and mouth pressures can differentiate obstructive (low FEV1/FVC) and restrictive (normal FEV1/ FVC, low TLC) patterns, detect hyperinflation (high TLC and FRC) and respiratory muscle weakness (reduced mouth pressures). The TLCO and KCO measure the integrity of the bloodgas barrier, being reduced in em physema, interstitial lung diseases and pulmonary vascular pathology. The KCO (as % predicted) is high in extrapulmonary restriction (pleural, chest wall and respiratory neuromuscular disease), and in loss of lung units provided the structure of the lung remaining is normal. Thus, the KCO distinguishes extrapulmonary (high KCO) causes of restriction from intrapulmonary causes (low KCO). Significant hypoxaemia (low PaO2) normally provokes compensatory hyperventilation and lowering of the PaCO2. Surrogates for arterial blood gases, avoiding arterial puncture, include pulse oximetry, arterialized capillary samples and transcuta neous PO2 and PCO2 probes.

MEFV MIFV PImax PEmax Gas exchange CO TLCO KCO VA

Forced expiratory volume in one second Forced vital capacity Slow vital capacity Total lung capacity Functional residual capacity (the relaxed endexpiratory volume) Inspiratory capacity (TLC FRC) Residual volume (TLC VC) Expiratory reserve volume (FRC RV) Peak expiratory flow Forced expiratory flow after 75% of VC expired alternative nomenclature: MEF25 [max expiratory flow with 25% VC remaining in the lung] Maximum expiratory flow-volume curve started from TLC Maximum inspiratory flow-volume started from RV (syn: MIP) lowest mouth pressure during a maximum inspiratory effort from RV or FRC (syn: MEP) highest mouth pressure during a maximum expiratory effort from TLC Carbon monoxide (syn: DLCO) transfer factor for carbon monoxide (syn: diffusing capacity) (syn: TL/VA) rate of uptake of carbon monoxide Alveolar volume (measured by gas dilution, during the TLCO measurement; VA 90% TLC, but <90% TLC when FEV1/FVC ratio is reduced) Fractional concentration of inspired oxygen (often as percentage) Haemoglobin concentration Arterial gas tension [P = partial pressure] Inspired oxygen partial pressure (reduced at altitude, unlike FIO2) Percentage saturation of haemoglobin with oxygen in arterial blood Percentage saturation of Hb with oxygen using pulse oximetry
Q3

FIO2 Hb PaO2, PaCO2 PIO2 SaO2%

Keywords arterial blood gases; flowvolume curves; KCO; lung function

algorithm; lung volumes; mouth pressures: pulse oximetry; spirometry

This article is an overview of pulmonary function testing. Those responsible for Pulmonary Function Laboratories should consult a recent informative series of papers from the American Thoracic Society/European Respiratory Society Task Force on Standardization of lung function testing.15 An up-to-date review of pulmonary exercise testing (not dealt with in this article) is also available.6 Pulmonary function tests (PFTs) measure many aspects of lung performance or reserve (Table 1). PFTs are quantitative, objective measures of normality or abnormality and, importantly, of improvement or deterioration in response to treatment.

SpO2%

Table 1

J M B Hughes DM FRCP is Honorary Professorial Fellow at the National Heart and Lung Institute, Imperial College Faculty of Medicine, Hammersmith Hospital, London, UK. Competing interests: none declared.
Q1

They can be repeated at will without any hazard or trouble to the patient. Pulmonary function testing is done in most situations where respiratory symptoms are persistent, but some specific indications are:  part of the workup in suspected chronic obstructive pulmonary disease (COPD) and asthma  analysis of the restrictive pattern of lung function (low TLC and normal FEV1/VC ratio); the TLCO can distinguish interstitial lung disease from chest wall or respiratory muscle causes  pre-operative assessment
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Investigations

 investigation of dyspnoea in the absence of other respiratory symptoms. To what extent are the lungs involved?  screening for pulmonary involvement in systemic disease (connective tissue, heart failure, sickle cell, vasculitis, etc).

What is normal and what is abnormal?

A reliable result for FEV1, for example, depends on the skill of the operator and the cooperation of the patient, unlike a measurement of haemoglobin.5,7 While instrument or analytical errors are randomly distributed, performance errors underestimate the true value. Therefore, it is usual to take the best of the three highest FEV1 measurements (provided the best is within 5% of the next best and they are technically acceptable), and to reject lower values. The same reasoning applies to the FVC.3 In the TLCO measurement, the inspired VC should be within 10% of actual FVC (or slow VC) for the measurement to be accepted; it is acceptable to take the mean of the two highest TLCO values (which, in general, will correspond to the two highest VA values).4 For comparison to normal, patients measurements are referred to regression equations derived from normal populations, taking age, height, and gender into account; there are other factors which are important in the natural variability amongst so-called healthy people, such as habitual activity (muscle strength), nutrition (thoracic and abdominal fat and muscle), BMI and environment (altitude, climate, air pollution, smoking), but their effect on the regression equations is small and can be neglected. Ethnic differences present a problem.7 Some non-Caucasian people have lung volumes which are up to 15% less for a given age and height, but it is thought that nutrition in pregnancy and childhood is responsible, so such differences are disappearing. Measurements of gas exchange (PaO2) and transfer efficiency (KCO) have no ethnic or gender differences. For PFT measurements in Europe and North America, where reference values are weighted towards Caucasian subjects, a practical solution would be to note the ethnic origin in the PFT report, rather than correct the lung volumes by an arbitrary figure. Systemic disease in childhood (e.g. sickle cell anaemia) may reduce expectations. Ideally, the reference population for normality should encompass equal numbers of men and women in each age

cohort from 20 to 80 years of age, who are never smokers, are free from respiratory disease, and live locally. This ideal is only rarely achieved.8 The ERS recommendations pool reference equations from many sources and many countries.9 Pellegrino et al.5 provides a comprehensive account of refer ence equations. Another problem is how to express abnormality. Percent predicted normal (% pred.) has the virtue of simplicity for the busy clinician, with less than 80% pred. being considered abnormal, but ignores the variability on either side of the regression line, called the residual standard deviation (RSD) (1.64 RSD includes 90% of a population with a normal or Gaussian distribution).7 The standardized residual (SR) = observed predicted value/RSD. Only 5% of a reference population will have SR greater than +1.64 and another 5% will have an SR less than 1.64, and results within this range can be considered normal. An SR from1.65 to 2.5 represents mild impairment, between2.5 and 3.5 moderate impairment, and beyond 3.5 severely abnormal (note that for some tests (RV, for example) SR greater than +1.65 and above is abnormal). Although the use of standard deviations in the form of SR is more respectable scientifically than the simpler and more user-friendly % pred., it too has its problems. Because each regression equation has a constant RSD, irrespective of the range of height or stature, there is a bias in favour of short and old people. Thus, Table 2 shows discordance between estimates of impairment based on % pred. versus SR.7 The first line of Table 2 shows the big influence of height and age on predicted values. Although all three subjects have an identical VC % pred., the abnormality in terms of departure from the 90% confidence limits (bottom of the range or SR) is greatest for the young, tall man and least for the old, short man. So what should the PFT report contain? Most laboratories would quote the actual value, the % pred. and the range. Clinicians find % pred. easy to assimilate. SR gives a better quantitative feel than looking at the range, and probably should replace it (but with a note appended to the report saying SR 1.64 is abnormal but SR may underestimate abnormality in old subjects with small stature). There is always the danger of information overload if the PFT report contains too many numbers.

Measurements of forced vital capacity in male subjects of different ages and stature to show the discordance between estimates of % predicted and standardized residuals
White male FVC [L] predicted*,3 FVC [L] actual VC % predicted SD of regression coefficient [L] Range [1.64 SD] [L] Standardized residual (SR) 25 years, 1.85 m 5.7 3.7 64 0.6 6.74.7 3.3 Impairment 25 years, 1.55 m 3.9 2.5 64 0.6 4.92.9 2.4 Impairment 75 years, 1.55 m 2.6 1.7 64 0.6 3.61.6 1.5 Impairment

Moderate

Moderate

Moderate

Moderate

Mild

Normal

*FVC = 5.76H 0.026A 4.34 (H = height (m), A = age (years). FVC, forced vital capacity; VC, relaxed vital capacity; SD, standard deviation.

Table 2

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Investigations

Mechanics
Spirometry2,10 Obstructive versus restrictive patterns The maximal effort FVC is the most frequently performed test in pulmonary function laboratories (Figure 1a). The preceding (slow) inspiration must be maximal (TLC must be reached); the subject (without pausing) then exhales as hard and for as long as possible until the minimal lung volume (RV) is reached. See Miller et al.2 for acceptability criteria for FEV1 and FVC. The forced expiratory time will be less than 5 seconds in normal subjects but may be prolonged for more than 20 seconds in patients with airflow obstruction. Thus, the FVC depends, to a certain extent, on the duration of the expiration (Figure 1a). Attempts to standardize the FVC by using the forced expiratory volume exhaled after 6 s (FEV6)11 have not been widely taken up (note in Figure 1a the FEV6 underestimates considerably the true FVC), but the FEV6 and/or the slow VC (see below) are likely to be more reproducible than the FVC. The volume exhaled in the first second (FEV1) as a ratio of the total volume expired (FVC) is a measure of airflow obstruction. The normal FEV1/FVC ratio is 70% or more (there is some decline with ageing), less than 65% being definitely abnormal in those less than 65 years of age. From the spirogram (Figure 1a) two basic patterns can be distinguished the obstructive and the restrictive. Both reduce

the vital capacity (VC) by variable amounts, but for different reasons. Low VC in obstructive disease is caused by a slow rate of emptying due to airway narrowing, airway closure at low volumes and the difficulty in prolonging expiration for longer than 1520 seconds. In restrictive disease, the VC is reduced because the maximum volume (after the initial maximal inspiratory effort to TLC) is low, i.e. the lungs are too small, either due to intrapulmonary disease (fibrosis, loss of lung tissue) or due to extrapulmonary factors (weak inspiratory muscles, disease of the chest wall or pleura). Restrictive disease is defined as a reduced TLC. A mixed obstructive/restrictive pattern occurs when the FEV1/ FVC is low, and the TLC is also low (not normal or increased). This occurs typically in someone with COPD (usually mild) who develops an active interstitial lung disease. Forced expiratory volume in one second (FEV1) The distinction between obstructive and restrictive patterns is made on the basis of the emptying rate slow in obstructive disease and normal (or superfast) in restrictive disease (Figure 1a), characterized by the FEV1, but specifically by the FEV1/FVC ratio. The FEV1 is largely independent of expiratory effort, provided that the effort is applied sharply at the onset and that a threshold (40% maximum pressure) effort is reached. Effort

Expired airflow rates and volumes in obstructive versus restrictive diseases

a. Spirogram FEV1/FVC
4.0 0.75 7.5

b. MEFV curve Normal PEF Obstructive Restrictive FEF75 Expiratory f low (L.s 1)
5.0

0.47

Forced expiratory volume (L)

2.0

0.83

2.5

FEV1
0 0 1 3 6

FVC TLC
0 0 1.9 3.1

RV
4.0

Expired time (S)

FVC (L)

a. The spirogram. Expired volume from a forced manoeuvre, starting from TLC, plotted against time (seconds) with typical traces from a healthy subject and patients with obstructive and restrictive disease. FVC after 6 s (~FEV6) and FEV1 shown, with calculation of FEV1/FVC ratio. Note that in obstructive disease, the rising curve implies that the true FVC has not yet been reached b. Maximum expiratory flowvolume curve. Expiratory flow from a forced manoeuvre, starting from TLC, plotted against the FVC. Note descending limb is straight in the normal subject, scooped (or concave upwards) in obstructive disease, and straight, but truncated, in restrictive disease. PEF is indicated (for Normal curve only) but forced expiratory flow with 75% FVC expired (FEF75 ) is shown for all curves
MEFV, maximum expiratory flowvolume; TLC, total lung capacity; FVC, forced vital capacity; FEV , forced expired volume in one second; PEF, peak expiratory flow. 1

Figure 1

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Investigations

ndependence, and consequently reproducibility, increases as i airflow obstruction becomes more severe a useful attribute. FEV1 is also low in restrictive disease, so it is the FEV1/FVC ratio which is specific for airflow obstruction. Nevertheless, the FVC is less repeatable, so for follow-up the FEV1 is better than the FEV1/FVC ratio. Vital capacity (VC) The expiratory VC may be forced (FVC) or slow and relaxed (relaxed VC or just VC). Some laboratories prefer an inspiratory manoeuvre for the slow VC. A forced or rapid inspiratory VC (IVC) is used for:  the inspiration of the test gas mixture at the onset of the TLCO manoeuvre  in the detection of upper airway or extrathoracic airflow obstruction (see Figure 2). Some laboratories routinely measure the expired slow VC and report the FEV1/VC not the FEV1/FVC ratio (this is recommended by the ATS/ERS Task Force).5 The slow or relaxed VC is larger than the FVC in obstructive disease, but the differences are usually small unless the FEV1/FVC ratio is very low. In restrictive disease follow-up, VC (or FVC) as % pred. is a surrogate for TLC % pred. (all lung volumes change concordantly).

Normal spirometry and normal FEV1/FVC ratio does not xclude pulmonary microvascular disease (vasculitis, primary e pulmonary hypertension). Flowvolume curves In a maximum expiratory flowvolume (MEFV) curve (Figure1b), instantaneous flow is plotted against lung volume change. Peak expiratory flow (PEF) is reached shortly after the onset of expiration; flow declines subsequently because the airways narrow and lung elastic recoil (the effective driving pressure for maximal flow) declines as the lung gets smaller. Flow rates can be measured after 50% or 75% of the FVC has been expired (FEF50, FEF75), but inspection of the curve for scooping (see obstructive in Figure 1b) is more useful in practice, because the interindividual flow variability in a normal population is so large, although MEFV curves are very reproducible within an individual. If the flowvolume ratio is borderline for airflow obstruction (FEV1/FVC >65% or <75%), inspection of the latter third of the MEFV curve may confirm or refute the diagnosis. The maximum inspiratory flowvolume (MIFV) curve, which starts from residual volume (RV), taken together with the MEFV curve (Figure 2) is a sensitive indicator of extrathoracic airflow obstruction, either variable (Figure 2b) or fixed (Figure 2c). The reason for the difference between MEFV and MIFV curves is that

Expiratory and inspiratory maximal flowvolume curves

7.5 7.5

Expiratory flow (L.s-1)

5.0

5.0

MEFV
2.5

MEFV MEFV
2.5

TLC MIFV

RV

TLC MIFV

RV

TLC MIFV

RV

Inspiratory flow (L.s-1)

2.5

Ext.compression: goitre, acromegaly, OSA (episodic) Laryngeal polyp Weakness of tracheal wall 0 Volume (L) B

Tracheal stenosis

2.5

5.0 0

5.0 4 0

Volume (L) A

Volume (L) C

a. Expiratory and inspiratory flow plotted against expired volume for a normal subject. MEFV curve, except for upstroke and peak, is relatively effort (respiratory muscle) independent, but MIFV curve is respiratory muscle dependent. b. Flow limitation of MIFV, but not MEFV, curve occurs when extrathoracic airway is narrowed but remains compliant (flexible). The shape in OSA would occur during tidal breathing and with truncated flows and volumes. c. Flow limitation of both MEFV and MIFV curves occurs when extrathoracic airway is narrowed but is non-compliant.
MEFV, maximum expiratory flowvolume; MIFV, maximum inspiratory flowvolume; OSA, obstructive sleep apnoea; TLC, total lung volume; RV, residual volume.

Figure 2

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Inspiratory flow (L.s-1)

Expiratory flow (L.s-1)

Normal

Variable extrathoracic

Fixed extrathoracic

Investigations

the forces applied to airways inside or outside the thorax are quite different. The central intrathoracic airways are squeezed during forced expiration, but are distended during forced inspiration. In contrast, the extrathoracic airways are blown out on expiration and sucked in on inspiration. Flow limitation on the MEFV curve occurs in the central intrathoracic airways. The MIFV curve has a totally different shape from the MEFV curve. With maximal inspiration, flow is limited, not by the airways, but by the maximal force and speed of contraction of the muscles of inspiration. Although the extrathoracic airways are sucked in, they never become flow limiting in normal people. But if the upper airways are narrowed by external compression, luminal obstruction or wall weakness (Figure 2b), they will become flow limiting on inspiration, but not on expiration. Similar flow limitation during tidal breathing occurs episodically at night in obstructive sleep apnea (OSA) due to a combination of external compression (from fatty tissue) and loss of muscle tone in sleep. Since the MIFV curve is also dependent on inspiratory muscle strength, similar curves to Figure 2b may be seen with weakness of the diaphragm and other inspiratory muscles. Peak expiratory flow (PEF) Portable devices, specifically to measure peak flow, are popular with asthmatic patients who can monitor the variable component of their airflow obstruction, either at home or on holiday. PEF can also be read from the output of small handheld spirometers. PEF is not as reproducible, within an individual, as the FEV1, FVC or MEFV curve. By itself, it is not specific, being reduced in obstructive and restrictive disease. But, in an individual asthmatic patient, PEF is a very useful trend monitor. Reproducibility can be improved by telling patients to record the best reading from three consecutive efforts. Bronchodilator challenges2,5 The measurement of FEV1 and/or PEF following the inhalation of a bronchodilator (bd: generally a 2-receptor agonist) is a useful diagnostic and therapeutic test in patients with airflow obstruction. In asthma, the improvement in FEV1 may be greater than 0.5 litres, but in COPD it is usually less than 0.5 litres. Even small improvements in FEV1 following bd inhalation may relieve symptoms of dyspnoea or chest tightness, especially if the FEV1 itself is low (<1.0 litre). The FEV1 change can be expressed in absolute terms (+0.2 litre is considered a positive response), or relatively as % of predicted FEV1 as 100[FEV1 post bd FEV1 pre bd]/FEV1 predicted (+5% for a positive response). Lung volumes3 TLC, FRV and RV are absolute lung volumes, not volume changes like the vital capacity, inspiratory capacity (IC) or expiratory reserve volume (ERV). Their measurement, by body plethysmography or multibreath gas dilution, is more complex technically than spirometry or flowvolume curves. In airflow obstruction, TLC is generally normal and the VC reduced; hence RV (TLC VC) and the RV/TLC ratio are raised. In restrictive disease, the TLC is reduced by definition. A large TLC is seen in advanced emphysema, in giant bullous disease (often with emphysema), occasionally in severe asthma, and in 33% of cases of acromegaly. Residual volume is raised
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whenever there is generalized airflow obstruction, in congestive heart failure (the lungs are stiffer) and in expiratory muscle weakness. A low TLC and a low FEV1/FVC indicates a mixed obstructive and restrictive pattern, often restrictive disease in a life-long smoker, or following surgery to remove lung. Inspiratory capacity (IC) in airflow obstruction, particularly in emphysema and acute on chronic asthma, hyperinflation of the lung and chest wall during tidal breathing (and during exercise) increases the work of breathing and contributes to the sensation of dyspnoea. In hyperinflation, FRC and RV increase and the IC diminishes. IC = TLC FRC, and like VC (TLC RV), can be measured simply as a volume change. Measurement of IC, made with a spirometer after several tidal breaths, is an easy way of assessing dynamic hyperinflation (e.g. during COPD exacerbations12). IC increases following bronchodilator inhalation.13 IC reduction correlates with exercise impairment in COPD.14 Assessing respiratory muscle weakness15 Respiratory muscle weakness leads to a raised PaCO2 (hypercapnia) and a reduced VC. Unfortunately, these are insensitive indicators, not becoming abnormal until muscle power has fallen to 3050% of normal. More specific than the VC itself is the percentage fall in VC on adopting the supine position, which may be 3050% in diaphragm paralysis compared to less than 10% in normal subjects. The fall in supine VC is caused by the inability of a paralysed or severely weak diaphragm to develop enough tension to restrain a cranial shift of the abdominal contents. Other non-specific markers of respiratory muscle weakness are MEFV/MIFV curves (Figure 2b) and a high KCO (Table 3). A more specific test is the ability to develop a positive or negative pressure at the mouth against an obstruction. Maximum mouth pressures (PImax, PEmax) are simple measurements which record pressures during maximal inspiratory (at RV or FRC lung volumes; Mueller manoeuvre) or expiratory (at TLC; Valsalva) efforts against a closed airway. Patients may need coaching in what is an unfamiliar manoeuvre (a normal PImax and PEmax value is reassuring, but a low value should be treated with reserve and repeated after further practice); a more natural

What do the TLCO and PaO2 measure?

TLCO Potential for gas exchange Surface area for gas exchange (anatomy) Integrity of the blood gas barrier (pathology) Diffusion, not perfusion, dependent Normal in asthma Low in emphysema, ILD and CHF PaO2 Performance as a gas exchanger, i.e. physiology Efficiency of local matching of ventilation and perfusion (ventilation perfusion ratio); adequacy of global ventilation (PaCO2) Ventilation, perfusion and diffusion dependent Usually low in symptomatic asthma Relatively normal in emphysema, ILD and CHF

ILD, interstitial lung diseases; CHF, congestive heart failure.

Table 3

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Investigations

Gas exchange
Carbon monoxide transfer factor (TLCO) and arterial PO2 (PaO2) The TLCO and arterial blood gases are the two standard measurements, but they focus on different aspects of lung gas exchange, as can be seen from Table 3. The TLCO is a laboratory based measurement performed during breath holding at full inspiration (Figures 3 and 4), whereas PaO2 and PaCO2 are measured during quiet breathing in the clinic, ward or laboratory. PaO2 requires an arterial or ear lobe puncture, but TLCO needs only the inspiration and expiration of a test gas mixture. The single breath carbon monoxide transfer factor (TLCO)14,16 The TLCO is known as the diffusing capacity (DLCO) in North America and Australia. It is a much misunderstood measurement. The TLCO calculation from expired gas analysis is thought to be abstruse and complex, and little attention is paid to its interpretation clinically. In fact, in most pulmonary function laboratories, the TLCO is, after spirometry, the most frequently performed test, particularly in followup studies. The combination of spirometry and the transfer factor (with their components) two relatively simple measurements gives the clinician or scientist who understands the basic principles a powerful tool for addressing the question what is the functional and/or diagnostic abnormality? The algorithm in Figure 5 applies to 90% of patients passing through the pulmonary function laboratory. The respiratory manoeuvre is shown in Figure 3. CO is used in place of oxygen because it is diffusion limited, and tests the properties of the alveolarcapillary membranes in isolation. Helium is a reference gas, used to measure the alveolar volume (VA) seen by CO. To understand the TLCO and its interpretation, we need to go back to the work of August and Marie Krogh, the originators of the single breath TLCO in Copenhagen in 190914.14 The KCO (Figure 4) is a rate constant, representing the rate of alveolar
147 Volume

I ns p i r ation

(rapid )

act, that of sniffing, is becoming more popular. During a sniff, pressures at the back of the nose (in the pharynx) and in the oesophagus become more negative in proportion to the force generated by all the inspiratory muscles, of which the most important is the diaphragm. A more specific test for the diaphragm alone is a measurement of the pressure difference generated between the thoracic and abdominal cavities the oesophagealgastric pressure difference, called the transdiaphragmatic pressure (Pdi). This can also be measured by sniffing. The strength of the expiratory muscles the abdominal and internal intercostal muscles is important in generating an effective cough. Coughing, which is a natural manoeuvre like sniffing, produces in general higher maximum expiratory pressures than the Valsalva manoeuvre, but it does require the passing of a gastric balloon catheter. All these tests are volitional, i.e. require patient cooperation and motivation. In specialized centres, non-volitional tests are used when patients cannot cooperate fully because of pain, drowsiness or inattention; typically, this occurs in a post-operative patient in Critical Care Units. Non-volitional tests involve stimulation of the phrenic nerves. An indication for non-volitional tests might be the investigation of patients who are difficult to wean from ventilators.

The set up and breathing protocol for the single breath (CO) TLCO measurement
Single breath TLCO manoeuvre 0.3% CO 14% He 18% O 2

Single breath

FACO FAHe Spirometer

CO2+ H 2O analysis

He + CO analysis Dead space wash-out Volume inspired Sample

Residual volume Effective breath-holding time (RV)

0

Expiration

Time (seconds)

10

TLCO, transfer factor for carbon monoxide.

Figure 3

uptake of CO in % per second; it is an index of alveolar efficiency, the TLCO of a single alveolus, as it were. Therefore, the TLCO of all alveoli is KCO VA, after reference to barometric pressure minus water vapour pressure (Pb*).
TLCO =[KCO VA]/Pb* TLCO/VA=KCO/Pb* KCO (1) (2)

The Kroghs derivation of the single breath TLCO (equations 1 and 2) reminds us that the TLCO is the product of two components the same TLCO value can be produced by different combinations of KCO and VA,16 and that TLCO/VA or KCO is actually a rate constant [kCO/Pb*] and not the transfer factor corrected for lung volume. In fact, if the TLCO (in normal subjects) is measured at lung volumes less than TLC, TLCO/VA increases linearly as lung volume of the measurement diminishes, being about 150% of the value at TLC when the volume is 50% TLC, due to an increased surface to volume ratio per alveolus. This has an important clinical implication. In extrapulmonary restriction,

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Investigations

Concentrations of the test gases (CO and He) plotted against breath-hold time for the TLCO manoeuvre illustrating the origin and calculation of the two components (the slope [KCO] and the VA) from which the TLCO is derived
Helium (He) Carbon monoxide (CO)

TLCO graphical analysis

100

Gas concentration % inspired (log)

Hei inspired conc. COi Hei Het

exhalation sample

VA=VI 50

Het CO0 calculated from (COi (Het/ Hei ) slope = KCO Inspired vol. (VI) 10 Inhalation 0 5 10

recruits and distends the alveolar capillaries, increasing the efficiency of CO uptake. This is a loss of units pattern; the high KCO tells us that the lung remaining is normal and compensating for the tissue loss. Table 4 examines TLCO and its components (KCO and VA) in different pulmonary pathologies. In every instance TLCO is reduced, but the KCO is high in some circumstances (extrapulmonary restriction, and loss of units) and low in others, and this gives additional information and discrimination. The TLCO must be corrected for the effect of anaemia based on the current Hb level.4 In summary, in the presence of a low VA in restrictive disease, a high KCO suggests extrapulmonary restriction, or local (as opposed to diffuse) loss of aerated lung. In obstructive disease, VA will be lower than TLC, because of poor mixing in the short breath hold time, and KCO will be high, normal or low depending on the pathology involved (Table 4).

20

COt

Arterial PO2 and PCO2

The lower limit of PaO2 at sea level in a healthy person who is 40 years old is 11.6 kPa (88 mmHg).17 PaO2 falls by about 0.05 kPa (0.4 mmHg) per year, so the lower limit of normal at age 70 is 10 kPa (75 mmHg).17 There is no gender difference. PaCO2 does not change with age, being 4.35.3 kPa (3240 mmHg). In the elderly and obese, PaO2 is lower in the supine posture than in the erect. The measurement of PaO2 and PaCO2 usually requires arterial sampling and, for exercise studies, insertion of an arterial cannula. Sampling arterialized capillary blood from the vasodilated ear lobe is an alternative, but one which needs skill and practice. The lower the PaO2 the better the arterialized PO2 reflects true PaO2.18 Measurement of oxygen saturation by pulse oximetry (SpO2) Arterial and arterialized blood sampling, while not difficult or dangerous, require special skill and competence. Pulse oximetry, by contrast, is very quick, simple and non-invasive. A

Breath hold time (s)

TLCO, transfer factor for carbon monoxide; KCO, rate of uptake of carbon monoxide; VA, alveolar volume.

Figure 4

either due to respiratory muscle weakness or pleural restriction, the KCO (TLCO/VA) is 120150% of the TLC 100% pred. value. With the low VA, the product (TLCO) is still reduced, but not markedly. The KCO is also raised during exercise and also at rest if local blood flow per unit volume is increased (simulating exercise). Thus, after a pneumonectomy, pulmonary blood flow per unit volume in the remaining lung doubles, since cardiac output remains the same, and KCO averages 120% predicted. The increase of pulmonary flow and pulmonary artery pressure

Typical values for KCO, VA and TLCO in various pulmonary pathologies

Pathology Obstructive Asthma Emphysema Bronchiectasis (local loss of units) Obliterative bronchiolitis Restrictive Extrapulmonary (insp. muscle weakness, pleural) Cryptogenic fibrosing alveolitis (CFA/IPF) Loss of units (local disease/pneumonectomy) No obstruction or restriction Pulmonary vasculitis: 1y PHT Anaemia Table 4 KCO VA = TLCO Comment

NORM LOW+ NORM LOW HIGH+ LOW+ HIGH LOW LOW

NORM LOW LOW LOW LOW LOW LOW NORM NORM

NORM LOW+ LOW LOW LOW LOW+ LOW LOW LOW

No alveolar pathology. TLCO and KCO may be raised Alveolarcapillary destruction If remaining lung normal, KCO may be high Damage spreads from bronchioles to adjacent arterioles Lack of alveolar expansion pattern: underlying lung is normal Alveolarcapillary destruction Remaining lung normal with blood flow Microvascular loss: gas exchange area Lack of Hb molecules combining with CO

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Investigations

Typical spirometric, lung volume and transfer factor (TLCO and KCO) patterns for common pulmonary disorders
FEV1/FVC normal FVC low FVC

normal TLC (optional)

low TLC

normal TLC normal/high

low TLC normal/high low

restrictive TLCO TLCO

obstructive TLCO mixed obstructive /restrictive low

normal

low

normal

low

normal

KCO

KCO

KCO

KCO

KCO

KCO

normal

low

high+

high

normal

low normal ILD ASTHMA

normal

low

Normal

PVD

CW/Neuro

Loss of mixed units (loss of units/ILD)

BECTASIS

EMPHYSEMA BOLITIS

loss of units, local disease (absent or unaerated lung with normal function elsewhere). FVC, forced vital capacity; FEV1, forced expired volume in one second; T LCO, transfer factor for carbon monoxide; KCO , rate of uptake of carbon monoxide; PVD, pulmonary vascular disease; CW/Neuro, chest wall or neuromuscular disease; ILD,interstitial lung diseases; bectasis, bronchiectasis (local); bolitis, bronchiolitis.

Figure 5

probe is placed on a patients finger or ear lobe, and within three minutes (after an internal machine calibration) a reading of SpO2 (equivalent to SaO2) and pulse rate is available. The accuracy (SpO2 vs SaO2: between 1 and 2% actual saturation) depends upon good peripheral circulation and a strong pulse; warming the finger or ear by gentle rubbing or with vasodilator cream improves signal strength. The oximeter detects light at two wavelengths, corresponding to oxygenated and de-oxygenated haemoglobin. The signal is the difference in absorbance at each wavelength between the systolic peak of the pulse, which is dominated by the inflow of arterial blood, and the subsequent diastole. Carboxyhaemoglobin (COHb) and methaemoglobin absorb light at the same wavelength as deoxy-Hb, so that HbO2 is overestimated in the presence of HbCO (avoid smoking for at least 12 hours beforehand). Skin pigmentation is not a problem, but bright light and nail varnish should be avoided.

part from Pellegrino et al.,5 shows that patterns of test abnormalities emerge which are consistent with different clinical pathologies. Note the mixed obstructive/restrictive pattern (right side, middle) would warrant TLCO and KCO measurements but that these would not distinguish obstructive from restrictive pathology. Also, while normal FEV1/FVC, FVC and TLC, but low TLCO and KCO, suggests pulmonary vascular disease (PVD), early interstitial lung disease or emphysema is possible. Occasionally (not shown in Figure 5), the FEV1/FVC ratio is normal or near normal, FVC is reduced but TLC is normal and RV is increased.5 The MEFV may reveal a concave shape, or FEV1 and FVC may improve after bronchodilator inhalation; both suggest airflow obstruction.

Synthesis of mechanics and gas exchange

An algorithm (Figure 5), based on the three most commonly performed tests in pulmonary function laboratories and derived in
149

References 1  Miller MR, Crapo RO, Hankinson J, et al. General considerations for lung function testing. Eur Respir J 2005; 26: 15361. 2  Miller MR, Hankinson J, Brusasco V, et al. Standardization of spirometry. Eur Respir J 2005; 26: 31938.

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Investigations

3  Wanger J, Clausen JL, Coates A, et al. Standardization of the measurement of lung volumes. Eur Respir J 2005; 26: 51122. 4  MacIntyre N, Crapo RO, Viegi G, et al. Standardization of the single breath determination of carbon monoxide uptake in the lung. Eur Respir J 2005; 26: 72035. 5  Pellegrino R, Viegi G, Brusasco V, et al. Interpretative strategies for lung function tests. Eur Respir J 2005; 26: 94868. 6  Palange P, Ward SA, Carlsen KH, et al. Recommendations on the use of exercise testing in clinical practice. Eur Respir J 2007; 29: 185209. 7  Cotes JE, Chinn DJ, Miller MR. Lung function, 6th edn. Blackwell Publishing, 2006 [Chapters 2627]. 8  Roberts CM, MacRae KD, Winning AJ, Adams L, Seed WA. Reference values and prediction equations for normal lung function in a nonsmoking white urban population. Thorax 1991; 46: 102632. 9  Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. Lung volumes and forced ventilatory flows. Report of Working party Standardization of Lung Function Tests. Eur Respir J 1997; 6(suppl 16): 540. 10  Pride NB. Tests of forced expiration and inspiration. In: Hughes JMB, Pride NB, eds. Lung function tests: physiological principles and clinical applications. WB Saunders, 2000, p. 325. 11 Swanney MP, Jensen RL, Crichton DA, Beckert LE, Cardno LA, CrapoRO. FEV (6) is an acceptable surrogate for FVC in the spirometric diagnosis of airway obstruction and restriction. Am J Respir Crit Care Med 2000; 162: 91719. 12  Yernault JC. The birth and development of the forced expiratory manoeuvre: a tribute to Robert Tiffeneau (19101961). Eur Respir J 1993; 6(suppl 16). 13  Pellegrino R, Rodarte JR, Brusasco V. Assessing the reversibility of airway obstruction. Chest 1998; 114: 160712. 14 Albuquerque ALP, Nery LE, Villaa DS, et al. Inspiratory fraction and exercise impairment in COPD patients GOLD stages IIIII. Eur Respir J 2006; 28: 93944. 15  Moxham J. Respiratory muscles. In: Hughes JMB, Pride NB, eds. Lung function tests: physiological principles and clinical applications. WB Saunders, 2000. 16  Hughes JMB, Pride NB. In defence of the carbon monoxide transfer coefficient KCO (TL/VA). Eur Respir J 2001; 17: 16874. 17  Cerveri I, Zoia MC, Spagnolatti L, Berrayah L, Grassi M, Tinelli T. Reference values of arterial oxygen tension in the middle-aged and elderly. Am J Respir Crit Care Med 1995; 152: 93441.
Q2

18  Hughes JMB. Ear lobe sampling for PO2: is it accurate? Eur Respir J 1996; 9: 18485.

Further reading Hughes JMB, Pride NB, eds. Lung function tests: physiological principles and clinical applications. London: Saunders, 2000. West JB. Respiratory physiology: the essentials, 7th edn. Baltimore: Lippincott, Williams and Wilkins, 2005.

Practice points
A test result, in relation to regression equations taken from a healthy population, may be expressed as percent predicted, set against the normal range (1.64 SD) or as a standardized residual (SR) A low FEV1/FVC diagnoses airflow obstruction. FEV6 or the relaxed VC may be more reproducible than FVC  In mild airflow obstruction, the MEFV curve may give extra information, but at lower lung volumes the curve has a wide range of normality  Inspiratory capacity (IC) is a simple measure of hyperinflation in airflow obstruction  Low TLC with normal or high FEV1/FVC suggests restrictive lung disease; the TLCO and KCO values will distinguish extrafrom intra-pulmonary causes The transfer factor (TLCO) is the product of two components, the KCO (a rate constant) and the VA (the alveolar volume during the measurement). TLCO interpretation becomes more relevant functionally and clinically if notice is taken of their separate contributions

Acknowledgements
Professor NB Pride, Dr BG Cooper and Dr D Cramer kindly commented on an earlier version. Mr Doig Simmonds contributed the artwork.

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