Withholding bronchodilators

Subjects should arrive for investigations on their usual medication unless being assessed for bronchodilator responsiveness or bronchial provocation testing when the subject should be asked to withhold some of their inhaled medication, as outlined in table 1.

When considering the period of time for a medication to be inactive in the airways, it must be borne in mind that there will be no single point duration of activity that applies to every individual due to many confounding factors, which include the number of available receptors in the airways, the size of the individual, the mechanism, route and efficiency of delivery of previous doses of the drug. Pharmacokinetic studies in patients suggest that, for example, in salbutamol, 4–6 hours is the time required for lung function to return to predrug administration. Currently the generally accepted withhold times are those recommended in the ATS/ERS 2005 guidelines4 of 4 hours for short-acting beta-agonists and 12 hours for long-acting beta-agonists; however, many new compounds have been introduced recently.

By studying airway smooth muscle contraction using methacholine challenge testing, Davis et al21 showed the relative duration of bronchoprotection for a variety of commonly used respiratory medications. This gives some guide for the appropriate withhold times to establish clearance of these medications prior to testing when a baseline test (ie, without the support of medication) is required.

When asking patients to withhold medication, careful consideration should always be made regarding withholding any medication, and this should remain the responsibility of the healthcare professional requesting an assessment following administration of any medication.

There will be instances where this is clinically inappropriate or unsafe and treatment withdrawal will need to be agreed by the referring clinician. Local protocols should address this.

Indications for lung function testing

There is no specific evidence to absolutely contraindicate the performance of lung function. There are occasions when optimum results will not be obtained due to pre-existing conditions and this should be stated on the patient’s report, since the possible consequences of producing suboptimal results for a patient, for example, refusal for surgery based on apparently low lung function, should be based on poor physiology and not down to impaired effort.

Each case will have its individual risk versus benefit to the performance of lung function, and therefore a discussion should take place among relevant healthcare professionals to determine the most appropriate and safe way to proceed (table 2).

Contraindications for lung function testing

The majority of contraindications for pulmonary function testing are relative and depend on balancing the risk of any possible complications with the clinical need for the result. The general list of conditions held to necessitate caution is generally accepted to be the following:

• Haemoptysis of unknown origin (forced expiratory manoeuvre may aggravate the underlying condition).

• Pneumothorax.

• Unstable cardiovascular status (forced expiratory manoeuvre may worsen angina or cause changes in blood pressure) or ‘recent’ myocardial infarction or pulmonary embolus.

• Thoracic, abdominal or cerebral aneurysms (danger of rupture due to variation in thoracic pressure).

• ‘Recent’ eye surgery (eg, cataract).

• Presence of an acute illness or symptom that might interfere with test performance (eg, nausea, vomiting).

• Recent thoracic or abdominal surgery.

This list was mostly based on expert opinion22; however, an update to these contraindications23 examined each of these in closer detail and advocates that some of the conditions that it had previously been suggested needed a 6-week recovery period prior to testing could be safe after less than 3 weeks.

Consent

Consent is the principle that a person must give permission before they receive any type of medical treatment, test or examination. Consent is an essential component of both medical ethics and human rights law.

Consent is only valid if it is voluntary and informed. Importantly the person giving consent must have the capacity to make the decision. The following are the three keywords in the previous sentence:

• Voluntary: the decision to either consent or not to consent must be made by the person themselves and must not be influenced by pressure from clinical staff, friends or family.

• Informed: the person must be given all of the information in terms of what is involved, including the benefits and risks, and what happens if the test/treatment does not proceed.

• Capacity: the person must be capable of giving consent, which means they understand the information given to them, and they can use it to make an informed decision.

If an adult has the capacity to make a voluntary and informed decision to consent to or refuse a particular test or treatment, their decision must be respected.

Consent can be given through the following:

• Verbally: for example, by saying they are happy to have a test.

• In writing: for example, by signing a consent form for a complex test that may carry increased risks.

Someone could also give non-verbal consent, as long as they understand the treatment or examination about to take place, for example, holding out an arm for a blood test.

Consent should be given to the healthcare professional directly responsible for the person’s current tests or treatment. If the subject changes their mind at any point before the test commences, or even during the test, such as a cardiopulmonary exercise test, the test must be stopped.

People aged 16 or over are entitled to consent to their own treatment, and this can only be over-ruled in exceptional circumstances. Like adults, young people (aged 16 or 17) are presumed to have sufficient capacity to decide, unless there is significant reason indicating to the contrary.

Children under the age of 16 can consent if they are believed to have enough intelligence, competence and understanding to fully appreciate what is involved in their treatment. This is known as being ‘Gillick competent’. If the child is not Gillick competent then someone with ‘parental responsibility’ can consent for them. This could be the following:

• The child’s mother or father.

• The child’s legally appointed guardian.

• A person with a residence order concerning the child.

• A local authority designated to care for the child.

• A local authority or person with an emergency protection order for the child.

The person with parental responsibility must have the capacity to give consent.

Preparation

Subjects should be as relaxed as possible before and during the tests and should be seated for 5–10 min prior to testing.

For reasons of safety the patient should not stand during any investigations but should sit upright in a chair with arms with the equipment at the appropriate height, angle and distance.

Subjects should be asked to loosen tight-fitting clothing. Dentures should normally be left in place; if they are loose they may interfere with performance and are then best removed.

The purpose and nature of the test should be clearly and fully explained to the subject. The subject should be sitting comfortably with both feet flat on the floor and in an upright posture. The mouthpiece assembly should be adjusted to an appropriate height so that the chin is at 90° horizontal to the chest, thereby ensuring a straight upper airway. The tests are usually performed wearing tight-fitting noseclips to avoid unnecessary leaks.

When patients return for repeat testing, then ideally the time of day, the equipment and the operator should be the same.

Order of testing

There is no evidence for a usual order for performing lung function tests. However, healthcare professionals should be mindful of the influence manoeuvres may have on subsequent investigations.

For example:

• Performance of nitrogen washout prior to gas transfer.

• Potential for dynamic airway obstruction on repeat dynamic manoeuvres.

• The timing of bronchodilator administration for reversibility assessment.

• Undertaking gas transfer (CO) test after bronchodilator administration.

There should be appropriate delays between tests as indicated in the subsequent sections in this document. Department protocols will dictate the usual order of testing, although the clinical drivers for undertaking the investigations may help determine the most appropriate approach to the tests and their order.

Infection control

Infection control presents a number of issues within a testing laboratory, and different centres will be provided with different solutions to the same problems. The degree of risk of cross-infection of patients via lung function testing equipment remains unquantified. Based on currently available evidence, there is little justification for elaborate precautions for the majority of patients attending the laboratory, but attention to appropriate routine cleaning and disinfection protocols is important.2 24

There should be local policies, including cleaning protocols, which have been approved by local cross-infection teams.

Disinfection and sterilisation can be achieved by a variety of methods, although chemical methods should be used with caution for health and safety reasons. Identification of factors increasing the susceptibility or infectivity of particular patients, such as those with cystic fibrosis (CF), is important in determining appropriate precautions, and these precautions may be advised by national or international recommendations in relation to the specific disease.

Where patients are known to be infectious or are immunocompromised, additional precautions such as using a barrier filter is appropriate. Until further studies are able to quantify the degree of risk of cross-infection that lung function test equipment poses, the recommendations given in the 2003 review of Kendrick et al24 provide a practical approach to dealing with this problem.

Procedures and protocols

The standards set out in the various sections of this document enable a consistent approach to each diagnostic procedure and thus reduce variability in performance of the test. Standard operating procedures (SOPs) should be available and regularly updated to record local procedures and the rationale behind any deviation from standard practice. These documents should be ratified by local governance mechanisms. SOPs may require additional supporting documentation such as Risk or Control of Substances Hazardous to Health assessments.27

Equipment

Equipment used in routine diagnostic procedures should only be used according to manufacturers’ recommendations and must meet local legislative regulations for use in healthcare. Patients should not be tested on systems with any modifications to equipment or alteration to procedures unless they have been risk-assessed and approved through local governance mechanisms before use.

Because reference values rely on accurate measurement of patient demographics, it is important that equipment other than the diagnostic machines are also checked for accuracy, for example, stadiometers and weighing scales. Barometers and thermometers used to calculate the BTPS correction factors applied also need to be maintained and verified.

Personnel

Patient variability

In order to accurately identify changes in lung function indices that may be due to a disease process, it is important to minimise all variability in the measurements. A significant source of variability can be the patient.

Specific factors that are acknowledged to affect particular tests and the pretest instructions to be given to minimise variability have been discussed in the relevant sections of this document.

Some local standards will also likely apply to pretest instructions, for example whether the clinician interpreting the results will want to see baseline spirometry performed either prebronchodilator or postbronchodilator. Any known variance from these standard prerequisites needs to be recorded on the test report in the form of technical comments.

Overall the contribution that the practitioner makes can have a profound effect on the patient’s compliance and performance. Clear and precise instructions coupled with a firm and confident attitude will induce and encourage the best performance from the patient. With some reluctant patients it can be important to explain the reasons for a test in relation to the clinical context to gain cooperation, which is where a good background of clinical knowledge and experience is essential.

Test variability

Adherence to the principles described in this chapter will reduce the potential sources of error in testing procedures and ensure consistent and valid results are presented.

With good operator technique and good patient cooperation, it should be possible to get repeatable readings for any subdivision of lung volume that are <150 mL or <5%. It has been shown that coefficients of variation of <5% for spirometry, <7% for lung volumes and <9% for gas transfer are achievable.28

Introduction

Having obtained test results of lung function from a subject, a clinician needs to be able to interpret what these mean in the context of the patient’s clinical condition. Any given set of test results may need to be interpreted in isolation, and because lung function is related to the ethnicity, sex, age and height of the subject we need to be able to account for these first before we can decide if the subject’s results are in any way unusual. For this one relates the result to relevant reference values. (The ‘Standardised residuals (z-scores)’ section addresses how best to assess a subject’s result against their predicted value.)

If a clinician is following a patient longitudinally, then previously obtained results can be used as a reference to help see what is happening to this subject over time. (The ‘Grading severity’ section addresses some of the issues around longitudinal change.)

Sometimes it is necessary to decide how abnormal the result is for a subject. This may be to help prognosticate from the test result or to decide if a critical level has been achieved that triggers a change in management. (The ‘Grading severity’ section addresses how one can best assess the severity of any lung function deficit.)

Basic principles

The predicted value for a particular lung function index is obtained by using reference equations, which are discussed later (see ‘Which reference equations?’ section). Standardised residuals (SR; also known as z-scores) have long been32 and remain5 the preferred method for comparing the subject’s recorded value with the predicted value. Per cent of predicted is not an accurate method for making a comparison with the reference range (see ‘Per cent of predicted’ section). The reasoning behind this is explained in the following:

The values for lung function indices within the normal healthy population are known to vary according to age, sex and height of the subject. So in a large population sample there is a scatter of results. Figure 1 shows such a scatter for forced expiratory volume in 1 s (FEV₁) in men against age on the left and against height on the right.

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Figure 1

Plot of idealised population data for FEV₁ in men. The left panel shows a plot of FEV₁ against age (in years) for men of height 1.77 m and on the right a plot against height (in metres) for men aged 50 years. Source: Professor MR Miller. FEV₁, forced expiratory volume in 1 s.

Standardised residuals (z-scores)

The scatter of values seen in the young is approximately the same as that seen in the elderly. The same is true for values with respect to height. For a given age and height the results found in a large sample of a healthy population approximate to a Gaussian distribution, so it is possible to obtain a mean value for a given age and height, and the scatter is described by the SD of the distribution. The 95% and 90% confidence limits for the normal population can then be estimated as mean±1.96×SD and mean±1.645×SD, respectively. These values are taken from statistical tables and follow the scientific principles accepted by all science disciplines worldwide for data with normal distributions.

When deriving normal values for tests that are applied indiscriminately to the general population (eg, when undertaking unselected screening), the 95% confidence limits are usually taken, which means the lower limit of normal (LLN) is the mean, -1.96×SD, which approximates to the lower 2.5th percentile. Thus 2.5% of a healthy population might have a result below this level and yet be entirely normal. These would be deemed false positives. Because lung function tests are not applied indiscriminately in this way but are only undertaken when indicated by the presence of symptoms or other signs of disease, it is recommended5 to use an LLN of the lower fifth percentile (mean −1.645×SD), which trades some specificity for increased sensitivity in detecting true disease.

Figure 2 shows a patient’s observed result (O) plotted in the context of the population results together with the subject’s predicted value (P, the mean population value for someone of the same age, sex and height). The difference between O and P is called the subject’s residual. If this value is divided by the SD of all the residuals for the healthy population, it is called a standardised residual (SR).

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Figure 2

Plot of idealised population data for FEV₁: standardised residual (SR). FEV₁ is plotted against age for men of height 1.77 m with a subject’s value O and their predicted value P outlined. The sloping line denotes the predicted values against age. Thus, FEV₁SR=(observed FEV₁−predicted FEV₁)/RSD, where RSD is the residual SD taken from the healthy population used to make the prediction. Source: Professor MR Miller. FEV₁, forced expiratory volume in 1 s.

An SR is a dimensionless number which states how many SD the subject’s value is from predicted and this is identical to a z-score. A negative SR means the result is below predicted. An SR value of 0 means the result is identical to the predicted. So an SR of −1.645 puts the result on the fifth percentile and is at the LLN.

Percent of predicted

In the early 1960s an American textbook on respiratory medicine suggested that ‘a useful general rule is that a deviation of 20% from the predicted normal value is probably significant’.33 This recommendation came with no supporting evidence, but the practice has been widely applied ever since. Soon after this statement was made, a serious flaw in the use of per cent of predicted was exposed,34 and this problem was revisited over 20 years later.35 The problem is that the natural scatter of lung function data within the healthy normal population is not proportional to the mean value. This is best seen in figure 3, showing that for FEV₁ the LLN for older subjects is lower than 80% of predicted; this is also seen for forced vital capacity (FVC) and carbon monoxide transfer factor (TLco).

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Figure 3

Plot of idealised population data for FEV₁: 80% predicted and LLN. FEV₁ is plotted against age for men of height 1.77 m showing a thin line representing 80% of the predicted (pred) value and a thick line showing the true lower limit of normal (LLN), that is, the fifth centile value 25–70 years. Source: Professor MR Miller. FEV₁, forced expiratory volume in 1 s.

Figure 4 shows how for total lung capacity (TLC) the problem is the opposite way around, with the LLN being above 80% of predicted, which is also seen for FEV₁/FVC.

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Figure 4

Plot of idealised population data for TLC against height for men. The thin line represents 80% and 120% of the predicted (pred) value, and the thick line shows the true lower limit of normal (LLN) and the upper limit of normal (ULN), that is, the 5th and 95th centile values. Source: Professor MR Miller. TLC, total lung capacity.

Eighty per cent of predicted does not relate predictably to the true population LLN for all ages, for all heights or for both sexes because the magnitude and scatter of results in the healthy population are very different for different indices. This is demonstrated in table 3, which shows the LLN values for several lung function indices for three subjects of differing age, sex and height when expressed as per cent of predicted and also shows 80% of predicted when expressed as population centiles. It can be seen that LLN when expressed as per cent of predicted varies widely between subjects and indices.

Because of this variation, if the 20% deviation rule is applied to patient lung function data, about 20% of subjects will be misclassified in terms of their likely disease.33 A clinical diagnostic algorithm using per cent of predicted that gets one in five diagnoses wrong is clearly not one to recommend, and so per cent of predicted should not be used to assess if a patient’s result is unusual.

In table 3, if 80% of predicted equated to LLN, then the centile values would all be 5. Centiles above 5 indicate that 80% of predicted is above the LLN.

Forced expiratory volume in 1 s/forced vital capacityFEV₁/FVC

The Global Obstructive Lung Disease (GOLD) group in 200136 introduced the idea of using a fixed value of 0.7 for FEV₁/FVC as the cut-off for defining the presence of airflow obstruction. This was based on the results of one paper37 that suggested this was the LLN for men, but these authors found this was not true for women, where the LLN declined with age. The population sampled in this paper included very few elderly men, making it unreliable. Over 50 other studies worldwide38 have found that FEV₁/FVC declines with age in both sexes. Using a fixed ratio is incorrect practice and overdiagnoses obstruction in the elderly (especially men) and underdiagnoses it in younger people (especially women).39–41

Using LLN for FEV₁/FVC (see ‘Standardised residuals (z-scores)’ section) is the correct way to determine the presence of airflow obstruction. To illustrate this problem figure 5 shows a plot of FEV₁/FVC data against age from the Health Survey for England data in 200142 for men on the left and women on the right. It can be seen that there are more false positives in men compared with women and more false negatives in women compared with men when using the incorrect 0.7 criterion instead of LLN for defining airflow limitation.

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Figure 5

A plot of FEV₁/FVC against age. On the left are data for 4991 men and on the right for 5811 women. The horizontal line shows the 0.7 cut-off and the slanting line is the LLN. The points above both these lines are within the accepted range for both criteria. The points below both lines are abnormal by both criteria. The dark closed circles between the lines to the right of each plot are the points positive for airflow limitation by 0.7 but not by LLN (false positives). The open circles between the two lines to the left of each plot are abnormal by LLN but not by 0.7 (false negatives). Source: Professor MR Miller from the Health Survey for England 2001 data.42 FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity; LLN, lower limit of normal.

Which reference equations?

A large number of test results are needed from people who are free of any disease that may affect lung function with an adequate number of men and women and with a good range of ages and heights in order to be able to make a sensible prediction of what an individual’s lung function should be. It has been estimated that at least 150 subjects of each sex are needed in order to make a reasonable estimate of what the predicted values should be.43 Several data sets used in the past would not meet this criterion. The reference subjects should ideally also be of similar demographic and ethnic background to the people being tested. Clearly reference values taken from sampling elite athletes would not be appropriate for clinical patients since these athletes usually have supranormal lung function, which is why they are able to compete successfully in their sport.

Grading severity

This is often a vital point if it is thought that a particular intervention is warranted when a test reaches a certain value. Arbitrary cut-off points using per cent of predicted values of FEV₁ have been suggested to grade severity of chronic obstructive pulmonary disease (COPD),36 but no objective evidence supported this and per cent of predicted values retain age, sex and height bias. A valid way to grade severity should relate to subsequent survival, and it has been shown that z-scores are not ideal in this respect and per cent of predicted is not as good as other methods for grading FEV₁ values.48 An important point that helps to clarify this is that patients dying of severe CF at the age of 20 years have an absolute FEV₁ the same as a 70-year-old patient dying of COPD, and yet in terms of per cent of predicted the value of a patient with CF is much lower than that for the elderly patient with COPD. This problem led to poor outcomes for transplantation in children with CF when a fixed per cent of predicted value taken from adult practice was used to trigger transplantation, which was then being undertaken prematurely.49

The z-score thresholds for FEV₁ have been proposed for assessing the severity of airflow obstruction.50 This grading has been adapted in table 4 for the possible grading of other indices.

Severity classification in airflow obstruction is a two-stage process:

• The FEV₁/FVC (or FEV₁/VC) must be below the LLN (z-score <−1.645) to be classified as obstructive.

• Severity grading is then based on the FEV₁ z-score as above, with the exception that the mild classification would include any FEV₁ z-score ≥−2.

The grading system in table 4 will remove the sex, age and height bias implicit in per cent of predicted grading systems.50

FEV₁ (or FVC) standardised by a power of height has been shown to give a better prediction of survival in the general population compared with per cent of predicted51 and gave a better grading of COPD in terms of survival than the GOLD grading.52 In UK patients FEV₁/ht³ gave a good prediction of survival48; better still at predicting survival was the FEV₁ quotient (FEV₁Q), which is the FEV₁ divided by a sex-specific population first centile value (0.5 L in men, 0.4 L in women).41 FEV₁Q can be considered as the number of turnovers of the lower survivable limit that remain for the subject. Future work is needed to define and compare grading limits from FEV₁/ht³ and FEV₁Q, which better relate to survival than both per cent of predicted values, with their inherent problems (see ‘Per cent of predicted’ section), and z-scores.

Longitudinal trends

Following the progress of a patient during the management of their lung disease is the usual clinical scenario, and this raises the question of how best to monitor their lung function. As this involves a within-subject comparison, it is best to use the absolute values of various lung function indices taken together with an understanding of how much natural variation there is in each index on repeated testing so one can interpret whether an observed change is greater than can be expected by chance.53 Estimating true lung function decline can require observations over 5–10 years.54

There are many factors that can influence variability in lung function. Over time periods of less than 1 year, statistical methods of estimating variation are not sensitive. The normal variability over time will also depend on the disease process being monitored, for instance as described in COPD by Vestbo et al.55

Repeated testing of spirometry can lead to within-subject variations of up to 200 mL.53

Since reference equations (see ‘Which reference equations?’ section) are all derived from cross-sectional studies, z-scores derived from them are not ideal for monitoring longitudinal change since this is less on an annualised basis than that inferred from cross-sectional equations56 due to a cohort effect that has nothing to do with longitudinal change. The cohort effect is best understood by realising that individuals aged 80 years old whose data were included in a set of reference equations had different childhood exposures, nutrition and growth trajectory than those aged 30 years old included in the same data set.

Ethnicity

It has long been noted that, for example, the FVC of individuals of white Caucasians tends to be larger than that found in individuals of similar height of African descent. This could relate to a poorer socioeconomic background during childhood leading to poorer lung development or might be a true genetic effect. Current evidence favours the latter as the more powerful contributor to this effect.57 The GLI 2012 equations for spirometry have attempted to account for this effect.44 It has to be accepted that this is an imperfect fit and there are difficulties in ascribing ethnicity to individuals especially those of mixed descent.

Summary

It is important when using lung function to make clinical decisions to understand the potential problems associated with these data. Technical issues and patient issues may mean the results obtained are not true representations of the subject’s clinical condition.58

It is important that properly trained healthcare professionals undertake the tests and have the facility to add comments, pointing out if there were any technical issues which can be helpful to the clinician interpreting the findings.

It is recommended that the report states the z-score and normal range to determine whether there is an unexpected result for that individual. When determining the severity of any unexpected result, the classification as outlined in table 4 is currently recommended.

When providing a trend of lung function data over multiple visits, the serial display of absolute values is recommended.

Definitions

Equipment calibration/verification

Quality control must be performed on a regular basis to determine the accuracy and/or precision of the device using a known standard or signal. If barrier filters are used, then calibration or verification of the equipment must be performed with the filter inserted between the calibration syringe and the device.

Correct performance

The equipment and the subject are prepared for the test and the purpose and nature of the test are explained. It is useful to demonstrate the technique to the subject to enable better understanding of what is required of them. Ideally the subject should be sitting upright in a chair with arms, their feet flat on the floor. Patients should be asked to loosen tight-fitting clothing, where this is obviously restricting the movement of their chest wall and abdomen. Dentures should normally be left in place, unless they are loose, in which case it may be advisable to ask them to be removed. A noseclip is not essential for the measurement of forced expiratory manoeuvres; however, it is required for forced inspiratory manoeuvres and for relaxed manoeuvres.60

Relaxed vital capacity

Measurements of RVC, sometimes also referred to as SVC, should always be recorded prior to a forced manoeuvre, because forced manoeuvres may induce bronchospasm/obstruction. It is best practice to perform an initial measurement of an RVC manoeuvre because relying on FVC measurements alone can lead to an underestimation of lung volumes in the elderly and those with dynamic airway collapse (eg, COPD, emphysema).

RVC can be measured as part of another test (eg, static lung volumes) but should always be performed prior to any forced manoeuvre.

The subject is initially asked to breathe tidally through the mouthpiece, to establish a stable baseline at functional residual capacity (FRC). When the operator perceives that the subject is ready, they should be instructed to breathe in maximally and then to exhale fully at a sustained and steady flow rate until no further gas can be exhaled. It is important that the exhalation is continuous, and the subject should be encouraged to not hold back but to breathe out initially like a ‘big sigh’ followed by a determined effort to maximal exhalation. Consistent encouragement should be provided by the operator throughout, aiming to achieve a reproducibility of <150 mL between measurements.

Where specific equipment does not allow tidal breathing prior to the manoeuvre, it is essential that the operator observes and encourages the subject to ensure a maximal inhalation prior to attaching to the mouthpiece and that a tight seal is achieved quickly to prevent any effect on the measured exhalation.

Maximal flow-volume loop

For the accurate determination of forced expiratory indices, it is essential that the subject takes a maximal inhalation at the start of this manoeuvre, ensures that the exhalation is not delayed and is ‘blasted’ from the lungs as fast as they can, and that exhalation continues until no further gas can be exhaled.

The subject is again asked to breathe tidally through the mouthpiece to start. Once they are comfortable they are asked to take a maximal breath in and to exhale immediately ‘as hard and as fast as they can’. The exhalation should be encouraged throughout until the end of forced expiration criteria (see ‘End of forced expiration’ section) are achieved or the patient terminates the test. There should be minimal pause between achieving maximal inhalation and commencing exhalation (<1 s) as longer delays have been shown to impact on measured values of FEV₁ and PEF.61

Once maximal exhalation is achieved, the subject should be encouraged to immediately breathe back in, forcefully and maximally, to full inspiration.

Where specific equipment does not allow tidal breathing prior to the manoeuvre, it is essential that the operator observes and encourages the subject to ensure a maximal inhalation prior to attaching to the mouthpiece and that a tight seal is achieved quickly to prevent any effect on the measured exhalation.

The subject should be carefully observed throughout testing to ensure they maintain the appropriate effort throughout the duration of the blow and that they do not cough or hesitate at the start of the blow.

A minimum of 30 s should be left between repeat attempts to allow the patient, particularly those with airflow obstruction, to recover. Patients should not be made to attempt repeat manoeuvres before recovery is complete.

Acceptability criteria

The objective is to obtain the best result for the subject on the day of the test. Various aspects of the manoeuvre need to be considered in order to be sure the subject has achieved the very best result.

Failing to satisfy all these aspects does not necessarily invalidate the results completely but will mean that they will be a less reliable estimate of their true lung function. Rather than deleting all the data from unsatisfactory tests, it is better to retain these and then base the final results on the best tests obtained. A single unsatisfactory test result may still be able to answer a clinical question, for example whether the subject has sufficient function to be able to undergo a surgical procedure. If results are derived from tests that are in some aspects unsatisfactory, then the operator must draw attention to this fact in their technical comments.

Throughout test performance the subject should be observed to ensure that they are carrying out the instructions correctly, do not exhale prematurely or lose expired gas around the mouthpiece. These and other examples of incorrect performance can be observed on the flow-volume loop (figure 6) The subject must be encouraged to ensure that they continue to exhale until the flow of gas has ceased. In patients with airflow obstruction exhalation, either forced or relaxed, can be in excess of 10 s. A test will be suboptimal in the following circumstances:

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Figure 6

Examples of spirometry errors. The blue line is the ideal curve and the red line(s) the erroneous curves. Source: ARTP Spirometry Handbook.

• The patient did not inspire to TLC at the start*.

• A leak at the mouth.

• An obstructed mouthpiece due to tongue or false teeth.

• A poorly coordinated start to the manoeuvre, as indicated by a rise time of 10%–90% of PEF of greater than 150 ms, or a back-extrapolated volume of greater than 5% of the FVC or 0.1 L if the FVC is less than 2.0 L.3

• A cough within the first one second of the manoeuvre or later if it is deemed to have interfered with the blow.

• Early termination of the blow or a Valsalva manoeuvre**.

• The test was conducted with a submaximal effort.

*If the maximum forced expiratory manoeuvre is followed immediately by a full inspiration back to TLC and recorded as a single manoeuvre, then the Forced Inspiratory Vital Capacity (FIVC) must not exceed the FVC by more than 100 mL or 5% of FVC, whichever is the greater. If FIVC exceeds FVC by more than this, then it suggests the blow was not started from TLC. Correct calibration of the recording device to account for the differences (temperature and content) between expired and inspired air is crucial for this determination.

**Early termination of a test is not a reason to eliminate all data obtained from the manoeuvre as indices such as FEV₁ may not have been influenced and will still be valid.

A graphical display of the expiratory manoeuvre is essential to allow the operator to inspect the trace for accuracy. The correct aspect ratio for the graphical plot of a flow volume loop (flow versus volume) is two units of flow per one unit of volume.3

End of forced expiration

The end of forced expiration occurs when the subject can blow out no more air and defines the VC. Premature termination of the blow will lead to an underestimate of the FVC and will falsely increase the FEV₁/FVC ratio.

One of the indicators of the end of a forced expiration is a plateau on the spirogram with less than 0.025 L being expired over the last 1 s of the test. However, some subjects with severe airflow obstruction never achieve such a plateau even after exhaling for 20 s. Previously it has been suggested the blow should be maintained for at least 6 s in adults, but younger subjects may complete the manoeuvre in less time than this, as do patients with a severe restrictive defect. The operator should always encourage the subject to blow out for as long as possible. Failure to obtain a plateau and/or 6 s of exhalation is not ground to reject the blow. Exhalation times of >15 s are unlikely to change clinical decisions.3

Repeatability criteria

Subjects must perform a minimum of three technically acceptable maximum forced expiratory manoeuvres. The performance of at least three blows ensures a greater probability of obtaining an accurate result.

The chosen values for FVC and FEV₁ should not differ from the next best values for FVC and FEV₁ by more than 150 mL. In subjects with a FVC of <1.00 L, this difference should not be greater than 100 mL.

If the repeatability criteria are not achieved, then the manoeuvre can be repeated up to eight times, after which the probability of getting a better result is greatly reduced. If after all manoeuvres have been performed the above repeatability criteria have not been achieved, the results must not be rejected. The operator should label the results as not being repeatable allowing the interpreter to use the data accordingly. Poor repeatability means that the subject’s results are not a reliable estimate of their best function, so a further test may yield a different result due to the inherent variability in the subject.

For PEF about 90% of subjects can achieve three measures within 30 L/min (0.5 L/s)62 and 95% are within 40 L/min (0.67 L/s). Persisting beyond five attempts to achieve a repeatable PEF is not likely to improve the repeatability.3 The highest reading of at least three acceptable blows should be recorded. These should be within 40 L/min of each other.63

Selection of test results

The results chosen should be the greatest values from three technically acceptable tests (the FVC and FEV₁ may therefore be taken from different manoeuvres and FEV1/FVC calculated from these). Some electronic equipment automatically selects the best test, based on the individual manoeuvre, which gives the highest figure when FEV₁ and FVC are added together. This practice is not recommended.

If three technically acceptable and/or reproducible results are not achieved, the reason should be given in the report (eg, patient coughing or too unwell to perform the manoeuvre).

Results from recordings that do not meet all the above criteria for acceptability may still be useable with clinical discretion.

Potential problems

Many devices for recording spirometry now use flow as the primary measure rather than volume. Many devices (eg, pneumotachographs, ultrasonic flow heads) need to register the signal that represents zero flow prior to a test. If this is registered incorrectly then all subsequent flow measurements are incorrect. These are termed ‘zero flow registration errors’.

If volume accumulating spirometers are used (rolling-seal or wedge bellows), then cooling errors can occur since the gas at the moment of registering the exhaled volume is above ambient and subsequently cools. When a BTPS correction is made to FEV₁ and FVC using the ambient temperature, this assumes that the gas had reached ambient at the time the index value was recorded. This is untrue for FEV₁ and also untrue for FVC if it is registered within just a few seconds. These cooling errors tend to lead to FEV₁ being falsely high relative to FVC. Heating the volume accumulating spirometer to 33°C will remove these errors as this approximates to the expired gas temperature at the lips.

Rationale

The reasons for delivering a bronchodilator drug in the context of lung function testing may include the following:

• To see if useful improvement in lung function can be achieved.

• To record lung function post bronchodilator to see if airflow obstruction is still present.

• To help confirm the presence of asthma.

It has been argued that asking the patient whether any useful improvement is achieved may be a better indicator than any particular test for assessing ‘useful improvement’. However an improvement in FEV₁ by >4% of the subject’s predicted value has been found to be associated with useful improvement as assessed both by the subject and their peers.64

Recording postbronchodilator spirometry has been recommended for determining if someone has COPD. The idea being that any ‘reversible’ component will then have been relieved and it would be reasonable to presume that any remaining obstruction would be ‘fixed’. However bronchodilator response may be variable day to day so this is not entirely true.

There is debate about what degree of responsiveness would indicate the presence of asthma to distinguish it from other respiratory diseases. The result from short-term bronchodilator responsiveness alone is not a reliable method for making a diagnosis of asthma, as this clinical diagnosis is based on clinical examination and history together with diagnostic tests.63

Methods

Depending on the purpose of the test, other bronchodilator drugs that the patient is taking may need to be stopped for an appropriate time prior to testing (see ‘Withholding bronchodilators’ section) so that the response to the bronchodilator being assessed can be determined.

Maximal forced expiratory manoeuvres are undertaken (as described in ‘Spirometry’ section) to record FEV₁, FVC, RVC and PEF preadministration and postadministration of a bronchodilator. The drug used may be salbutamol or terbutaline for a β₂ agonist and/or ipratropium bromide for an anticholinergic agent. Delivery may best be undertaken by supervising the use of a metered dose inhaler with a spacer device, but a nebuliser could be used alternatively. An appropriate delay after administration must occur to allow the drug to achieve maximum effect (15 min for a β₂ agonist and 30 min for an anticholinergic agent).3 Administration and dose of any prescribed medication should be covered by local protocol.

Expressing the results

The absolute changes in FEV₁, FVC and PEF are to be recorded. There have been many suggested thresholds for determining if a clinically important degree of responsiveness has occurred,65 and all those based on percentage of baseline value and/or absolute change from baseline can lead to bias.

Previous practice has been to express the change as a per cent of the baseline value, but this leads to sex and size bias in the results, since the lower the baseline value the easier it is to achieve a given threshold percentage change. Also an absolute threshold criterion is often added and this biases results towards male sex being responders. It has been proposed that change should be expressed as per cent of the subject’s predicted value32 65 or as change in z-score66 as these methods are free from sex and size bias (box 1).

A change in FEV₁ of >8% of predicted has been shown to be associated with a subsequent survival advantage that would favour a diagnosis of asthma and active treatment.65 A change in z-score of 0.7 has also been proposed as a clinically meaningful change,66 and the authors also found that improvement of FVC postbronchodilator of >0.64 was more pronounced in those with the most severe airflow obstruction, suggesting a clinically important relief of hyperinflation.

Ideally bronchodilator response should be expressed as Δz-score for both FEV₁ and FVC, with the %predicted response being an acceptable alternative.

Definitions

Calculation of the lung volume subdivisions

Using the directly measurable values obtained from a spirometry manoeuvre and the indirectly measured lung volumes estimated by one of the techniques discussed in the following sections, the lung subdivisions can then be derived (figure 7):

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Figure 7

Static lung volumes shown on a volume versus time spirogram. The blue line is the ideal curve and the red line(s) the erroneous curves. Source: ARTP Spirometry Handbook. BTPS, body temperature and pressure saturated.

TLC can be calculated as either TLC=RV+VC or TLC=FRC+IC.

RV is either RV=FRC–ERV or TLC–VC.

The former equation is preferable and ideally should be calculated from measurements performed without the patient disconnecting from the mouthpiece as the RV can be miscalculated in patients with significant obstruction when using the VC from a separate spirometric measurement.4

Specific to whole body plethysmography

Measurement principles

This section relates to constant volume plethysmography.70 The principle of whole body plethysmography is based on Boyle’s law, which states that at a constant temperature, the volume (V) of a given mass of an ideal gas is inversely proportional to its pressure (P), that is, PV=K. The constant (K) is proportional to the mass of the gas (the number of moles) and its absolute temperature. Assuming that temperature remains constant (isothermal conditions of measurement), the following mathematical expression is developed:

P₁ × V₁=P₂ × V₂

Determination of TGV is possible if the lungs can be treated as a closed compartment and if alveolar pressure can be measured simultaneously to the changes in volume. At the end of a tidal expiration, with the airway open (ie, at FRC), P_ALV closely approximates P_MOUTH, which is equal to atmospheric pressure. The lungs are made a closed compartment by closing a shutter at the mouth at the end of a tidal expiration. This prevents airflow. The patient is instructed to make gentle panting efforts with the shutter closed. This causes rarefaction of the gas in the lungs during inspiratory efforts (TGV↑, P_ALV↓) and compression of the gas in the lungs during expiratory efforts (TGV↓, P_ALV↑).

TGV=P_MOUTH × ΔV/ΔP

As the panting manoeuvre commences at the end of a tidal expiration where P_MOUTH is equal to atmospheric pressure (P_B) the equation can be simplified to the following:

TGV=P_B × ΔV/ΔP

ΔV/ΔP represents the slope of the simultaneous changes in box volume versus the changes in P_MOUTH.

The measured TGV includes equipment dead space (which is known and documented by the manufacturer) as well as any volume inspired above resting end-expiratory lung volume at the moment of occlusion. FRC_PLETH is derived from TGV by subtraction of these two components of volume (figure 8).

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Figure 8

Body plethysmographic method for lung volume estimation. Body plethysmograph (body box) for measuring thoracic gas volume (VL). The subject (in B) relaxes at end–expiration (~FRC) with P_MOUTH=P_ALV=P_BOX=Patmospheric (Pb). The shutter (see A) is closed in C, and the subject pants slowly and gently; on inspiration VL is rarefied and increases by ºΔV, P_MOUTH falls and P_BOX rises (box gas is compressed by + ΔV lung). ΔP_BOX is plotted against ΔP_MOUTH . Subsequently, the shutter opens and inspiratory capacity is measured using the pneumotachograph signal (see A). Note calibrating signal for assessing ΔP_BOX in terms of ΔVbox. Reproduced from Hughes, ‘Physiology and Practice of Pulmonary Function’ published by the Association for Respiratory Technology & Physiology. FRC, functional residual capacity; P_ALV, alveolar pressure; P_BOX, barometric pressure; P_MOUTH, mouth pressure.

Assumptions of plethysmography

During plethysmographic measurements the airway opening is briefly occluded to hold the lung at a constant volume (normally at end expiration, ie, FRC). Respiratory efforts that compress and rarefy the thoracic volume are recorded. By relating changes in P_ALV (reflected by pressure changes at the airway opening during periods of no airflow) to changes in thoracic gas alveolar volume (reciprocal to pressure changes in the plethysmograph), TGV at the moment of the occlusion can be calculated. There are however a number of assumptions relating to this technique.

Equipment calibration/verification

Volume, flow and pressure measuring devices within the body plethysmograph should be calibrated daily or more frequently when atmospheric conditions are changeable. The leak time constant should be checked daily according to manufacturer recommendations.

Subject considerations

There may be reasons that a subject will be unable to perform body plethysmography and these could include the following:

• Conditions that prevent the subject from entering the plethysmograph cabinet or adequately performing the required manoeuvres.72

• Claustrophobia that may be aggravated by entering the plethysmograph cabinet.72

• Presence of devices or other conditions, such as continuous intravenous infusions with pumps or other equipment that will not fit into the plethysmograph, that should not be discontinued, or that might interfere with pressure changes (eg, chest tube, transtracheal O₂ catheter or ruptured eardrum).72

• Continuous oxygen therapy that should not be temporarily discontinued.72

Test performance

The equipment and the subject are prepared for the test figure 9 and the purpose and nature of the test are explained. It is useful to demonstrate the technique to the subject to enable better understanding of what is required of them.

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Figure 9

Effect of incorrect panting technique on plethysmograph trace. (A) Gentle, properly performed panting manoeuvre yielding a series of almost superimposed straight lines. (B) Panting with excessive force leading to hysteresis. (C) Grossly excessive panting manoeuvre yielding large, variable, invalid recording. (D) Demonstrates the effects of a leaking box seal.

A noseclip is required for the measurement. Dentures should remain in place as removal may introduce leaks at the mouthpiece. Ideally the subject should be sitting upright with their head in the neutral position while in the plethysmograph. The box door is closed and sufficient time is allowed for thermal equilibration prior to commencement of the test (the appropriate time for equilibration will depend on the particular box being used). A flange-type mouthpiece helps to prevent leaks during the measurements.

For lung volume measurement the subject should be requested to breathe normally on the mouthpiece. If there is excessive ‘looping’ of the trace, the flat of the hands can be placed against the cheeks to reduce their movement while the shutter is closed. However, raising the arms can lead to an alteration of FRC so time should be allowed for the FRC to adjust before proceeding. Prior to initiating the TGV manoeuvre, ensure there are no drift or leaks on the tidal volume trace.

The shutter is then closed at the end of a normal tidal expiration and the subject is asked to pant gently against the shutter at a frequency of approximately one breath per second. The shutter should remain closed for approximately 2–3 s to obtain 2–3 slopes of ΔP_MOUTH versus ΔP_BOX. Panting frequencies of >1.5 Hz may lead to errors and those <0.5 Hz may cause problems with the controlled leak of the body plethysmograph system; also panting pressures should not exceed ±1 kPa.4 A series of almost superimposed straight lines separated by only a small thermal drift on the ΔP_MOUTH versus ΔP_BOX plot should be seen. Without removing the mouthpiece the subject then performs an RVC manoeuvre immediately after the shutter is reopened. Some equipment allows these manoeuvres to be recorded prior to the shutter being closed.

This whole procedure should be repeated until a minimum of three technically acceptable measurements have been obtained. The subject may be permitted to remove the mouthpiece and take a short pause between measurements.

It is important that each ΔP_MOUTH versus ΔP_BOX trace is inspected and the line of best fit adjusted manually if necessary.

The measured TGV is the volume of intrathoracic gas at the time the airway was occluded. If this was not at the true FRC (figure 10), then an appropriate adjustment should be made to obtain the correct FRC (FRC_PLETH).

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Figure 10

Volume correction must be applied to TGV to determine FRC_PLETH. FRC, functional residual capacity measured by whole body plethysmography; TGV, thoracic gas volume.

Repeatability criteria

At least three FRC_PLETH values that are technically acceptable and agree within 5% (ie, the difference between the highest and lowest values divided by the mean is ≤5%) should be obtained and the mean value reported. If there is a larger deviation, additional values should be obtained until three values agree within 5% of their mean, and the mean value should be reported.

Quality control

Standard quality control procedures should be sufficient (biological control, volume/flow/pressure calibrations and leak check). However, if more detailed quality control procedures (eg, for research) are required, then a lung volume isothermal simulator, often referred to as an isothermal flask, can be used.68 73

Measurement principles

At end-tidal expiration the volume of gas in the lungs (FRC) is unknown. It is known that this gas contains approximately 79% nitrogen; by measuring this volume of nitrogen, the FRC can be estimated. In this method the subject breathes 100% oxygen, which washes out the nitrogen from the lungs, and the total volume of nitrogen exhaled is measured (figure 11).

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Figure 11

Calculation of functional residual capacity (FRC): breath by breath method.

Equipment

The components of a system comprise a flow transducer (heated wire flow sensor, ultrasonic flow sensor or pneumotachograph), an oxygen supply delivered via a demand valve or a flow bypass/reservoir system, a method of nitrogen analysis and a mouthpiece assembly with valve control.

Commercial systems provide automatic control of the equipment and incorporate calibration and quality control software to ensure the accuracy of lung volume measurements.

Equipment calibration/verification

The calibration of the gas analysers and flow transducer should be checked daily using certified gases and a calibration syringe. A record should be kept highlighting any trends in drift. Gas analysers should also be checked for linearity on a quarterly basis (if the system allows). FRC calibration should be verified daily by using a syringe of known volume (typically 2–3 L). A weekly biological control check should also be made by measuring the FRC in a normal control subject (see ‘Quality assurance’ section).

If using a filter, it is important to deduct the volume of the filter from the FRC measurement. This facility is built into the software of most commercial systems.

Subject considerations

• System leaks may occur if the patient has a perforated eardrum (if the Eustachian tube is patent, atmospheric nitrogen could enter the system).

• Subjects should not be tested if their supplemental oxygen therapy cannot be discontinued for a period that would allow the air in their lungs to return to ambient conditions.

• Breathing 100% oxygen can be dangerous in patients who retain CO₂. Since most patients tend to increase tidal breathing while attached to lung function equipment, CO₂ retention is not normally a problem. It is important that the equipment provides a continuous reading of end-tidal CO₂ throughout the test to check it does not increase.

• Patients who are receiving bleomycin are at risk of developing pulmonary toxicity when breathing high concentrations of oxygen. For this reason, it is advised that lung volumes should not be measured using the nitrogen washout test.74

• It is important to note that other tests which may be influenced by oxygen breathing (eg, transfer factor, blood gases and so on) should not be performed immediately after measuring FRC. To allow the partial pressure of oxygen (PO₂) to return to baseline before proceeding with a further test, at least twice the previous washout duration must have elapsed.75 76

Test performance

As with all lung volume measurements, a flange-type mouthpiece should be used for this procedure to prevent leaks during the course of the measurement.

The purpose and nature of the test are explained. The height of the mouthpiece should be adjusted so that the patient is sitting upright. Both feet should be positioned on the floor directly in front of the seat. The patient should not be able to view the recording during the course of the test as this may influence their breathing pattern. The patient is connected to the mouthpiece with noseclip attached. Once a stable breathing pattern is obtained, the subject is switched into breathing 100% oxygen at the end of a normal tidal expiration.

The subject continues with tidal breathing on 100% oxygen until the concentration of expired nitrogen falls below 1.5% for three consecutive breaths. If this is not achieved within 10 min the test should be terminated and a note made of the final FRC reading, the remaining expired nitrogen concentration and that the end of test criterion was not satisfied.

The time taken for the nitrogen washout test will vary depending on the degree of airflow obstruction present. The duration of the test will be very similar to the helium dilution method.

Once the FRC measurement is complete, a minimum of three acceptable VC measurements should be made by asking the patient to perform a relaxed exhalation to RV, followed by a maximal inspiration to TLC. This is the preferred method in patients with airflow obstruction where marked differences in VC may be observed between IVC and EVC manoeuvres. At least 30 s rest should be allowed between measurements, and repeatability between the best two VC measurements should be within 150 mL (figure 12).77 78

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Figure 12

(Left) Normal washout profile. (Right) Abnormal washout profile typical of emphysema.

The time taken for the nitrogen washout test will vary depending on the degree of airflow obstruction present. The duration of the test will be very similar to the helium dilution method.

Repeatability criteria

Traditionally one technically acceptable result has been reported; however, there is little published evidence to support this as best practice and caution should therefore be used in the interpretation of a single FRC N₂ measurement.4 ERS/ATS guidelines recommend performing three measurements.76 The time between measurements must be at least twice the length of time of the previous test to allow alveolar gas concentrations to return to normal. Repeatability between technically acceptable measurements should be within 10% and the average value quoted.

Quality control

It is important that a true FRC is measured, so care must be taken to ensure the switch to breathing 100% oxygen occurs at the end of a tidal breath during a period of stable tidal breathing. Most computerised systems will automatically adjust the FRC for small switch-in errors of less than 500 mL.

As the exhaled nitrogen is being analysed at the mouthpiece on a breath-by-breath basis, the exhaled nitrogen profile will instantly display a spike should any leak occur at the mouthpiece or via the nose (figure 13). The test should then be discontinued and not repeated until twice the duration of the failed test has elapsed. System leaks occur most frequently as a consequence of the lips not being tightly sealed around the mouthpiece or a poorly fitting noseclip.

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Figure 13

Nitrogen washout profile demonstrating a leak.

Measurement principle

Multiple breath gas dilution measurements of static lung volumes are based on the principle that helium (being used as a physiologically inert tracer gas) of known concentration contained in a spirometer of known volume will be diluted by alveolar gas when the subject is switched into the system and a closed spirometer circuit is maintained (figure 14). A circulating pump within the spirometer maintains an even distribution of the test gases and the volume of the circuit is kept constant by absorbing the CO₂ that the subject produces during the measurements and replenishing the O₂ taken up. After a few minutes of tidal breathing, the tracer gas should be evenly distributed throughout the subject’s lungs, and a second, lower tracer gas concentration will be established, hence allowing the calculation of the FRC.

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Figure 14

Calculation of FRC: helium (He) dilution method. Closed circuit for He equilibration and calculation of thoracic gas volume and FRC_He. System volume includes spirometer and all tubing and so on, up to the valve in the mouth, and is filled initially with 10% He. Because of CO₂ absorption and O₂ consumption, spirometric trace has rising baseline, made horizontal by continuous O₂ addition. Time course of He equilibration and in normal and in patient with chronic obstructive pulmonary disease (COPD) shown. Reproduced from Hughes, ‘Physiology and Practice of Pulmonary Function’, published by the Association for Respiratory Technology & Physiology. FRC, functional residual capacity; IC, inspiratory capacity; TLC, total lung capacity.

Helium (He) is traditionally chosen as the tracer gas in multiple breath gas dilution methods as it is easily measurable in low concentrations with the degree of accuracy required and the analysers require little maintenance.

To calculate the unknown value (FRC), the following equation can be used:

FRC=V₁ × ((He₁ − He₂)/He₂)

where V₁=circuit vol, He₁=initial helium concentration and He₂=final helium concentration.

All measurements are made at ambient temperature, pressure and saturated with water vapour. The appropriate correction factor must be applied to allow values to be reported at BTPS. If the equipment used does not have a built-in thermometer and barometer to automatically correct for room temperature and P_BOX, then these variables should be entered into the software prior to testing.

Equipment

For this steady-state method the basic components of a closed circuit include a spirometer (eg, a rolling-seal spirometer), a circulating pump, helium analyser, O₂ source and CO₂ absorber. An O₂ analyser is desirable, but not essential. Most equipment are now fully computerised, but the test conditions should be easily configurable by the operator. Optimum equipment characteristics are shown in the ‘Equipment specifications: helium dilution’ section).

Quality control

The volume calibration of the spirometer should be checked daily and its linearity weekly. The helium analyser should be calibrated daily, and should be checked for linearity on a quarterly basis with different gas mixtures within the usual measurement range. Alternatively, the change in helium concentrations can be recorded when a known volume of air is introduced into the circuit from a calibration syringe. The volume of air added can be calculated from the helium dilution using the FRC equation (see ‘Measurement principles’ section) and compared with the actual volume introduced, although care should be taken with applying the correct volume correction factor if calculated using the manufacturer’s software.

Tubing should be checked regularly for leaks and the CO₂ absorber replenished as soon as signs of colour change are observed (CO₂ absorber mediums usually have a colour indicator that changes colour when the absorber is depleted). Manufacturers usually suggest changing the absorber after a predetermined number of tests. All other cleaning and maintenance should be carried out on a regular basis as recommended by the equipment manufacturer.

Measurement procedure

The closed circuit is prepared according to the manufacturer’s instructions with the appropriate volume, which is a mixture of air, oxygen and helium (typically using a cylinder of premixed gas containing 14% helium, 18% O₂, balance air). This represents volume V₁ and comprised the dead space of the equipment and the total volume of gas in the circuit. The gases are mixed within the circuit by the circulating pump, and the helium concentration should be recorded once the circuit has been allowed to stabilise (He₁).

The subject, wearing a noseclip, should be given adequate time for their breathing to adapt to the mouthpiece before the measurement of FRC begins. They should then be switched into the system at the end of a normal tidal exhalation. The subject should continue to breathe tidally through the mouthpiece throughout the test. Ideally the patient should not be able to see the chart trace or the computer screen during measurements as this can influence their breathing pattern. The volume of the circuit is maintained by either manual or automatic addition of O₂ as it is consumed and also to replace the CO₂ which has been absorbed (figure 14).

The helium concentration should be observed throughout the test and equilibrium will be considered to have been reached when the helium concentration varies by ±0.02% (if absolute values are displayed) or FRC varies by ±0.025 L (if FRC is displayed) over a 30 s period.4 This is the He₂ value, which is required for the subsequent calculation of FRC. If the readings have not stabilised after 10 min have elapsed, then the readings should be noted at this point and the fact that a stable reading has not been achieved should be recorded.

Once a stable FRC (or helium) reading has been established (or after 10 min if no stable readings have been achieved), the subject should be asked to perform a relaxed ERV manoeuvre, followed by an IC manoeuvre and then a VC manoeuvre. In patients with significant airflow obstruction, sufficient time should be allowed for the patient to return to FRC in between manoeuvres to negate the effects of air trapping. The highest technically acceptable values for ERV, IC and VC should be used for subsequent calculations. Depending on the equipment (and software) used, the VC, IC and ERV manoeuvres may be performed at the start of the test or at the end after a stable FRC has been established. Measurements made after the determination of FRC are of greater physiological relevance. Up to three measurements of ERV may be performed, with the mean of all technically acceptable ERV manoeuvres used in subsequent calculations.79

Repeatability criteria

Evidence suggests that the intertest variability is so small that only one test needs to be performed; however, more attempts will improve accuracy.79 If a second measurement of FRC is to be made, there should be an interval equivalent to the duration of the first measurement (or 10 min, if no stable FRC was obtained) before the second measurement begins. The value quoted for FRC should be a mean of the two values, assuming that there is no significant difference (ie, <0.2 L between the values). Repeatability between technically acceptable measurements should be within 10% and the average value quoted. The highest values for ERV and IC from the two measurements should be used to calculate the subdivisions of lung volume.

Equipment specifications: helium dilution

Potential sources of error

The main sources of measurement error when measuring lung volumes by helium dilution are subject error or technical error. With the exception of switch-in errors (see Technical errors below), the most common problem encountered during measurement is leak. The definition of what constitutes a leak has never been published, but should be considered when the volume of oxygen added to the spirometer circuit exceeds the expected metabolic requirements (typically 0.20–0.25 L/min or 0.04 L/kg/min) or when the system is not maintained at the turn in volume. A leak should also be suspected when current results for FRC are significantly different from previous values for the same subject (even if stability criteria have been met), especially if there is no apparent change in the subject’s clinical condition.

Introduction

The primary function of the lungs is to exchange gas between the atmosphere and the pulmonary circulation. The ability of the lungs to exchange gas across the alveolar capillary membrane is determined by its structural and functional characteristics. Structurally these include lung volume, path length, membrane thickness, the surface area of the lungs and the capillary blood volume. Functionally it is influenced by the level of ventilation and perfusion of the lung and its matching, haemoglobin (Hb) levels, blood transit time, the alveolar capillary membrane characteristics and the chemical reaction rate with Hb (θ). In the lung function laboratory, CO is used as a surrogate for oxygen. CO is an ideal test gas because it has the same diffusion coefficient and rate of reaction with Hb as oxygen, binds to the same site on the Hb molecule, and their respective Hb dissociation curves are affected in the same way by temperature, O₂, CO₂, pH and 2–3 diphosphoglycerate (DPG). In addition, its high affinity for Hb (210 times that of oxygen) means that the PO₂ remaining in the physiological state does not influence the measurement. Additionally, CO is safe to breathe at low concentrations and easy to measure by infrared/electrochemical analysis.

The Roughton and Forster equation from 195781 partitions alveolar-capillary diffusion of oxygen and CO into a membrane component (Dm), a red cell component (θ) and a capillary blood volume component (Vc).

Equation 1, the Roughton and Forster equation:

1/Tl=1/Dm+1/θ.Vc

where Tl is the transfer factor, Dm is the membrane diffusing capacity, θ is the rate of reaction of CO with Hb, and Vc is the capillary blood volume in contact with the inhaled CO.

Although there is more than one technique for measuring CO uptake (and it is acknowledged that other techniques have been tried), this section will describe the single-breath technique, which is the most widely adopted and the one for which regression equations are readily available.

Definitions

• TLco: transfer factor, the product of Kco and V_A.

• Kco: transfer coefficient, the rate of transfer of gas between the alveoli and the erythrocytes into the alveolar capillaries.

• V_A: alveolar volume, the volume of the lungs during the measurement of gas transfer.

• V_IN: volume inspired, the volume of test gas inhaled during the measurement of gas transfer.

• Dm: the diffusing membrane capacity.

• Vc: the pulmonary capillary blood volume.

• θ: theta, the chemical reaction rate of CO with Hb.

Measurement principles

Gas transfer is governed by Fick’s law of diffusion, which states that ‘the rate of transfer of a gas through a membrane of constant thickness is proportional to its surface area (A) and the difference in gas partial pressure between the two sides (P₁−P₂), and inversely proportional to the membrane thickness (t)’. Consequently, TLco is the product of the rate of CO uptake (Kco) and the alveolar volume (V_A) (see equation 2).

Equation 2, Fick’s law of diffusion:

dV/dt=A/T×D×(P₁−P₂)

Volume of gas (per unit time)=area/thickness × diffusion constant × (partial pressure 1 – partial pressure 2).

CO uptake is measured as a concentration fall in alveolar CO per unit time per unit driving pressure. Alveolar volume is determined by the dilution of a tracer gas in the RV and the volume of gas inspired (V_IN). Analysis of Kco and V_A individually provides information on disease pathology that would not be identified by the use of TLco alone.

The SI units of transfer factor are mmol/min/kPa and represent the uptake of a gas (mmol/min) per unit pressure gradient (kPa). The SI unit of transfer coefficient (Kco) is mmol/min/kPa/L. The ATS continues to prefer traditional units of mL/min/mm Hg. To convert from SI to traditional units, divide by 0.335. To convert from traditional units to SI, divide by 2.987.

Single-breath technique

Procedure

Correct performance

The correct performance of gas transfer measurements requires the subject to exhale maximally (unforced) to RV then inspire maximally to TLC and hold their breath for approximately 10 s. This is followed by a complete exhalation. The importance of each of these steps is outlined in the following sections.

Inspiration

It is important that subjects familiarise themselves with the equipment prior to commencement of the measurement. Therefore they should be encouraged to breathe tidally, while wearing a noseclip, through the mouthpiece for a minimum of five breaths or until normal, steady breathing is noted. Once stable the subject is asked to exhale to RV.

Once at RV, the patient is connected to the test gas mixture and requested to inhale as far as possible. This inhalation should be to at least 90% of the subject’s previously best measured VC.

The influence of lung volume on gas transfer is widely known, with decreases in lung volume resulting in an underestimation of TLco and an overestimation of Kco because the surface to volume ratio for CO increases as alveoli become smaller (figure 15) . TLco falls because V_A falls more than Kco rises. At lung volumes of greater than 90% of the subject’s VC, both TLco and Kco have reached an approximate plateau and therefore further increases will have little effect on the estimate. Evidence suggesting that lowering the V_IN to 85% influences measured TLco by less than 5% should be reviewed with caution due to the limited number of participants.84 It would be acceptable to suggest that if technically satisfactory tests were obtained but a V_IN of 90% was not achieved, data from tests where a V_IN of 85% or more was achieved could be analysed; however, the individual reporting the results should be aware of the reduced inspired volume and its potential impact on results.85

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Figure 15

Effects of lung volume on both the TLco and the Kco from residual volume to TLC.175 Kco, gas transfer coefficient for carbon monoxide; RV, residual volume; TLC, total lung capacity; TLco, carbon monoxide transfer factor.

In addition to the inspired volume requirements specified above, the inhalation should be rapid and ideally achieved within 2 s in normal subjects; however, 85% of V_IN must be inspired in <4.0 s.7

Breath hold

The breath hold time should be set at 10±2 s.85 It is important that the subject relaxes during breath holding and should be encouraged to not breathe out (Valsalva) or breathe in (Müller), as this will alter the intrathoracic pressure and the pulmonary haemodynamics, resulting in either an increase (breathing in) or decrease (breathing out) in TLco.

The breath hold time calculation method by Jones and Meade is the recommended method. With this method breath hold time is calculated from 0.3 of the inspiratory time until halfway through the sample.83

The Ogilvie breath hold method tends to overestimate TLco when airflow obstruction is present. This is due to the increased time it takes to obtain an alveolar sample in airflow obstruction and that the Ogilvie method terminates at the beginning of the alveolar sampling period. In contrast the Jones-Meade method includes a proportion of the alveolar sample time and consequently offers the least overestimation of TLco in the presence of airflow obstruction.

Washout and sample collection

During exhalation, following breath hold, the initial portion is discarded (washout) since this contains gas from the anatomical and instrument dead space.

Systems using a sample collection technique require the volume of washout to be set in advance, usually between 750 and 1000 mL.83 In patients with small VC this value can be reduced to allow sufficient sample volume; however, it must be recognised that this will inevitably lead to some contamination of sample gas with dead space gas, ultimately reducing the measured transfer factor.

After the dead space gas has been discarded, a sample representative of alveolar gas is analysed. This sample volume is typically between 500 and 1000 mL and will depend on the response time of the system’s gas analysers. With traditional systems this means that subjects with small VC may require adjustments to the washout and sample volumes in order to achieve a result. Where settings for washout and/or sample volume are reduced, this should be clearly documented to allow the individual interpreting the results to acknowledge the potential impact on measured values.

Modern rapid gas analysis systems allow the operator to inspect the continuous exhaled gas concentration curves and more accurately identify the end of dead space washout. Huang and Macintyre86 found that 50% of patients tested had dead space contaminate the sample using the ATS/ERS criteria (arbitrary 750–1000 mL) when compared with visual analysis of exhaled gas concentration; this leads to a falsely low TLco measurement. It is therefore vital with these systems to inspect the exhaled gas waveforms to ensure that the sample is taken from the alveolar plateau, that is, the initial fall in exhaled tracer gas concentration from inspired values to the plateaus at expired values. Rapid gas analysis systems enable the operator to identify more accurately the end of washout enabling true alveolar gas concentrations to be obtained in patients with much smaller VC and in those with increased dead space.

Time between manoeuvres

Since the previous ARTP/British Thoracic Society guidelines1 were published in 1994, there has been little if any new evidence with regard to the time required to wait in between tests. An interval is required to allow adequate time for tracer gas to be eliminated from the lungs and prevent interference with subsequent tests. In the absence of new evidence the recommendation to allow at least 4 min between tests remains. It should be recognised that patients with severe airflow obstruction may require longer time intervals to completely remove tracer gas from their lungs. Failure to achieve reproducible results in this patient group may indicate this. With newer rapid gas analysis systems, by sampling expired CO prior to the test sample inhalation, it is possible to determine the CO baseline so that time between tests can be minimal (<2 min).

End of test criteria

A minimum of two technically acceptable gas transfer manoeuvres should be performed with a maximum of five (see figure 16 for illustration of a technically acceptable trace). Five gas transfer manoeuvres will increase carboxyhaemoglobin (COHb) by approximately 3.5%, which will ultimately decrease measured transfer factor by 3.5%.87 TLco results should be within the repeatability criterion of 0.67 mmol/min/kPa, Kco within 0.10 mmol/min/kPa/L and alveolar volume within 5%.88 89 The mean of two technically acceptable manoeuvres should be reported.

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Figure 16

A technically acceptable TLco trace. Reproduced from Hughes, ‘Physiology and Practice of Pulmonary Function’, published by the Association for Respiratory Technology & Physiology. TLco, carbon monoxide transfer factor. FACO, Fraction of Carbon Monoxide in Alveolar Gas. FAHE, Fraction of Helium in Alveolar Gas.

Correction for Hb concentration

As part of the Pathology Harmonisation Initiative in 2012, the units of measurement for Hb were standardised to g/L.90 If a subject’s Hb is >190 g/L or <117 g/L, then the adjusted transfer factor will be 10% lower or higher respectively than that recorded. It is desirable that measurements of TLco be reported at a standard Hb of 146 g/L for adult men and adolescents and 134 g/L in adult women and children <15 years.91 92

The following is the equation for adult men and adolescents:

The following is the equation for adult women and children <15 years:

TLco,ad=TLco,ob [(9.38+Hb)/(1.7*Hb)]

where TLco,ad and TLco,ob are the adjusted and observed TLco, respectively, and Hb is the patient’s measured Hb concentration. It should be noted that these equations were developed using Hb in g/dL and therefore Hb values in g/L will need to be adjusted to g/dL (Hb g/dL=Hb g/L/10) prior to putting them into the equation. If a correction for Hb concentration has been made, then this should be made clear on the report form.

Correction for CO concentration

CO inhalation from pollution or cigarette smoking forms COHb, which will influence measured transfer factor values. First, by occupying Hb binding sites, it produces an ‘anaemia effect’, lowering the measured gas transfer value. Second, increased partial pressure of CO in the blood will reduce the driving pressure for CO diffusion between the alveoli and the capillary blood. The impact on measured TLco is a 1%–2% reduction for every 1% increase in COHb.16 17 As endogenous COHb (1%–2%) would have contributed to the measured TLco values used to generate predicted equations, adjustment for COHb is only recommended when COHb values are greater than 2%.

Correction for CO:

Transfer factor for nitric oxide

The transfer factor of the lung for nitric oxide (Tlno) is potentially of interest. However, at present this technique is not used in routine respiratory assessments. Despite a number of clinical papers suggesting its usefulness, there is further work needed.

Introduction

Blood gas sampling and analysis play a vital role in the diagnosis of clinical problems and monitoring of possible treatment modalities such as supplemental oxygen (O₂) or assisted ventilation.

Blood gas analysis can measure several indices, which can aid diagnosis when interpreted in relation to the clinical state of the patient. Blood gases reflect the ability of the cardiopulmonary system to maintain the relationship between cellular respiration and supply of O₂ and elimination of carbon dioxide (CO₂) via the lungs.

Nomenclature

This nomenclature was taken from Rowe and Arrowsmith93 (A, alveolar; a, arterial; Fi, inspired fraction; P, partial pressure exerted; S, saturation).

Acid-base balance

Acid-base balance is tightly regulated by the respiratory system and renal system to maintain a pH between 7.36 and 7.42. The relationship between P_aCO₂/acid [H⁺] and bicarbonate/base [HCO₃] is shown in figure 17.

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Figure 17

Acid-base nomogram.175 PCO₂, partial pressure of carbon dioxide.

Blood gas normal ranges

Table 6 shows the blood gas reference values.

Measurement of arterial blood gases

National and international guidelines recommend accurate and reliable measurement of arterial blood gases (ABGs) that must comply with specific criteria for the prescription of long-term oxygen therapy (LTOT).36 95–97 The ‘gold standard’ technique for blood gas analysis is arterial blood obtained via an indwelling arterial catheter (most often sited at the radial artery in adults) or by arterial puncture.

By nature of the complexity and invasiveness of arterial catheterisation, this method is usually reserved for the intensive care setting where patients may require frequent blood gas testing. Technical and safety considerations determine that for most patients who require blood gas analysis, placement of an arterial catheter is either not justified or only for a limited period (such as serial measurements during cardiopulmonary exercise testing).

Arterial blood is most often sampled by arterial puncture using a needle and syringe. Although traditionally performed by medical staff, arterial sampling is now often practised by senior healthcare scientists who have met the acceptable competency standards required by local policy. Importantly periodic re-evaluation relative to common precautions, correct syringe preparation, site determination, puncture technique, sample aspiration, storage and disposal of blood specimens, as well as postpuncture care should be performed.98

Capillary blood gas sampling

Acknowledging the invasive nature and discomfort that can be associated with direct arterial puncture, the method of arterialised earlobe capillary sampling can be used as an alternative method to determine pH, PCO₂ and PO₂. It is the least invasive and safest blood collecting technique and can be performed by all healthcare personnel following suitable training.110 The relative simplicity and safety profile of capillary blood sampling and the necessity for only small volumes (90–150 µL) of blood make the method an attractive substitute for arterial sampling. However, the clinical value of capillary blood gas results depends on the extent to which pH, PCO₂ and PO₂ of capillary blood accurately reflect pH, PCO₂ and PO₂ of arterial blood.

Pulse oximetry

Pulse oximetry is a non-invasive technique for monitoring SpO₂ either continuously or as a ‘spot check’. Pulse oximeters are often used for serial or continuous measurements of SpO₂ and pulse rate during physiological tests.

The SpO₂ (%) measured by pulse oximetry is not always identical to the actual arterial oxygen saturation (SaO₂); there is potentially a ±2%–3% error in SpO₂ measurements, but generally the two readings are considered close enough for clinical purposes. Pulse oximetry simultaneously measures the pulse rate (beats per minute), but users should be aware that artefact can also give rise to incorrect readings and that it may not necessarily correspond to actual heart rate.

Commonly the sensor is placed on a thin part of the patient’s body, usually a fingertip, toe or earlobe, or in the case of an infant, across a foot. The device passes two wavelengths of light (red and infrared) through the capillary bed to a photodetector. It measures the changing absorption of each of the wavelengths (typically 660 nm and 940 nm), allowing it to determine the absorption due to the pulsing arterial blood alone, while excluding the confounding effects of venous blood, skin, bone, muscle and fat.

As with any recording, it is essential that the inspired oxygen (or room air) and whether or not the patient is ventilated is recorded, which is key to the interpretation of any recorded data.

Introduction

The scope of this section is limited to non-invasive tests of respiratory muscle function and associated pulmonary function tests which may suggest the presence of respiratory muscle weakness. All the tests described could be undertaken within a clinical physiology department.

Direct assessment of respiratory muscle strength cannot be performed; however, methods based on measuring the pressure-generating capacity of the respiratory muscles have been developed. Simple non-invasive volitional manoeuvres can be undertaken to determine the absence, rather than the presence, of profound respiratory muscle weakness and so avoid the necessity of further complex, invasive, non-volitional tests, which may be needed to elucidate and diagnose true respiratory muscle weakness.

Equipment

Measurements of airway pressures are used to provide a surrogate index of respiratory muscle output rather than directly measuring respiratory muscle contractile properties. Pressures measured during volitional manoeuvres reflect the synergistic action of several respiratory muscle groups, whereas those produced by motor nerve stimulation reflect the contractility of the individual muscles under investigation, for example, phrenic nerve stimulation to assess diaphragm function.

The ATS/ERS have jointly published guidelines describing the appropriate characteristics for equipment required to measure respiratory muscle function.116 When measuring maximum inspiratory and expiratory pressures generated during volitional manoeuvres, a pressure transducer with a resolution of approximately 0.05 kPa (0.5 cmH₂O) and a range of up to ±20 kPa (±200 cmH₂O) should be sufficient. Transducers should have a flat frequency response up to 15 Hz. Validation to ensure linearity across the entire operating range should be performed regularly. This should be performed with the tubing and any additional fittings connected as these can significantly affect transducer performance. This is of particular relevance when measuring sniff nasal inspiratory pressure (SNIP) due to rapid pressure changes that occur during the manoeuvre.

A visual display of the pressure waveform produced during the manoeuvre is advantageous as visual inspection can help ensure the manoeuvre has been performed correctly. This is of particular relevance for sniff pressures when a short sharp effort is required to produce a rapid pressure spike which conforms to the recommended characteristics. The sampling frequency of the recording system should be at least 100 Hz to provide an accurate representation of the generated pressure.

Measurements of respiratory muscle strength are generally unfamiliar manoeuvres, so an experienced operator should provide careful instructions and a demonstration of the test procedure, as well as provide encouragement, motivation and feedback in order to obtain the best results.

Maximal static inspiratory and expiratory pressures

Maximal static inspiratory pressure (PImax) and maximal static expiratory pressure (PEmax) (referred to as maximal inspiratory pressure and maximal expiratory pressure in older literature) performed at FRC reflect the pressure generated by the respiratory muscles alone. Manoeuvres performed at RV for PImax or TLC for PEmax also reflect the significant additional contribution from lung and chest wall recoil. Although this contribution can be significant if weakness is present, clinical measures and normal values of PImax and PEmax do not conventionally correct for respiratory system recoil. Many reference ranges for PImax were developed in healthy subjects performing the manoeuvre from FRC rather than towards RV despite clinical testing, requiring the patient to exhale fully before performing a maximal inspiratory effort.

Patients generally find it easier to perform PImax from RV and PEmax from TLC, and adopting such an approach helps to standardise measurement. In addition the force-generating capacity of the respiratory muscles is directly influenced by the lung volume at which the test is performed as this will directly affect the operating length of the muscles themselves. In addition, despite tests being performed at fixed lung volumes, these may not completely represent isometric conditions, and gas compression and rarefaction result in muscle shortening or lengthening, and changes in muscle force–velocity and force–length relationships.117–119 Despite the complex relationship between respiratory muscle force generation and the pressure produced in the thorax or mouth and the varying contribution of the muscle force–length relationship and lung and chest wall recoil, PImax and PEmax reflect global respiratory muscle strength.

Equipment

Self-contained electronic devices with either a digital display or computer display are commercially available. The ATS/ERS statement116 recommends a short rigid tube connected to a valve which allows the manoeuvre to be performed and the mouthpiece occluded following a short period of normal breathing. The device should contain a small air leak (2 mm internal diameter and 20–30 mm in length) to prevent glottis closure during the PImax manoeuvre and prevent the patient from generating pressure using their cheek muscles during the PEmax manoeuvre. A flanged mouthpiece is generally recommended due to their ease of use by patients and the ability to form a leak-free seal. The type of mouthpiece employed can significantly affect the pressure generated,120 particularly PEmax, although it is felt to be of little significance in clinical testing.116

Patients with severe orofacial muscle weakness may be unable to form a leak-free seal using a standard mouthpiece and a face mask interface may be used. A tube interface, consisting of a large diameter rubber tube pressed firmly against the face around the lips, may be used in patients who do not have respiratory muscle weakness but who break the seal around a mouthpiece or face mask during the manoeuvre, most commonly during the PEmax manoeuvre.120 121 Reference ranges are available for both the flanged mouthpiece and tube interface.116 122

Test performance

With the patient seated and wearing a noseclip, they should be instructed to seal (pinch) their lips firmly around the mouthpiece. If a good seal is hard to obtain, either the patient or the operator can use their hands to press the lips against the mouthpiece during each manoeuvre.123 Alternatively, a face mask interface or tube mouthpiece (as described in the equipment section above) can be used. If a satisfactory seal cannot be achieved, an alternative test of respiratory muscle strength such as SNIP should be used.

• PImax: the patient should be instructed to exhale slowly and fully to RV and then perform a sustained maximum inspiratory effort against the occlusion. It has been described to patients as ‘sucking in hard, like trying to suck up a thick milkshake through a straw’.

• PEmax: the patient should be instructed to inhale fully to TLC and then perform a sustained maximum expiratory effort against the occlusion. It has been described to patients as ‘blowing up an uninflated party balloon’.

The patient should be encouraged to maintain pressure generation for a minimum of 1.5 s, as estimated by the operator, and the largest negative (PImax) or positive (PEmax) pressure sustained for at least 1 s (not a transient spike) is recorded figure 18.116 The patient should be allowed to rest for approximately 1 min between manoeuvres and the manoeuvre repeated until the operator is confident a maximal manoeuvre has been performed,116 which may need five or more attempts.124 125 The largest value for PImax and PEmax should be reported alongside the predicted value and the lower limit of the normal range (table 7). At least three additional measures should be performed if the last measurement was the largest of the testing session or if the second largest measurement was less than 90% of the largest. The operator should aim for the variability across measurements to be less than 1 kPa (10 cmH₂O)124 or less than 20% across the largest three values.116 In general approximately 85% of healthy adults achieve less than 1 kPa difference between measurements.126 127 Because the tests require volitional effort, it is good practice to report the degree of patient cooperation and effort alongside the test results.

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Figure 18

Maximum static mouth pressure traces. Mouth pressure versus time during maximal expiratory and inspiratory manoeuvres against an obstructed mouthpiece. Maximum pressure is sustained for approximately 3 s. PEmax and PImax measured as mean pressure over 1 s around peak pressure. Adapted from the American Thoracic Society/European Respiratory Society statement, 2002.120Reproduced from Hughes, ‘Physiology and Practice of Pulmonary Function’, published by the Association for Respiratory Technology & Physiology. PEmax, maximal static expiratory pressure; PImax, maximal static inspiratory pressure; RV, residual volume; TLC, total lung capacity.

Sniff nasal inspiratory pressure

SNIP is a non-invasive test of inspiratory muscle strength requiring the patient to perform a short, sharp sniff, during which nasal inspiratory pressure is measured by means of a bung inserted in one nostril connected by a catheter to a suitable pressure transducer. As the test involves a simple natural manoeuvre, it is relatively easy for patients to achieve maximal efforts with a little practice. The most patent nostril for testing is selected by asking the patient to sniff while occluding alternate nares.

SNIP generally produces pressures in excess of those obtained during a PImax manoeuvre.128 The nose acts like a Starling resistor with flow through the unoccluded nostril remaining low during SNIP and independent of driving pressure. In severe airways obstruction pressure, transmission through the lungs to the nose may be impeded,129 but otherwise the pressure measured in the nostril closely reflects intrathoracic pressure and inspiratory muscle strength.120 130

Equipment

Self-contained electronic devices with either a digital or computer display are available. Sniff bungs of different sizes are available commercially. A sensitive transducer (resolution of approximately 0.05 kPa (0.5 cmH₂O) and a range of up to ±20 kPa (±200 cmH₂O)) with a flat frequency response up to 15 Hz, with the SNIP bung and tubing attached, should be used. Validation to ensure linearity across the entire operating range should be performed regularly.

Performance

Prior to testing the patient should be asked about nasal patency and upper airway obstruction relevant to performance of the SNIP test. Clearing any nasal congestion by blowing the nose prior to testing can help improve test performance. With the patient seated comfortably and the sniff bung wedged firmly in a patent nostril, they should be instructed to make short, sharp, maximal sniffs through the unoccluded nostril, starting from relaxed end expiration (FRC) with the peak pressure being measured for each attempt. Suitable sniffs for analysis show a regular upstroke on the pressure trace and sharp peak and total sniff duration of less than 0.5 s.131 As the sniff is a natural manoeuvre, it can be performed easily, and reproducibly, by most patients with little practice. Most patients are able to achieve a maximal effort with encouragement from the operator in less than 10 attempts. At least three additional measures should be performed if the last measurement was the largest of the testing session or if the second largest measurement was less than 90% of the largest. The largest peak pressure for SNIP should be reported alongside the predicted value and the lower limit of the normal (see table 8).

Interpretation

These tests are volitional requiring patient motivation and cooperation and can exclude clinical respiratory muscle weakness if pressures within the normal range are achieved. Low pressures may reflect either muscle weakness or poor test performance. Tests of respiratory muscle strength such as PImax, PEmax and SNIP used in isolation tend to overdiagnose weakness. Multiple tests of respiratory muscle function increase both diagnostic precision and make assessment possible in a range of clinical circumstances.132 It is best practice when assessing inspiratory muscle strength to perform both PImax and SNIP measurements. If low values are obtained then referral for advanced testing at a specialist centre should be considered.

Reference ranges

The normal ranges are wide, so that values in the lower quarter of the normal range are compatible both with normal strength and with mild or moderate weakness. The ATS/ERS statement on respiratory muscle testing116 indicates that significant respiratory muscle weakness is excluded if PImax reaches −8 kPa (−80 cmH₂O), or if PEmax exceeds 8 kPa (80 cmH₂O) for males, or 6 kPa (60 cmH₂O) for females, or SNIP reaches −7 kPa (−70 cmH₂O) in males or −6 kPa (−60 cmH₂O) in females. A normal PEmax with a low PImax suggests isolated diaphragmatic weakness.

Evans and Whitelaw133 reviewed the available data and compiled estimated mean reference values and lower limits of normal for PImax and PEmax (table 7) that demonstrate the normal age-related decline of maximal respiratory pressures and sex differences. Male and female data are reported separately, with male exceeding female values for PImax by 34%–66% and PEmax by 41%–57%, depending on age. Age also correlated with respiratory muscle strength and was therefore used as the independent variable in prediction equations.

For male and female PImax the weighted means of the slopes and intercepts for flange mouthpiece data of Hautmann et al134 and Windisch et al.135 Male PEmax used the weighted means of the slopes and intercepts for flange mouthpiece data from Vincken et al,136 Wilson et al137 and Neder et al.138 Female PEmax used the data from Neder et al.138

PImax, SNIP and PEmax can reliably track change in respiratory muscle strength139 and guide clinical management.140–144 Based on data from studies in healthy subjects,145 a change of more than 2.5 kPa (25 cmH₂O) can be used as the threshold to identify true change in respiratory muscle strength. No correlation has been observed between smaller improvements in PImax or PEmax and symptoms.146–148

Erect versus supine VC

A reduced VC is common in respiratory muscle weakness and reflects both inspiratory and expiratory weakness, preventing full inflation and expiration, respectively, as well as reduction in lung and chest wall compliance, which are observed in patients with chronic respiratory muscle weakness.149 150 The change in VC is however less sensitive than PImax, SNIP and PEmax in mild weakness.151 In adults a fall in VC greater than 30% when supine compared with the upright posture is indicative of isolated or disproportionate diaphragm weakness.152 The marked change in VC is a result of the action of gravity on the abdominal contents and the change in diaphragm geometry and load. The change in VC from standing to supine in healthy subject is approximately 5%–10%.153

Performance

The procedure is not particularly well defined, but the patient should be fully supine; however, this will depend on how well the patient can tolerate this posture due to orthopnoea. Semirecumbency may be a better approach under such circumstance, but this should be recorded.

Specialist respiratory muscle function tests

Sniff oesophageal pressure is a test that is only carried out in more specialist centres but is recognised as the best overall volitional measure of inspiratory muscle strength.154 This is an invasive test with discomfort from swallowing an oesophageal balloon. Sniff transdiaphragmatic pressure can be obtained in a similar manner using a second pressure catheter located in the stomach to provide a measure of abdominal pressure. Measuring the gastric pressure during a maximal cough reflects expiratory muscle strength and better discriminates expiratory muscle weakness141 than PEmax. The transdiaphragmatic pressure can be elicited by unilateral or bilateral electrical or magnetic phrenic nerve stimulation providing a non-volitional but invasive and unpleasant measure of inspiratory muscle contractility.155 156 Additionally recording the diaphragm electromyogram using an oesophageal electrode catheter allows phrenic nerve and diaphragm function to be assessed.157

Although PImax, PEmax and SNIP provide easily applicable tests of respiratory muscle strength, such tests are volitional and should be best viewed as simple screening tools. Clinical weakness can be excluded if high pressures within the normal range are achieved. Low pressures are difficult to interpret, indicating either muscle weakness, poor test performance or the impact of pulmonary function; airway pressure measurements during dynamic manoeuvres such as sniff may be affected by airway calibre resulting in poor pressure equilibration across the lung to the upper airway. PImax, PEmax and SNIP used in isolation therefore tend to overdiagnose weakness.

It is therefore best practice when assessing inspiratory muscle strength to perform both PImax and SNIP measurements.132 If low values are obtained then referral for advanced testing at a specialist centre should be considered.

PImax SNIP and PEmax may be more reliable when tracking change by regular, repeated testing.139 A change of more than 25 cmH₂O can be used as the threshold to identify true change in respiratory muscle strength.145

In addition to the usual contraindications (see ‘Contraindications for lung function testing’ section), there are also conditions where suboptimal performance of volitional tests of respiratory muscle strength is likely:

• Chest or abdominal pain of any kind.

• Oral or facial pain exacerbated by a mouthpiece.

• Stress incontinence.

• Dementia or confused state.

• Chest infection or acute exacerbation of lung disease.

Paediatric spirometry

The spirometry test protocol is very similar to adults: It should be performed with the child wearing a noseclip and seated in an adjustable chair ensuring the child’s feet can touch the floor. There should be a minimum of three attempts; however, since children often need several attempts to perfect the technique and do not fatigue as readily as adults, there should be no set number of maximum attempts. Young children often have to perform >10 attempts to achieve repeatable results. In order to ensure the child maintains concentration levels, there should be no minimum wait time between successive attempts.

Start of test criteria for older children (>6 years) is similar to adults with a back extrapolation volume of <5% of FVC or 100 mL, whichever is the greater. However, in preschool children (<6 years), due to increased relative lung volume to airway size, back extrapolation criteria is more lenient with an absolute back extrapolation of <75 mL or 10% of FVC, whichever is the greater.159 There is no minimum forced expiratory time requirement in children. Younger children will empty their lung volume rapidly, with preschool children often completing exhalation in <1 s. A volume plateau on the volume–time graph can assist in determination of successful end of forced expiration. The exception to this is in preschool children, where lung emptying is rapid, when the end of test criteria is successful if the volume curve is approaching a plateau on the volume–time graph. It is important to note that practice attempts should not be discarded and all efforts recorded within the software of the equipment. For paediatric spirometry, repeatability of FEV₁ and FVC differs for preschool and school-age children. In all children the child should ideally perform at least three technically acceptable attempts, but results should not be discarded if this is not the case. In school-age children the highest and second highest values for FEV₁ and FVC should be within 100 mL or 5%, whichever is the greater value, while for preschool children this value should be 100 mL or 10%, whichever is greater.

In paediatric spirometry visual feedback incentives or games must be available in order to aid the child to perform the test correctly. Visual incentives can also help sustain the expiratory effort to achieve the best FVC. Ideally the games should be manually adjustable to enable the difficulty to be adjusted to ensure the operator can achieve the desired outcome with each child. The use of these incentives helps ensure that the spirometry session is seen more as a ‘game’ than a ‘test’.

The display should have a zoom capability to view results from young children appropriately.

The reporting of spirometric values should follow that of adult guidelines with the best FEV₁ and FVC reported from all accurate measured attempts with flow data reported from the flow volume loop with the greatest sum of FEV₁+FVC. FEV₁ should not be reported if the forced expiratory time is <1 s, using the FEV_0.75 instead. In this circumstance the ratio of FEV_0.75/FVC should be used to define airflow obstruction using the GLI 2012 LLN for this index.44 Technical comments on the acceptability and repeatability should always be included in the report, particularly when the technique is suboptimal.

In the assessment of bronchodilator response, the standard procedure should be to administer 400 μg of salbutamol via a metered dose inhaler plus spacer device. A noseclip should be worn to ensure mouth breathing, and in younger children a face mask with the spacer may be required. The absolute change and percentage change from baseline should be reported.

Paediatric static lung volumes

Body plethysmography is often the first method of choice when measuring static lung volumes in paediatrics for several reasons; it is well tolerated by children (>6 years) and several efforts can be made in a short space of time. Also the currently recommended reference data for paediatric lung volumes160 were performed using body plethysmography. In addition to lung volume measurements, airway resistance can be easily measured in children during the plethysmography protocol. This should be performed prior to FRC occlusions during initial tidal breathing and the child should be instructed to breathe tidally at 30–40 breaths per minute.161 If animations are available they can be used to facilitate obtaining this breathing frequency, otherwise the operator should guide the child’s respiratory rate.

A footrest should be available for children whose feet do not touch the floor. If this is required, the box calibration should be performed with the step inside the box. Children often find it difficult to perform adequate relaxed VC manoeuvres and therefore forced manoeuvres can be considered.

Paediatric single-breath gas transfer for CO

The measurement of gas transfer in paediatric patients follows the same process as for adults. Measuring gas transfer in children is not part of ‘routine’ lung function assessments, but it is still an important clinical tool in certain patient groups frequently seen in specialist centres.

The complexity and practicalities of the single-breath technique mean that the measurement can be challenging in young children <6 years. If using slow responding gas analysers, some small children may not be able to exhale a large enough sample volume (1.2 L) to achieve a valid result. However, most children from age 6 to 7 years and onwards should attempt the measurement if there is a clinical need. With fast responding gas analysers it is possible to determine lung gas transfer in subjects with a VC <1.2 L (see ‘Washout and sample collection’ section). Test performance is very similar to an adult patient; however, there is no need to emphasise a relaxed exhalation prior to inhalation of the gas mix. As mentioned in the ‘Spirometry’ section, many young children will be more likely to reach RV if they perform a forced manoeuvre. The other modification from the adult protocol is that the inspired volume threshold is lowered to be at least 85% of the measured VC.

Refer to ‘Measurement of carbon monoxide transfer factor’ section for more information on test protocol and quality control.

Paediatric respiratory muscle testing

Assessment of respiratory muscle function in children involves an integrated approach using both direct and indirect tests of respiratory muscle function. The most common tests performed in children measure the pressures generated within the thorax during maximal ‘sniffing’ (SNIP), inspiratory (PImax) or expiratory (PEmax) manoeuvres. All three of these tests require maximal effort and cooperation from the child to perform accurate manoeuvres; despite this, children as young as 4 years can perform maximal SNIP manoeuvres and can usually generate PImax and PEmax successfully from the age of 5–7 years.

SNIP reflects inspiratory diaphragmatic strength in children and should be used as the first-line test of inspiratory respiratory muscle function. The technique is relatively non-invasive and intuitive to young children and can be performed longitudinally to monitor the effects of progressive neuromuscular disorders such as Duchenne muscular dystrophy. It is performed using a pressure transducer attached to a nasal probe that is seated in one nostril. The ‘sniff’ manoeuvre is then performed through the unobstructed contralateral nostril by performing a maximal short ‘sharp’ sniff. Performing the manoeuvre from FRC rather than RV is more common in paediatric practice due to intuition; however, it is important to document which method is used and then to be consistent for any longitudinal assessments as the two different lung volumes may produce differing results. It is not uncommon to perform >10 attempts in order to obtain accurate maximal efforts with efforts made through both nostrils to counter the effects of poor airflow through either nostril. The operator should aim to obtain accurate maximal efforts aiming for the best two attempts agreeing within 10% of each other.

Paediatric reference equations available to assess abnormality are available.162 163 A SNIP value greater than the LLN rules out significant diaphragmatic weakness; however, a low value is not diagnostic of weakness. In the case of a low value, a PImax manoeuvre should be performed if not already routine practice. A normal value in either of these measures can rule out significant inspiratory respiratory muscle weakness.

Indirect measures of respiratory muscle function also play a key role in assessment. These may include spirometry, cough PEF, the monitoring of blood gases and the simple measurement of respiratory frequency and tidal volume. Spirometry, alongside tests such as SNIP, remains the key measurement of indirect muscle function and should be performed at every visit, as soon as the child is old enough. FVC and cough PEF in particular should be monitored longitudinally. An FVC of <1.1 L coupled with a cough PEF of <160 L/min is associated with an increased risk of severe chest infections in children with neuromuscular disorders; however, caution should be applied when using these cut-offs as they do not consider the age/size of the child.164 Cough PEF should be performed routinely at each visit and measured using a fast-response pneumotachograph as opposed to a handheld PEF metre.165 Spirometry may also play a role in highlighting isolated diaphragmatic weakness by performing the test in supine position. A >25% reduction of VC in the supine position can be regarded as significant for diaphragm weakness.166

In summary routine follow-up of children with neuromuscular disease should include at the least measures of spirometry, SNIP and cough PEF, with the addition of PImax and PEmax when needed. It is imperative that these results are plotted as trend data and interpreted in a longitudinal manner in known neuromuscular patients.

‘Paediatric Reference Values’

Despite similar functions, the size, shape and composition of the respiratory system change dramatically from infancy to adulthood. At birth, all generations of the conducting and respiratory branches have been generated; however, it is estimated that only a third to half of the adult complement of alveoli are present at birth.167 Consequently infants/young children have a large airway size relative to lung volume. Rapid increases in size and number of alveoli occur in infancy and early childhood, with lung function increasing 20-fold during the first 10 years of life.168 During childhood, FVC outgrows FEV₁, leading to decreases in FEV₁/FVC, with these trends being reversed during adolescence.169 Accurate descriptions of the ‘normal range’ need to take these physiological factors into account if respiratory impairment is to be detected accurately.

The principles behind normative reference data are based on the theory that a summary measure of values obtained from ‘normal’ individuals will represent the range of values expected in a healthy population. A literature search on PubMed will reveal hundreds of paediatric reference equations relating to different populations, age groups and nationalities. Until recently, no lung function reference equation spanned the entire lifespan, with many focusing on discrete age groups (eg, preschool children (3–6 years), school-aged children (often commencing at 6–8 years of age and finishing at 16–18 years of age) or adults (some commencing at 25 years of age)). This resulted in different reference equations being ‘stitched together’ so that a wider age range could be tested without the user needing to manually switch between equations when testing patients of different ages. However, arbitrary breakpoints between specific age groups can lead to serious misinterpretation of results, particularly when trending results over time in a growing child (figure 19).170

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Figure 19

A comparison of reference equations.176 (Top) An amalgamation of the Rosenthal (paediatric) and the European Community for Coal and Steel (adult) equations. (Bottom) The multiethnic Global Lung Initiative equations. Source: ARTP Practical Handbook of Spirometry.176 FEV₁, forced expiratory volume in 1 s.

The all-age, multiethnic GLI spirometry reference equations44 should be used routinely for paediatric spirometry. The GLI equations offer a smooth transition across the ages (ie, no changes from paediatric to adult equations) and a well-defined LLN for all ages. Approximately 30 000 out of the 74 000 subjects in the GLI data set were <20 years of age.

At the time of publication the GLI reference equations were only available for spirometry and gas transfer, with equations for static lung volumes expected in future publications. Table 9 summarises the reference equations that are most appropriate for the other paediatric lung function tests. It is unrealistic to expect a single set of reference data to include multiple lung function indices over the entire age range and for multiple ethnic groups. Therefore the most appropriate equations have been selected with the knowledge that the manufacturers of lung function equipment are able to develop appropriate ‘prediction modules’ which represent the appropriate reference equation for each index. When interpreting lung function it is important to take into consideration the limitations of each reference equation and ensure, where applicable, these limitations are clearly documented on each report.

The GLI spirometry equations focused on indices recommended by the ATS/ERS guidelines (ie, FEV₁, FVC, FEV₁/FVC and FEF_25-75)3 and were only able to develop robust equations where there were sufficient data. PEF and FEF_xx subdivisions were not included; however, there are several publications that have demonstrated that FEF does not offer any interpretative advantage over FEV₁ and FEV₁/FVC.171–173

The plethysmographic lung volume equations48 suggested in table 9 are limited to Caucasian children, and caution should be applied when interpreting results from non-Caucasian children and those going through puberty or transitioning to adulthood.

All reports should state ethnicity and include a comment to state if results have been adjusted for ethnicity. Results should be interpreted using z-scores and the LLN as discussed in the ‘Reference values’ section. For the longitudinal assessment of lung function tests, the absolute value alongside the z-score should be plotted over time. As children have a rapidly developing respiratory system, plotting the absolute values alone will not provide a meaningful assessment of the z-score alongside the absolute value allows for the current age and growth of the child to be considered.