© 2007 American Thoracic Society doi: 10.1164/rccm.200605-642ST
An Official American Thoracic Society/European Respiratory Society Statement: Pulmonary Function Testing in Preschool ChildrenTHIS OFFICIAL STATEMENT OF THE AMERICAN THORACIC SOCIETY (ATS) AND THE EUROPEAN RESPIRATORY SOCIETY (ERS) WAS APPROVED BY THE ATS BOARD OF DIRECTORS, SEPTEMBER 2006, AND THE ERS EXECUTIVE COMMITTEE, DECEMBER 2006
Section 1. The Next Frontier Peter D. Sly (Chair), Nicole Beydon, Stephanie D. Davis, Claude Gaultier, Enrico Lombardi, Mohy G. Morris, Janet Stocks Section 2. Clinical Implications Sheila A. McKenzie (Chair), Paul Aurora, Francine M. Ducharme, Michael J. R. Healy, Bent Klug, Paul C. Seddon, Janet Stocks
Section 3. Spirometry Paul Aurora (Co-chair), Howard Eigen (Co-chair), Hubertus G. M. Arets, Stephanie D. Davis, Marcus H. Jones, Janet Stocks, Robert S. Tepper, Daphna Vilozni
Section 4. Tidal Breathing Measurements Paul C. Seddon (Chair), Julian L. Allen, Karin C. Lødrup Carlsen, Oscar H. Mayer
Section 5. The Interrupter Technique Enrico Lombardi (Chair), Hubertus G. M. Arets, Nicole Beydon, Hans Bisgaard, Claude Gaultier, Bent Klug, Sheila A. McKenzie, Peter J. F. M. Merkus, Paul C. Seddon, Peter D. Sly
Section 6. The Forced Oscillation Technique Francçois Marchal (Chair), G. Michael Davis, Francine M. Ducharme, Graham L. Hall, Zoltán Hantos, Ellie Oostveen
Section 7. The Multiple-Breath Inert Gas Washout Technique Per M. Gustafsson (Chair), Janet Stocks, Paul Aurora, J. Jane Pillow, Monika Gappa
Section 8. Bronchial Responsiveness Tests Nicole Beydon (Chair), Hans Bisgaard, Claude Gaultier, Enrico Lombardi, Michael Silverman, Peter D. Sly, Janet Stocks, Nicola M. Wilson
In older children, measuring lung function is integral for understanding respiratory physiology and for clinical assessment. Pulmonary function tests for infants and children younger than 2 years are used as both research and clinical tools. The usefulness of these tests has benefited from approximately 15 years of work by joint American Thoracic Society (ATS)/European Respiratory Society (ERS) working parties and task forces (1, 2). However, children aged 2 to 6 years old represent one of the major challenges in lung function assessment. Evaluating lung function in this age group is important, not only for clinical reasons but also due to the considerable growth and development of the respiratory system that occurs, with associated changes in lung mechanics (3). Children commonly present with recurrent cough and wheeze during this period. Many of these children will lose their symptoms as they grow, yet others will continue to have asthma that persists into adult life (4). The treatment implications of these two clinical patterns are different, yet we are currently hampered by a lack of objective assessments to help distinguish between these two patterns. In addition, children recovering from chronic neonatal lung disease and children with cystic fibrosis (CF) are prone to recurrent or persistent respiratory symptoms. Objective assessments of pulmonary function in these children would be expected to improve clinical management. The importance of continuous, longitudinal assessments of lung function from birth throughout childhood cannot be underestimated in understanding the evolution and natural history of disease processes. Preschoolers present a number of special challenges. The children are generally too old to sedate for pulmonary function testing (PFT), as is done with infants, and measurement of lung function under anesthesia is neither ethically acceptable nor physiologically relevant to clinical management. Children in this age group are not able to voluntarily perform many of the physiological maneuvers required for the pulmonary function tests used in older children and adults. They have a short attention span and are easily distracted. Due to these issues, the children need to be engaged and encouraged by the operator to participate in the test.
A number of pulmonary function tests have been attempted in conscious children within the preschool age group. These include the following: standard spirometry (5–11), maximal flow referenced to functional residual capacity ( As has been stressed by the ATS/ERS Working Party on Infant Pulmonary Function Testing, no matter which test is being used the operator must be given access to raw data from the equipment. As the field develops and the knowledge of respiratory physiology in this age group expands, having access to raw data will allow investigation of different and more appropriate algorithms and may result in improved disease discrimination. The joint ATS/ERS task force has produced recommendations for the tests currently used in the preschool age group. Each section of this document was written by a subcommittee of the present task force, and includes the current knowledge and recommendations to guide technical and clinical practice. These recommendations were based on reliable scientific evidence, documented by references, and validated by the subcommittee experts. However, in many situations, insufficient data exist to make definitive recommendations. This document highlights the current state of knowledge and where further data are needed. Recommendations will need to be revised periodically until sufficient evidence has been collected to make definitive guidelines in certain situations. This document will address the following topics: (1) clinical implications of PFT in preschool children, (2) spirometry, (3) tidal breathing measurements, (4) the interrupter technique, (5) the FOT, (6) gas washout techniques, and (7) bronchial responsiveness tests. Specifications for equipment used in an infant/preschooler pulmonary function laboratory have been previously reported (32), and a review of these systems and their hygiene aspects is beyond the scope of these recommendations. However, it is important to highlight that the total apparatus dead space should be minimized where possible, although this requirement does not preclude the use of bacterial filters, and should in general be lower than 1.5 to 2 ml/kg body weight (32). The main aim of these recommendations is to provide a resource for the user of these preschool techniques, to facilitate good laboratory practice, interpretation of measurements, and comparison among centers. These recommendations are expected to help the development of future methodological research in either single- or multicenter clinical studies, which are needed to support strong recommendations. Manufacturers may refer to the technical aspects of this document for developing proper equipment and software. The ideal pulmonary function test in preschool children is one that is applicable to any age so that longitudinal studies can be conducted monitoring individual children from infancy to adulthood, simple to perform, safe, reproducible, sensitive enough to detect changes with growth and distinguish clearly between health and disease, and acceptable to both the subject and parents. As with pulmonary function tests in infants, special attention must be paid to the measurement conditions under which the tests are performed, and the impact of these measurement conditions on the accuracy of test results must be considered. A pulmonary function laboratory that is "preschool-aged child friendly" is of the utmost importance. These young children must be made to feel comfortable in the laboratory environment if they are to perform the measurements accurately. The pulmonary function technician has a significant impact on the comfort level of the child. This type of environment may be achieved through a combination of friendly conversation, songs, or through distraction with a videotape or book. During tidal breathing, the level of distraction must be enough to take the child's attention away from his or her breathing, but not so exciting that the child breathes irregularly. Accurate measurements of height and weight using calibrated stadiometers and scales are essential; however, these procedures can be challenging in an active preschooler. Safety and hygiene requirements have been covered in adult guidelines, but it should be noted that additional safety precautions are necessary for preschool subjects. These include, but are not limited to, the need for constant adult supervision while the child is in the laboratory. For accurate interpretations of the lung function data, particularly where longitudinal assessments are to be made, it is essential to record data on environmental and hereditary factors likely to impact on lung growth, including the following: sex; ethnic group; family history of asthma and atopy; cigarette smoke exposure, both pre- and postnatal; allergen exposure, including pets; and relevant current and past medical history and medication use. The developmental stage of the preschool-aged child will be an important determinant of the child's success at performing pulmonary function tests. This influence will be greatest in tests requiring more active cooperation from the child. For example, young children frequently have difficulties in performing the forced expiratory maneuvers required for spirometry. They can either blow "hard" or "long," but frequently cannot blow both hard and long. Measurements that can be made during tidal breathing, such as forced oscillation, the interrupter technique, and gas washout techniques, may be more suitable for the child unable to accurately perform spirometry. If forced expiratory measurements are to be performed, these should be performed after the tidal measurements, because it is easier to "wind up" young children than to wind them down. In addition, deep inhalation may change bronchial tone in children with asthma. The physiological developmental stage of the respiratory system must also be considered in determining which outcome variables are applicable to this age group. For example, recent studies have demonstrated that the forced expiratory volume at 1 second to forced vital capacity (FEV1/FVC) ratio in healthy 5- to 6-year-old children is approximately 90 to 95% (5, 6, 30, 31, 33), and is even higher in younger children. In older children and adults, the physiological and clinical utility of FEV1 is due to its location on the effort-independent (flow-limited) part of the maximal forced expiratory flow–volume (MEFV) curve, which descends to lung volumes as low as 85 to 90% of exhaled vital capacity and reflects intrinsic properties of the respiratory system. The ability to maintain flow limitation at low lung volumes depends largely on the strength of the chest wall muscles to maintain sufficient driving pressure. It is highly likely that children in the preschool age group will not have the chest wall muscle strength to maintain flow limitation to lung volumes as low as 90% of exhaled vital capacity. Although this concept is not new (34), forced expiratory volumes at 0.75 second (FEV0.75) or at 0.5 second (FEV0.5) have not been adopted in clinical practice. Systematic research will be needed to determine the appropriate outcome variables for spirometry in this age group. The answer to the question "Which test should be used in the preschool age group?" depends on the clinical/research question being asked. As is the case in other age groups, no one test will answer all questions. The interrupter technique is easily implemented and is suitable for use in epidemiological studies, particularly those involving measurements in the field. Measurements capable of reflecting changes in the lung parenchyma, such as gas washout techniques and, potentially, forced oscillation, are likely to be more suitable for detecting early lung disease in a condition such as CF, which is known to start in the lung periphery. The clinical and research role of measuring bronchodilator responses and of provocation testing will need to be evaluated. Again, systematic studies using a number of tests will be needed before we know with certainty the place for each test in our clinical armamentarium. In summary, measurement of lung function in preschool-aged children is now feasible. However, much work remains to be done in standardizing how these tests are performed, and in understanding the most appropriate role for the various tests in the study of growth and development of the respiratory system and in the clinical management of children in this age group.
It is now recognized that, given encouragement and suitable measurement conditions, most children between 2 and 6 years old can undertake PFT. Although there is little doubt about the value of these tests in clinical or epidemiological research, their influence on clinical management in an individual remains debatable. The clinical usefulness of any measurement depends on how well it can discriminate between health and disease and how reproducible it is from day to day so that disease progression and response to treatment can be assessed within each child individually. Considerable further work is required to develop appropriate reference data for this age group, with which to reliably distinguish the effects of disease from that of growth and development, together with information on within-subject repeatability and the relative sensitivity and specificity of these tests for distinguishing health from disease. In the meantime, the following recommendations apply:
Evidence accumulating over the last 5 years indicates that PFT in children aged 2 to 6 years produces technically satisfactory measurements using tidal breathing, the interrupter technique, forced oscillation, spirometry, and multiple-breath washout (MBW) methods (26, 31, 35–43). However, the extent to which these measurements are clinically useful in the management of the individual child needs careful consideration. This section will consider the evidence base for the clinical value of lung function measurements in the individual preschool child. It should be noted that many of the issues raised may be equally true in the older child or adult (44), and the clinical value of infant pulmonary function tests also has to be determined (45). It is often claimed that the assessment of a pulmonary function test will help diagnosis, assist prognosis, monitor disease progress, and measure the effect of therapeutic interventions (46). An objective test would supplement history and physical examination in subjects with respiratory problems, which are notoriously difficult to obtain in childhood wheezing disorders (47). The evidence base of clinical decision making (i.e., deciding what is the best test or group of tests for the individual) lags far behind that for treatments (44). A recent review of the value of PFT in adults suggested that many tests used for diagnosis and for assessing a known condition were not supported by high-level evidence (48). For the clinician, it is important to know how helpful PFT is in distinguishing health from disease and in monitoring disease progress in the individual. The epidemiologist and clinical researcher are more interested in comparing measurements in groups and describing the average effects of interventions. PFT could also be helpful in monitoring progress and the response to treatment in children suffering from wheezing disorders, CF, and chronic lung disease of infancy.
Under perfect conditions, most pulmonary function tests discussed in this document can be undertaken successfully in the majority of preschool children older than 3 years. These tests were developed by researchers primarily interested in their application to groups of children to understand the progress of lung development and disease, and the effect of interventions. For their application to the management of individuals, feasibility depends on many more factors than just whether the patient can undertake the test. For example, of 72 preschool children with and without CF, only 58% were able to produce an acceptable forced expiration lasting 1 second, although 73% could manage an FEV0.5 (11). In other words, the international quality-control requirements for spirometry, which are commonly derived from studies in adults, could not be met, although alternative criteria may be feasible. The ATS has made recommendations for training and qualifications of personnel conducting pulmonary function tests. Unlike the measurement of peak flow in a respiratory clinic by the physician managing the patient's care, preschool tests require time and patience by technicians trained in the techniques that can help young children to perform at their best, who can maintain the equipment, and who can understand the procedure well enough to know when a result is or is not acceptable. In some cases, a laboratory operator may not meet normal training criteria for PFT but has particular skills in working with young children. In such cases, flexibility is recommended. Some of the tests are suitable for use in the ambulatory setting or in the community, but most require laboratory equipment.
Choosing Reference Data Reference equations are essential to express pulmonary function in relation to that which would be expected for healthy children of similar age, sex, body size, and ethnic group. The choice of reference equations directly influences the interpretation of pediatric pulmonary function data, and this can have a significant impact on patient care and research (49–52). Most lung function data are normally distributed or can be transformed to such, so that 90% of "normal" values are found within the range of mean ± 1.65 SD (with 95% within ± 1.96 SD). Lung function variables in healthy subjects and those with respiratory symptoms and/or disease often overlap to such an extent that a normal lung function measurement does not exclude disease. Clearly abnormal lung function measurements will often, but not necessarily, be associated with symptoms and disease. The tests for which preliminary reference data are available are listed in Table 1. Ideally, data from healthy children should be evenly distributed across the age range from 2 to 6 years, but in many studies, there are few data in children younger than 4 years, and this could result in distortion of any derived prediction equations. Inspection of the datasets should identify those in which there are a disproportionate number of older children, although, regrettably, plots of raw data are not always presented in published reports. Display of the raw data plotted against height or age also allows the potential user to assess whether linear regression is appropriate when modeling the data and whether data are normally distributed about the regression line (e.g., whether approximately equal numbers lie above and below 2 SDs from the regression line). Evidence for differences among ethnic groups and between sexes should also be considered. Data from spirometry, and resistance measured by Rint and plethysmographic sRaw, have so far shown similar results for boys and girls, but some sex differences may exist with respect to the FOT technique (see SECTION 6).
The most important consideration when choosing reference data is that the method, equipment, and software used to collect the data should be the same as that used by the clinician for his or her patients. In the oscillation technique, regression equations for total respiratory resistance can differ considerably (16), which may reflect the different methods used. This is true also for the interrupter technique, in which the most important consideration is the calculation of pressure (53), which differs according to the algorithm used (see SECTION 5). Particular caution is required when undertaking techniques such as plethysmography and spirometry using commercially available equipment. The default prediction equations from such equipment will almost always be based on reference data derived from older subjects, possibly resulting in serious misinterpretation if applied to preschool children.
Using Reference Data
Height or age as the main predictor?
Expressing results.
In this document, the different aspects of variability are named as follows: repeatability is the within-occasion (short-term) variability and reproducibility is the between-occasion (long-term) variability. Therefore, variability refers to either short- or long-term changes. To evaluate the variability of a test, it is necessary to know both the within-occasion repeatability and between-occasion reproducibility of the measurements in healthy children and in those with respiratory complaints. If PFT is to be used to measure the effect of an intervention, such as response to a bronchodilator, then the variability of the test over the same time interval as the expected response to treatment should be known. Only then can the clinician decide whether any observed change can be ascribed confidently to the bronchodilator (or other intervention) rather than simply reflecting intrinsic variability of the measurement or disease state over the same period (57). Variability may differ between studies due to factors such as technical differences and differences in population, or issues such as the interval between repeated tests, methods of analyses, inclusion criteria for technically acceptable data, and so forth.
Within-Occasion Repeatability
The definition of a single "measurement" varies among different techniques. Thus, with the interrupter technique, it is generally reported as the median of five or more satisfactory readings, whereas with spirometry, the best of three technically acceptable readings is usually reported. The intrameasurement repeatability is usually expressed as a coefficient of variation (CV), which is the SD expressed as a percentage of the mean (i.e., 100 x SD/mean). For example, the repeatability of Rint assessed by CV may differ among studies (see the tables in the online supplement) (25). The within-occasion intermeasurement repeatability is often reported as the coefficient of repeatability (CR)—that is, twice the SD of the mean difference between two series of baseline measurements, performed a few minutes apart, without any intervention, in a group of children. The CR defines the limits above and below an individual measurement within which 95% of second measurements will lie. Finally, some authors have expressed variability using the SD of the mean difference between two measurements and divide it by
Between-Occasion Reproducibility
The arguments about the potential usefulness of tests in clinical decision making have been discussed recently (44). Although clinical decision making is not an exact science, it may be guided by international recommendations. Because diagnosing mild asthma does not necessarily imply treatment with drugs, such as corticosteroids, then the typical threshold values that have been quoted recently for a positive test in preschool children (Table E5) are probably useful, provided the clinician knows the likelihood of a false-positive test (Figure 1). This is where clinical judgement and other tests, such as tests of atopic status, must complement PFT (60).
Before the clinician selects a pulmonary function test, he or she must know what the results are likely to be in children with the disorder(s) that is being considered. There is a large overlap between measurements in children with mild asthma or isolated cough and healthy children (40).
Asthma Because of the great overlap of measurements between healthy subjects and those with previous wheeze, the diagnostic accuracy of baseline PFT is generally very poor in any age group. Bronchodilator responsiveness (BDR) has been recommended in the workup of adults and children with asthma for whom measurements of BDR give a much better diagnostic profile than that obtained from baseline lung function data. For example, in a study of 48 healthy and 82 previously wheezy children aged 2 to 5 years or younger, 76% of those with asthma had a BDR (expressed as a ratio of baseline Rint–postbronchodilator Rint) of 1.22 or greater (40). The sensitivity for this value was therefore 0.76. By contrast, although 70% of healthy children had values below 1.22 (indicating a specificity of 0.70), 30% did not—that is, their BDR was 1.22 or more (giving a value for 1-specificity [i.e., false positive] of 0.3). Plotting sensitivity and 1-specificity against each other for a range of baseline and BDR Rint values produces receiver operating curves (ROC) (62) (see Figure 1). The diagnostic profiles for PFT for asthma and their threshold values are detailed in Table E5. It should be noted that the confidence intervals for these figures are quite wide. Rint, FOT (measured at 5 Hz), and plethysmographic sRaw appear to have similar profiles for the thresholds given (Table E5). Data to calculate the specificity and sensitivity of BDR measurements for wheeze in preschool children measured using spirometry are not available. The data available from a small group of young children suggest that the diagnostic profile of spirometry for BDR may be poor because there is so much overlap between measurements in children with and without lung disease (39). Although challenge testing to demonstrate bronchial hyperresponsiveness in preschool children is possible (see SECTION 8), the feasibility of pharmacological challenges in consecutive children younger than 5 years as a clinical tool outside a research laboratory has yet to be reported. The accuracy and repeatability of the bronchial hyperresponsiveness tests are dependent on the technique used (63, 64).
CF Lung Disease
There is a paucity of information regarding between-occasion reproducibility for spirometric or FOT techniques in children younger than 5 years. For 7-year-old children, the CV for FEV1 was found to be 8.3%, which corresponded to a between-occasion reproducibility of 23% (68). This means that we cannot be 95% confident that any difference less than 23% between two measurements made on different occasions represents a true change. In a clinical trial of the effect of inhaled corticosteroids, FEV1 changed by a mean of 5% over 6 weeks (69). This change would not be detected in the individual with confidence using spirometry. However, in a more recent study that included a large population of healthy preschool children, the CV for FEV1 was found to be 2.7% (5), and more studies are needed to document this issue. Similarly, in a study using the interrupter technique, the between-occasion reproducibility in healthy children was 32% of predicted, but, for stable children who had been heard to wheeze within the previous 6 weeks, this rose to 52% of predicted (Table E4) (57). In a trial of the effect of corticosteroids on Rint in preschool children, the group of children who were skin-prick-test positive were shown to benefit significantly after 6 weeks of treatment (41). However, the mean group improvement in Rint of 16% would not have been detected with confidence for the individual. Between-occasion reproducibility of bronchial responsiveness, using an increase of sRaw of 40% to define a positive response, has been assessed using both cold air challenge (13 young children) (64) and methacholine challenge (8 children) (70). Although these preliminary results are encouraging, far more children need to be studied to confirm these findings. Thus, for measuring progress in the individual, changes in measurements between occasions must be interpreted with caution.
Although there is little doubt about the value of PFT in clinical or epidemiological research, its influence on clinical management in an individual remains debatable. Reference data derived from older subjects should not be extrapolated for use in younger children and standardized equipment and techniques to derive appropriate reference data for this particular age group should be developed. The clinical usefulness of any measurement depends on how well it can discriminate between health and disease and how reproducible it is from one occasion to another so that disease progression and response to treatment can be assessed. For these purposes, we need to know the within-subject variability both within and between test occasions. The within-occasion repeatability of some tests is good enough to make the diagnostic profile of BDR testing reasonably robust, but there is little information about the clinical value of these tests for bronchial challenge (BC) testing in very young children. Little is known about the between-occasion reproducibility for these tests, and more data are needed if we are to distinguish what constitutes a clinically significant change within an individual as a result of disease progression or response to treatment. There is increasing evidence of the significant contribution of these tests as a means of providing objective outcome measures in clinical or epidemiological research studies.
Technically acceptable spirometry is possible in the preschool-aged child. This section of the document provides an update on existing reviews and makes recommendations specific to the preschool age regarding measurement conditions, data collection, interpretation, and reference values. A number of issues still need clarification, but the following recommendations may facilitate comparison among centers:
Spirometry is the most frequently used method for measuring lung function. The reliability of this technique is dependent on standardized methodology with regard to equipment, data acquisition, and data interpretation. Detailed criteria for spirometry in adult subjects have been published by the ATS, and by the ERS (71, 72), and have recently been updated in a combined document by these societies (73). Spirometry is commonly performed in adults and in school-age children (those aged 6–16 yr), but recent reports have confirmed that preschool children are also able to perform these maneuvers (5, 6, 8–11, 65, 74, 75). Recent reports have demonstrated that both preschool and school-age children have difficulty meeting some of the quality-control criteria (11, 74, 76) outlined in the ATS/ERS guidelines. The aims of this section of the document are to summarize what is currently seen to be good laboratory practice, and to provide recommendations for users of this technique in preschool children. Although consensus has been reached on some aspects, there are few published data regarding quality control in this age group, and many of the recommendations in this section are based on the consensus of the working party members rather than on published evidence.
To perform spirometry, the older child or adult must inspire to total lung capacity (TLC), exhale forcefully to residual volume (RV), and repeat the maneuver several times until reproducible flow–volume curves are evident. The repeatability of these curves is dependent on expiratory flow limitation (defined as the flows being independent of effort). A trained adult subject should be able to perform repeated maneuvers in which FEV1 and FVC are within 5% of each other. Quality-control criteria for adult subjects specify how quickly the subject should increase flow at the beginning of the expiration and what the duration of the expiratory maneuver should be. Acceptability criteria for preschoolers should differ from adult criteria for two reasons. First, young children have small absolute lung volumes and large airway size relative to lung volume compared with older children and adults. Forced expiration is therefore completed in a shorter time, certainly more quickly than the 6 seconds recommended for adults, but sometimes more quickly than 1 second. More than one report has described how the descending limb of the flow–volume curve is convex in young children, indicating rapid cessation of flow toward the end of the maneuver (10, 11, 74). It is not yet clear whether this pattern is entirely the result of physiological differences, or whether it is partly effort related, but either way the criteria to determine the end of test in adults are not appropriate for the preschool age group. Second, the start of test in adults is assessed by measuring the VBE, either as an absolute or as a percentage of FVC. A recent report has confirmed that VBE in children is typically lower than in adults, whereas VBE/FVC is higher (11). Both findings can be simply explained by the much smaller absolute lung volumes of very young subjects. Results from spirometry, specifically FEV1, serve as outcome measures for clinical trials in older children and adults. However, preschoolers often do not exhale for more than 1 second; therefore, FEV1 may not be an accurate index of bronchial obstruction in this age group. Recent studies have explored the utility of FEV0.5 or FEV0.75 as outcome measures in this age group (11, 74). The terminology and definitions for the indices from forced expiration are reported in Table 2. There are no published data regarding measurement of slow vital capacity or maximal voluntary ventilation in the preschool age group. These measurements are not covered by this document.
Equipment Hardware. Spirometers for use in preschool subjects must be capable of measuring instantaneous flows with an accuracy of at least ±5%. Dead space should be minimized where possible, although this requirement does not preclude the use of bacterial filters. Otherwise, recommendations for equipment for use in adult subjects apply.
Software. Manufacturers of spirometry equipment should consider animated incentives in software intended for preschool children. These incentives should be designed to encourage rapid and prolonged expiration. Incentives that encourage tidal breathing and maximal inspiration may also be helpful.
Graphics display.
Personnel
Measurement Conditions
Data Collection The maneuver may be performed with the child in the standing position, or in an upright, seated position. There are no data testing whether body posture or the use of noseclips has any effect on spirometry results in preschool children. During the maneuver, the operator should ensure that the child's lips are sealed around the mouthpiece, and that the maneuver commences with minimal hesitation. Online observation of the flow–volume and volume–time traces is helpful for assessing adequate start of test, expiratory flow limitation, and whether the end of test has been achieved. If an incentive program is to be used, the style of this incentive should be tailored to the child. The aim is to stimulate the child to produce a maximal expiration, and this is best achieved by allowing the child to almost achieve the target on early expirations, and to just achieve it when the operator judges that the child is making a maximal effort. If the target is set too low, then the child will cease expiration prematurely. If the target is set too high, then the child may be discouraged. It may be helpful to use a flow-driven incentive for initial training, but this should be substituted for a volume-driven incentive (that encourages prolonged expiration) when maneuvers are to be recorded (4, 10). A minimum of three maneuvers should be recorded. For some children, it may be helpful to allow 10 or more attempts, and this should be considered if technique is improving with successive maneuvers. Again, this must be tailored to the individual, and the operator should be wary of exhausting the child or inducing bronchoconstriction in subjects with asthma.
Criteria for Accepting Data The principles of spirometry quality control in preschool children are the same as for adults. First, it is necessary to visually inspect the flow–volume and volume–time traces, and exclude maneuvers that are visibly inadequate. Maneuvers should be excluded if the flow–volume curve does not demonstrate a rapid rise to peak flow, and a smooth descending limb, with no evidence of cough or glottic closure. The start of test should be quantified by calculating the VBE. There is only one published study reporting this index in the preschool age group, and this suggests that the VBE criteria for adults are inappropriate for the preschool age group (11). These investigators reported that more than 80% of the studied preschool population achieved a VBE of less than or equal to 80 ml or less than 12.5% of the FVC. Alternative criteria are presented, but these should be viewed as a guide to assist visual inspection, rather than as exclusion criteria per se. The end of test should be quantified by reporting the point of cessation of flow. It is known that many preschool children cannot sustain forced expiration for 1 second, let alone the 6 seconds previously stipulated for adults (11), and the forced expired time should be reported but should not be used to exclude maneuvers. Several centers have reported that the descending portion of the flow–volume curve is convex in healthy preschool children (6, 10, 11, 74). This pattern should not be misinterpreted as early termination. One study has reported exponential curve fitting from the volume–time trace as a method for estimating end of test in school-age children (79). This method has not been tested in the preschool age group, and cannot be recommended at this time. If cessation of flow occurs at greater than 10% of peak flow, then this maneuver should be classified as showing premature termination. It may be possible to report timed expiratory volumes from such a maneuver, but FVC and forced expiratory flows cannot be reported.
Data Reporting
Repeatability The current repeatability criteria for adult spirometry are not appropriate for preschool children (11), and modifications are suggested. Ideally, the subject should produce at least two acceptable curves, where the second highest FVC and FEVt are within 0.1 L or 10% of the highest value, whichever is greater. Using a noninvasive approach of applying negative pressure during the forced exhalation maneuver, it has been demonstrated that the preschool-aged child is capable of achieving flow limitation (75). It is also recognized that preschool children may produce one technically excellent maneuver during a session but be unable to produce a second that is within the usual repeatability boundaries. In such cases, laboratories should have the option of reporting results from this single maneuver, if the operator is convinced that it was technically satisfactory. For each child, an estimate of repeatability should be made where possible, but poor repeatability should not lead to automatic rejection of results. The number of technically satisfactory maneuvers and the repeatability results should always be reported.
Reference Data
Recent studies have shown that the preschool-aged child is capable of performing a reliable, reproducible forced expiratory maneuver. Adult criteria for acceptability are not appropriate for this age group, and modified preschool criteria are recommended. Preschool recommendations for spirometry are essential to facilitate multicenter collaboration and comparisons among laboratories. The working party recommends that these guidelines be reviewed and updated regularly. Future areas of research include the following:
Tidal breathing measurements include (1) analysis of tidal expiratory flow and (2) analysis of thoracoabdominal motion. For both techniques, much of our knowledge is based on studies in infants. Tidal expiratory flow analysis can be performed either on flow signals collected at the airway opening (with mask/mouthpiece and pneumotachometer) or volume signals collected at the chest wall (with ribcage and abdominal bands). For tidal expiratory flow analysis,
Thoracoabdominal motion analysis is performed on volume signals collected at the chest wall (rib cage and abdomen) usually by respiratory inductance plethysmography (RIP). For thoracoabdominal motion analysis,
For both types of analysis, further study is needed before the techniques can be applied to clinical practice. In particular, the inherent variability, sensitivity to change in airway caliber, and relationship to other measures of airway obstruction specifically in preschool children require further investigation. It is unlikely that either technique will prove to be a very sensitive measure of small airway obstruction, but either or both may find a place, for example, in assessment of acute illness or in epidemiological studies.
Techniques included here are all those in which spontaneous tidal breathing is studied without any interference other than simply recording—that is, no interruption to flow, no forced flow, no change in inspired gases. Recording tidal breathing without interference is appealing because it requires minimal cooperation, and may reflect "real life" because frequent measurements are possible, even during acute respiratory conditions. These measurements can be made awake or during sleep, but sleep measurements, focusing on apnea, are not the focus of these recommendations. Two techniques are discussed. Tidal expiratory flow analysis evaluates the configuration of tidal expiratory flow–time and flow–volume traces. Analysis of thoracoabdominal motion evaluates the relationship between rib cage and abdominal excursions during tidal breathing.
Background Analysis of flow patterns during forced expiratory maneuvers has long been accepted to be useful (80). Furthermore, it has been recognized (81–83) that flow patterns during tidal expiration may appear different in adults and children with respiratory problems, whether these are examined on a flow–time plot or a flow–volume plot. The challenge has been to move from such general gestalt observations, to measurements that relate in a meaningful and proportionate way to underlying properties of the respiratory system.
Tidal breathing is a complex phenomenon. Flow ( Total respiratory system resistance is determined by chest wall, lung tissue, and airway resistance. Airway resistance derives from (1) small and large intrapulmonary airways; (2) the glottis, which changes aperture during the respiratory cycle under complex neural control; (3) the pharynx, a muscular tube under neural control; and (4) the mouth/nose. Clearly, it is unlikely that any measurement derived from tidal expiratory flow patterns will relate in a simple way to one of these factors (e.g., small airway resistance). Measurements made on tidal expiratory flow have been shown to be empirically useful in certain circumstances. However, both researchers and clinicians need to be aware that, although making these measurements is simple, interpreting them is not.
Procedures
The measurements required are as follows: flow ( Data should be digitized at a minimum of 50 Hz (100 Hz minimum is recommended at high respiratory rates) (88). Equipment dead space should be minimized to avoid altering respiratory control and pattern (see SECTION 1). The "best" method for collecting flow data (mask, mouthpiece, or chest wall measurements) has not been determined, and in terms of variability and ability to detect airway obstruction, the three methods have not been compared. It cannot be assumed that normative values collected using one method can be applied to data collected using another. Although, in infants, measurements have usually been made during sleep, this is not feasible in preschool children. Because arousal and respiratory drive are likely to affect tidal flow patterns, measurements should be standardized to the quiet awake state (86, 89). Posture (supine, sitting, or standing) may also affect tidal measurements (90): it should preferably be standardized to sitting, but in any event should be stated clearly. Measurement conditions are very important (91). A specific point for tidal breathing measurements is that the child's breathing pattern must be both natural and stable, despite the unfamiliarity both of surroundings and of breathing through a face mask or mouthpiece (for details, see SECTION 1).
It is essential to be able to visualize the signal in real time to ensure that the respiratory pattern is stable and regular before starting data recording. Ideally, both types of plot should be available: Finally, although computerized algorithms (and breath selection [92]) are helpful, it is essential that the software be transparent. It should be clear to the operator how the values are derived, and it should be possible to go back to the raw data to inspect tidal curves, to select manually which epochs are to be analyzed, and if necessary, calculate the indices (and any new indices developed in the future) by hand (84).
Data Analysis
Each of these indices is an imperfect attempt to describe an aspect of the shape of expiratory tidal flow, whether plotted with respect to time or volume. It is likely that much more information could be extracted from the loops, either to quantify small airway obstruction or to distinguish it from large or upper airway obstruction, but currently the appropriate mathematical analysis remains elusive. Thus far, most research has considered the two (closely related) peak tidal expiratory flow measures, tPTEF/tE and VPTEF/VE. In general, it is observed that adults (83) and children (86) with obstructive respiratory diseases reach peak tidal flow earlier (and hence after a smaller expired volume) during expiration. There is increasing evidence that the timing of PTEF is due to an interaction between the mechanical properties of the lungs and airways, on the one hand, and central control of breathing, on the other. In tracheostomized cats, it is possible to predict the timing of PTEF using a model based on two factors: the time constant of the respiratory system and the time constant of decay of postinspiratory inspiratory muscle activity (97, 98). It has been speculated (83) that individuals with airway obstruction "sense" that they do not "need" as much braking of expiration, and relax their inspiratory muscles more promptly at the end of inspiration. The measures based on fitting a linear regression to late expiration (94) are an attempt to mimic the single-breath measurement of passive mechanics of the respiratory system (99), requiring the assumption that there is no muscle activity in late expiration. The measures of the shape of the flow–volume loop after peak are an attempt to quantify the more rapid fall-off in flow in the presence of small airway obstruction.
Interpretation of Results Most studies reporting variability of tidal breathing indices have reported CV, rather than CR, and have only studied tPTEF/tE and VPTEF/VE. Only one study has reported variability in a sample including (but not exclusively) preschool children (86). The results for tPTEF/tE are summarized in Table 5.
Repeatability differs with age and possibly with disease status. Stocks and colleagues (93) found a wider repeatability coefficient in infants younger than 6 weeks compared with older infants. However, all studies reporting intraindividual CV in normal subjects have found very similar results, between 20 and 26%. For tPTEF/tE, in contrast to forced expiratory parameters, Morris and Lane (analyzing 10 breaths) found that variability was lower in adults with severe airway obstruction than in healthy adults (83), but van der Ent and coworkers (86) did not find this in their children with (milder) airway obstruction.
Reference values.
Clinical applications. A number of studies (100–103) have shown that reduced tPTEF/tE in early infancy is associated with increased subsequent wheezing, but with low predictive value, and no data on tidal breathing parameters beyond infancy.
Adults (83, 94), children (86, 89), and infants (104–107) with wheezing disorders have lower mean tPTEF/tE and VPTEF/VE values than control subjects in most reported studies—although with considerable overlap between groups. One study in schoolchildren with asthma (108), and one in adolescents with CF (109), found no difference in tidal parameters compared with control subjects. Attempts to correlate tidal measures with direct measures of lung function have yielded mixed results. In infants, VPTEF/VE have correlated poorly with measures of respiratory resistance such as Raw (104), specific airway conductance (sGaw) (105), and lung resistance (RL) (110), but correlated reasonably well with
Background This method is an attempt to quantify the clinical sign of rib recession in young children with increased work of breathing from any cause, which may be due to increased resistance or reduced compliance. In health, the rib cage moves outward during inspiration completely in phase with the outward movement of the abdomen. With progressive increase in the work of breathing (and hence negative intrathoracic pressure generated), the rib cage (particularly, the compliant rib cage of the young child) lags behind abdominal movement, and in severe cases may even move inward initially (114). Thoracoabdominal motion analysis examines the degree to which chest and abdominal excursions are out of phase (asynchronous). TAA should, then, be increased by increased respiratory resistance (upper or lower airways, lung tissue), decreased lung compliance (CL) (parenchymal disease), and increased chest wall compliance (floppy rib cage, neuromuscular disease).
Procedures Relative calibration using the Qualitative Diagnostic Calibration (116) method can be performed electronically using analytic software. Volume calibration can also be performed with input from a pneumotachometer through an analog-to-digital convertor. The pneumotachometer should be linear over the flow range appropriate for patient size and breathing pattern. We would recommend that relative calibration be used for all measures of TAA, with ideally an absolute volume calibration for the measures listed in the list below under "Measures requiring volume calibration." A recent refinement of RIP uses a single spiral coil around chest and abdomen to measure absolute volume change (without the need for pneumotachometer calibration), which can be partitioned into chest and abdominal components. If lung or lower airway pathology is the issue of interest, as with tidal flow analysis, recordings should be made during quiet wakefulness, preferably in the sitting position (99). It is feasible to measure both thoracoabdominal motion and tidal flow parameters at the same time in awake preschool children (99).
Data Analysis
Computerized analysis of some of the above is available and satisfactory, but it is essential to check that the raw data are suitable. For example, phase angle analysis on rib cage–abdominal loops is meaningless for figure-8–shaped loops.
Interpretation of Results
Reference Values.
Clinical Applications.
There have been few studies in children comparing TAA measures either with other measures of pulmonary function, or between children with airway disease and control subjects. Studies in adults with chronic obstructive pulmonary disease have shown MCA/VT values above 1.0 (124) (no comparison with controls), and an asynchrony index significantly greater than that in control subjects (125) (but no difference in
Analysis of tidal expiratory flow patterns and analysis of thoracoabdominal motion are both promising techniques for assessing lung function in the preschool child, but there are significant limitations and major gaps in our knowledge. Both techniques have the ability to make measurements rapidly and repeatedly with minimum disturbance to the child, and they are applicable from infancy to adulthood. In research, these tests can be used in large-scale epidemiological studies, and may be one way of bridging the gap between infant and cooperative measurements. In clinical work, these methods have potential in acute respiratory diseases where other techniques cannot be applied. Both techniques have the drawback of being indirect measures of lung function, influenced by other factors (respiratory drive, chest wall characteristics). It is unlikely, on current evidence, that either is a particularly sensitive measure of small airway disease. Much of our present knowledge is extrapolated from infants and adults: considerable work remains to be done on the technical aspects and clinical relevance of tidal techniques in the preschool child.
The interrupter technique is currently in routine use in several laboratories for the evaluation of lung function in preschool children. Multiple reports have established the interrupter technique to be feasible and repeatable in preschool children, to have a good correlation with "gold standard" techniques, and to be able to detect changes in airway caliber. The clinical interpretation of the interrupter resistance (Rint) in preschool children has been recently made easier by the availability of reference values for this age group. However, the use of different methods makes it difficult to compare the results obtained in different laboratories and underlines the need for standardization for the interrupter technique. In this section of the document, we provide the current recommendations for the use of the interrupter technique in preschool children, including measurement conditions and data collection, quality control of measurements, data analysis and report, and interpretation of results. However, many issues regarding the interrupter technique still need to be clarified. Future studies will have to determine the best algorithm to calculate mouth pressure during the occlusion and to establish the cutoff value for a decrease in Rint beyond which bronchodilator response should be considered clinically significant. The role of Rint as the primary outcome in challenge tests and its place in PFT in preschool children also remain to be determined. With the current state of knowledge, the following recommendations are presented in an attempt to make the technique used to measure interrupter resistance more uniform and to facilitate data comparison between centers:
The interrupter technique was first reported in 1927 (127) and was improved in the 1970s–1980s (128–135). With the availability of commercial devices, the assessment of Rint in preschool children has recently become increasingly popular. However, different implementations of the technique make it difficult to compare the results obtained in different laboratories and highlights the need for recommendations for the interrupter technique. A variant of the classical technique was also proposed, the so-called opening interrupter technique, in which mouth pressure (Pmo) is measured at the end of the occlusion and flow is measured right after valve opening (136). This section discusses the classical interrupter technique, because the opening technique has not been widely used and Rint values obtained with this variant are not comparable to those obtained with the classical technique.
The principle of the interrupter technique is that, during a sudden airflow interruption at the mouth, alveolar pressure and Pmo will rapidly equilibrate. Rint is defined as this pressure divided by the airflow measured immediately before interruption. The total time of interruption is not longer than 100 milliseconds as this time is too short to be recognized and too short to allow the initiation of voluntary breathing against the occlusion (137). Schematically, when mouth airflow is suddenly interrupted (Figure 5), there will be a rapid initial change in Pmo (Pinit) followed by a slower change (Pdif) up to a plateau (Pel) (138). Pinit is virtually instantaneous and reflects the pressure difference due to the airway resistance at the time of interruption (132, 133). Pinit will reflect the pressure drop across all Newtonian resistance of the respiratory system, which includes conducting airways, lung tissue, and the chest wall (130). During tidal breathing, Pinit, and thus Rint, will include a component of both lung tissue and chest wall resistance, not only airway resistance. Pdif is due to the viscoelastic properties of the respiratory tissues and reflects stress adaptation (relaxation or recovery) within the tissues of the lung and chest wall, plus any gas redistribution (pendelluft) between pulmonary units with different pressures at the time of interruption (132, 133, 138). The final plateau represents the pressure due to the elastic recoil of the respiratory system and may take several seconds to be reached (138).
In the real world, between the rapid and the slow change in Pmo after airflow interruption there is a series of rapid oscillations in pressure (Figure 6A) due to the inertia and compressibility of the air column in the airways. These oscillations are more or less damped depending on the time constant of the system (chest wall–lungs–upper airways–equipment) (132). The presence of the rapid oscillations in Pmo makes it difficult to determine Pinit. Several methods have thus been proposed to extrapolate Pinit, and it has also been suggested to use the pressure at the end of the interruption instead. An analysis of the postocclusion rapid oscillations has also been proposed (139, 140), which can give additional information about the inertive and elastic properties of the thoracopulmonary system. The greater the component of Pdif that is incorporated into Rint measurement, the higher Rint will be with respect to pure airway resistance, and the more it will approach resistance of the whole respiratory system. Even when Pmo is linearly back-extrapolated to the beginning of the interruption (as in Figure 6A), it still partially depends on the final parts of the pressure–time curve. A comparison of the different methods of calculation of Pmo is reported below, in DATA ANALYSIS.
The main assumption of the interrupter technique is that Pmo and alveolar pressure rapidly equilibrate after interruption. Ventilation dishomogeneities or severe bronchial obstruction, as well as compliance of the upper airways (mainly cheeks), may increase the time necessary for Pmo and alveolar pressure to equilibrate. This is a crucial point, because in this case, alveolar pressure will be underestimated. Theoretical studies have suggested that, when mild or moderate bronchial obstruction is present, airway resistance may be estimated with enough accuracy by the interrupter technique if compliant upper airways are supported during measurements (132, 140). Supporting the child's cheeks during Rint measurements is then an effective method to reduce the influence of upper airway compliance when bronchial obstruction is mild to moderate. When bronchial obstruction is severe, however (airway resistance increased 10-fold above normal), the time necessary for Pmo and alveolar pressure to equilibrate may be extremely long and Rint may then be lower than airway resistance (141).
Equipment The interrupter technique is performed using a flowmeter, a pressure measurement device, and a flow interruption system (valve) (Figure 7). Specifications for equipment used in an infant/preschooler pulmonary function laboratory have been previously reported (32). Commercial equipment is readily available and is in common use. A review of these systems and their hygiene aspects is beyond the scope of these recommendations.
Total apparatus dead space should be minimized (see SECTION 1). Low-resistance bacterial filters should be used. If a filter other than the one recommended by the manufacturer is used, the potential effect of the filter on flow and pressure measurements must be investigated and reported and the filter resistance taken into account when reporting results. The efficiency of the valve is critical for the accuracy of Rint measurements, because a small volume of gas continues to pass through the valve during closure. Valve closure time should be less than 10 milliseconds (32, 142) and the absence of valve leakage verified by the manufacturer (143). The distance between the valve and the pressure transducer is also important, as it can affect the postocclusion pressure transients, and this should be reported by the manufacturer (32). Calibration or verification of the accuracy of the flowmeter should be performed each day. Pressure measurement devices of the latest technology are usually very stable, but pressure calibration should be checked on a regular basis using a calibrated pressure manometer (32).
Data Collection The test should be performed with the child seated. The child is asked to wear a noseclip and breathe quietly through a disposable mouthpiece and bacterial filter (Figure 8). The mouthpiece has to be held between the teeth and the lips must be sealed around its circumference. The child's neck should be slightly extended, with the cheeks supported by the operator's hands to decrease upper airway compliance (Figure 8). The test is best performed by two operators, one keeping the mouthpiece in the right position and checking that the lips are sealed around it and the other one supporting the child's cheeks to detect any tongue movements. Although studies in healthy children have not shown a significant difference between measurements made with and without the cheeks supported (21), this practice is still recommended because cheek support is likely to be important in children with obstructive airway diseases and during challenge tests. When the child is breathing quietly, the valve automatically closes in response to a preset trigger (flow or volume) and stays closed for about 100 milliseconds. The child cannot predict the valve closure but can hear its noise. This procedure is repeated until the desired number of interruptions has been obtained.
Mouthpiece. A mouthpiece (2.0–2.7 cm in diameter) and a noseclip should be used for Rint measurements in preschool children. Standard oronasal face masks should be avoided because these masks add an additional compliant compartment and do not allow any assessment to be made of the relative contributions from nasal and oral pathways. This is a very important point, because nasal resistance is a major contributor to total airway resistance. In an attempt to overcome this problem, a modified face mask with an integral mouthpiece was proposed (144). One study has compared Rint measurements using this modified face mask with measurements using a mouthpiece and noseclip in 50 children aged 4 to 7 years (145). The two measurements were equally repeatable, but mean Rint values obtained using the face mask were significantly higher than those using the mouthpiece and noseclip. Furthermore, the wide CR suggests that the two methods cannot be used interchangeably (145).
Interruption trigger.
Expiration/inspiration.
Number of acceptable interruptions.
Quality Control of Measurements Some commercial devices allow the operator to see the pressure–time trace after each interruption and decide right away whether or not the interruption was acceptable before going on with a new interruption. Other devices allow the operator to see the pressure–time curves only after a certain number of interruptions. In the latter case, at least 10 interruptions should be performed before reviewing the traces. The ability to also visualize flow–time traces and Pmo–flow as an X–Y plot would be advantageous, and manufacturers are encouraged to include these features in future software developments. In some studies (23, 150), measurement sets with an intrameasurement CV higher than 15 to 20% have been rejected. However, each technically acceptable interruption should be included in the analysis.
Data Analysis
Mean/median.
Variability The interrupter technique has been shown to have a good variability in preschool children. Using 2 SDs from the mean difference between two sets of measurements as the definition of repeatability, Bridge and coworkers (24) found a within-occasion repeatability (about 30 s apart) in expiration of 0.21 kPa · L–1 · s in 2- to 3-year-old children, 0.17 kPa · L–1 · s in 3- to 4-year-old children, and 0.15 kPa · L–1 · s in 4- to 5-year-old children. Similar repeatability values have also been reported by other within-occasion studies (  1–30 min between the two sets of measurements) (21, 23, 57, 158). The studies so far published on between-occasion reproducibility (21, 22, 57, 158) also show similar results, with a between-occasion reproducibility (11 d to 2.5 mo between the two sets of measurements) similar to within-occasion repeatability, in healthy children (22, 57, 158) and children with a history of wheeze or cough (21). However, a higher between-occasion variability has been reported in children with chronic cough or a history of wheeze (57). Table 6 shows the within-occasion repeatability and between-occasion reproducibility of the interrupter technique, as well as its intrameasurement variability, in the various studies (21, 22, 24–27, 57, 158, 159). Interobserver variability using the classical interrupter technique is also acceptable in preschool children. Bridge and colleagues (24) found that interobserver variability was similar to the individual variability between two sets of measurements, albeit one operator was inexperienced.
Reference Values The availability of reference values obtained from a sample of the healthy population is also important for the interpretation of a pulmonary function test. Several studies have recently been published on reference values for the classical interrupter technique in preschool children (21–25, 53, 56) (Table 7). A comparison of the reference values obtained by the different labs is complicated by the fact that the methods used were not always identical. No difference in reference values was found between males and females (21–23, 25, 53, 56). In most studies (21–23, 25, 56), standing height was the main predictor of Rint in children after adjusting for age and weight. Further large-scale longitudinal studies are required to produce internationally applicable reference values for use in preschool children.
It is important to note that the intersubject repeatability of Rint in the general population is quite wide (21, 22, 25, 53, 56) and higher than the intrasubject repeatability (21–24, 57, 157).
Response to Bronchodilators Until more studies are published on the bronchodilator response in healthy preschool children using the classical interrupter technique, a bronchodilation test should be considered clinically significant when the decrease in Rint after bronchodilator exceeds within-occasion repeatability between two sets of measurements established in 30 to 50 subjects for each individual laboratory.
Challenge Tests The use of the interrupter technique in the exercise BC test is extremely difficult because of the need for taking measurements during tidal breathing at the end of the exercise. However, one study has performed Rint measurements 10 minutes after the exercise challenge in 50 schoolchildren (162). When compared with spirometry performed 10 minutes after the exercise challenge and PEF 5, 10, 15, and 20 minutes after the exercise challenge, the interrupter technique had a good sensitivity and specificity in detecting the airway response (162).
We have provided the current recommendations for the use of the interrupter technique in preschool children. However, many issues regarding the interrupter technique still need to be clarified. Future studies will have to determine the best algorithm to calculate mouth pressure during the occlusion and to establish the cutoff value for a decrease in Rint beyond which bronchodilator response should be considered clinically significant. The role of Rint as the primary outcome in challenge tests and the usefulness of the interrupter technique in comparison with other techniques for PFT in preschool children remain to be determined.
The FOT is a simple, noninvasive technique performed during tidal breathing that is relatively easy to apply in preschool children. An external pressure wave is applied, usually at the mouth, and the resulting pressure–flow relationship is analyzed in terms of respiratory impedance. The latter expresses the impediment to flow in the respiratory system that includes both frictional losses and elastic and inertial loads. The FOT has been successfully performed in settings ranging from the field study to the emergency room. A number of studies have demonstrated that the FOT was able to identify airway obstruction and responses to bronchodilators and bronchoconstrictors. This section of the document provides an update on existing reviews and issues recommendations specific to the preschool age. A number of issues yet need clarification, particularly those relevant to identification of airway obstruction.
Lack of active cooperation and noninvasiveness are key features of the FOT, which is therefore increasingly used in young children. The measurement has been successfully performed in various settings: for example, the pulmonary function laboratory, patients' bedside, the emergency room, in school and in kindergarten. This section of the document will update existing reviews (163, 164) and issue recommendations relevant to routine applications in PFT.
Lung mechanics is most easily understood when pressure generated by the respiratory muscles (transpulmonary pressure) is related to VT and flow. Dividing the relevant pressure difference by flow and by the change in volume yields, respectively, lung resistance (kPa · L–1 · s) and elastance (kPa · L–1), the reciprocal of compliance. These terms do not add up algebraically, but lung impedance, as the complex sum of lung resistance and reactance, expresses the overall impediment to flow within the lung. Lung resistance is the part of impedance associated with frictional losses in the airways and the lung parenchyma (i.e., with the component of the transpulmonary pressure in phase with flow). Lung reactance, a much less familiar term, is, in this simple example, proportional to elastance or to the component of pressure in phase with volume, a close estimate of which is transpulmonary pressure during breathing at very slow frequency (i.e., near zero flow). Instead of the respiratory muscles, the FOT uses an external P or  fluctuation and measures the mechanical response of the respiratory system in terms of the resulting or P (165–167). The P– relationship is described by the respiratory impedance (Zrs). As in the above example, Zrs has an in-phase component, or real part or respiratory resistance (Rrs), and an out-of-phase component, or imaginary part or respiratory reactance (Xrs). Rrs represents the sum of viscous resistances of which airway resistance is the most significant. Xrs is determined by apparent elasticity (the relationship between P and volume), and inertive properties (the relationship between P and volume acceleration), which are opposite in sign. Rrs and Xrs are expressed as a function of oscillation frequency (f) and the use of different frequencies offers an extra dimension of data, which can be used via model-based estimations of mechanical components of the respiratory system (166, 168, 169). The reader unfamiliar with complex arithmetic may find the relevant and detailed information elsewhere (see, e.g., Reference 164), although a full understanding of these mathematical concepts is not necessary to the routine clinical use of the FOT.
Equipment Setups. The FOT can be implemented in several configurations, depending on the sites of application of the driving signal and recording of the mechanical response. The most commonly used arrangement is the measurement of the input impedance and this will be detailed here. The oscillatory signal is applied at the airway opening where and P are measured. Alternatively, the transfer respiratory impedance may be obtained by varying P at the chest and measuring at the mouth. The technique has the advantage of eliminating most of the upper airway artifact (see below) and separating airways and tissues impedances. Its application in children has been limited mostly to research studies (170, 171).
In the standard input impedance technique, Zrs is defined as the relationship between transrespiratory pressure and the airway
Transducer specifications. For detailed technical specifications, the reader is referred to previous publications (163, 164).
Oscillation signal.
Calibration.
Data Collection Trials should first be performed to allow the child to learn to breathe calmly into the apparatus through an appropriately sized mouthpiece. Standard oronasal face masks should be avoided because these masks add an additional compliant compartment and do not allow assessment to be made of the relative contributions from nasal and oral pathways. The child should be seated comfortably with his or her head in a slightly extended or neutral position. A noseclip is worn if a mouthpiece is used. The child should be instructed to breathe calmly and avoid obstructing the mouthpiece with his or her tongue. It is imperative that the child's cheeks and floor of the mouth are firmly supported by the parents or a technician to minimize upper airway wall vibrations. The acquisition should cover several breathing cycles but be short enough to limit possible episodes of hyperventilation and swallowing. An acceptable acquisition time is 8 to 16 seconds. The number of acquisitions should be sufficient to calculate and report a mean and CV (see below) of at least three to five technically acceptable measurements. Data should always be reported as Rrs measured at one or several frequencies. In this document, Rrs at a given frequency (f) will be noted Rrsf. The measured data cannot be substituted by any curves or parameters from model fittings.
Quality Control
Measurement reliability. The coherence function (  2) has been proposed to characterize the quality of the estimates of Zrs with pseudorandom oscillations. The 2 is a number between 0 and 1, similar to a correlation coefficient that provides an index of causality between the input and the output of a linear system. It is therefore decreased in the presence of nonlinearities or extraneous noise (175). An empirical value of 2 = 0.95 has been suggested as an acceptance limit for the Zrs values. However, the appropriateness of this value as a reliability index of Rrs and Xrs depends on the signal-to-noise ratio in the measurement and on the computation method (e.g., size and number of blocks) (176). In addition, there has so far been no systematic study of which cutoff value may most accurately eliminate corrupted data in preschool children. It is believed that no general recommendation can be given on the threshold value of the 2 in preschool children. The reproducibility of successively recorded Zrs data (e.g., in terms of CV) provides a solid and computation-independent assessment of the quality of the measurements at every frequency point, and is therefore recommended as a reliability index (see below). With a single frequency, the Zrs mean and SD for all oscillation cycles may be computed within a measurement and it is possible to automatically reject those Zrs data lying outside the 99% confidence interval (177). An alternative is to assess the divergence of each flow oscillation cycle with the reference sinusoid (178).
The routine interpretation of FOT measurements is based on the assumption that Rrs represents the sum of airway and tissue resistances, of which airway resistance is the most significant component above a few Hz, and Rrs is therefore considered a reasonable surrogate of airway resistance (179). The fact that Rrs decreases with increasing frequency and approaches a plateau indicates the presence of parallel pathways. In children, the upper airway wall motion is perhaps the most significant factor (180). In patients with airway obstruction or induced bronchoconstriction, peripheral inhomogeneity (181–183) and bronchial compliance (184) represent additional pathways. Elevation of Rrs toward lower frequencies also reflects the contribution of tissue resistance, which has marked negative frequency dependence (168). In healthy subjects, Rrs exhibits an increase with frequency above 10 to 15 Hz: this is attributed to multiple mechanisms, such as airway wall compliance, gas compressibility in the central airways, and inertial distortion of the velocity profile (185). Xrs is negative at low frequencies, reflecting the elastic properties of the respiratory tissues, whereas its higher frequency values are determined by the increasing inertial forces. The frequency dependence of Xrs is also affected by inhomogeneities and central airway shunt. Despite interpretation problems of the frequency dependence of Zrs, the multiple-frequency measurements have the potential to allow the structural exploration of respiratory mechanics, whereas, as noted above, the single-frequency oscillations are more applicable in the tracking of Rrs within the respiratory cycle. Figure 11 illustrates the frequency dependence of Zrs measured pre- and post-bronchodilator in a 4-year-old child.
Variability A test should include a minimum of three measurements. The repeatability within that test is expressed for Rrs or Zrs by CV (see SECTION 2). The average CV was reported to be 6.2% for Rrs5 in preschool children (186), 8% for Rrs8, and 9% for Rrs16 (187). The values are similar to those in older children (188–190) and healthy adults (191, 192). In healthy preschool children, the reported within-occasion between-test CR (see SECTION 2) of Rrs5 ranges from 6.1 to 10.2% (174, 186, 193).
Reference Values
Despite the lack of standardization in measuring procedures and equipments (many studies used a number of custom-made devices), Figure 12 shows reasonably good agreement among most studies. Nevertheless, two curves are clear outliers. The uppermost corresponds to data obtained with the child breathing through a face mask and nasal breathing likely accounted for a generally higher Rrs (174). Rrs in the lowermost curve was calculated from the measured Zrs using an approximation for the phase between pressure and flow (188). Some studies have reported average Rrs values obtained from several Zrs measurements (186, 188, 189), but others report Rrs values obtained from one single measurement (174, 193).
The summary information reported here is based mainly on data pertaining only to preschool children, although some are derived from studies also involving school-aged children. Most studies were designed to validate the FOT with other techniques, to assess its ability to detect airway obstruction in children with disease as compared with healthy children, and to quantify airway obstruction and airway responsiveness to bronchodilators or bronchoconstrictors. The feasibility of the FOT in acutely ill, untrained preschool children measured in the emergency room ranged from 20% in 3 year olds to more than 80% in 5 year olds (17). In laboratory or field settings, higher values of 80 to 100% have been obtained in healthy preschool children or stable preschool patients (19, 174).
Asthma
In placebo-controlled studies, FOT was useful to document therapeutic response to bronchodilators, such as theophylline, terbutaline, or ipratropium bromide (197–207). The criteria (and cutoff values) for diagnosis of meaningful reversibility post-bronchodilation are reported in Table 9. Significant Rrs5 responses to
The FOT was probably one of the first techniques applied to preschool children to estimate the airway response to methacholine and histamine (211). Here also, the most useful parameters are obtained at the lowest frequencies. In wheezy preschool children, changes in FOT paralleled those observed with plethysmography, interrupter resistance, or spirometry (144). In contrast, response to methacholine measured by FOT compared with transcutaneous partial pressure of oxygen provided conflicting results, which may reflect different characteristics of the subjects as well as of the equipment (63, 144, 212, 213). FOT tracking of changes in airway caliber with time during methacholine-induced bronchoconstriction allowed the demonstration of significant alteration in the mechanical coupling between conducting airways and lung parenchyma in the form of increased volume dependence of Rrs (214) and significant reversibility of Rrs after deep inhalation (215). Rrs at 5 or 6 Hz was reported to differentiate healthy from asthmatic airway response to a free run challenge (216) but, when evaluating cold air challenge, appeared to be less sensitive than the sRaw (64).
Other Conditions
The FOT holds the promise of significantly improving the diagnosis of airway obstruction, quantifying the magnitude of airway reversibility and hyperreactivity, helping in the adjustment of therapy, and monitoring disease progression. The commercial development of the FOT has allowed the rapid expansion of the technique to a broader range of clinical laboratories. This increase in use as a clinical tool needs to be carefully assessed to ensure that the FOT develops in such a way as to allow comparisons between different centers. The majority of reports in the literature have defined Rrs at a specific frequency as the primary outcome variable. Further studies are needed to establish firm criteria based on z scores. It is likely that a panel of other FOT indices including Xrs and resonant frequency may be useful in diagnosing airway obstruction. The model analysis of Zrs data also represents a tool for better description of airway obstruction and understanding of mechanisms involved, such as heterogeneous bronchoconstriction, central versus peripheral airway constriction, parallel inhomogeneities, airway wall compliance, or lung distension.
Before general criteria for reversibility can be firmly established, a clearer picture of the within-occasion, between-test repeatability must emerge. Furthermore, characterization of healthy subjects' airway response to placebo and
The MBW method is used to assess ventilation distribution in the lungs and to measure the FRC. MBW can be performed in children from any age group because it requires a minimum of cooperation. The lung clearance index (LCI), which is the cumulative expired volume required to clear an inert gas from the lungs, divided by the FRC, is a sensitive marker of airway disease. The MBW method appears to be particularly useful as a tool to evaluate lung function in preschool children because it requires only passive cooperation and tidal breathing. Currently, MBW is performed routinely in preschool children in only a limited number of laboratories, presumably because suitable equipment is not commercially available. Several different inert marker gases with low solubility in blood and tissues can be used for MBW. The most well known is nitrogen (N2), which can be washed out from the lungs by letting the patient breathe pure oxygen (100% O2). Other gases, such as argon (Ar), helium (He), or sulfur hexafluoride (SF6), may also be used, but measuring these gases may require expensive equipment, such as a mass spectrometer. More recently, an MBW method has been introduced that is based on indirect assessment of inert tracer gas concentrations by continuous mainstream recording of the molar mass of the gas inspired and expired using ultrasound technique. There is a lack of comparative studies assessing the importance of using different marker gases, equipment, and procedures. Furthermore, in published MBW studies, different indices on ventilation maldistribution have frequently been reported. Consequently, there is a need for standardization of the MBW procedures. Apart from recommendations about the use of the MBW method in preschool children, this document provides some suggestions regarding more advanced use of the recordings for detailed assessment of peripheral airway function by analysis of the progression of the concentration-normalized phase III slope from each subsequent breath in the washout. It is not expected that any particular MBW system, equipment, or setup will be used universally; therefore, general recommendations are given to facilitate uniformity between the centers using MBW.
Effective mixing of the resident gas in the lungs with the fresh inspired gas via the peripheral airways is essential for gas exchange. Several serious chronic lung diseases in children, such as CF lung disease and obliterative bronchiolitis, affect particularly the peripheral airways (arbitrarily defined as airway generation 8 or higher). The resistance of the peripheral airways contributes little to overall airway resistance (226, 227), and spirometry findings or airway resista |
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to obtain the within-subject SD (SDw) (
4 yr) have shown a significant change in tidal parameters (
2-agonist in wheezy infants (
, "phi") or %. This can be calculated from X–Y plots of rib cage against abdominal excursion (
10% or 
