Forced expiratory manoeuvres

Transcription

1 CHAPTER 4 Forced expiratory manoeuvres S. Lum, J. Stocks Portex Respiratory Unit, University College London, Institute of Child Health, London, UK. Correspondence: S. Lum, Portex Respiratory Unit, Respiratory Physiology and Medicine, University College London, Institute of Child Health, 30 Guilford St, London, WC1N 1EH, UK. s.lum@ich.ucl.ac.uk The aim of this chapter is to describe the technical aspects of undertaking forced expiratory manoeuvres from infancy to school-age, together with a discussion regarding normative values, interpretation of results and the potential applications of these tests for the various age groups both in research and in clinical management. The chapter will focus primarily on the practical aspects of undertaking and interpreting measurements, as details of the underlying theoretical background have been published previously [1 6]. Due to the nature of the tests, and the marked differences between assessing sleeping, supine, passive infants and older, awake and (potentially) cooperative children, details regarding measurements of forced expiration in infants and young children (up to around 2 yrs of age) will be considered first, followed by a description of spirometry in older children. In the latter section, emphasis will be placed on the special adaptations required when assessing preschool children (i.e. those aged 3 6 yrs). Spirometric measurements have been performed by children older than 6 8 yrs of age shortly after the technique was first established in adults, but early attempts to extend these to preschool children were either limited to partial flow volume manoeuvres [7], or resulted in high failure rates in full forced expiratory manoeuvres due to the child s inability to grasp the concepts of, and the lack of necessary coordination. Indeed, it is only during the last decade that the feasibility of regularly obtaining technically acceptable results in this age group has become apparent [8 10]. Descriptions of partial flow volume curves in infants were published 30 yrs ago [11 13], but it was not until 2000 that the first attempts to standardise this procedure were published [14, 15]. By contrast, the interval between the first descriptions of obtaining full forced expiratory manoeuvres in infants [14, 16 18] and recommendations as to how to undertake these measurements [19] was much shorter. Infants Technical aspects Although infants cannot be instructed to perform forced expiratory manoeuvres, partial forced expiratory flow volume (PEFV) curves can be produced by wrapping an inflatable jacket around the infant s chest and abdomen and allowing them to breathe through a facemask and flowmeter. This technique is usually referred to as the squeeze or the tidal rapid thoraco-abdominal compression (RTC) technique. Guidelines for performing the RTC technique have been described fully [15]. Briefly, the jacket is connected via a tap/valve to a pressure source with a pressure relief valve set to blow-off at pressures above the maximum required to inflate the jacket (e.g. y12 15 kpa). After at Eur Respir Mon, 2010, 47, Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2010; European Respiratory Monograph; ISSN x. DOI: / x

2 FORCED EXPIRATORY MANOEUVRES least five regular tidal breaths, an initial jacket pressure (Pj) of 2 3 kpa is usually applied at end inspiration, which applies a pressure around the chest and abdomen to force expiration. This manoeuvre is repeated with increasing Pj (1 2 kpa increments) until no further increase in flow is observed (i.e. flow limitation assumed to have been reached) or until a maximum Pj is reached at which the highest flow is obtained. This Pj is often referred to as optimal and must be established for each infant on each test occasion. Not only does the efficiency of the jacket to transmit force vary according to manufacturer and the way in which the jacket has been fitted on any given occasion, but the pressure required to achieve flow limitation varies markedly according to underlying pathophysiology. Thus a Pj as low as 2 kpa may be sufficient to attain flow limitation in an infant with airway disease, with higher Pj inducing glottic closure and/or negative flow dependence [14], while in healthy infants, a Pj of up to kpa may be required. Jacket efficiency can be measured dynamically using oesophageal manometry, but is more commonly assessed statically by performing an airway occlusion immediately prior to jacket inflation [20]. An increase in intra-thoracic pressure of at least 2 kpa is recommended during jacket inflation, except in infants with marked airway obstruction when flow limitation will be achieved at lower compression pressures [15]. The primary outcome from the tidal RTC is maximal flow at functional residual capacity (V9max,FRC). Due to the variability of end-expiratory level (EEL) in infants, which can have a marked effect on V9max,FRC, it is recommended that V9max,FRC is recorded as the mean of the three highest technically acceptable results [21]. Potential limitations of the tidal RTC include the fact that 1) airway function is only assessed over the tidal range; 2) maximal flows are reported at functional residual capacity, which is not a stable landmark, especially in young infants in whom EEL may be dynamically elevated; 3) any change in functional residual capacity due to disease, therapeutic intervention or bronchial challenge may confound interpretation of results; 4) flow limitation may be difficult to achieve in healthy infants; and 5) application of a sudden external force during the RTC may induce early inspiration, especially in infants with lung disease, thereby precluding calculation of V9max,FRC. The raised volume RTC (RVRTC) technique is an adaptation of the tidal RTC technique, wherein the infant s lungs are passively inflated towards total lung capacity (TLC) using a preset pressure before applying RTC. This enables full forced expiratory manoeuvres to be obtained in infants as in adults. The RVRTC technique may be more reproducible and sensitive than the RTC technique as it provides the means of assessing airway function over an extended volume range. Equipment for the RVRTC technique is as for tidal RTC with the addition of an external air supply and equipment for raising lung volume. Technical details, safety aspects and measurement protocol have been described previously [19]. In brief, optimisation of head/shoulder position to achieve maximum patency of the upper airway is essential to obtain smooth, reproducible flow volume (FV) curves and great care must be taken to avoid gastric distension by careful positioning of the infant and minimising the number of manoeuvres performed. Attempts to collect data from the RVRTC technique should cease if there is evidence of sequential reduction in FVC or inflation volume from one trial to the next, or any clinical signs of regurgitation or vomiting. To facilitate collaboration and comparison of results between centres, it has been suggested that the airway inflation pressures used during RVRTC manoeuvres should be standardised to 30 cmh 2 O (2.94 kpa) [19]. Accuracy and reproducibility of results derived from the RVRTC depend on linearity of the flowmeter over the extended flow volume range, delivery of a precise airway inflation pressure in the breath prior to RTC and ensuring that a brief volume plateau is achieved at end inflation before forcing expiration (fig. 1) [22]. As for the tidal RTC technique, the optimal Pj must be assessed for each infant when using RVRTC [23]. 47

3 S. LUM AND J. STOCKS Flow ml s -1 Volume ml Plateau on volume trace Jacket pressure kpa Airway opening pressure kpa 2 1 Pao pressure plateau Jacket inflated Manoeuvres are repeated until at least two technically acceptable RVRTC FV curves, reproducible to within 10% of highest, have been obtained at optimal Pj. RVRTC manoeuvres should generally be performed at the end of a test protocol due to the potential effect of lung inflations on respiratory mechanics [24]. Commonly reported RVRTC parameters include forced vital capacity (FVC), forced expiratory volume in 0.5 s (FEV0.5), forced expiratory flow at 75% of FVC (FEF75%) and FEF25 75%. In infants younger than 3 months, FEV0.4 should also be reported because rapid lung emptying at this age may preclude measurements beyond 0.5 s [25, 26]. Forced flows and volumes should be reported from the best curve, defined as the one with either the highest sum of FVC and FEV0.5 (or FEV0.4) or the highest sum of FVC and FEF25 75% [19]. Figure 2 shows an overlay of the tidal RTC and RVRTC forced expiratory flow volume (FEFV) curves from the same infant. Although considerable progress has been made in developing and validating the RVRTC technique, several technical and physiological issues require further investigation, including 1) the best way to adjust for body temperature, barometric pressure and saturated with water vapour under these conditions (BTPS)/drift correction in RVRTC data; 2) performance of the flowmeter if pressurised during the manoeuvres; and 3) influence of volume history on RVRTC parameters, etc. (see online supplement of American Thoracic Society (ATS)/European Respiratory Society (ERS) consensus statement 2005 [19]). Normative FEFV data in infants 5 10 Time s Fig. 1. Raised volume rapid thoraco-abdominal compression time-based trace. The upward slope of the volume signal denotes inspiration and the downward slope denotes expiration. In instances where the initiation of jacket inflation is timed to occur simultaneously to the release of inflation pressure, due to the rise time required for jacket inflation, no spike on airway opening pressure (Pao) will be observed. Ideally, lung function results should be expressed as z-scores (or SD scores), which represent a mathematical combination of the measured value as a percentage of that predicted and the between-subject variability into a single number. This accounts for sex, age- and height-related variability in measured outcomes and greatly facilitates interpretation of results within an individual [27]. Despite the introduction of the RVRTC technique, measurement of V9max,FRC using the tidal technique remains the most popular method for assessing airway function in infants and young children. Collation of existing data from 459 infants on 654 occasions 48

4 FORCED EXPIRATORY MANOEUVRES Flow ml s V'max,FRC 0 F= Volume ml 0-50 Fig. 2. Overlay of the tidal and raised volume forced expiratory flow volume curves from the same infant. : raised volume flow volume curve; : partial flow volume curve. V9max,FRC: maximal flow at functional residual capacity; F: flow. from three centres, using similar techniques and equipment, enabled sex-specific prediction equations to be developed for V9max,FRC during the first 20 months of life [21]. At any given height, infant girls have higher flows than boys, emphasising the need for sex-specific reference equations for V9max,FRC. It should be noted that whether using the tidal or raised volume RTC, calculation of forced expired flows at specified lung volumes are highly dependent on algorithms used to correct to BTPS conditions or compensate for any drift in the volume time signal. These may differ markedly according to equipment used such that published reference values are not appropriate for data collected using recently released commercially available equipment (see below). RVRTC. Reference equations based on 155 healthy infants from two centres, aged weeks have been published [28], and were found to be appropriate for data collected in our own centre prior to 2002, in that the mean z-score for FVC, FEV0.5 and FEF25 75% from 163 healthy infants studied during the first 2 yrs of life using our original RASP equipment [29, 30] was within 0.5 z-scores of these predicted published norms. However, the extent to which these normative data are applicable to other populations or data collected using different equipment has yet to be established. A new generation of infant lung function equipment, which complies with most of the recommendations of the joint ATS/ERS taskforce [19] is now commercially available. Analysis of more recent data collected from 125 healthy infants within our department suggests RVRTC data collected with the current Jaeger Masterscreen version 4.54 (VIASYS; CareFusion, Yorba, CA, USA) are significantly lower, such that if based on the Jones normative data [28], the lower limit of normal (calculated from the mean 49

5 S. LUM AND J. STOCKS z-score SD in these healthy infants) would be -2.9 for FVC, -3.6 for FEV0.5 and -3.3 for FEF25 75%, rather than the expected threshold of -2 z-scores. Similar discrepancies are seen when comparing V9max,FRC data, wherein the mean SD z-score from contemporary data ( ) collected from 125 healthy infants 6 weeks -2 yrs of age with the Jaeger system was when calculated according to published reference data [21], giving a lower limit of normal of -3.9 z-scores. We are still investigating the cause for these discrepancies, which may be linked to the way in which BTPS and drift corrections are applied in different systems, but these findings emphasise the urgent need to establish reference data that are appropriate for the actual equipment used and for the inclusion of a control group tested with identical equipment and protocols in research studies. In the meantime, caution must be exercised when interpreting results from infants with lung disease with the lower limit of normal being set to at least -3 z-scores to avoid overdiagnosis. Similar evaluations need to be undertaken with other current commercially available systems. Clinical applications Due to the enormity of published data available and space restraints, only key papers and those published within the last 2 yrs will be reviewed with a summary of clinical applications according to common lung diseases. Since application of forced expired manoeuvres in infants generally requires sedation for the infant and availability of dedicated, skilled personnel to conduct the tests, use of the RTC and RVRTC techniques are generally still limited to the research environment [31 35]. The limited availability of reliable reference ranges for infants, and the dependence of those available on precise equipment and protocols, limits the clinical usefulness of such tests in individual infants. Similarly, there is a paucity of information regarding both shortterm variability of FEFV parameters in infants and the most appropriate thresholds to use when interpreting change following bronchodilator or airway challenge [36 38]. Cystic fibrosis. Recent reviews on lung function testing in infants with cystic fibrosis (CF) have provided clear evidence that both forced flows and volumes from the RVRTC are significantly reduced in infants with CF compared with controls, suggesting that airway dysfunction and increased airway reactivity are present early in the course of the disease [33, 39]. The clinical usefulness of V9max,FRC is more controversial, since in the presence of any gas trapping (which is often an early sign of small airways disease in these children), V9max,FRC will be overestimated [33, 40]. Airway function, as reflected by FEVt and FEF% from the RVRTC, is diminished shortly after diagnosis in infants clinically diagnosed with CF, even without a prior history of respiratory illness [41], and this reduction persists during early childhood [29, 42]. More recently, LINNANE et al. [43] found that FEV0.5 was normal when measured shortly after CF diagnosis by newborn screening but diminished in those above 6 months of age despite good nutrition and ongoing care in specialist CF centres [43]. Several attempts had been made to relate function to structure [44, 45] or inflammation and infection [43, 46 48] but the results are conflicting. In contrast to older children with CF (see below), FEV0.5 and FEF25 75% from the RVRTC identified lung function abnormalities in a similar (although not necessarily the same) proportion of CF infants as did the lung clearance index from the multiple-breath washout technique, suggesting that complementary information may be obtained by undertaking both tests in this population [49]. Bronchopulmonary dysplasia and pre-term birth. A comprehensive review of clinical applications of FEFV manoeuvres in infants delivered prematurely with or without 50

6 FORCED EXPIRATORY MANOEUVRES bronchopulmonary dysplasia (BPD) has been published [34]. There is consistent evidence that V9max,FRC remains persistently low throughout the first 3 yrs of life in children with BPD, irrespective of classification ( new or old BPD) or treatment strategies [34]. Decrements in V9max,FRC have also been reported in otherwise healthy pre-term infants at 1 yr of age [50], emphasising the importance of sequential measurements and use of an appropriate control group when interpreting the long term effects of respiratory disease or neonatal management. FEV0.5 and FEF% from the RVRTC technique also indicate ongoing airflow obstruction of mild-to-moderate severity, reductions in flow being most pronounced at low lung volumes, suggesting dysfunction of the peripheral airways [34]. Wheeze. Recently, BORREGO et al. [32] demonstrated that after adjustment for sex, age, length and maternal smoking, forced flows and volumes from the RVRTC, but not V9max,FRC, were significantly reduced during the first 2 yrs of life in young children with recurrent physician confirmed wheeze compared with prospective healthy controls, and between wheezy subgroups according to clinical risk factors. Similarly, LLAPUR et al. [44] reported a significant reduction in baseline FEF75% z-score in infants with recurrent wheeze, with no significant change in any of the RVRTC parameters following inhaled bronchodilator. This lack of bronchodilator effect, as assessed by RVRTC, in wheezy infants, concurs with previous studies [31, 51]. However, GOLDSTEIN et al. [37] reported a mild bronchodilator effect in healthy infants, this effect being greatest in the youngest infants and in those exposed to pre- or post-natal tobacco smoke. While it is feasible to use the RVRTC during methacholine challenge [36, 38, 52, 53], this is a complex undertaking and there are currently no standards for dosage regimes or guidelines regarding appropriate cut-offs for use in infants and children [54], which limits its clinical applicability. Preschool/school-age Technical aspects Equipment and test performance standards for obtaining spirometric measurements in older children and adults were updated by the joint ATS/ERS task force in 2005 [6, 55]. Most of the technical aspects for undertaking spirometric assessments in preschool children are similar to spirometry in older children and adults. However, when assessing young children, it is essential to gain the trust of the child, allow sufficient time for training and ensure that he/she enjoys performing the measurements, even if initial attempts are less than technically perfect. This requires personnel with specific qualities and a child friendly environment. Guidelines for more standardised data collection and analysis of spirometry in preschool children have been published recently [9]. For successful assessments, the preschool child must learn how to do the FEFV manoeuvre in three distinct steps, namely how to: 1) take a deep breath to full inflation, 2) blow out forcefully, and 3) continue to blow out forcefully until no more air can be expired or until the technician tells you to stop [1, 9, 56]. Interactive computerised incentives may be used to encourage the manoeuvre but are not mandatory. While the principles of spirometry quality control in preschool and school-age children are essentially the same as for adults, criteria for acceptable data need to be modified to reflect the fact that forced expiration is completed much faster than in older subjects, such that the recommended 6 s minimum forced expiratory time (FET) for adults [9, 57] is inappropriate for young children, especially those with healthy lungs. Similarly, criteria 51

7 S. LUM AND J. STOCKS for repeatability based on differences in absolute volumes or flows are inappropriate in children due to the reduced size of the lungs and airways. Children.10 yrs of age can generally perform forced expiratory manoeuvres to meet currently established acceptability criteria for start of test, end of test, FET and reproducibility for FEV1, FVC and peak expiratory flow (PEF) [56], although lung emptying is still frequently completed within,6 s and more emphasis should be placed on inspection of the volume plateau at end expiration than the FET. The main differences in quality control criteria for technically acceptable data between adults, school-age and preschool children are summarised in table 1. There is an urgent need to develop an international standardised over-read score for spirometry in young children, for use in both research and clinical management. Once some consensus has been reached, such age-specific quality control criteria could be incorporated into all spirometric equipment. Automated computer classification of FEFV is to be discouraged since this frequently leads to rejection of acceptable and acceptance of unsuitable data, especially in inexperienced hands. However, computer-generated messages regarding apparent failure to attain age-specific quality control could be a useful adjunct at time of data collection and/or analysis. More importantly, manufacturers should be encouraged to calculate and report critical quality control factors in a readily exportable manner, to assist objective over-read and scoring. The success rate of spirometric assessments improves with age, but varies markedly according to centre. Thus, while 70 80% of preschool children were able to produce technically acceptable data that comply with age-modified ATS/ERS guidelines in some studies [57], others have reported much lower success, with up to 90% failure to meet criteria due to glottic closure, nonmaximal effort (38% each) or premature termination (19%) [58]. Preschool children do require a longer period of training, particularly on a first visit, and may willingly undertake up to 20 manoeuvres (which are completed much faster than in older subjects) without exhaustion until they perfect their technique [57]. Limiting the total number of manoeuvres in preschool children to eight, as recommended by the ATS for older children adults, will result in much lower success. Although there is increasing use of spirometry outside the lung function laboratory, there is still concern about the overall quality and delivery of such office spirometry [59] with conflicting advice regarding its use [60, 61]. We have recently shown that with appropriate training, quality control and on-going supervision, technically acceptable spirometry results in school children can be achieved under field conditions by trained personnel, thus increasing the feasibility and reliability of this technique for future clinical and epidemiological research studies [62]. Reporting of results In children, FVC, FEV0.5, FEV0.75, FEV1 and at least one flow index (to include either FEF25 75% or FEF75%) should be reported, together with raw flow volume data (ideally at least three technically acceptable loops) to enable reconstruction of loops for off-line over-read and quality control as required (table 1). Other indices that should be recorded for quality control purposes should include PEF, FET and backextrapolated volume [9], together with a record of the repeatability of these parameters (absolute and percentage differences between the best and next best manoeuvres), number of satisfactory attempts, posture and whether or not nose-clips were used. In contrast to its value during infancy [25, 29, 30, 49] and potential application during exercise challenge in young children [63], FEV0.5 appears to discriminate relatively poorly between healthy preschool children and those with lung disease. This probably reflects developmental changes in the expiratory time constant. During infancy, the airways are relatively large in relation to lung volume and therefore lung emptying 52

8 FORCED EXPIRATORY MANOEUVRES Table 1 Suggested quality control criteria for technically acceptable spirometry data according to different age groups # Quality control criteria Adult School-age children (6 16 yrs) Start of test criteria: backextrapolated volume Within test criteria ƒ5% or 150 ml FVC, whichever is greater The FV loop should be free from artefact, e.g. cough, glottic closure that influences measurement ƒ5% or 100 ml FVC ", whichever is greater The FV loop should be free from artefact, e.g. cough, glottic closure that influences measurement End of test criteria Duration of FE i6 s Duration of FE: no specified duration + End-expiratory volume End-expiratory volume plateau,0.025 L plateau 1 ( eyeballed ) for i1 s Repeatability: difference between two highest values of FVC and FEV1 Within 150 ml Within 5% FVC or,100 ml if FVC,1000 ml Preschool children (,6 yrs),10% or 75 ml FVC [9, 57] " The FV loop should be free from artefact, e.g. cough, glottic closure that influences measurement Duration of FE: no specified duration End-expiratory volume plateau e or approaching a plateau ( eyeballed ) ƒ100 ml or within 10% of highest value FVC: forced vital capacity; FV: flow volume; FE: forced expiration; FEV1: forced expiratory volume in 1 s. # : age range is a very approximate guide and may need adjustment according to size or developmental stage, e.g. in ex-pre-term children. " : currently there is no evidence regarding the magnitude of back-extrapolated volume in school-age children that needs to be reported in future. Although recent American Thoracic Society/European Respiratory Society guidelines suggested an upper limit of 12.5% for back-extrapolated volume in preschool children [9, 57], in reality we have found that such a leniency may be associated with a visibly slow start and that the vast majority of children aged,6 yrs can easily achieve,10% or 75 ml once sufficiently coached. + : there is an argument for not judging quality based on forced expiratory time at all during childhood and adolescence as in health, lung emptying may be very rapid. 1 : ideally there should be a volume change of,5% of FVC over the last 0.5 s, however, at present, software does not measure this, and the operator therefore needs to inspect the volume time trace carefully for evidence of an end-expiratory plateau. e : ideally there should be a volume change,5% of FVC over the last 25% of total expired time, however, at present software does not measure this, therefore the operator should look for an end-expiratory plateau on the volume time trace. Note: neither the absolute nor the percentage difference of outcome variables between the best two curves are automatically calculated by many commercially available spirometers. Manufacturers should be encouraged to record these as exportable parameters based on best two acceptable curves. Although an automated scoring system could potentially be incorporated into commercial equipment, where this has been done in the past it has often led to over-reliance and consequent exclusion of adequate and acceptance of unacceptable flow volume manoeuvres (J. Hankinson, Hankinson Consulting, Inc., Valdosta, GA, USA; personal communication). A better approach would be for age-specific warnings to be generated by the computer software, the appropriateness of which the operator can consider during subsequent data collection or analysis, and for key quality control parameters to be calculated and reported by the software. occurs rapidly during forced expiration (often,1 s). Consequently, FEV0.5 tends to be reached at low lung volumes and probably reflects the global output of both peripheral and central airway function in infants [64]. Subsequent post-natal growth in lung volume is, however, more rapid than that of airway calibre. With the consequent lengthening of the expiratory time constant and slowing of lung emptying with growth, FEV0.5 will occur at a relatively higher lung volume in preschool children than in infants (fig. 3). Such developmental changes may explain why FEV0.75, appears to be a more sensitive parameter than FEV0.5 for identifying lung disease during the preschool years [42]. By contrast, the use of FEV1 as a measure of airway function in early life may be limited by the number of healthy children in whom this can be calculated, and the fact that values of FEV1 in healthy preschool children often approximate FVC [10, 57, 65, 66]. Further work is needed to explore the relationship of FEV at different timed intervals with growth. Current evidence suggests that when using spirometry, different 53

9 S. LUM AND J. STOCKS b) a) 1000 Flow ml s FEF79% Flow L s FEF62% Volume ml Volume L Fig. 3. Developmental changes in the rate of lung emptying: position of the forced expiratory volume in 0.5 s (FEV0.5) on the forced expiratory flow (FEF) volume curve. In this example, FEV0.5 during a) infancy is recorded when 79% of forced vital capacity (FVC) has been expired, whereas b) 3 yrs later, only 62% of FVC has been expired in the first 0.5 s of the forced expiration. outcomes may be required at different ages or disease stages. There is increasing evidence that despite the relatively wide between-subject variability, FEF25 75% may be a more useful and sensitive outcome measure in young children than FEVt [42, 67, 68]. A further advantage of this outcome is that, in contrast to FEVt, the same parameter, derived from measurements over a similar portion of the expired FVC, can be reported at all ages, provided care is taken to ensure complete expiration to residual volume. Recent publication of spirometry reference equations that incorporate this outcome [69] should facilitate use of forced expiratory flows in both research studies and clinical management. It has been suggested that inclusion of forced inspiratory as well as forced expiratory manoeuvres may be helpful in identifying upper airway obstruction in preschool children [70], although the feasibility and clinical usefulness of this approach in routine clinical practice has yet to be demonstrated. Normative data Like most medical observations, reliable interpretation of pulmonary function results relies on the availability of appropriate reference data to help distinguish between health and disease and to assess the severity and nature of any functional impairment. The overwhelming number of published reference equations for spirometry [71] complicates the selection of an appropriate reference. The use of inappropriate reference equations, and misinterpretation even when using potentially appropriate equations, can lead to serious errors in both under- and overdiagnosis, with its associated burden in terms of financial and human costs [1, 10, 27, 55, 65, 72 75]. Overdependence on fixed cut-offs to define abnormality, irrespective of well-recognised age-related changes, further magnifies these problems [76, 77]. Forced expired flows and volumes are highly dependent on body size and age, where height is a proxy for chest size, and age reflects maturity. During childhood and adolescence, growth is particularly rapid with lung function increasing 20-fold during the first 10 yrs of life (fig. 4). By contrast, once peak lung function has been attained 54

10 FORCED EXPIRATORY MANOEUVRES FEV0.5 ml Height cm Fig. 4. Forced expiratory volume in 0.5 s (FEV0.5) from birth to school age, showing the rapid increase due to lung and somatic growth over this period. h: infant (0 2 yrs); n: preschool (3 6 yrs); #: school-aged (.6,10 yrs). during early adulthood, this peak being some 5 yrs later in males than females, there is a steady age-related decline in spirometric parameters (fig. 5). While the precise age at which lung growth ceases depends on whether cross-sectional or longitudinal data are inspected, height, age, sex and ideally ethnic group must always be taken into consideration when defining the normal range for spirometric lung function. Although accurate identification and interpretation of changes in lung function as a result of disease or treatment requires knowledge of normal variability over time in healthy subjects [1, 78], most reference ranges are based on cross-sectional samples, and there remains a paucity of data regarding either short or longer-term repeatability of spirometry. 6 5 Predicted value Age yrs Fig. 5. Height-adjusted predicted median values for forced expiratory volume in 1 s (-----; L), forced vital capacity ( ; L) and forced expiratory flow at 25 75% of forced vital capacity (???????; L?s -1 ) from early childhood through to 80 yrs in male subjects only, showing the rise and subsequent fall of spirometric lung function with growth and ageing. Adapted from reference [27], with permission from the publisher. 55

11 S. LUM AND J. STOCKS As described above, adaptation of techniques and quality control criteria, together with provision of child friendly environments have now made it possible to obtain spirometric measurements in children as young as 3 yrs of age. While these advances make it possible to assess lung function continuously from early childhood through adulthood, in practice, clinical application has remained limited by the lack of appropriate reference data for young children,5 yrs of age [10]. Interpretation of results is further complicated if different equations with arbitrary break points between different age groups are used when undertaking serial measurements in the same child. This may lead to shifts in predicted values and confusion when it comes to clinical management as the child grows. With these limitations in mind, a recent international initiative was established to develop improved reference ranges for young children [65]. The resultant Asthma UK centiles charts for spirometry, which are based on data from 3,777 healthy white children,7 yrs of age studied in 15 centres, spread across 11 countries and four continents [69], also link seamlessly with an all-age reference [79]. This will facilitate interpretation of spirometry results from 3 80 yrs. These new equations can be installed into commercially available equipment upon request from any manufacturer [65], which should facilitate their implementation into clinical and research practice. The collated dataset reflects a variety of equipment, measurement protocols and population characteristics and may be generalisable across different populations. These equations improve existing paediatric equations by considering the increased between-subject variability in younger children to define a more appropriate agedependent lower limit of normal (5th centile or z-scores). Of particular note is the higher between-subject variability found among younger children, which must be taken into account in both clinical management and research studies. Thus, the betweensubject coefficient of variation (CV) for FEV1 decreases from 17% at 3 yrs to 11% at 20 yrs, such that the lower limit of normal (LLN) is not 80% at all ages, as so commonly assumed, but 66% predicted at 3 yrs and 78% predicted by 20 yrs, with similar variability for FVC. The between-subject CV is even greater for FEF25 75%, but shows less age dependence, such that the normal range for FEF25 75% lies between % predicted in a 3-yr-old and % predicted in a 20-yr-old. Expression of results as centiles or z-scores overcomes the need to remember these age dependent thresholds of abnormality [10, 27]. Despite these recent advances and availability of some spirometric reference data from healthy black and Hispanic children [80, 81], there remains a paucity of suitable equations for ethnic groups other than white Europeans, especially among young children. As demonstrated recently, previous attempts to correct for ethnic differences have been oversimplistic [82]. Much of the apparent ethnic variability in lung physiology may in fact be attributable to differences in body size, physique and composition, such that the need to categorise ethnicity when interpreting lung function data could be greatly reduced by adjusting for such information. Firm evidence in this field will require application of identical equipment and spirometric protocols, together with careful assessments of anthropometry and body composition, to a large multi-ethnic sample of children across as wide an age range as possible. Interpretation of results Guidance on interpretative strategies for spirometry has been published previously [1, 72] and is essential reading. An obstructive ventilatory defect is characterised by a disproportionate reduction of maximal airflow from the lung in relation to the maximum volume (i.e. vital capacity (VC)) that can be displaced from the lung and is 56

12 FORCED EXPIRATORY MANOEUVRES defined as FEV1/VC,5th percentile of predicted. As FEV1/FVC is related to age and height [27, 69], it is essential to use the LLN derived from appropriate reference equations rather than any fixed cut-off for FEV1/FVC such as 0.7 [76, 83, 84]. The earliest change associated with airflow obstruction is usually diminished flow at low lung volumes (FEF75% or FEF25 75%) as reflected by the concave shape of the FV curve, although this reduction is not specific for small airways disease in individual patients. A restrictive pattern may be suspected when the VC is reduced, FEV1/VC is increased (.85 90%) and the FVC curve shows a convex pattern, although sometimes this pattern may also be due to submaximal inspiratory or expiratory efforts and a reduced VC alone does not prove restrictive ventilatory defect [72]. Assessment of TLC using plethysmography or gas dilution techniques may be required to confirm the diagnosis of restrictive lung disease. A mixed ventilatory defect is characterised by a combination of obstruction and restriction, and is defined by a reduction of FEV1/VC and TLC,5th percentile of predicted [72], and are difficult to distinguish using spirometry alone [1]. Clinical applications As for infants, due to the volume of relevant publications and space restraints, only key papers and a selection of recent publications illustrating the use of spirometry in children with common lung diseases will be discussed. Clinical management. The arguments about the potential usefulness of tests in clinical decision-making have been discussed previously [85 87]. While spirometry remains the most commonly used technique for assessing lung function in children and has been shown to be a sensitive marker in discriminating between health and disease in clinical research (see below), its usefulness in the clinical management of individual children will depend on the age of the child as well as the type and severity of disease. As discussed above, clinical interpretation of spirometry results depends on the reference population selected, as well as knowledge of the age-specific short and longer term within-subject variability in health and disease. In many clinical scenarios, the best reference is the child s own baseline results when well, to which subsequent changes can be related. Even so, knowledge of expected variability over time with adjustment for the correlated nature of repeated measurements is required for proper interpretation of such changes [78]. The within-day variation of spirometry for children with CF has been reported to be similar during pulmonary exacerbations and during clinical stability [88]. Among school-age children, spirometry is most frequently used as an adjunct to clinical management in those with wheezing or asthma. A workshop summary and literature review on the natural history of asthma has been published recently [89]. Several studies have demonstrated that clinical assessments made by emergency physicians, community paediatricians and even paediatric pulmonary specialists may underestimate the degree of obstruction in patients with asthma and that the addition of spirometry has a significant positive impact on management [86, 87, 90]. PEF has been shown to underestimate the severity of obstruction when compared with FEV1 [90], such that the National Asthma Education and Prevention Program Expert Panel Report 3 no longer recommends use of PEF when assessing asthma severity [91]. Serial measurements in children with asthma suggested a greater annual loss in percentage predicted post-bronchodilator FEV1 among those with the most pronounced disease progression [92]. When used in conjunction with symptom history, FEV1/FVC has been found to be more useful than FEV1 and FEF25 75% when determining asthma severity in adolescents [93], the reliability of such determinations being improved by use of appropriate LLN according to the age of the subject, rather than a fixed cut-off [94]. 57

13 S. LUM AND J. STOCKS Serial measures of spirometry are routinely performed in children with CF. Although the clinical utility of such measures has been questioned recently [95], the rate of decline in FEV1 for children with CF has been shown to be predictive of death [96, 97] and to identify high-risk subgroups within the CF population [98]. Spirometry is being increasingly used to assess cross-sectional and longitudinal changes in lung function in sickle cell disease [99 101]. Assessment of bronchial responsiveness and reactivity Spirometric measurements are routinely used to assess both bronchodilator response and bronchial challenge in children aged.6 yrs [102, 103]. Guidelines based on measurements made in older subjects [54, 104] are currently being updated by the ATS/ ERS and need to be adapted for use in children. Recommendations for assessing bronchodilator responsiveness (BDR) in younger children have been published recently [9]. The specificity and sensitivity of spirometric bronchodilator measurements in preschool children with wheeze are not yet available, although studies are currently evaluating this issue. Preliminary data suggest that the diagnostic profile of spirometry for BDR may be poor in very young children due to the overlap between those with and without lung disease and hence their feasibility and/or utility in younger children, in whom alternative techniques tend to be used [ ], has yet to be demonstrated. Clinical and epidemiological research. Spirometric indices have been widely used as outcome measures in longitudinal follow-up of children with lung diseases such as asthma [108, 109], CF [29, 43, 47, 68], BPD [67, ] and sickle cell anaemia [99 101]. These studies have been designed to elucidate the evolution of disease processes, assess BDR [37, 106] and reactivity [53, 105, 107], and response to therapeutic interventions [63, 88, 115]. They have also been widely used in epidemiological research studies, including those designed to identify early determinants of subsequent lung health [8, 37, 80, 106, 109, 116]. FEV1 and FEV1/FVC have been the commonest outcomes reported, but there is increasing evidence that FEF25 75% may be more sensitive in younger children [42, 67, 68]. FEV1 is relatively insensitive for detecting early changes in lung disease in cystic fibrosis [68, ] and, even when abnormal, displays a very slow rate of decline that makes it unsuitable for clinical monitoring or for use as an outcome measure in research studies of young children with CF. With the increased emphasis on early intervention, there is a pressing need for alternative surrogate markers that can reliably detect early CF lung disease, such as the lung clearance index from the multiple-breath washout technique [39, 95, 120] (see also chapter 6 of this European Respiratory Monograph). Long-term reductions in FEV1 have been consistently demonstrated in children born pre-term, these being most marked in those with a prior history of BPD [110, 112, 113, 121], and associated with structural changes on high-resolution computed tomography [122]. Airway hyperresponsiveness has been reported to be associated with pre-term birth and more so in those with a stormier neonatal course, as described for infants, but the interpretation of such data is limited by the lack of standards for dosage regimes or guidelines regarding appropriate cut-offs for use in children. Conclusions and future directions During the past decade, enormous advances have been made in the field of paediatric FEFV manoeuvres, with increasing use of the RVRTC in infants, widespread 58

14 FORCED EXPIRATORY MANOEUVRES application of spirometry in preschool children and development of improved all-age reference equations. Despite its feasibility in children as young as 3 yrs and its widespread use for assessing airway function in both clinical and research settings, spirometry may be relatively insensitive to early lung disease, especially if outcomes are limited to FEV1 such that alternative or additional lung function techniques may be required when determining the nature and magnitude of lung disease in early life. If the utility of spirometric measurements is to be optimised, either as an adjunct in clinical management or as objective outcome measures in clinical and epidemiological research, there remains an urgent need for the following: 1) development of revised reference equations for both the tidal and raised volume RTC that are appropriate to current commercially available infant lung function equipment and explore underlying reasons for observed equipment specific differences in outcome parameters; 2) development of age-specific over-read templates for quality benchmark of RVRTC/ spirometry data in infants, preschool and school-age children; 3) provision of guidance on the essential background information (e.g. birthweight, gestational age, passive smoke exposure, prior medical history), which should be recorded at time of measurement to facilitate interpretation of results; 4) extension of all-age spirometry reference ranges for use in all individuals from 3 yrs upwards, irrespective of ethnic origin; and 5) exploration of the effect of growth and development on spirometric outcome variables such as timed FEVs and the FEVt/FVC ratio and the potential impact this may have on the utility of different outcomes at different ages, or in different diseases. Summary Forced expiratory manoeuvres can now be applied from birth throughout childhood, and continuous reference equations for white subjects of European descent are available from 3 80 yrs with which to characterise normal lung growth, assess the nature and severity of disease and monitor disease progression or resolution in both clinical and research settings. Outcomes derived from raised volume forced expiratory flow volume manoeuvres have proved to be among the most sensitive lung function tests for use in infants, but are relatively invasive, require sedation of the infant and considerable expertise during data collection and analysis, such that their use is generally limited to the research setting. Furthermore, published reference data for either the tidal or raised volume rapid thoraco-abdominal compression may not be appropriate for infant data collected with the current generation of commercially available equipment. There is an urgent need to develop appropriate quality control and over-read criteria for spirometry for both preschool and school-age children, and to extend spirometry reference ranges for use in all subjects, irrespective of ethnic origin. Despite its feasibility in children as young as 3 yrs and its widespread use for assessing airway function in both clinical and research settings particularly with respect to long-term impact of early life events, spirometry may be relatively insensitive to early lung disease, especially if outcomes are limited to forced expiratory volume in 1 s such that alternative lung function techniques may be required when determining the nature and magnitude of lung disease in early life. Keywords: Children, infants, lung function test, raised volume technique, spirometry. 59

15 S. LUM AND J. STOCKS Statement of interest None declared. Support statement S. Lum was funded by the Medical Research Council, London, UK. References 1. Castile RG. Pulmonary function testing in children. In: Chernick V, Boat TF, Wilmott RW, et al., eds. Kendig s Disorders of the Respiratory Tract in Children. 7th Edn. Philadelphia, Elsevier, 2006; pp Dawson SV, Elliott EA. Wave-speed limitation on expiratory flow a unifying concept. J Appl Physiol 1977; 43: Hyatt RE, Schilder DP, Fry DL. Relationship between maximum expiratory flow and degree of lung inflation. J Appl Physiol 1958; 13: McNamara JJ, Castile RG, Glass GM, et al. Heterogeneous lung emptying during forced expiration. J Appl Physiol 1987; 63: Mead J. Expiratory flow limitation: a physiologist s point of view. Feder Proc 1980; 39: Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J 2005; 26: Taussig LM. Maximal expiratory flows at functional residual capacity: a test of lung function for young children. Am Rev Respir Dis 1977; 116: Eigen H, Bieler H, Grant D, et al. Spirometric pulmonary function in healthy preschool children. Am J Respir Crit Care Med 2001; 163: Beydon N, Davis SD, Lombardi E, et al. An official American Thoracic Society/European Respiratory Society statement: pulmonary function testing in preschool children. Am J Respir Crit Care Med 2007; 175: Stanojevic S, Wade A, Lum S, et al. Reference equations for pulmonary function tests in preschool children: a review. Pediatr Pulmonol 2007; 42: Adler SM, Wohl ME. Flow volume relationship at low lung volumes in healthy term newborn infants. Pediatrics 1978; 61: Taussig LM, Landau LI, Godfrey S, et al. Determinants of forced expiratory flows in newborn infants. J Appl Physiol 1982; 53: Godfrey S, Bar-Yishay E, Arad I, et al. Flow volume curves in infants wih lung disease. Pediatrics 1983; 72: Le Souëf PN, Castile R, Motoyama E, et al. Forced expiratory maneuvers. In: Stocks J, Sly PD, Tepper RS, et al., eds. Infant Respiratory Function Testing. 1st Edn. New York, John Wiley & Sons, Inc., 1996; pp Sly P, Tepper R, Henschen M, et al. Standards for infant respiratory function testing: tidal forced expirations. Eur Respir J 2000; 16: Turner DJ, Lanteri CJ, Le Souëf PN, et al. Improved detection of abnormal respiratory function using forced expiration from raised lung volume in infants with cystic fibrosis. Eur Respir J 1994; 7: Turner DJ, Stick SM, Le Souëf KN, et al. A new technique to generate and assess forced expiration from raised lung volume in infants. Am J Respir Crit Care Med 1995; 151: Feher A, Castile R, Kisling J, et al. Flow limitation in normal infants: a new method for forced expiratory maneuvers from raised lung volumes. J Appl Physiol 1996; 80: ATS/ERS Consensus Statement. Raised volume forced expirations in infants: recommendations for current practice. Am J Respir Crit Care Med 2005; 172: