Novel Physiologic Tests to Assess Lung Disease in Children

NOVEL PHYSIOLOGIC TESTS TO ASSESS LUNG DISEASE IN CHILDREN

Enrico Lombardi, Claudia Calogero

Section of Respiratory Medicine, “Anna Meyer” University-Hospital for Children, Florence, Italy

INTRODUCTION

Lung function measurements have for long been limited in young children by their poor cooperation and difficulty in performing voluntary forced manoeuvres. Although spirometry and other adult-type pulmonary function tests (PFTs) are routinely performed in school children, until recently measuring lung function in children younger than 6 has been generally considered very difficult or even impossible. The use of sedation has made it feasible to measure lung function in infants and toddlers up to the age of 1.5-2 yr and standards for infant PFTs have been published between 2000 and 2001, although these tests are generally not used routinely in clinical practice because of the need for sedation and the time required for the procedures. Preschool children, namely 2-5 year-olds, have thus remained for long a real challenge for physiologists, because they are too old to be sedated and too young to perform the manoeuvres required for adult-type PFTs.

During the past century several non-invasive techniques, only requiring tidal breathing without sedation, have been developed. Around the end of the century these techniques have been shown to be feasible in preschool children. In 2007 the “American Thoracic Society/European

Respiratory Society Working Group on Infant and Young Children Pulmonary Function Testing” published the technical recommendations for PFTs in preschool children (1), with the aim of making the techniques used in the different laboratories more uniform and allowing comparison among centres. Recently, many studies have shown the clinical applications of these techniques in preschool children. In this review we will focus on the new techniques available for lung function measurements in preschool children and their clinical applications.

1 INTERRUPTER TECHNIQUE

The measurement of respiratory resistance using the interrupter technique (Rint) is based on the principle that during a sudden interruption of the tidal airflow alveolar pressure and mouth pressure (Pmo) would equilibrate and Rint can be calculated as the ratio of pressure change divided by the flow measured immediately before (“classical” technique) or after (“opening” technique) the interruption. Rint reflects the resistance of the respiratory system (airways, lung tissue, and chest wall). Because of the viscoelastic properties of the tissues of the respiratory system, Rint will approach pure airway resistance if Pmo is measured at the beginning of the interruption (“classical” technique), while it will reflect the resistance of the whole respiratory system if Pmo is measured at the end of the interruption (“opening” technique).

The recently issued technical recommendations for the “classical” interrupter technique in preschool children (1) can be summarized as follows: the child should be seated, breathing through a mouthpiece and bacterial filter, wearing a noseclip, and with the cheeks supported; the interrupter valve should close in less than 10 ms and the interruption should not last longer than 100 ms (to avoid active breathing during the interruption); the interruptions should be triggered by a flow set to coincide with peak expiratory flow; ten interruptions should be recorded to obtain at least five acceptable manoeuvres and the median of all technically acceptable manoeuvres should be reported.

Rint has a good feasibility in preschool children, between 81% and 98%, both in the ambulatory setting and in the field (1). The intra-measurement coefficient of variation (CV) is around 12% (1) in healthy children and in those with asthma or cystic fibrosis (CF). The short-term inter-measurement coefficient of repeatability (CR, 2 SD of the difference between two measurements) is 0.17-0.28 kPa.L-1.s (1) in healthy children and children with recurrent wheezing.

A similar long-term CR has been shown in healthy children (1), while conflicting results have been reported in children with a history of respiratory symptoms (1). Several reference equations have been published for preschool and school children (1); these data have been collated for the

“classical” interrupted technique and one international set of reference equations has been recently

2 published (2). Data on bronchodilator response (BDR) are also largely available for Rint (1); a recent study has shown that a decrease in Rint >0.25 kPa.L-1.s (corresponding to >1.25 Z-score) had

80% sensitivity and 82% specificity in detecting children with respiratory symptoms at the time of testing (3). Rint BDR has been shown to have a sensitivity of 24-76% in discriminating children with a history of recurrent wheezing from healthy children, with a specificity of 70-92%. Rint can also been used in bronchial challenge tests in association with other lung function indices (1) and has been used in epidemiological studies and clinical trials.

FORCED OSCILLATION TECHNIQUE

The forced oscillation technique (FOT) is also performed at tidal breathing, thus being very suitable for preschool and poorly cooperating children. Its underlying principle is that an external pressure wave applied at the airway opening will cause changes in airflow and Pmo that can be measured to determine the impedance of the respiratory system (Zrs), with its two components resistance (Rrs) and reactance (Xrs). Rrs is the in-phase component (or “real part”) of Zrs and reflects the frictional losses of the respiratory system; Xrs is the out-of-phase component (or

“imaginary part”) of Zrs and reflects the apparent elasticity and inertive properties of the respiratory system (1). The simultaneous use of a range of frequencies (pseudorandom noise or recurrent impulses) allows to study the frequency-dependence of the respiratory system through model-based analysis of the complex signals (1). Rrs is considered to be a reasonable estimate of airway resistance at 6-8 Hz, while the component of tissue resistance is also reflected at lower frequencies.

According to the recently issued technical recommendations for FOT in preschoolers (1): the test should be performed with the child seated, breathing through a mouthpiece, and wearing a noseclip with the cheeks supported; the excitation frequencies should include the range 4–8 Hz; the acquisition period should be at least 8–16 s; the mean of 3 to 5 measurements should be reported; a

CV (SD to mean ratio) should be calculated for every frequency and used as a reliability index.

3 The feasibility of FOT in preschool children also ranges between 79% and 95%. Regarding inter-measurement repeatability, most studies report a short-term CR of 0.20-0.26 kPa.L-1.s for Rrs and 0.12-0.25 kPa.L-1.s for Xrs, with similar values for long-term CR. Several reference equations are available for preschool and older children (1). Bronchodilation data are also available (1) and most studies report as significant a decrease in Rrs between 20% and 40% with respect to baseline.

FOT has been used in clinical studies on children with asthma, CF, and a history of premature birth and has been shown to have a sensitivity of 90% and a specificity of 53% in discriminating children with probable asthma from healthy children.

PLETHYSMOGRAPHIC SPECIFIC AIRWAY RESISTANCE

With respect to conventional whole body plethysmography, the advantage of this technique is that it only requires tidal breathing, without the need of breathing against a closed shutter.

Specific airway resistance (sRaw) is the product of airway resistance (Raw) by thoracic gas volume

(TGV) and is simply calculated by measuring the change of plethysmographic volume (Vbox) and the change in airflow (ΔV’), thus avoiding the panting manoeuvre against a shutter required to measure TGV and calculate Raw: sRaw = (ΔVbox / ΔV’) x (Pamb - PH20), where Pamb is the ambient pressure and PH20 is the pressure of water vapour at 37° C.

The technical details of sRaw measurements in preschool children have recently been reviewed by Bisgaard and Nielsen (4). Electronic compensation for body temperature and pressure, saturated (BTPS) conditions is usually used to adjust for changes in humidity and temperature of the gas during the respiratory cycle. The child seats in the body box breathing at 30-45 breaths per minute. sRaw is calculated as the median of 5 technically acceptable specific resistance loops (4).

sRaw is also very feasible in young children (with a feasibility of 57% in 2-year-olds) and repeatable (short-term CR 0.17-0.22 kPa/s and similar long-term repeatability) (4). Reference values are available, although the different methods used highlight the need for standardisation (4).

BDR data are also available: a 25% sRaw decrease with respect to baseline has been found to have

4 66% sensitivity and 81% specificity in discriminating between asthmatic and healthy preschool children (4). sRaw has also been used in clinical and epidemiological trials (4).

MULTIPLE BREATH WASHOUT

Nitrogen washout using 100% oxygen was the first multiple breath washout (MBW) technique described for assessing functional residual capacity (FRC) and ventilation inhomogeneity during tidal breathing. Recently, other inert non-resident gases have been used (helium, argon, sulphur hexafluoride) and several indices reflecting overall ventilation inhomogeneity have been reported. One of the most commonly used is the lung clearance index (LCI), which is the number of lung volumes (expressed in FRCs) required to complete the washout (1). A more sophisticated approach is represented by the concentration-normalised phase III slope analysis of the washout curve, but more work is needed before this analysis can be routinely used in preschool children (1).

Technical recommendations for MBW have been recently published (1): measurements should be performed with the child seated and breathing regularly through a mouthpiece or a sealed face mask; if a non-resident inert marker gas is used, a sufficiently long wash-in period is needed; washout should continue until the end-tidal marker gas concentration has fallen below 1/40th of the starting concentration over three subsequent breaths; the mean LCI values from two washouts, in which FRC differs less than 10%, should be reported.

The feasibility of LCI is good in preschool children (between 75 and 84%) (5). LCI shows no change with age or growth in healthy subjects (1). LCI has been successfully used in children with CF and asthma, and has been shown to be sensitive, robust, and clinically useful in detecting peripheral lung disease (1). A recent paper has reported that MBW is more sensitive than spirometry and plethysmography in detecting abnormal lung function in preschool children with cystic fibrosis (5). The American Thoracic Society and European Respiratory Society are currently working to produce further guidelines on the MBW measurements.

5 CONCLUSIONS

These techniques have proved to be feasible a reproducible in poorly cooperating children.

Furthermore, proper reference values are often available. Their ability in detecting changes in airway calibre makes them potentially useful tools in research and routine clinical practice, especially for the preschool age range. However, their capability to clearly distinguish between health and disease and to make a difference in the long-term outcome of the respiratory illnesses remains to be established.

REFERENCES

1. 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: 1304-1345.

2. Merkus PJFM, Stocks J, Beydon N et al. Reference ranges for interrupter resistance technique:

the Asthma UK Initiative. Eur Respir J 2009 Dec 23, epub ahead of print.

3. Mele L, Sly PD, Calogero C et al. Assessment and validation of bronchodilation using the

interrupter technique in preschool children. Pediatr Pulmonol 2009, in press.

4. Bisgaard H, Nielsen KG. Plethysmographic measurements of specific airway resistance in

young children. Chest 2005; 128: 355-362.

5. Aurora P, Bush A, Gustafsson P et al. Multiple-breath washout as a marker of lung disease in

preschool children with cystic fibrosis. Am J Respir Crit Care Med 2005; 171: 249-256.