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* From the COPSAC Clinical Research Unit (Dr. Bisgaard), Department of Pediatrics, Copenhagen University Hospital, Gentofte; and Pulmonary Service (Dr. Nielsen), Department of Pediatrics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Correspondence to: Hans Bisgaard, MD, DMSci, Professor of Pediatrics, Copenhagen University Hospital, Gentofte, DK-2900 Copenhagen, Denmark; e-mail: Bisgaard{at}copsac.dk
| Abstract |
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Key Words: airway resistance child method preschool specific airway resistance
| Introduction |
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Plethysmography was introduced by DuBois et al3 in 1956 for the assessment of Raw. The measurement of Raw requires a two-step procedure, with initial appraisal of the specific Raw (sRaw) through simultaneous recording of air flow and plethysmographic volume (Vpleth) swing during tidal breathing, and subsequent measurements of the thoracic gas volume (TGV) through recording of Vpleth swing and the corresponding mouth pressure swing while the subject performs tidal inspiratory and expiratory breathing (panting) against a closed shutter. Raw is then calculated as the ratio of sRaw/TGV. The procedure for measurement of TGV is poorly tolerated by young children, who often refuse or who perform the breathing maneuver against the closed shutter unsatisfactorily. Omitting this latter step provides measurements of sRaw and greatly facilitates the procedure allowing its use even in young children as suggested in 1976 by Dab and Alexander,45 but was not assessed until the recent decade.
Plethysmographic measurements of sRaw have lately been successfully adapted and approved for use in children from 2 years of age.67891011121314151617181920212223 Appropriate use of an adapted facemask, and an adult accompanying the child in the box has increased acceptance of this method.8 The approach to measurements of flow and pressure swing in a plethysmograph during tidal breathing is noninvasive and acceptable for use in awake young children from 2 years of age. The technique allows measurements during normal tidal breathing and requires only the passive cooperation of the child, independent of the childs ability to follow verbal instructions.
It is the aim of this article to further a wider dissemination of measurements of sRaw in young children in research as well as in clinical practice. With this aim, this article explains the simple principles of sRaw measurements, reviews the data on the validity of the method in young children, proposes a protocol for assessing sRaw, and suggests areas for future research.
| Physics |
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Any increase, however, of Raw or increase of TGV or both results in an elevated sRaw. Similarly, sRaw will decrease if either Raw or TGV or both are minimized, and a normal sRaw would indicate that both Raw and TGV must be in a normal range. That is why sRaw is the more dynamic parameter, as supported in empiric data comparing sRaw and Raw in asthmatics and healthy children.24 In summary, sRaw is always reflecting the complete respiratory tract, consisting of both resistive and volume properties.
| Measurements of sRaw |
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) while seated inside a sealed, volume-constant box equipped with a pressure transducer that records changes of pressure inside the plethysmograph (Fig 1
). This enables the measurement of the variations of the pressure in the plethysmograph due to the compression of the lung gas volume during expiration and decompression during inspiration through the breathing cycle, ie, the effort driving the flow is reflected as the pressure swing within the box. Calculating the Raw from pressure difference and flow is analogous with Ohms law of resistance in an electric circuit.
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Vpleth) is measured through the change in box pressure. The simultaneous recordings of
and
Vpleth are depicted as the specific resistance loop and the inserted straight parameter line from which sRaw is calculated (Fig 2
):
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Vpleth/
) corresponds to 1/tan ß as shown in Figure 2, Pamb is ambient pressure, PH2O is the pressure of water vapor at body temperature, and Pamb PH2O is the approximate thoracic gas pressure.
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| Equipment |
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| Practical Aspects |
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Seating of the Child
The child is seated upright in the box with the neck slightly extended and with avoidance of flexion or rotation, since measurement of Raw is influenced by the position of the neck that may compress the airways. To ensure slight neck extension as well as to improve cooperation of the patient, a monitor showing video cartoons may be placed in front and above the patient during all measurements. Communication via microphone and loudspeaker ensures instruction of the child and adult during testing. The walls of the box should not be touched during measurement, since this confounds the pressure (volume) signal.
Accompanying Adult in the Box
If the child refuses to enter the whole-body plethysmograph alone or otherwise is uncooperative, sRaw measurements may be attempted with an adult person accompanying the child inside the plethysmograph.8 sRaw measured by this procedure shows good agreement with values obtained from the child alone.8 It is recommended for the adult to perform a constant slow expiratory maneuver for a period of 20 s, which allows sufficient time for measurement of sRaw of the child. Such a maneuver gives rise to a slight continuous drift of the signal measuring
Vpleth, which is corrected for by the data-processing software together with the drift from temperature buildup, and is easily separated from the more rapid pressure swing of the childs breathing. Most commercial software compensates such slow drift expected from temperature buildup and will therefore adapt to the accompanying adult. Breath-hold has also been successfully attempted2025 but introduces a risk of thoracic or abdominal excursions, causing disturbance less likely to occur during a continuous expiratory maneuver.
Mouthpiece/Facemask
Measurement of lung function normally requires the subject to wear a nose clip and keep the lips sealed around a mouthpiece. In young children, such requirements detract from acceptance. With a standard facemask, the child is likely to breathe through the nose. To overcome these difficulties, we recommend a facemask with a large cushion, which ensures a good seal and stabilizes the cheeks and chin.6 To avoid nasal breathing, a built-in flexible tube ensures that the mouth remains open (ie, a mouth opener and not an actual mouthpiece since the seal is secured by the facemask).
Respiratory Breathing Frequency
sRaw measurements performed with commercially available electronic body temperature and pressure, saturated (BTPS) compensation exhibit positive frequency dependency.826 When electronic BTPS compensation is used, measurements should be made at breathing frequencies of 30 to 45 breaths/min, which will also reduce the risk of disturbance caused by irregular breathing. Most children of 2 years and 3 years of age breathe at the required frequency either spontaneously or as a result of the use of facemask, but coaching of children > 3 years old may be required.
Collection of Measurements
The child should be seated in the closed box for at least 1 min prior to lung function testing to stabilize temperature buildup in the box. Once testing is started, spirometry traces will be monitored; when a stable breathing pattern, defined from a regular tidal volume-time curve, and a breathing rate within the target range have been established, five separate, specific resistance loops will be collected.
Blinding of Measurements
Treatment with placebo provided significant bronchodilation in a double-blind study.17 This suggests an observer bias in the conduct of the measurements despite a carefully described protocol. Likewise, a placebo effect was seen with the interrupter technique and impulse oscillometry.17 Such observer bias is probably inherent to any lung function measurement. Therefore, it is recommended that whenever possible the operator should be kept unaware of the history of the patient tested.
| Quality Control of Measurements |
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Pressure builds up in the box while the door is closed due to rising temperature. This constant drift in the box pressure is compensated for in most commercially available data-processing software.
sRaw Estimates
sRaw is calculated as the median value of five technically satisfactory specific resistance loops. Figure 2 illustrates how different estimates of sRaw may be calculated from the specific resistance loop depending on how various parameter lines are applied on the loop and the slope of such lines. The method used for calculation of sRaw should always be stated: sRawTOT is the parameter line connecting the flow points at maximum change in Vpleth (pressure); sRaw
max is the parameter line connecting the maximum flow points; sRaw0.5 or sRaw0.2 are the parameter lines connecting the points where the flow reaches fixed values such as 0.5 L/s or 0.2 L/s, respectively; sRaw50% is the parameter line connecting the points where the flow is 50% of the maximal flow reached (not shown, but resembles sRaw0.5 or sRaw0.2); sRawMID is the parameter line through the relevant midpoints of the lines formed by the intersections of the loop at the flow values ± 0.5 L/s.
sRawTOT seems to be more sensitive or as sensitive as other methods of estimating the total resistance, although this estimate may have a higher variability as compared with sRaw0.2 and sRaw50%.12 However, detailed comparisons of such different algorithms need to be further studied.
BTPS Correction
Vpleth caused by changes in temperature and humidity of the air inspired by the subject during the measurements needs to be adjusted to BTPS, particularly at low breathing frequency.2627 Most commercially available plethysmographs perform an electronic compensation to simulate conditioning of the inspired and expired air. This affects the accuracy of sRaw measurements and has been reported to cause significant overestimation.826 Using a heated rebreathing system, Buhr et al24 found a negative breathing-frequency dependence of sRaw, which tends to counteract the positive frequency dependence found with electronic compensation.
Equipment-Specific Adjustments
Correction must be made for the dead space of the apparatus. Correction must be made for the resistance of the pneumotachograph (Rscreen)28:
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| Acceptance |
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At the age of 2 years, 57% of untrained healthy children (n = 28) completed the measurement.10 At the age of 3 years, 65% of untrained healthy children (n = 31) completed measurements.10 Likewise, in a large birth cohort study of 766 children, 66% completed measurements at 3 years of age.20
The main reason for failure to obtain measurements was that the child was unfamiliar with the facemask.10 A short period of training can improve the acceptance, since the majority of very young children will accept the facemask if they are allowed to spend some time playing with it. In conclusion, sRaw allows measurements from 2 years of age.
| Reference Values |
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max. Neither measurement of sRaw showed any significant correlation with gender, age, weight, or height.10 Other studies52930 have reported values of sRaw
max ranging from 0.45 to 1.0 kPa/s. The difference is probably due to the use of electronic BTPS compensation in the former study and heated rebreathing system in the latter. Such substantial differences between the absolute values in currently available reference materials emphasize the need for standardization. Relating sRaw measurements to the available reference data assumes the use of similar method. The relation to reference values should preferably be expressed as z-scores (deviation in multiplex of the SD of the reference material).
| Reliability |
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Long-term Repeatability (Weeks):
No long-term data on repeatability in healthy young children exist. However, repeatability 1 month apart in young children with asthma showed an ICC of 0.87 between occasions,9 similar to the within-occasion ICC in healthy subjects.10
Between-Observer Repeatability
SDw of measurements obtained by two trained observers according to a predefined protocol is greater than the within-observer variability. This between-observer variability of sRaw appeared to be reduced when sRaw was calculated as sRaw0.2 or sRaw50% instead of the sRawTOT.12
Accuracy
Accuracy of sRaw has been evaluated against measurements under BTPS conditions, which showed that the available electronic BTPS compensation causes significant overestimation in children.826
Sensitivity
The sensitivity to pharmacologically induced changes of airway patency (eg, by inhalation of bronchoconstrictor or bronchodilator agents) as well as during acute severe asthma was comparable for sRaw, transcutaneous oxygen, and impulse oscillometry measurements in young children from 2 years of age. Their sensitivity was better than that of spirometry and interrupter airway resistance.67
| Response to Bronchodilators |
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Secondly, healthy young children have an inherent bronchomotor tone as seen from a 16% decrease in sRaw after inhaled ß2-agonist.17 Asthmatics bronchodilate significantly more than healthy children, attesting to their increased bronchomotor tone.17 Receiver operating curve analysis has suggested three SDw units (corresponds to a change of 25%) as the optimal cut-off level for discriminating healthy and asthmatic preschool children, providing a sensitivity of 66%, a specificity of 81%, and predictive value of a positive test result of 84%.17 The discrimination by sRaw was found to be better than that obtained by the interrupter and impulse oscillometry techniques. In conclusion, it is recommended to use a 25% decrease in sRaw relative to the predicted value as the cut-off to screen for asthma in young children.
| Challenge Tests |
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Cold dry air hyperventilation challenge is an alternative stimulus for the test of bronchial hyperresponsiveness. It can be performed as a single-step test with a good acceptability. Software that visually prompts the child to hyperventilate is available and will be provided as shareware (www.copsac.dk). Cold dry air hyperventilation with sRaw as outcome provides a good separation between asthmatic and nonasthmatic young children with a sensitivity of 68%, specificity of 93%, and predictive values of positive and negative test results of 93% and 69%, respectively, which is superior to the use of interrupter airway resistance and impulse oscillometry in such challenge. The long-term repeatability is good, with a correlation coefficient of 0.96 between sRaw responses to cold dry air hyperventilation challenge repeated within 8 weeks.14 Hyperventilation with dry air at room temperature may be an even simpler and less expensive test similar in mechanism to that of cold dry air hyperventilation challenge. However, responsiveness to cold dry air hyperventilation exceeded responsiveness to dry air challenge and cold dry air hyperventilation seemed to induce refractoriness in contrast to dry air challenge, probably because of the additional stimulus from airway cooling.19 This suggests cold dry air hyperventilation as the preferred method.
In conclusion, cold and/or dry air hyperventilation challenge is feasible in young children from 2 years of age. Whole-body plethysmography (sRaw) seems superior to other methods separating asthmatics from healthy control subjects. Change in sRaw in response to cold and/or dry air hyperventilation challenge may be used as a diagnostic test for asthma in young children.
| Discrimination Between Health and Disease |
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sRaw was significantly increased compared to healthy control subjects in random11 and selected groups of 2- to 6-year-old asthmatics.1314151724 sRaw was reported in 110 consecutive 2- to 5-year-old children who had a history of three or more episodes of wheezing after the age of 1 year. sRaw was measured while the children were without clinical symptoms. Fourteen percent had sRaw values greater than the 97.5% range for healthy children,11 representing a significant proportion of subclinically impaired lung function in young asthmatics. Similarly, sRaw related significantly to history of recurrent wheeze in a longitudinal birth cohort study.20
Antiasthma treatments have been evaluated in young children, including the effects of inhaled corticosteroid,15 leukotriene receptor antagonist,13 and short-acting17 and long-acting ß2-agonists.16 Confirming the effects of these classic antiasthma treatments in young asthmatic children substantiate the relevance of the sRaw measurements and their ability to separate controlled from uncontrolled asthma.
sRaw has been shown to be a relevant objective parameter used in serial18 and cross-sectional23 measurements in preschool children with cystic fibrosis. In a 4-year prospective study18 with serial measurements of sRaw, a consistently abnormal, increased level of sRaw was demonstrated from preschool to school age, but not by measurements with impulse oscillometry or interrupter resistance.
| Future Directions |
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Interactive software with visual prompts should serve as an instructional aide for the child to target the relaxed tidal breathing pattern and the breathing rate and provide biofeedback. Reference materials should be included in the software of the plethysmograph with allowance for the use of individual materials. Reporting of measurements should add the z-score.
The protocol proposed in this article on measurements of sRaw should be further explored. Optimal breathing frequency, number of loops collected, and criteria defining the line through the flow-pressure loop need to be further validated, and the best method to reduce the confounding effect of an accompanying adult should be studied (breath-hold vs slow exhalation).
Long-term repeatability should be determined, and more comprehensive multicenter reference values from healthy children of different ethnicity should be collected. Determination of intercenter reproducibility and variability of the technique has important relevance for its application to multicenter clinical trials. Further studies in chronic lung diseases such as cystic fibrosis, bronchopulmonary dysplasia, and congenital malformations in the airways are important and feasible with the sRaw method since knowledge of lung function in such diseases during preschool age is very limited.
| Conclusions |
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| Footnotes |
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max = parameter line connecting the maximum flow points; sRaw0.2 = parameter line connecting the points where the flow reaches 0.2 L/s; sRaw0.5 = parameter line connecting the points where the flow reaches 0.5 L/s; sRaw50% = parameter line connecting the points where the flow is 50% of the maximal flow; TGV = thoracic gas volume;
= air flow; Vpleth = plethysmographic volume;
Vpleth = change in plethysmographic volume Received for publication September 9, 2004. Accepted for publication December 16, 2004.
| References |
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This article has been cited by other articles:
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H. Bisgaard, M. N. Hermansen, L. Loland, L. B. Halkjaer, and F. Buchvald Intermittent inhaled corticosteroids in infants with episodic wheezing. N. Engl. J. Med., May 11, 2006; 354(19): 1998 - 2005. [Abstract] [Full Text] [PDF] |
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