Multiple Breath Inert Gas Washout Research Articles

P42 Comparison of Ventilation Heterogeneity Indices Derived from Multiple Breath Inert Gas Washout

Introduction and objectivesMultiple breath inert gas washout (MBW) is a technique for quantifying ventilation heterogeneity (VH). Commonly-used indices of VH such as lung clearance index (LCI) may be biased by...

Advances in infant and preschool lung function testing

Background: Infant lung function tests are currently performed in more than 100 centres worldwide. Increasingly, centres in the AsiaPacific region are purchasing expensive and specialized equipment for this purpose. Equipment for testing preschool equipment is generally less expensive than equipment required for testing infants but assessing preschool children is tricky and requires investment in both time and human resources to get the right people for the job of working with such single-minded individuals. Pulmonary function testing in research: Infant and preschool lung function testing is being used in several research contexts. Recent studies that have used these tests have helped advance our knowledge on the early pathophysiology of diverse respiratory conditions such as cystic fibrosis, infant and preschool wheezing, childhood asthma, broncho-pulmonary dysplasia, as well as providing insights into aspects of lung growth and development. Pulmonary function testing in clinical practice: Infant and preschool lung function tests are also widely used (rightly or wrongly) for clinical evaluation. To be of benefit in clinical practice pulmonary function testing needs to be able to identify diminished lung function that may require a clinical response (this depends on good healthy control or reference data), to monitor disease status over time (depends on data on repeatability in both health and disease) and the response to therapeutic interventions (data on short-term repeatability required). Interpretation is currently limited in all these areas but general consensus is that the tests are on the cusp of being used routinely in clinical practice. Tests used in infants: The most popular tests in infants are those assessing forced expiratory flows and volumes (such as the raised volume and tidal rapid thoraco-abdominal compression techniques), plethysmography to measure functional residual capacity, and tests of ventilation inhomogeneity (such as the multiple breath inert gas washout). Limitations include the need for sedation, labour costs, lack of reference data and lack of longer-term repeatability data. Commercial equipment for each of these tests is, however, available. Tests used in preschool children: Popular tests in preschool children include those performed during tidal breathing such as the forced oscillation technique, resistance interrupter technique and multiple breath washout. Forced expiration using spirometry, with or without incentive, is also possible and widely used in preschool children. The technique of measuring the specific airways resistance is widely used in Europe and is in the process of undergoing standardization. Intervention studies and clinical trial networks: One outcome of lung function testing in infants and preschool children over the past few decades has been the insight gained into this crucial period of lung development where early insults to the developing lung architecture may have life-long effects in both chronic respiratory disorders and health. In the future, it is crucial that interventions are targeted early in life in order to prevent, rather than limit or reverse, the development of lung disease or maldevelopment of the lung. Infant and preschool lung function tests have been proposed as potential outcomes of such early intervention studies and have been used recently in this context. Multi-centre clinical trial networks are being developed for such studies that necessitate ongoing efforts to standardise the tests, develop quality assurance programs and facilitate better interchange of data between centres. Summary: Disappointingly, some of the limitations that have hindered interpretation of the results of infant (in particular), but also preschool, lung function tests over the past three decades are still to be overcome. However, advances in knowledge through research studies that have incorporated these tests, the commercial availability of several tests, the increasing number of centres gaining experience in their use and the recognition of the crucial role of early lung development in life-long lung health have served to highlight the importance of overcoming the limitations so that infant and preschool lung function tests can be used routinely in clinical practice.

Ventilation inhomogeneity in children with primary ciliary dyskinesia

BackgroundThe lung clearance index (LCI) derived from the multiple breath inert gas washout (MBW) test reflects global ventilation distribution inhomogeneity. It is more sensitive than forced expiratory volume in 1...

Small airway function, exhaled NO and airway hyper-responsiveness in paediatric asthma

Asthma is a chronic inflammatory airway disorder known to involve the peripheral airways. Current guidelines state that diagnosis and treatment should be guided by symptoms and spirometry. FEV(1) is, however, a poor marker of small airway function and correlates poorly with asthma control and airway inflammation. To assess the contribution of small airway dysfunction and inflammation in paediatric asthma. A secondary aim was to study the associations between small airway dysfunction, airway inflammation and airway hyper-responsiveness (AHR). Small airway function was measured as LCI, S(cond) and S(acin), evaluated with the SF(6) multiple breath inert gas washout (MBW) technique, in 47 asthmatic children and 74 healthy controls. Exhaled NO at multiple exhalation flow rates including 50mL/s (FENO(50)) was assessed to calculate alveolar NO and bronchial NO flux (a surrogate for airway inflammation). AHR was evaluated with isocapnoic dry air hyperventilation challenge in the asthmatic children. S(cond) was elevated in 31 (66%) and S(acin) in 18 (38%) of the asthmatic subjects. LCI was increased and FEV(1) decreased in 7 (15%) of the subjects with asthma. Individuals with AHR had higher S(cond) (p=0.001) and FENO(50) (p<0.0001) than those without AHR. The levels of FENO(50) and bronchial NO flux were elevated in asthmatic subjects compared with healthy controls. In asthma, S(cond) correlated with FENO(50) (r(s)=0.42, p=0.003) and alveolar NO (r(s)=0.40, p=0.011), and S(acin) correlated with alveolar NO (r(s)=0.40, p=0.015). Dysfunction of small conducting airways is associated with airway inflammation and hyper-responsiveness in paediatric asthma.

Intervention trials and ventilation distribution in mild cystic fibrosis lung disease: will it all come out in the wash?

The identification of clinically relevant end-points for use in clinical trials of new treatments in cystic fibrosis (CF) lung disease is an ongoing problem for physicians and researchers working in the field of CF care. Lung disease almost certainly starts in early infancy 1–6 and is progressive, leading to significant structural lung disease in the preschool years 7. Despite this, the majority of young children with CF tend to have spirometry within the normal range at early school age 1, 8, 9. It is well recognised that relying on spirometry alone to identify children at risk of progressive lung disease has significant limitations. This has led to renewed emphasis on the assessment of physiological outcomes in infancy and the preschool years, as well as increased focus on lung function tests that are more sensitive to early lung dysfunction than spirometry 10–13. One such outcome is the assessment of ventilation inhomogeneity obtained from the multiple breath inert gas washout test (MBW), the most commonly reported outcome being the lung clearance index (LCI). A significant advantage of this technique is that it can be applied from infancy through to adulthood, with only minor changes in equipment and methodology, particularly from the preschool years onwards 14–16. The LCI has been shown to be abnormal in the presence of normal spirometry in both preschool children 7 and older children with CF 9, 17–22, suggesting that it is a more sensitive marker of early lung disease in such …

Lung Clearance Index and HRCT are complementary markers of lung abnormalities in young children with CF

RationaleHigh resolution computed tomography (HRCT) is a more sensitive tool for detecting early cystic fibrosis (CF) lung disease than either spirometry or plain radiography, but its relationship to other measures...

Reproducibility of multiple breath washout indices in the unsedated preterm neonate

Multiple breath inert gas washout (MBW) is gaining popularity for measurements of resting lung volume and ventilation inhomogeneity. Test reproducibility is an important determinant of the clinical applicability of diagnostic tests. The between-test reproducibility of variables derived from MBW tests in newborn infants is unknown. We aimed to determine the within-test repeatability and short-term between-test reproducibility of MBW variables in unsedated preterm infants. We hypothesized that measurements obtained within a 3-day interval in clinically stable preterm infants would be reproducible and suitable for use as an objective clinical outcome measurement. In this cross-sectional observational study, clinically stable hospitalized preterm infants whose parents had given informed consent for MBW studies were tested twice within 72 hr during quiet, unsedated sleep. Functional residual capacity (FRC), lung clearance index (LCI), and the first and second to zeroeth moment ratios (M(1):M(0); M(2):M(0)) were computed from MBW traces obtained using a mainstream ultrasonic flowmeter and 4% sulphur hexafluoride (MBW(SF6)). Within-test repeatability and between-test reproducibility were determined. Within-test repeatability (expressed as a coefficient of variability (C(v))) for differences between two and four replicate measurements on the same test occasion, were 9.3% (FRC), 9.0% (LCI), 7.6% (M(1):M(0)), and 15.6% (M(2):M(0)), respectively. The within-test C(v)'s were not statistically different to the between-tests C(v)'s, which were 7.7% (FRC), 10.3% (LCI), 6.1% (M(1):M(0)), and 13.0% (M(2):M(0)), respectively. Among unsedated preterm infants, between-test reproducibility over a 3-day interval was similar to within-test repeatability. The wide limits of agreement may limit the application of these measures to detect a clinically significant change in condition in small preterm infants.

A whisper from the silent lung zone

Multiple breath inert gas washout (MBW) is now regarded as "an insightful, sound, and useful tool to explore the lung and its response to injury in all of its compartments". We describe the important finding of pronounced intra-acinar airways response to indirect challenge testing, detected using MBW but missed by spirometry, in an adolescent with evidence of airway inflammation, and a background of severe respiratory syncytial virus (RSV) infection as an infant. These tests were performed as part of an 18-year follow up of a cohort with severe RSV infection (requiring hospitalization) in the first year of life, and has previously reported significantly higher rates of symptoms of allergic asthma and other features of atopic disease at 13 years in comparison to age matched controls. Small airway dysfunction and ventilation inhomogeneity have emerged as important features of early respiratory disease processes, and this case report provides further evidence supporting its important role in reactive airways disease.

Effects of cystic fibrosis lung disease on gas mixing indices derived from alveolar slope analysis

S(cond) and S(acin) are derived from analysis of concentration-normalized phase III slopes (Sn(III)) of a multiple breath inert gas washout. Studies in healthy and COPD subjects suggest these reflect ventilation heterogeneity in conducting and acinar airway zones respectively, but similar studies in cystic fibrosis (CF) are lacking. S(cond), S(acin) and lung clearance index (LCI, a measure of overall gas mixing efficiency) were measured in 22 adults and 18 children with CF and 17 adult and 29 child controls. Plethysmography and gas transfer measurements were performed in adults, and spirometry in all subjects. S(cond) was elevated in almost all CF patients, including children with mild disease and normal LCI. However, S(cond) did not correlate with other measurements and appeared to reach a maximum; further increase in ventilation heterogeneity being restricted to S(acin). The nature and/or severity of CF lung disease may invalidate assumptions underlying the ability to separate phase III slope analysis of ventilation heterogeneity into proximal and peripheral components, and LCI may be a better indicator of gas mixing in this population.

Multiple-breath inert gas washout and spirometry versus structural lung disease in cystic fibrosis

Background: A sensitive and valid non-invasive marker of early cystic fibrosis (CF) lung disease is sought. The lung clearance index (LCI) from multiple-breath washout (MBW) is known to detect abnormal...

Tidal volume dependency of gas exchange in bronchoconstricted pig lungs

Independent of airway pressure, pulmonary resistance is known to fall with increasing tidal volumes, traditionally thought to result from radial traction on the airways. R. C. Anafi and T. A. Wilson (J Appl Physiol 91: 1185-1192, 2001) recently presented a model of a single terminal airway that explains the tidal volume-associated fall in resistance with an additional mechanism pertinent to narrow airways: a stable, nearly closed airway that is challenged with an increase in tidal volume "pops open" to become a stable, well-opened airway, and thus resistance drops suddenly. To test this model in vivo, the effects of high (24 ml/kg) and low (9 ml/kg) tidal volume in bronchoconstricted lungs were assessed using 1) the multiple inert gas elimination technique (MIGET) and 2) a 15-breath multiple breath inert gas washout (MBW) technique in anesthetized pigs. With high tidal volume, ventilation/perfusion (Va/Q) mismatch was reduced (log SD Q from 1.30 +/- 0.11 to 1.09 +/- 0.12, P < 0.05), and blood flow to lung units with Va/Q ratios < 0.1 was significantly reduced (37 +/- 4% of cardiac output to 7 +/- 4%, P < 0.05). Dynamic compliance was twice as high during high-tidal-volume ventilation (P = 0.002). MBW analysis revealed that, while heterogeneity of ventilation during bronchoconstriction was not significantly different between either low or high tidal volume (log SD Vmbw = 1.39 +/- 0.09 and 1.34 +/- 0.02, respectively), preinspiratory lung volume (PILV) decreased by 42% with low-tidal-volume ventilation (P < 0.05), whereas it did not change with high-tidal-volume ventilation. The higher PILV during high tidal volume is also consistent with Anafi and Wilson's model. In summary, the outcomes from MIGET, and to some extent the MBW, in our anesthetized and mechanically ventilated pigs are consistent with a bistable terminal airway model as proposed by Anafi and Wilson. However, our data do not allow exclusion of other mechanisms that may lead to improved ventilatory distribution when tidal volume is increased.

Early detection of cystic fibrosis lung disease: multiple-breath washout versus raised volume tests

Lung clearance index (LCI), a measure of ventilation inhomogeneity derived from the multiple-breath inert gas washout (MBW) technique, has been shown to detect abnormal lung function more readily than spirometry in preschool children with cystic fibrosis, but whether this holds true during infancy is unknown. To compare the extent to which parameters derived from the MBW and the raised lung volume rapid thoraco-abdominal compression (RVRTC) techniques identify diminished airway function in infants with cystic fibrosis when compared with healthy controls. Measurements were performed during quiet sleep, with the tidal breathing MBW technique being performed before the forced expiratory manoeuvres. Measurements were obtained in 39 infants with cystic fibrosis (mean (SD) age 41.4 (22.0) weeks) and 21 controls (37.0 (15.1) weeks). Infants with cystic fibrosis had a significantly higher respiratory rate (38 (10) vs 32 (5) bpm) and LCI (8.4 (1.5) vs 7.2 (0.3)), and significantly lower values for all forced expiratory flow-volume parameters compared with controls. Girls with cystic fibrosis had significantly lower forced expiratory volume (FEV(0.5) and FEF(25-75 )) than boys (mean (95% CI girls-boys): -1.2 (-2.1 to -0.3) for FEV(0.5) Z score; FEF(25-75): -1.2 (-2.2 to -0.15)). When using both the MBW and RVRTC techniques, abnormalities were detected in 72% of the infants with cystic fibrosis, with abnormalities detected in 41% using both techniques and a further 15% by each of the two tests performed. These findings support the view that inflammatory and/or structural changes in the airways of children with cystic fibrosis start early in life, and have important implications regarding early detection and interventions. Monitoring of early lung disease and functional status in infants and young children with cystic fibrosis may be enhanced by using both MBW and the RVRTC.

Effect of smoke inhalation on viscoelastic properties and ventilation distribution in sheep

Smoke inhalation injuries are the leading cause of mortality from burn injury. Airway obstruction due to mucus plugging and bronchoconstriction can cause severe ventilation inhomogeneity and worsen hypoxia. Studies describing changes of viscoelastic characteristics of the lung after smoke inhalation are missing. We present results of a new smoke inhalation device in sheep and describe pathophysiological changes after smoke exposure. Fifteen female Merino ewes were anesthetized and intubated. Baseline data using electrical impedance tomography and multiple-breath inert-gas washout were obtained by measuring ventilation distribution, functional residual capacity, lung clearance index, dynamic compliance, and stress index. Ten sheep were exposed to standardized cotton smoke insufflations and five sheep to sham smoke insufflations. Measured carboxyhemoglobin before inhalation was 3.87 +/- 0.28% and 5 min after smoke was 61.5 +/- 2.1%, range 50-69.4% (P < 0.001). Two hours after smoke functional residual capacity decreased from 1,773 +/- 226 to 1,006 +/- 129 ml and lung clearance index increased from 10.4 +/- 0.4 to 14.2 +/- 0.9. Dynamic compliance decreased from 56.6 +/- 5.5 to 32.8 +/- 3.2 ml/cmH(2)O. Stress index increased from 0.994 +/- 0.009 to 1.081 +/- 0.011 (P < 0.01) (all means +/- SE, P < 0.05). Electrical impedance tomography showed a shift of ventilation from the dependent to the independent lung after smoke exposure. No significant change was seen in the sham group. Smoke inhalation caused immediate onset in pulmonary dysfunction and significant ventilation inhomogeneity. The smoke inhalation device as presented may be useful for interventional studies.

Multiple-breath washout in preschool children – FRC and ventilation inhomogeneity

The open-circuit multiple-breath inert gas washout method is used to measure functional residual capacity and also to quantify ventilation distribution. The technique is readily applicable in preschool children as it requires quiet tidal breathing. Guidelines for data collection and interpretation in this age group will shortly be published by the European Respiratory Society and the American Thoracic Society.

Lung Function Tests in Neonates and Infants with Chronic Lung Disease: Global and Regional Ventilation Inhomogeneity

This review considers measurement of global and regional ventilation inhomogeneity (VI) in infants and young children with acute neonatal respiratory disorders and chronic lung disease of infancy (CLDI). We focus primarily on multiple-breath inert gas washout (MBW) and electrical impedance tomography (EIT). The literature is critically reviewed and the relevant methods, equipment, and studies are summarized, including the limitations and strengths of individual techniques, together with the availability and appropriateness of any reference data. There has been a recent resurgence of interest in using MBW to monitor lung function within individuals and between different groups. In the mechanically ventilated, sedated, and paralyzed patient, VI indices can identify serial changes occurring following exogenous surfactant. Similarly, global VI indices appear to be increased in infants with CLDI and to differentiate between infants without lung disease and those with mild, moderate, and severe lung disease following preterm birth. While EIT is a relatively new technique, recent studies suggest that it is feasible in newborn infants, and can quantitatively identify changes in regional lung ventilation following alterations to ventilator settings, positive end expiratory pressure (PEEP), and administration of treatments such as surfactant. As such, EIT represents one of the more exciting prospects for continuous bedside pulmonary monitoring. For both techniques, there is an urgent need to establish guidelines regarding data collection, analysis, and interpretation in infants both with and without CLDI.

Inert gas washout in preschool children

The multiple-breath inert gas washout (MBW) method is used to measure the efficiency of ventilation distribution in the lungs and to measure the functional residual capacity (FRC). It involves recordings of the concentration of an inert marker gas and respiratory flow at the airway opening when a subject breathes through a sealed facemask or a mouthpiece. The MBW method is particularly useful for lung function testing in preschool children (2-6 years) because it requires only passive cooperation and tidal breathing. The lung clearance index (LCI) is the cumulative expired volume required to clear an inert gas from the lungs, divided by the FRC. The LCI has been shown to be more sensitive than spirometry or airway resistance measurements in detecting lung function abnormalities in young children with cystic fibrosis (CF). The MBW method may be useful also for screening for several other disorders that affect the peripheral airways in children.

Gas mixing efficiency from birth to adulthood measured by multiple-breath washout

Efficient mixing of inspired gas with the resident gas of the lung is an essential requirement of effective respiration. This review focuses on one method for quantifying ventilation inhomogeneity: the multiple-breath inert gas washout (MBW). MBW has been employed as a research tool in adults and school age children for more than 50 years. Modifications allowing data collection in infants and preschoolers have been described recently. Indices of overall ventilation inhomogeneity, such as the lung clearance index and moment ratios, are raised in many infants with lung disease of prematurity, and in young children with cystic fibrosis. These indices may be more sensitive than other lung function measures for the early detection of airway disease. We describe, for the first time, a development of the MBW analysis that allows calculation of acinar and conductive zone inhomogeneity indices in spontaneously breathing children. Although methodological and analytical issues remain, the future clinical and research applications of MBW justify accelerated research in this field.

Multiple-Breath Washout as a Marker of Lung Disease in Preschool Children with Cystic Fibrosis

Sensitive measures of lung function applicable to young subjects are needed to detect early cystic fibrosis (CF) lung disease. Forty children with CF aged 2 to 5 years and 37 age-matched healthy control subjects performed multiple-breath inert gas washout, plethysmography, and spirometry. Thirty children in each group successfully completed all measures, with success on first visit being between 68 and 86% for all three measures. Children with CF had significantly higher lung clearance index (mean [95% CI] difference for CF control 2.7 [1.9, 3.6], p < 0.001) and specific airway resistance (1.65 z-scores [0.96, 2.33], p < 0.001), and significantly lower forced expired volume in 0.5 seconds (-0.49 z-scores [-0.95, -0.03], p < 0.05). Abnormal lung function results were identified in 22 (73%) of 30 children with CF by multiple-breath washout, compared with 14 (47%) of 30 by plethysmography, and 4 (13%) of 30 by spirometry. Children with CF who were infected with Pseudomonas aeruginosa had significantly higher lung clearance index, but no significant difference in other lung function measures, when compared with noninfected children. Most preschool children can perform multiple-breath washout, plethysmography, and spirometry at first attempt. Multiple-breath washout detects abnormal lung function in children with CF more readily than plethysmography or spirometry.

Method for assessment of volume of trapped gas in infants during multiple-breath inert gas washout.

A breath-by-breath inert gas washout method for assessment of the volume of trapped gas in the lungs (V(TG)) in sedated sleeping infants is described. It is based on washin using a gas mixture containing 4% sulfur hexafluoride (V(TG,SF6)) and washout with air. A mass spectrometer was used for continuous gas concentration measurements, and a Fleisch no. 0 pneumotachometer for flow measurement. When equilibration of the tracer gas was achieved with tidal breathing washin, five passive inflations with a maximum positive airway pressure of 20 cm of H(2)O were performed to ensure filling of lung spaces not communicating during tidal breathing. After tidal washout of the tracer gas by air until the end-tidal concentration was 1/40th of its starting concentration, five passive inflations with air were instituted again. The V(TG,SF6) was calculated from the volume of SF(6) mobilized by these large breaths, and expressed as the corresponding volume of air. Triplets of V(TG,SF6) determination in 8 infants aged 9-31 months with varying degrees of airway obstruction showed an average volume of 13.7 mL (range, 4.7-25.0). The average SD of the triplets was 2.1 mL (range, 0.1-5.5 mL). Subjects with high V(TG,SF6)/FRC results demonstrated lower maximal expiratory flow at FRC (V'(max)FRC) results (Z-scores) and greater inhomogeneity of ventilation distribution than those with low trapped gas volumes. It is concluded that gas trapping can be assessed with acceptable precision with this washout method. Further studies are needed to establish the sensitivity and usefulness of the method in infants with various types of airway pathology.

The importance of a source term in modeling multibreath inert gas washout

The single path model (SPM) of airway gas transport with a distributed blood source term was used to simulate multiple breath inert lung gas washout of N 2, He, and SF 6 after total body equilibration with these gases. Normalized phase III inert gas washout slopes were computed for each breath and compared with published experimental data obtained under similar conditions on human subjects. The model predicts a normalized slope asymptote which agrees with experimental results within two standard deviations or less of the mean, depending on the lengths and diameters assumed in the acinar airways of the SPM. In the model and in the human subject data, the asymptote represents the development of a quasi-steady state in which the volume of inert gas exhaled at the mouth is equal to the volume transported into the acinar airways by the pulmonary blood during each breath. The present study indicates that at least in the steady state, airway inhomogeneity is not essential to model lung washout data, and that a distributed blood source term in the SPM yields good agreement with experiment.