Consensus statement for inert gas washout measurement using multiple- and single- breath tests.

Inert gas washout tests, performed using the single- or multiple-breath washout technique, were first described over 60 years ago. As measures of ventilation distribution inhomogeneity, they offer complementary information to standard lung function tests, such as spirometry, as well as improved feasibility across wider age ranges and improved sensitivity in the detection of early lung damage. These benefits have led to a resurgence of interest in these techniques from manufacturers, clinicians and researchers, yet detailed guidelines for washout equipment specifications, test performance and analysis are lacking. This manuscript provides recommendations about these aspects, applicable to both the paediatric and adult testing environment, whilst outlining the important principles that are essential for the reader to understand. These recommendations are evidence based, where possible, but in many places represent expert opinion from a working group with a large collective experience in the techniques discussed. Finally, the important issues that remain unanswered are highlighted. By addressing these important issues and directing future research, the hope is to facilitate the incorporation of these promising tests into routine clinical practice.

Lung clearance index: clinical and research applications in children.

Multiple breath washout (MBW) has been demonstrated to be sensitive for assessing ventilation inhomogeneity (VI). VI is supposed to reflect changes in peripheral airways which are not apparent using spirometry. The lung clearance index (LCI) is the most robust parameter to quantify VI, and is largely independent of age; therefore, it potentially qualifies as a surrogate outcome parameter for clinical and research purposes, particularly during childhood. This review summarizes the current evidence regarding the clinical value of measuring LCI in children. Feasibility, reproducibility and diagnostic accuracy have been demonstrated; available data confirm that LCI is superior to spirometry in detecting small air way disease. However, there is little information regarding the value in the individual patient, and sparse longitudinal data looking at its prognostic value. Currently, only in patients with Cystic Fibrosis, it appears likely that knowledge of LCI will be useful for routine clinical management.

Multiple breath washout with a sidestream ultrasonic flow sensor and mass spectrometry: a comparative study.

Over recent years, there has been renewed interest in the multiple breath wash-out (MBW) technique for assessing ventilation inhomogeneity (VI) as a measure of early lung disease in children. While currently considered the gold standard, use of mass spectrometry (MS) to measure MBW is not commercially available, thereby limiting widespread application of this technique. A mainstream ultrasonic flow sensor was marketed for MBW a few years ago, but its use was limited to infants. We have recently undertaken intensive modifications of both hardware and software for the ultrasonic system to extend its use for older children. The aim of the current in vivo study was to compare simultaneous measurements of end-tidal tracer gas concentrations and lung clearance index (LCI) from this modified ultrasonic device with those from a mass spectrometer. Paired measurements of three MBW, using 4% sulfur hexafluoride (SF(6)) as the tracer gas and the two systems in series, were obtained in nine healthy adult volunteers. End-tidal tracer gas concentrations (n = 675 paired values) demonstrated close agreement (95% CI of difference -0.23; -0.17%, r(2) = 1). FRC was slightly higher from the MS (95%CI 0.08;0.17 L), but there was no difference in LCI (95%CI -0.10; 0.3). We conclude, that this ultrasonic prototype system measures end-tidal tracer gas concentration accurately and may therefore be a valid tool for MBW beyond early childhood. This prototype system could be the basis for a commercial device allowing more widespread application of MBW in the near future.

Lung clearance index for monitoring early lung disease in alpha-1-antitrypsin deficiency.

Patients with alpha-1-antitrypsin deficiency (AATD) and a PI-ZZ genotype are at high risk to develop severe emphysema during adulthood. However, little is known about early stages of emphysema and disease manifestation in other PI-types. Spirometry is commonly used for monitoring although early manifestation of emphysema is suspected within the peripheral airways that are not accessible by forced expiratory manoeuvres. We hypothesized that the Lung Clearance Index (LCI) derived from multiple breath nitrogen-washout (N2-washout) is useful to bridge this diagnostic gap. Patients from age 4 years onward and different PI-types performed N2-washout and spirometry. Results were compared to controls. 193 patients (4-79 years, 75% PI-ZZ) and 33 controls (8-60 years) were included. Mean (SD) LCI in patients was 9.1 (3.1) and 6.3 (0.6) in controls (p ≤ 0.001). 47% of adult patients with other than PI-ZZ genotypes and 39% of all patients with normal spirometry had abnormal LCIs. The LCI measured by N2-washout discriminates between patients with AATD and controls, reflects AATD related lung disease in all stages and appears to identify early peripheral lung changes in younger age than spirometry. We conclude that a normal spirometry does not exclude presence of AATD related lung disease even in genotypes other than PI-ZZ.

Clinical application of inert gas Multiple Breath Washout in children and adolescents with asthma.

INTRODUCTION: Children with asthma often have normal spirometry despite significant disease. The pathology of the small airways in asthma may be assessed using Multiple Breath Washout (MBW) and calculating the Lung Clearance Index (LCI). There are only few studies using MBW in children with asthma and existing data regarding bronchodilator effect are contradictory. The aim of the present pilot study was to compare LCI in asthma and controls and assess the effect of salbutamol in children with asthma on the LCI. METHODS: Unselected patients with a diagnosis of asthma visiting the outpatient department of our hospital between 04-2010 and 03-2011 were recruited and compared to a healthy control group. MBW was performed as inert gas MBW using sulfurhexafluorid (SF6) as the tracer gas. Clinical data were documented and spirometry and MBW (EasyOne Pro, MBW module, NDD Switzerland) were performed before and after the use of salbutamol (200-400 µg). Healthy controls performed baseline MBW only. RESULTS: 32 children diagnosed with asthma (4.7-17.4 years) and 42 controls (5.3-20.8) were included in the analysis. LCI differed between patients and controls, with a mean LCI (SD) of 6.48 (0.48) and 6.21 (0.38) (P = 0.008). Use of salbutamol had no significant effect on LCI for the group. CONCLUSION: These pilot data show that clinically stable asthma patients and controls both have a LCI in the normal range. However, in patients the LCI is significantly higher indicating that MBW may have a role in assessing small airways disease in asthma.

Tracking Lung Clearance Index and chest CT in mild cystic fibrosis lung disease over a period of three years.

INTRODUCTION: Lung disease remains the main cause of morbidity and mortality in patients with Cystic Fibrosis (CF). To detect lung disease before clinical symptoms become apparent, sensitive tools are essential. Spirometry is used for monitoring, but the FEV1 remains frequently normal throughout childhood. The Lung Clearance Index (LCI) calculated from Multiple Breath Washout (MBW) was introduced at the CF centre Innsbruck in 2007 for assessing ventilation inhomogeneity in patients with mild lung disease. We hypothesized that LCIs in 2007 are of prognostic value for the presence or absence of structural lung changes in later years. METHODS: Between 2007 and 2010 MBW, spirometry and ultra-low-dose HR-CT were prospectively tracked in 36 patients (6-53 years) with a mean FEV1 ≥ 80% predicted in 2007. RESULTS: At study start the majority of patients had abnormal CT scores and LCI results. While CT and spirometry remained largely stable throughout the study, LCI results slightly improved but still correlated with CT scores in 2010. LCI results in 2007 correlated with CT scores in 2010 while FEV1 did not. In 86% the LCI value in 2007 was indicative for the presence or absence of structural lung changes in 2010. CONCLUSION: The LCI is a sensitive tool for detecting and tracking pulmonary changes. Extended structural changes are unlikely if the LCI is normal. The LCI has the potential to be used for monitoring the progression of early CF lung disease and assessing the effect of treatment in both clinical care and research settings.

Calculation of the capnographic index based on expiratory molar mass-volume-curves--a suitable tool to screen for cystic fibrosis lung disease.

BACKGROUND: Volumetric capnography reflecting the course of CO2-exhalation is used to assess ventilation inhomogeneity. Calculation of the slope of expiratory phase 3 and the capnographic index (KPIv) from expirograms allows quantification of extent and severity of small airway impairment. However, technical limitations have hampered more widespread use of this technique. Using expiratory molar mass-volume-curves sampled with a handheld ultrasonic flow sensor during tidal breathing is a novel approach to extract similar information from expirograms in a simpler manner possibly qualifying as a screening tool for clinical routine. The aim of the present study was to evaluate calculation of the KPIv based on molar mass-volume-curves sampled with an ultrasonic flow sensor in patients with CF and controls by assessing feasibility, reproducibility and comparability with the Lung Clearance Index (LCI) derived from multiple breath washout (MBW) used as the reference method. METHODS: Measurements were performed in patients with CF and healthy controls during a single test occasion using the EasyOne Pro, MBW Module (ndd Medical Technologies, Switzerland). RESULTS: Capnography and MBW were performed in 87/96 patients with CF and 38/42 controls, with a success rate of 90.6% for capnography. Mean age (range) was 12.1 (4-25) years. Mean (SD) KPIv was 6.94 (3.08) in CF and 5.10 (2.06) in controls (p=0.001). Mean LCI (SD) was 8.0 (1.4) in CF and 6.2 (0.4) in controls (p=<0.001) and correlated significantly with the KPIv (p=<0.001). CONCLUSION: Calculation of the KPIv based on molar mass-volume-curves is feasible. KPIv is significantly different between patients with CF and controls and correlates with the LCI. However, individual data revealed a relevant overlap between patients and controls requiring further evaluation, before this method can be recommended for clinical use.

Feasibility and variability of measuring the Lung Clearance Index in a multi-center setting.

The Lung Clearance Index (LCI) is superior to spirometry in detecting early lung disease in cystic fibrosis (CF) and correlates with structural lung changes seen on CT scans. The LCI has the potential to become a novel outcome parameter for clinical and research purposes. However longitudinal studies are required to further prove its prognostic value. Multi-center design is likely to facilitate realization of such studies. Therefore the aim of the present study was to assess multi-center feasibility and inter-center variability of LCI measurements in healthy children and adolescents. Comparative measurements were performed in unselected patients with CF to confirm previous single-center results. LCI measurements were performed in eight centers using the EasyOne Pro, MBW Module (ndd Medical Technologies, Zurich, Switzerland). The overall success rate for LCI measurements was 75.5%, leaving 102/151 measurements in healthy volunteers and 139/183 measurements in patients with CF for final analysis. Age ranged between 4 and 24 years. Mean LCI (range of means among centers) was 6.3 (6.0-6.5) in healthy volunteers and thus normal. Inter-center variability of center means was 2.9%, ANOVA including Schffé procedure demonstrated no significant inter-center differences (P > 0.05). Mean LCI (range of means among centers) was 8.2 (7.4-8.9) in CF and thus abnormal. Our study demonstrates good multi-center feasibility and low inter-center variability of the LCI in healthy volunteers when measured with the EasyOne Pro MBW module. Our data confirm published LCI data in CF. However, central coordination, quality control, regular training, and supervision during the entire study appear essential for successfully performing multi-center trials.

Short-term effect of physiotherapy on variability of the lung clearance index in children with cystic fibrosis.

Multiple breath washout (MBW) for measuring the lung clearance index (LCI) has been proposed as a non-invasive tool for detecting early cystic fibrosis (CF) lung disease. The LCI is highly repeatable and reproducible in healthy subjects. In patients with CF, within-test variability is low. However, application of physiotherapy (PT) immediately preceding MBW may affect LCI variability in CF patients and thus interpretation of repeat measurements and treatment effects. Therefore, the aim of the present study was to prospectively assess the short-term effect of PT on LCI in CF patients in order to address the question whether or not standardized timing of PT and MBW has to be considered when introducing MBW into clinical CF management. Twenty-seven out of 32 patients (5.7-15.9 years) with CF successfully performed two technically acceptable MBW tests with the EasyOne Pro, MBW Module (ndd, Switzerland) at intervals of 1(1/2) hr. Sixteen out of 27 received 30 min PT in between, whereas 11/27 did not.Repeatability expressed as intraindividual coefficient of variation (CV) was 6.1% pre-PT and 6.5% post-PT. Mean difference (95% CI) of LCI between the two tests was -0.20 (-0.51; 0.11). Reproducibility (SD) was 4.6% (3.1). Repeatability was 4.2% and 7.1% without intervention. Mean difference (95% CI) of LCI between 1st and 2nd test was 0.07 (-0.22; 0.35). Reproducibility (SD) was 2.6% (2.1).In conclusion, PT does not have a consistent effect on the LCI. Repeatability was slightly poorer than published for healthy subjects possibly reflecting variable mucus plugging, and, thus, variable trapped air in patients with CF. Reproducibility was good and independent on intervention. From our data, we conclude that timing of PT in relation to MBW can be ignored when designing study protocols or when interpreting longitudinal data and treatment effects.

Sensitivity of Lung Clearance Index and chest computed tomography in early CF lung disease.

It is widely accepted that CF lung disease starts before clinical symptoms become apparent or spirometry deteriorates. Computed chest tomography (CT) is the reference method for identifying structural changes in CF; however, radiation exposure limits its use as a monitoring tool. It has been suggested that the Lung Clearance Index (LCI) measured by Multiple Breath Washout (MBW) for assessing ventilation inhomogeneity is a more sensitive surrogate marker than spirometry allowing non-invasive monitoring of CF lung disease. The aim of this study was to prospectively investigate the diagnostic accuracy of the LCI in comparison to CT in CF patients with early lung disease and normal FEV(1) (>80% pred.). MBW and ultra-low-dose CT were performed in 34 patients (6-26 years). LCI was abnormal in 76.5% subjects. LCI and CT correlated significantly in 82.3%. LCI was related to presence and extent of structural lung changes observed on CT with a sensitivity of 88%. Diagnostic accuracy of the LCI for detecting CF lung disease in patients with normal FEV(1) was good when compared to CT. Results indicate that structural changes are unlikely if a normal LCI is measured. We speculate that serial measurements of the LCI for assessing ventilation inhomogeneity may help to identify early structural lung disease and help to reduce the individual cumulative radiation dose. The LCI may be a suitable surrogate marker for monitoring progression of CF lung disease and effect of treatment in both, clinical care and research settings.

Lung clearance index: normal values, repeatability, and reproducibility in healthy children and adolescents.

There is increasing interest in using the Multiple Breath Washout technique and the lung clearance index (LCI) for detecting early pulmonary changes, for example, in cystic fibrosis lung disease. However, there are still limited data regarding equipment specific reference ranges, repeatability and reproducibility. The aim of this prospective study was to assess within-test repeatability, short term reproducibility and long term reproducibility, and to establish normal values for the LCI in healthy children and adolescents using the sidestream ultrasonic flow sensor (EasyOne Pro, MBW Module, ndd Medical Technologies, Switzerland). Fourty-four volunteers (5.3-20.3 years) were recruited for the 1st test. Twenty-two out of 44 were measured on a 2nd test occasion after an interval of 1 hr (2nd test). Thirty-four out of 44 agreed to come back for a follow up test 6-15 months later (3rd test). Mean LCI (SD) was 6.2 (0.4), 6.3 (0.4), and 6.0 (0.4) at the 1st, 2nd, and 3rd test. The upper limit of normal was 7.0 for all subjects. Within-test repeatability was 5.1%. Short-term reproducibility (1st test vs. 2nd test) was 4.2% with a mean difference of -0.13 (95% CI -0.350; 0.087). Long-term reproducibility (1st test vs. 3rd test) was 5.1%, with a mean difference of 0.017 (95% CI -0.016; 0.348). With this low variability of the LCI for both, within and between tests, our study demonstrates reliability and robustness of equipment, protocol and analysis and the reliability of the MBW technique in general. The present data will help to interpret the effect of therapeutic interventions and interpretation of longitudinal data in patients with pulmonary diseases.

A novel sidestream ultrasonic flow sensor for multiple breath washout in children.

OBJECTIVE: Inert gas multiple breath washout (MBW) for measuring Lung Clearance Index using mass spectrometry and 4% sulfur hexafluoride (SF(6)) as the tracer gas has been shown to be sensitive for detecting early Cystic Fibrosis (CF) lung disease. However, mass spectrometry requires bulky equipment and is expensive to buy and maintain. A novel sidestream ultrasonic device may overcome this problem. The aims of this study were to assess the feasibility and clinical validity of measuring lung volume (functional residual capacity, FRC) and the LCI using the sidestream ultrasonic flow sensor in children and adolescents with CF in relation to spirometry and plain chest radiographs. PATIENTS AND METHODS: MBW using the sidestream ultrasonic device and conventional spirometry were performed in 26 patients with CF and 22 healthy controls. RESULTS: In the controls (4.7-17.7 years) LCI was similar to that reported using mass spectrometry (mean (SD) 6.7 (0.5)). LCI was elevated in 77% of the CF children (6.8-18.9 years), whereas spirometry was abnormal in only 38.5%, 61.5%, and 26.9% for FEV(1), MEF(25), and FEV(1)/FVC, respectively. This was more marked in children <10 years. LCI correlated with the Crispin-Norman score, whereas FEV(1) did not. CONCLUSIONS: Sidestream ultrasonic MBW is a valid and simple alternative to mass spectrometry for assessing ventilation homogeneity in children.