Change In Lung Clearance Index Research Articles

Maximal exercise does not increase ventilation heterogeneity in healthy trained adults.

The effect of exercise on ventilation heterogeneity has not been investigated. We hypothesized that a maximal exercise bout would increase ventilation heterogeneity. We also hypothesized that increased ventilation heterogeneity would be associated with exercise‐induced arterial hypoxemia (EIAH). Healthy trained adult males were prospectively assessed for ventilation heterogeneity using lung clearance index (LCI), Scond, and Sacin at baseline, postexercise and at recovery, using the multiple breath nitrogen washout technique. The maximal exercise bout consisted of a maximal, incremental cardiopulmonary exercise test at 25 watt increments. Eighteen subjects were recruited with mean ± SD age of 35 ± 9 years. There were no significant changes in LCI, Scond, or Sacin following exercise or at recovery. While there was an overall reduction in SpO2 with exercise (99.3 ± 1 to 93.7 ± 3%, P < 0.0001), the reduction in SpO2 was not associated with changes in LCI, Scond or Sacin. Ventilation heterogeneity is not increased following a maximal exercise bout in healthy trained adults. Furthermore, EIAH is not associated with changes in ventilation heterogeneity in healthy trained adults.

A randomized controlled trial to evaluate the lung clearance index as an outcome measure for early phase studies in patients with cystic fibrosis

BackgroundOutcome measures that can evaluate treatment efficacy are important to enhance development of new therapeutic agents for Cystic Fibrosis (CF). We investigated whether the lung clearance index (LCI) measured by multiple breath washout (MBW) can detect a treatment effect of hypertonic saline (HS) inhalation after single dosing within a 24 h period. MethodsIn this randomized controlled cross-over trial, CF patients received inhalation of HS and isotonic saline (IS). MBW and spirometry were performed at 5 time points over 24 h. LCI was measured using both a nitrogen washout technique (LCIN2) and sulfur hexafluoride as a tracer gas (LCISF6). The primary endpoint was the change in the LCIN2 between baseline and 24 h. Secondary endpoints included change in LCISF6 and spirometry outcomes. ResultsTwenty-one patients were randomized. Sixteen completed all study visits and all time point measurements. Eighteen patients contributed to the intention to treat analysis. Significant changes were not detected for either LCI or the spirometry outcomes. However, the primary outcome parameter (change in LCI between the baseline visits and 24 h after inhalation) demonstrated a trend towards improved LCI, in the HS treatment arm compared with the IS treatment arm, −0.60 LCIN2 (SE 0.32), p = 0.08); similar trends were not observed for spirometric measures. The overall effect size of HS was smaller than in previous studies of longer duration. ConclusionsThese data suggest that LCI may potentially be used as an outcome measure in early phase trials with therapeutic agents that have a larger treatment effects than a single inhalation of HS.

Changes in multiple breath washout measures after raised volume rapid thoracoabdominal compression maneuvers in infants

Multiple breath inert gas washout (MBW) measurements in infants are performed supine and often obtained under sedation and thus are combined with other lung function tests such as raised volume rapid thoracoabdominal compression (RVRTC). In this study, we sought to determine the effects of RVRTC maneuvers on MBW measures. Compared with tests performed prior to RVRTC, MBW measured after RVRTC was associated with a small reduction in functional residual capacity and a more pronounced decrease in cumulative expired volume in both healthy children and children with obstructive lung disease (cystic fibrosis or recurrent wheeze) indicating a more efficient washout after the raised volume maneuvers. Lung Clearance Index (LCI) decreased significantly in infants with respiratory disease (change in LCI of -0.24 units post RVRTC; standard error (SE) ± 0.07 units; P = 0.0004), but not in healthy infants (change in LCI of -0.08 units; SE ± 0.11 units; P = 0.44). As the RVRTC maneuver affects MBW measurements in infants, the timing of testing procedures needs to be standardized in longitudinal studies.

Impact of Software Settings on Multiple-Breath Washout Outcomes.

Background and ObjectivesMultiple-breath washout (MBW) is an attractive test to assess ventilation inhomogeneity, a marker of peripheral lung disease. Standardization of MBW is hampered as little data exists on possible measurement bias. We aimed to identify potential sources of measurement bias based on MBW software settings.MethodsWe used unprocessed data from nitrogen (N2) MBW (Exhalyzer D, Eco Medics AG) applied in 30 children aged 5–18 years: 10 with CF, 10 formerly preterm, and 10 healthy controls. This setup calculates the tracer gas N2 mainly from measured O2 and CO2concentrations. The following software settings for MBW signal processing were changed by at least 5 units or >10% in both directions or completely switched off: (i) environmental conditions, (ii) apparatus dead space, (iii) O2 and CO2 signal correction, and (iv) signal alignment (delay time). Primary outcome was the change in lung clearance index (LCI) compared to LCI calculated with the settings as recommended. A change in LCI exceeding 10% was considered relevant.ResultsChanges in both environmental and dead space settings resulted in uniform but modest LCI changes and exceeded >10% in only two measurements. Changes in signal alignment and O2 signal correction had the most relevant impact on LCI. Decrease of O2 delay time by 40 ms (7%) lead to a mean LCI increase of 12%, with >10% LCI change in 60% of the children. Increase of O2 delay time by 40 ms resulted in mean LCI decrease of 9% with LCI changing >10% in 43% of the children.ConclusionsAccurate LCI results depend crucially on signal processing settings in MBW software. Especially correct signal delay times are possible sources of incorrect LCI measurements. Algorithms of signal processing and signal alignment should thus be optimized to avoid susceptibility of MBW measurements to this significant measurement bias.

Lung clearance index in cystic fibrosis subjects treated for pulmonary exacerbations.

Pulmonary exacerbations are important clinical events for cystic fibrosis (CF) patients. Studies assessing the ability of the lung clearance index (LCI) to detect treatment response for pulmonary exacerbations have yielded heterogeneous results. Here, we conduct a retrospective analysis of pooled LCI data to assess treatment with intravenous antibiotics for pulmonary exacerbations and to understand factors explaining the heterogeneous response.A systematic literature search was performed to identify prospective observational studies. Factors predicting the relative change in LCI and spirometry were evaluated while adjusting for within-study clustering.Six previously reported studies and one unpublished study, which included 176 pulmonary exacerbations in both paediatric and adult patients, were included. Overall, LCI significantly decreased by 0.40 units (95% CI -0.60- -0.19, p=0.004) or 2.5% following treatment. The relative change in LCI was significantly correlated with the relative change in forced expiratory volume in 1 s (FEV1), but results were discordant in 42.5% of subjects (80 out of 188). Higher (worse) baseline LCI was associated with a greater improvement in LCI (slope: -0.9%, 95% CI -1.0- -0.4%).LCI response to therapy for pulmonary exacerbations is heterogeneous in CF patients; the overall effect size is small and results are often discordant with FEV1.

Using the same cut-off for sulfur hexafluoride and nitrogen multiple-breath washout may not be appropriate.

Recent evidence suggests that results from multiple-breath washout (MBW) using nitrogen (N 2 ) as washout gas are different to those obtained by using sulfur hexafluoride (SF 6 ). Explanations were mainly related to different MBW equipment and gas properties. We aim to mention a new aspect, namely using the same cut-off in both techniques to determine lung clearance index (usually 2.5% of initial tracer concentration) irrespective of additional contribution of tissue-nitrogen in N 2 -MBW. In a simple model calculation we subtracted 1% tissue-N 2 from the N 2 -MBW in real washout traces from two children, one with cystic fibrosis (CF) and one healthy. This "SF 6 -washout simulation" decreased LCI differently in the children. In the healthy subject 1/40 th (2.5%) was achieved two breaths earlier compared to the original signal and changed LCI from 6.7 to 5.9 (12%), while in CF 1/40 th was achieved 19 breaths earlier leading to a LCI decrease from 13.7 to 10.0 (27%). It would have been required to wash out SF6 until 1/66 th (1.5%) to be comparable to N 2 washout at 1/40th (2.5%), or to stop N2-MBW already at 3.5% of the starting concentration to make both techniques comparable. We show that a basic physiological-mathematical difference between both techniques additionally accounts for different sensitivities and poor agreement between SF 6 - and N 2 -MBW. The best way of adjusting for the contribution of tissue-N 2 needs to be examined in future studies. Thus, despite increasing use in different disease groups, the books on MBW technology are obviously not closed yet.

EPS04.1 Longitudinal changes in lung clearance index in children with CF

Lung clearance index (LCI), a marker of gas mixing efficiency, is a promising parameter to assess lung function in patients with CF. In cross-sectional data, LCI is often abnormal, even in subjects with normal FEV 1 . Few data are available on long-term evolution of LCI. Objectives LCI was measured prospectively in children with CF during routine follow-up. Changes in LCI were evaluated after 2 years, to explore the magnitude of changes and the relation with changes in FEV 1 . Methods LCI was measured with the Ecomedics Exhalyzer D, using a N 2 washout. Spirometry was performed at the same visit. An LCI higher than 8.3 and a FEV 1 Z-score lower than 1.97 were considered abnormal. Results In 42 patients with a median age of 12.2 years (range 5.8 to 17.2), two measurements were compared with median interval of 21 months (range 18 to 27). At first timepoint (T1), median LCI was 9.4 (range 6.0 to 14.5) and median FEV1 Z-score –0.6 (range –4.1 to 2.0). Over the observation period, individual changes in both parameters occurred, but on the whole major changes were unusual: FEV1 Z-score was normal but LCI was abnormal at T 1 in 23 patients, and this remained so at T2 in 21; both FEV 1 and LCI were normal at T1 in 12 patients, this remained so at T2 in 11; both FEV 1 Z-score and LCI were abnormal at T1 in 7 patients, and this remained so at T 2 in 6. Abnormal FEV 1 and normal LCI was never seen. Conclusion In 23/42 children with CF, FEV1 z-score was normal but LCI z score was abnormal and this remained so 2 years later in all but two subject. These data further support the notion that measuring LCI brings additional information especially in the group of children with normal FEV 1 .

WS21.3 Acute changes in the lung clearance index after physiotherapy in children with cystic fibrosis

Objectives The lung clearance index (LCI) is becoming a prominent endpoint for assessing interventions in cystic fibrosis (CF) concurrent with daily physiotherapy. We examined the acute time-course of change in LCI following positive expiratory pressure (PEP) chest physiotherapy in children with an acute pulmonary exacerbation of CF. Methods To assess the repeatability of our LCI measurements, 71 children, aged 8–18, with stable CF performed multiple-breath nitrogen washout (MBNW) reporting LCI. For the main study, 39 children, aged 8–18, admitted for acute exacerbations of CF were recruited on day 5 of admission to perform MBNW, spirometry and body plethysmography prior to supervised PEP. MBNW was then performed immediately after PEP, and at 1, 2 and 3 hours post-intervention. All lung function tests were repeated 24 hours after baseline measurement. Results Repeatability, expressed as the coefficient of variation (CoV), of LCI was 6.1(3.2)% in subjects with stable CF and 8.7(3.4)% in those with a pulmonary exacerbation. PEP significantly increased LCI, peaking at 1 hour post-intervention (8.82 to 9.81, p Conclusion The CoV for LCI was low in stable CF but increased in those with pulmonary exacerbations. In subjects with a pulmonary exacerbation of CF, ventilation inhomogeneity (LCI) acutely increases after physiotherapy on a background of overall improvement over 24 hours. This indicates standardisation of time of LCI measurement with respect to physiotherapy is required.

Evidence of an Acinar Response following Treatment for Exacerbation in Adult Patients with Cystic Fibrosis

Background: Treating acute infectious exacerbations in cystic fibrosis (CF) patients with intravenous antibiotic therapy leads to variability in lung function and the ventilation distribution response. Part of the variable lung clearance index (LCI) response could be associated with the variable peripheral effects of intravenous antibiotic administration. Objectives: We explored to what extent the peripheral lung zones of CF patients could contribute to lung function improvements following treatment for infectious exacerbations. Methods: Over a 1-year period, 15 adult CF patients admitted for acute exacerbations were recruited. Lung function and multiple breath washout (MBW) tests were performed on the day of admission and at discharge. From the MBW test, we obtained acinar and conductive indices of ventilation heterogeneity and LCI. Results: The mean age (±SD) was 26 ± 5 years. Upon admission, the FEV₁ was 54 ± 16% predicted and the LCI was 181 ± 26% predicted. After treatment, the average FEV₁ increased to 61 ± 20% predicted (p < 0.001) and the LCI decreased to 173 ± 28% predicted (p = 0.042). The change in LCI was associated with a change in acinar (ρ = +0.54; p = 0.039) but not in conductive ventilation heterogeneity (p > 0.1). Conclusions: In CF patients in whom an improvement in LCI was obtained after treatment for an acute infectious exacerbation, this was paralleled by a decrease in acinar ventilation heterogeneity.

Lung clearance index: should we really go back to nitrogen washout?

To the Editor: A recent editorial in the European Respiratory Journal [1] recognises that the fundamental scientific data on lung clearance index (LCI) obtained by sulfur hexafluoride (SF6) multiple-breath washout (MBW) have paved the way for clinical use of LCI. Although the editorial stresses the need for standardisation, it also appears to suggest that SF6 can be replaced by nitrogen (N2) as the washout gas. We (Innovision ApS, Odense, Denmark) are the manufacturer of the AMIS 2000 medical mass spectrometer system that, using user-specific software and hardware, was adapted to perform MBW. The AMIS 2000-based devices are now considered the “gold standard” device for SF6 LCI measurements in cystic fibrosis patients by opinion leaders in the field [2]. This device has been used in the vast majority of studies demonstrating the clinical value of SF6 LCI in cystic fibrosis patients, with one recent notable exception: the demonstration of the change in LCI caused by Ivacaftor in cystic fibrosis patients with normal forced expiratory volume in 1 s, where a prototype version of our other system, Innocor, adapted for open-circuit SF6 LCI, was used [3]. The AMIS 2000 adapted MBW system is too …

Lung Clearance Index as an Outcome Measure for Clinical Trials in Young Children with Cystic Fibrosis. A Pilot Study Using Inhaled Hypertonic Saline

Lung clearance index (LCI), measured by multiple breath washout (MBW), is a noninvasive measure of ventilation inhomogeneity that holds promise as an objective physiologic endpoint for clinical trials in infants and preschool children with cystic fibrosis (CF). To study the feasibility of using LCI to assess treatment effect outcomes in CF trials of infants and preschoolers. The Infant Study of Inhaled Saline trial was a multicenter, randomized, controlled trial of hypertonic (7%) versus isotonic (0.9%) saline inhaled twice daily for 48 weeks in children with CF under 6 years of age. LCI measurements were performed in a single-center pilot substudy at baseline and 48 weeks using a respiratory mass spectrometer and sulfur hexafluoride as the tracer gas. LCI measurements were standardized using published normative data (zLCI) to account for height-related changes in LCI during early childhood. A generalized estimating equation model with an interaction between treatment group and test occasion was used to estimate a treatment effect. A total of 27 participants were randomized; 25 participants, aged (median [range]) 2.6 (0.34-4.95) years, had acceptable baseline and follow-up LCI measures. On average, LCI decreased in the hypertonic saline group (n = 12) by 1.19 z-scores units (95% confidence interval [CI] = -2.46 to 0.06), and remained stable in the isotonic saline group (n = 13) at 0.81 (95% CI = -0.40 to 2.02). A significant treatment effect was observed for zLCI (2.01; 95% CI = 0.26 to 3.76; P = 0.025). MBW testing is feasible in an interventional study in infants and preschool children with CF. These pilot findings support the development of MBW and LCI as an objective outcome measure in interventional trials in young children with CF, and provide estimates for sample size calculations for future studies.

The effect of dornase alfa on ventilation inhomogeneity in patients with cystic fibrosis

Outcome measures to assess therapeutic interventions in cystic fibrosis (CF) patients with mild lung disease are lacking. Our aim was to determine if the lung clearance index (LCI) can detect a treatment response to dornase alfa in paediatric CF patients with normal spirometry. CF patients between 6-18 yrs of age with FEV(1 )≥ 80% pred were eligible. In a crossover design, 17 patients received 4 weeks of dornase alfa and placebo in a randomised sequence separated by a 4-week washout period. The primary end-point was the change in LCI from dornase alfa versus placebo. A mixed model approach incorporating period-dependent baselines was used. The mean ± sd age was 10.32 ± 3.35 yrs. Dornase alfa improved LCI versus placebo (0.90 ± 1.44; p = 0.022). Forced expiratory flow at 25-75% expired volume measured by % pred and z-scores also improved in subjects on dornase alfa (6.1% ± 10.34%; p = 0.03 and 0.28 ± 0.46 z-score; p = 0.03). Dornase alfa significantly improved LCI. Therefore the LCI may be a suitable tool to assess early intervention strategies in this patient population.

Using index of ventilation to assess response to treatment for acute pulmonary exacerbation in children with cystic fibrosis

The use of alternative more sensitive measures has become a focus of research in CF. The utility of indexes of ventilation, Lung Clearance Index (LCI) and peak aerobic capacity (peak VO(2)), were studied as assessment tools in gauging response to intravenous (IV) therapy in acute pulmonary exacerbation, in comparison to the more commonly used index of forced expiratory volume in 1 sec (FEV(1)). The utility of a previously published clinical score was further explored. Patients aged 8-18 years admitted for IV antibiotic treatment of a pulmonary exacerbation were recruited. Spirometry, plethysmography, multiple breath nitrogen washout, exercise testing, and Cystic Fibrosis Clinical Score (CFCS) were performed on admission and prior to discharge. Twenty-eight patients were recruited, with a mean (range) age of 13.7 (8; 17) years, 16 female and 12 male. Mean (range) admission FEV(1) was 61.4 (28; 92)% predicted, or z-score -3.09 (-6.15; -0.52), FVC 83.0 (38; 120)% predicted, or z-score -1.71 (-5.66; -1.17), and Shwachman-Kulczycki 68.9 (50; 90). FEV(1) increased by 7.0% (P < 0.01) from admission to discharge. Mean (range) admission LCI, 10.10 (6.87; 14.83), decreased by 3.8% (P = 0.03). Mean (range) admission peak VO(2) (ml/kg/min), 31.2 (23.4; 45.4), increased on discharge by 6.6% (P < 0.01). Proposed clinical thresholds, based on the available variability data, highlighted the heterogeneity of response in lung function tests. Mean (range) admission CFCS, 26.5 (19; 39), decreased to 19.9 (13; 31) on discharge, a 25.2% improvement (P < 0.01). CFCS demonstrated improvement in 27 of 28 patients. Changes in peak VO(2) (r = -0.50, P = 0.02) and LCI (r = 0.48, P = 0.01) correlated with CFCS change. In children with mild-to-moderate CF, whilst statistically significant improvement in both LCI and peak VO(2) were seen, heterogeneity of response was evident. The most consistent improvement was seen in CFCS. Correlation of LCI and peak VO(2) with change in clinical score (CFCS) was seen. The full clinical significance of these changes in LCI and peak VO(2) needs to be evaluated further with additional variability data. The CFCS may be useful in the assessment of response to treatment in CF but requires formal validation.

Effect of cardiopulmonary bypass and aortic clamping on functional residual capacity and ventilation distribution in children

To characterize factors that contribute to lung function impairment after cardiopulmonary bypass, we assessed functional residual capacity and ventilation homogeneity during the perioperative period in children with congenital heart disease who are to undergo surgical repair. Functional residual capacity and lung clearance index were measured by using a sulfur hexafluoride washout technique in 24 children (aged 0-10 years). Measurements of functional residual capacity and ventilation distribution were performed after induction of anesthesia, at different stages of the surgical procedure, and up to 90 minutes after skin closure. Anesthesia was standardized, and ventilator settings, including the fraction of inspired oxygen, were kept constant throughout the study period. Sternotomy and retractor insertion led to a significant increase in functional residual capacity (mean [SD], 24% [14%]), followed by a similar percentage decrease in the resting volume after a significant reduction in pulmonary blood flow during cardiopulmonary bypass with aortic clamping. Although reestablishing pulmonary blood flow increased functional residual capacity (10% [6%]), chest closure led to a decrease in functional residual capacity of 36% (14%) that only slightly improved during the first 90 minutes after surgical intervention. Changes in lung clearance index were affected conversely compared with changes in functional residual capacity at all assessment times. These results confirmed that chest wall condition and pulmonary circulation affect lung volumes and ventilation homogeneity. Although opening of the chest wall improved alveolar recruitment and ventilation homogeneity, blood flow appeared essential for alveolar stability, presumably by exerting a tethering force caused by the filled capillaries on the alveolar walls and therefore contributing to an increase in resting lung volume.