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Sensor errors resulting in elevated values of N 2 concentration [N 2 ] in commercial multiple-breath washout (MBW) devices have been shown to prolong the washout and result in erroneously high functional residual capacity (FRC) and lung clearance index (LCI) values. The errors also affect the indices of conductive and acinar ventilatory heterogeneity ( S cond and S acin ) although the mechanism by which this change in values occurs remains unclear. Exploring these effects also provides a timely opportunity to examine the appropriateness of the algorithm used to calculate these indices. Using a two-compartment model with differing specific ventilation (SV) such that the lower SV unit empties late, noise-free MBW were simulated both corrected and uncorrected for the recent sensor error. S cond was calculated using regression of normalized phase III slope (Sn III ) against lung turnover (TO) from a TO range starting at 1.5 and ending at an upper turnover (TO upper ) between 4 and 8 (default 6) over a range of simulated values. The principal effect of the sensor error was that as the MBW proceeded the phase III slope of successive breaths was normalized by an increasingly overestimated [N 2 ], resulting in Sn III values that fell precipitously at high TO, greatly reducing S cond . Reanalysis of previously published data and of simulated data showed a large proportional bias in S cond , whereas S acin was only minimally affected. In adult subject data, reducing TO upper below 5.5 was associated with a large drop of up to ∼60% in S cond calculated from data corrected for sensor error. Raising the upper TO limit elevated S cond by ∼20% but with a large concomitant increase in variability. In contrast to S cond , S acin was relatively unaffected by changes in TO upper with changes of <3%. This work serves to emphasize that the upper limit of TO of 6 represents an appropriate upper limit for the calculation of S cond . NEW & NOTEWORTHY Sensor errors that elevated values of N 2 concentration in commercial multiple-breath washout (MBW) devices resulted in errors in calculated parameters including S cond and S acin . We examined the mechanism of the change in values produced by these errors and explored the appropriateness of the calculation of S cond and S acin . This work serves to emphasize that the current algorithm in use is appropriate for the calculation of S cond and S acin .

Cystic fibrosis (CF) lung disease is characterized by increased ventilation inhomogeneity (VI), as measured by multiple-breath washout (MBW). Lung clearance index (LCI) is the most reported VI outcome. This study aimed to evaluate historically published reference equations for sulfur hexafluoride (SF 6 ) MBW outcomes, to data collected using updated commercial SF 6 MBW equipment, and to produce device-specific equations if necessary. SF 6 MBW was performed in 327 healthy children aged 0.1-18.4 yr [151 (46%) girls], 191 (58.4%) <3 yr. z-Scores were calculated from published reference equations (FRC and LCI) and multivariate linear regression was performed to produce device-specific reference equations. Due to increasing residual standard deviations with increasing LCI values, investigation of methods for improvement were investigated, based on the relationship between VI and dead space ventilation (VD/VT; dead space volume/tidal volume) in a cohort of 59 healthy children, 26 children with CF ( n = 138 test occasions), and 49 adults with lung disease. Historical SF 6 MBW reference equations were unsuitable for EXHALYZER D data. In contrast to LCI and log 10 (LCI), 1/LCI (ventilation distribution efficiency; VDE) was linearly related to VD/VT, with z-scores linearly related to its absolute values. Reference equations were reported for VDE and log 10 (FRC). Significant predictors for VDE and log 10 (FRC), respectively, were log 10 (age) and sex, and log 10 (height), sex, and posture. VDE is potentially a better index of VI than LCI, particularly in more advanced CF lung disease and also for longitudinal monitoring. Further confirmatory clinical studies, particularly longitudinal imaging studies of structural or ventilatory changes, are warranted. NEW & NOTEWORTHY Lung clearance index (LCI) is the most used outcome from the multiple-breath washout test. As known for decades, the LCI is not linearly related to dead space ventilation, giving difficulties interpreting changes over time and in clinical trials. We present a new and improved outcome based on LCI, the ventilation distribution efficiency (VDE), which solves this problem by being linearly related to dead space ventilation. A pediatric age range reference equation for VDE is presented.

Recent studies indicate limited utility of nitrogen multiple-breath washout (N 2 MBW) in infancy and advocate for using sulfur hexafluoride (SF 6 ) MBW in this age-group. Modern N 2 MBW systems, such as EXHALYZER D (ECO MEDICS AG, Duernten, Switzerland), use O 2 and CO 2 sensors to calculate N 2 concentrations (in principle, N 2 % = 100 - CO 2 % - O 2 %). High O 2 and CO 2 concentrations have now been shown to significantly suppress signal output from the other sensor, raising apparent N 2 concentrations. We examined whether improved EXHALYZER D N 2 signal, accomplished after thorough examination of this CO 2 and O 2 interaction on gas sensors and its correction, leads to better agreement between N 2 MBW and SF 6 MBW in healthy infants and toddlers. Within the same session, 52 healthy children aged 1-36 mo [mean = 1.30 (SD = 0.72) yr] completed SF 6 MBW and N 2 MBW recordings (EXHALYZER D, SPIROWARE version 3.2.1) during supine quiet sleep. SF 6 and N 2 SPIROWARE files were reanalyzed offline with in-house software using identical algorithms as in SPIROWARE with or without application of the new correction factors for N 2 MBW provided by ECO MEDICS AG. Applying the improved N 2 signal significantly reduced mean [95% confidence interval (CI)] differences between N 2 MBW and SF 6 MBW recorded functional residual capacity (FRC) and lung clearance index (LCI): for FRC, from 26.1 (21.0, 31.2) mL, P < 0.0001, to 1.18 (-2.3, 4.5) mL, P = 0.5, and for LCI, from 1.86 (1.68, 2.02), P < 0.001, to 0.44 (0.33, 0.55), P < 0.001. Correction of N 2 signal for CO 2 and O 2 interactions on gas sensors resulted in markedly closer agreement between N 2 MBW and SF 6 MBW outcomes in healthy infants and toddlers. NEW & NOTEWORTHY Modern nitrogen multiple-breath washout (N 2 MBW) systems such as EXHALYZER D use O 2 and CO 2 sensors to calculate N 2 concentrations. New corrections for interactions between high O 2 and CO 2 concentrations on the gas sensors now provide accurate N 2 signals. The correct N 2 signal led to much improved agreement between N 2 MBW and sulfur hexafluoride (SF 6 ) MBW functional residual capacity (FRC) and lung clearance index (LCI) in 52 sleeping healthy infants and toddlers, suggesting a role for N 2 MBW in this age-group.

Multiple breath nitrogen washout (MBNW) indices provide insight into ventilation heterogeneity globally [lung clearance index (LCI)] and within acinar (S acin ) and conducting (S cond ) airways. Normal aging leads to an accelerated deterioration of S acin in older adults, but little is known about the contribution of peripheral airway function to changes in pulmonary function indices reflecting expiratory airflow [forced expiratory volume in one second (FEV 1 )/forced vital capacity (FVC)] and gas trapping [residual volume (RV)/total lung capacity (TLC)] with aging. We aimed to examine associations between MBNW and FEV 1 /FVC as well as RV/TLC in healthy adults, and to determine if these relationships differ in older (≥50 yr) versus younger subjects (<50 yr). Seventy-nine healthy adult volunteers aged 23-89 yr with no cardiac or respiratory disease and a smoking history of <5 pack-years underwent spirometry, plethysmography, and MBNW. After adjustment for sex, height, and body mass index, the following relationships were present across the entire cohort: S acin was inversely related to FEV 1 /FVC (R 2  = 0.22, P < 0.001); S acin and S cond were positively related to RV/TLC (R 2  = 0.53, P < 0.001); on separate analyses, the relationship between S acin and FEV 1 /FVC was strongest in the older group (R 2  = 0.20, P = 0.003) but markedly weaker in the younger group (R 2  = 0.09, P = 0.04); and S acin and S cond were related to RV/TLC in older (R 2  = 0.20, P = 0.003) but not younger subgroups. No relationships were observed between LCI and FEV 1 /FVC or RV/TLC. Changes in FEV 1 /FVC and RV/TLC are at least in part due to changes in peripheral airway function with aging. Further studies of the relationships between MBNW and standard pulmonary function indices may prove useful for their combined application and interpretation in obstructive airways disease. NEW & NOTEWORTHY This study explores associations between multiple breath nitrogen washout (MBNW) and standard pulmonary function indices reflecting expiratory airflow [forced expiratory volume in one second (FEV 1 )/forced vital capacity (FVC)] and gas trapping [residual volume (RV)/total lung capacity (TLC)] in healthy adults across a wide range of ages. We have demonstrated statistically significant relationships between MBNW and FEV 1 /FVC as well as RV/TLC. These findings provide novel evidence of the contribution of peripheral airway function to changes in standard pulmonary function indices with aging.

The detrimental effects on breathing pattern during multiple breath inert gas washout (MBW) have been described with different inhaled gases [100% oxygen (O 2 ) and sulfur hexafluoride (SF 6 )] but detailed comparisons are lacking. N 2 - and SF 6 -based tests were performed during spontaneous quiet sleep in 10 healthy infants aged 0.7-1.3 yr using identical hardware. Differences in breathing pattern pre and post 100% O 2 and 4% SF 6 exposure were investigated, and the results obtained were compared [functional residual capacity (FRC) and lung clearance index (LCI)]. During 100% O 2 exposure. mean inspiratory flow ("respiratory drive") decreased transiently by mean (SD) 28 (9)% ( P < 0.001), and end-tidal CO 2 (carbon dioxide) increased by mean (SD) 0.3 (0.4)% units ( P < 0.05) vs. air breathing prephase. During subsequent N 2 washin (i.e., recovery phase), the pattern of change reversed. No significant effect on breathing pattern was observed during SF 6 testing. In vitro testing confirmed that technical artifacts did not explain these changes. Mean (SD) FRC and LCI in vivo were significantly higher with N 2 vs. SF 6 washout: 216 (33) vs. 186 (22) ml ( P < 0.001) and 8.25 (0.85) vs. 7.55 (0.57) turnovers ( P = 0.021). Based on these results, SF 6 based MBW is the preferred methodology for tests in this age range. NEW & NOTEWORTHY Inert gas choice for multiple breath inert gas washout (MBW) in infants has important consequences on both breathing pattern during test performance and the functional residual capacity and lung clearance index values obtained. Data suggest the detrimental effect of breathing pattern of 100% O 2 and movement of O 2 across the alveolar capillary membrane, with direct effects on MBW outcomes. SF 6 MBW during infancy avoids this and can be further optimized by addressing the sources of technical artifact identified in this work.

The forced oscillation technique (FOT) can provide unique and clinically relevant lung function information with little cooperation with subjects. However, FOT has higher variability than spirometry, possibly because strategies for quality control and reducing artifacts in FOT measurements have yet to be standardized or validated. Many quality control procedures rely on either simple statistical filters or subjective evaluation by a human operator. In this study, we propose an automated artifact removal approach based on the resistance against flow profile, applied to complete breaths. We report results obtained from data recorded from children and adults, with and without asthma. Our proposed method has 76% agreement with a human operator for the adult data set and 79% for the pediatric data set. Furthermore, we assessed the variability of respiratory resistance measured by FOT using within-session variation (wCV) and between-session variation (bCV). In the asthmatic adults test data set, our method was again similar to that of the manual operator for wCV (6.5 vs. 6.9%) and significantly improved bCV (8.2 vs. 8.9%). Our combined automated breath removal approach based on advanced feature extraction offers better or equivalent quality control of FOT measurements compared with an expert operator and computationally more intensive methods in terms of accuracy and reducing intrasubject variability. NEW & NOTEWORTHY The forced oscillation technique (FOT) is gaining wider acceptance for clinical testing; however, strategies for quality control are still highly variable and require a high level of subjectivity. We propose an automated, complete breath approach for removal of respiratory artifacts from FOT measurements, using feature extraction and an interquartile range filter. Our approach offers better or equivalent performance compared with an expert operator, in terms of accuracy and reducing intrasubject variability., (Copyright © 2017 the American Physiological Society.)

Multiple-breath inert gas washout (MBW) is ideally suited for early detection and monitoring of serious lung disease, such as cystic fibrosis, in infants and young children. Validated commercial options for the MBW technique are limited, and suitability of nitrogen (N 2 )-based MBW is of concern given the detrimental effect of exposure to pure O 2 on infant breathing pattern. We propose novel methodology using commercially available N 2 MBW equipment to facilitate 4% sulfur hexafluoride (SF 6 ) multiple-breath inert gas wash-in and washout suitable for the infant age range. CO 2 , O 2 , and sidestream molar mass sensor signals were used to accurately calculate SF 6 concentrations. An improved dynamic method for synchronization of gas and respiratory flow was developed to take into account variations in sidestream sample flow during MBW measurement. In vitro validation of triplicate functional residual capacity (FRC) assessments was undertaken under dry ambient conditions using lung models ranging from 90 to 267 ml, with tidal volumes of 28-79 ml, and respiratory rates 20-60 per minute. The relative mean (SD, 95% confidence interval) error of triplicate FRC determinations by washout was -0.26 (1.84, -3.86 to +3.35)% and by wash-in was 0.57 (2.66, -4.66 to +5.79)%. The standard deviations [mean (SD)] of percentage error among FRC triplicates were 1.40 (1.14) and 1.38 (1.32) for washout and wash-in, respectively. The novel methodology presented achieved FRC accuracy as outlined by current MBW consensus recommendations (95% of measurements within 5% accuracy). Further clinical evaluation is required, but this new technique, using existing commercially available equipment, has exciting potential for research and clinical use., (Copyright © 2016 the American Physiological Society.)

Imaging studies describe significant ventilation defects across a wide range of cystic fibrosis (CF) related lung disease severity. These are unfortunately poorly reflected by phase III slope analysis-derived Scond and Sacin from multiple-breath washout (MBW). Methodology extending previous two-lung compartment model-based analysis is presented describing size and function of fast- and slow-ventilating lung compartments from nitrogen (N2) MBW and correlation to obstructive lung disease severity. In 37 CF subjects (forced expiratory volume in 1 s [FEV1] mean [SD] 84.8 [19.9] % predicted; abnormal lung clearance index [LCI] in 36/37, range 7.28-18.9) and 74 matched healthy controls, volume and specific ventilation of both fast and slowly ventilated lung compartments were derived from N2-based MBW with commercial equipment. In healthy controls lung emptying was characterized by a large compartment constituting 75.6 (8.4)% of functional residual capacity (FRC) with a specific ventilation (regional alveolar tidal volume/regional lung volume) of 13.9 (3.7)% and a small compartment with high specific ventilation (48.4 [15.7]%). In CF the slowly ventilated lung compartment constituted 51.9(9.1)% of FRC, with low specific ventilation of 5.3 (2.4)%. Specific ventilation of the slowly ventilated lung compartment showed stronger correlation with LCI (r2 = 0.70, P < 0.001) vs. Sacin (r2 = 0.44, P < 0.001) or Scond (no significant correlation). Overventilation of the fast lung compartment was no longer seen in severe CF lung disease. Magnitude and function of under- and overventilated lung volumes can be derived from routine N2 MBW in CF. Reported values agree with previous modelling-derived estimates of impaired ventilation and offer improved correlation to disease severity, compared with SnIII analysis., (Copyright © 2014 the American Physiological Society.)