Cindy Thamrin

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 Volume, Breathing Pattern and Ventilation Inhomogeneity in Preterm and Term Infants

Background Morphological changes in preterm infants with bronchopulmonary dysplasia (BPD) have functional consequences on lung volume, ventilation inhomogeneity and respiratory mechanics. Although some studies have shown lower lung volumes and increased ventilation inhomogeneity in BPD infants, conflicting results exist possibly due to differences in sedation and measurement techniques. Methodology/Principal Findings We studied 127 infants with BPD, 58 preterm infants without BPD and 239 healthy term-born infants, at a matched post-conceptional age of 44 weeks during quiet natural sleep according to ATS/ERS standards. Lung function parameters measured were functional residual capacity (FRC) and ventilation inhomogeneity by multiple breath washout as well as tidal breathing parameters. Preterm infants with BPD had only marginally lower FRC (21.4 mL/kg) than preterm infants without BPD (23.4 mL/kg) and term-born infants (22.6 mL/kg), though there was no trend with disease severity. They also showed higher respiratory rates and lower ratios of time to peak expiratory flow and expiratory time (t PTEF/t E) than healthy preterm and term controls. These changes were related to disease severity. No differences were found for ventilation inhomogeneity. Conclusions Our results suggest that preterm infants with BPD have a high capacity to maintain functional lung volume during natural sleep. The alterations in breathing pattern with disease severity may reflect presence of adaptive mechanisms to cope with the disease process.

Assessment of bronchodilator responsiveness in preschool children using forced oscillations

Background: The forced oscillation technique (FOT) requires minimal patient cooperation and is feasible in preschool children. Few data exist on respiratory function changes measured using FOT following inhaled bronchodilators (BD) in healthy young children, limiting the clinical applications of BD testing in this age group. A study was undertaken to determine the most appropriate method of quantifying BD responses using FOT in healthy young children and those with common respiratory conditions including cystic fibrosis, neonatal chronic lung disease and asthma and/or current wheeze. Methods: A pseudorandom FOT signal (4–48 Hz) was used to examine respiratory resistance and reactance at 6, 8 and 10 Hz; 3–5 acceptable measurements were made before and 15 min after the administration of salbutamol. The post-BD response was expressed in absolute and relative (percentage of baseline) terms. Results: Significant BD responses were seen in all groups. Absolute changes in BD responses were related to baseline lung function within each group. Relative changes in BD responses were less dependent on baseline lung function and were independent of height in healthy children. Those with neonatal chronic lung disease showed a strong baseline dependence in their responses. The BD response in children with cystic fibrosis, asthma or wheeze (based on both group mean data and number of responders) was not greater than in healthy children. Conclusions: The BD response assessed by the FOT in preschool children should be expressed as a relative change to account for the effect of baseline lung function. The limits for a positive BD response of −40% and 65% for respiratory resistance and reactance, respectively, are recommended.

Normative data for lung function and exhaled nitric oxide in unsedated healthy infants

Despite association with lung growth and long-term respiratory morbidity, there is a lack of normative lung function data for unsedated infants conforming to latest European Respiratory Society/American Thoracic Society standards. Lung function was measured using an ultrasonic flow meter in 342 unsedated, healthy, term-born infants at a mean±sd age of 5.1±0.8 weeks during natural sleep according to the latest standards. Tidal breathing flow–volume loops (TBFVL) and exhaled nitric oxide (eNO) measurements were obtained from 100 regular breaths. We aimed for three acceptable measurements for multiple-breath washout and 5–10 acceptable interruption resistance (Rint) measurements. Acceptable measurements were obtained in ≤285 infants with high variability. Mean values were 7.48 mL·kg−1 (95% limits of agreement 4.95–10.0 mL·kg−1) for tidal volume, 14.3 ppb (2.6–26.1 ppb) for eNO, 23.9 mL·kg−1 (16.0–31.8 mL·kg−1) for functional residual capacity, 6.75 (5.63–7.87) for lung clearance index and 3.78 kPa·s·L−1 (1.14–6.42 kPa·s·L−1) for Rint. In males, TBFVL outcomes were associated with anthropometric parameters and in females, with maternal smoking during pregnancy, maternal asthma and Caesarean section. This large normative data set in unsedated infants offers reference values for future research and particularly for studies where sedation may put infants at risk. Furthermore, it highlights the impact of maternal and environmental risk factors on neonatal lung function.

Fluctuation phenotyping based on daily fraction of exhaled nitric oxide values in asthmatic children

BACKGROUND Fraction of exhaled nitric oxide (Feno), a marker of airway inflammation, has been proposed to be useful for asthma management, but conclusions are inconsistent. This might be due to the failure of mean statistics to characterize individual variability in Feno values, which is possibly a better indicator of asthma control than single measurements. OBJECTIVE We characterized fractal fluctuations in daily Feno values over time and the relationship between Feno values and symptom scores. We investigated whether these are associated with asthma severity, control, and exacerbation risk. METHODS Daily Feno values and symptom scores over 192 days in 41 atopic asthmatic children from the Childhood Asthma Respiratory Inflammatory Status Monitoring study were analyzed. Two methods of time-series analysis were used: detrended fluctuation analysis to quantify fractal patterns in fluctuations in daily Feno values (α value) and cross-correlation to quantify the strength of the relationship between daily Feno values and symptom scores. The associations of α values and cross-correlation with markers of asthma severity and control were assessed by means of regression analysis. RESULTS Daily fluctuations in Feno values exhibited fractal-type long-range correlations. Those subjects receiving higher doses of inhaled corticosteroids at study entry had a significantly lower α value, corresponding to more random fluctuations in Feno values in those with greater inhaled corticosteroid need. The cross-correlation between Feno values and symptom scores was significantly higher in those subjects who had exacerbations. CONCLUSIONS Fluctuation in Feno values and their cross-correlation to symptom scores contains information on asthma severity and control. Methods that quantify the complexity of asthma over time might assist in identifying asthmatic subjects with concordance between eosinophilic inflammation and symptoms and thus increased exacerbation risk.

Fractals for physicians

There is increasing interest in the study of fractals in medicine. In this review, we provide an overview of fractals, of techniques available to describe fractals in physiological data, and we propose some reasons why a physician might benefit from an understanding of fractals and fractal analysis, with an emphasis on paediatric respiratory medicine where possible. Among these reasons are the ubiquity of fractal organisation in nature and in the body, and how changes in this organisation over the lifespan provide insight into development and senescence. Fractal properties have also been shown to be altered in disease and even to predict the risk of worsening of disease. Finally, implications of a fractal organisation include robustness to errors during development, ability to adapt to surroundings, and the restoration of such organisation as targets for intervention and treatment.

A new double-tracer gas single-breath washout to assess early cystic fibrosis lung disease

In cystic fibrosis (CF), tests for ventilation inhomogeneity are sensitive but not established for clinical routine. We assessed feasibility of a new double-tracer gas single-breath washout (SBW) in school-aged children with CF and control subjects, and compared SBW between groups and with multiple-breath nitrogen washout (MBNW). Three SBW and MBNW were performed in 118 children (66 with CF) using a side-stream ultrasonic flowmeter setup. The double-tracer gas containing 5% sulfur hexafluoride and 26.3% helium was applied during one tidal breath. Outcomes were SBW phase III slope (SIIIDTG), MBNW-derived lung clearance index (LCI), and indices of acinar (Sacin) and conductive (Scond) ventilation inhomogeneity. SBW took significantly less time to perform than MBNW. SBW and MBNW were feasible in 109 (92.4%) and 98 (83.0%) children, respectively. SIIIDTG differed between children with CF and controls, mean±sd was -456.7±492.8 and -88.4±129.1 mg·mol·L−1, respectively. Abnormal SIIIDTG was present in 36 (59%) children with CF. SIIIDTG was associated with LCI (r= -0.58) and Sacin (r= -0.58), but not with Scond. In CF, steeply sloping SIIIDTG potentially reflects ventilation inhomogeneity near the acinus entrance. This tidal SBW is a promising test to assess ventilation inhomogeneity in an easy and fast way.

Variability of lung function predicts loss of asthma control following withdrawal of inhaled corticosteroid treatment

Background One aspect of a multidimensional approach to understanding asthma as a complex dynamic disease is to study how lung function varies with time. Variability measures of lung function have been shown to predict response to β2-agonist treatment. An investigation was conducted to determine whether mean, coefficient of variation (CV) or autocorrelation, a measure of short-term memory, of peak expiratory flow (PEF) could predict loss of asthma control following withdrawal of regular inhaled corticosteroid (ICS) treatment, using data from a previous study. Methods 87 adult patients with mild to moderate asthma who had been taking ICS at a constant dose for at least 6 months were monitored for 2–4 weeks. ICS was then withdrawn and monitoring continued until loss of control occurred as per predefined criteria. Twice-daily PEF was recorded during monitoring. Associations between loss of control and mean, CV and autocorrelation of morning PEF within 2 weeks pre- and post-ICS withdrawal were assessed using Cox regression analysis. Predictive utility was assessed using receiver operator characteristics. Results 53 out of 87 patients had sufficient PEF data over the required analysis period. The mean (389 vs 370 l/min, p<0.0001) and CV (4.5% vs 5.6%, p=0.007) but not autocorrelation of PEF changed significantly from prewithdrawal to postwithdrawal in subjects who subsequently lost control, and were unaltered in those who did not. These changes were related to time to loss of control. CV was the most consistent predictor, with similar sensitivity and sensitivity to exhaled nitric oxide. Conclusion A simple, easy to obtain variability measure of daily lung function such as the CV may predict loss of asthma control within the first 2 weeks of ICS withdrawal.

Associations between fluctuations in lung function and asthma control in two populations with differing asthma severity

Background Lung function is a major criterion used to assess asthma control. Fluctuation analyses can account for lung function history over time, and may provide an additional dimension to characterise control. The relationships between mean and fluctuations in lung function with asthma control, exacerbation and quality of life were studied in two independent data sets. Methods Data from 132 adults with mild to moderate asthma and 159 adults with severe asthma were analysed separately. Fluctuations in twice-daily peak expiratory flow (PEF) over 6 months were measured by α, representing the strength of correlation with past lung function and potentially asthma stability. α and mean percentage predicted PEF (%predPEF) were plotted with and compared between patients grouped by asthma control defined by recent GINA (Global Initiative for Asthma) guidelines, the Asthma Control Questionnaire score, exacerbations and Asthma Quality of Life Questionnaire score. Associations of α and %predPEF with these outcomes were examined using multiple regression analyses. Results Both α and %predPEF differed with and were significantly associated with GINA-defined asthma control in both the mild to moderate and severe asthma groups. Only α was related to whether or not exacerbations occurred in mild to moderate asthma, while %predPEF was more significantly related than α in severe asthma. In those with severe asthma, only %predPEF was significantly related to Asthma Control Questionnaire and Asthma Quality of Life Questionnaire scores. Conclusion Lung function history quantified by fluctuation analysis provides additional information to mean lung function, and may help characterise the current state of asthma control. It may also potentially aid in phenotyping clinical asthma.

Tidal Volume Single Breath Washout of Two Tracer Gases - A Practical and Promising Lung Function Test

Background Small airway disease frequently occurs in chronic lung diseases and may cause ventilation inhomogeneity (VI), which can be assessed by washout tests of inert tracer gas. Using two tracer gases with unequal molar mass (MM) and diffusivity increases specificity for VI in different lung zones. Currently washout tests are underutilised due to the time and effort required for measurements. The aim of this study was to develop and validate a simple technique for a new tidal single breath washout test (SBW) of sulfur hexafluoride (SF6) and helium (He) using an ultrasonic flowmeter (USFM). Methods The tracer gas mixture contained 5% SF6 and 26.3% He, had similar total MM as air, and was applied for a single tidal breath in 13 healthy adults. The USFM measured MM, which was then plotted against expired volume. USFM and mass spectrometer signals were compared in six subjects performing three SBW. Repeatability and reproducibility of SBW, i.e., area under the MM curve (AUC), were determined in seven subjects performing three SBW 24 hours apart. Results USFM reliably measured MM during all SBW tests (n = 60). MM from USFM reflected SF6 and He washout patterns measured by mass spectrometer. USFM signals were highly associated with mass spectrometer signals, e.g., for MM, linear regression r-squared was 0.98. Intra-subject coefficient of variation of AUC was 6.8%, and coefficient of repeatability was 11.8%. Conclusion The USFM accurately measured relative changes in SF6 and He washout. SBW tests were repeatable and reproducible in healthy adults. We have developed a fast, reliable, and straightforward USFM based SBW method, which provides valid information on SF6 and He washout patterns during tidal breathing.