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Effect of posture on lung ventilation distribution and associations with structure in children with cystic fibrosis
JCF-01440; No of Pages 6
Journal of Cystic Fibrosis xx (2017) xxx – xxx www.elsevier.com/locate/jcf
Original Article
Effect of posture on lung ventilation distribution and associations with structure in children with cystic fibrosis☆,☆☆ Kathryn A. Ramsey a,b,c , Caroline McGirr a , Stephen M. Stick a,b,d , Graham L. Hall a,b,e,⁎,1 , Shannon J. Simpson a,b,1 , on behalf of AREST CF 2 a Telethon Kids Institute, Subiaco, Western Australia, Australia Centre for Child Health Research, University of Western Australia, Crawley, Western Australia, Australia Cystic Fibrosis Research and Treatment Centre, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA d Respiratory Medicine, Princess Margaret Hospital for Children, Subiaco, Western Australia, Australia e School of Physiotherapy and Exercise Science, Curtin University, Bentley, Western Australia, Australia b
c
Received 21 October 2016; revised 23 January 2017; accepted 24 January 2017 Available online xxxx
Abstract Background: We assessed the effect of posture on ventilation distribution and the impact on associations with structural lung disease. Methods: Multiple breath washout (MBW) was performed in seated and supine postures in 25 healthy children and 21 children with CF. Children with CF also underwent a chest CT scan. Functional residual capacity (FRC), lung clearance index (LCI) and moment ratios were calculated from the MBW test. CT scans were evaluated for CF-related structural lung disease. Results: FRC was lower in the supine than in the seated posture, whereas LCI was higher in the supine than in the seated posture. In children with CF, associations between LCI and the extent of structural lung disease were stronger when performed in the supine posture. Conclusions: Body posture influences lung volumes and ventilation distribution in both healthy children and children with CF. MBW testing in the supine posture strengthened associations with structural lung damage. © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Keywords: Multiple breath washout; Lung clearance index; Computed tomography; Cystic fibrosis; Child; Posture; Ventilation distribution
☆ Author contributions: KAR performed the literature search, data collection, data analysis, data interpretation, and manuscript writing. CG contributed to data collection, data analysis, data interpretation and manuscript writing. SJS, SMS and GLH contributed to the literature search, were responsible for study design and oversaw the data analysis, data interpretation, and manuscript writing. GLH takes final responsibility for the data and study. ☆☆ Funding: Funding for the AREST CF program was obtained from the Cystic Fibrosis Foundation Therapeutics (SLY04A0, STICK09A0), the National Health and Medical Research Council of Australia (NHMRC; APP513730 and Centre of Research Excellence #1000896) and University of Western Australia (Research Development Award). K Ramsey (APP1088389), G Hall (APP 1025550) and S Simpson (APP1073301) are NHMRC Research Fellows. ⁎ Corresponding author at: Children's Lung Health, Telethon Kids Institute, 100 Roberts Road, Subiaco, WA 6008, Australia. E-mail address: [email protected] (G.L. Hall). 1 These authors jointly contributed as senior authors. 2 The full membership of the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) is available at http://www.arestcf.org.
1. Introduction Multiple breath inert gas washout (MBW) tests measure the efficiency of ventilation distribution by measuring the rate of clearance of a marker gas from the lungs. The MBW test involves tidal breathing of a marker gas that can either be a resident gas (e.g. nitrogen) or inert gas (e.g. sulphur hexafluoride). As a tidal breathing test MBW is feasible across the entire pediatric age range [1]. Infant MBW testing typically involves the use of inert gases with the infant sleeping in a supine position with or without sedation. Assessments of MBW in older children are performed awake, in a seated position with video distraction used to promote relaxed breathing. The lung clearance index (LCI) is a marker of global ventilation distribution derived from the MBW test. LCI is elevated
http://dx.doi.org/10.1016/j.jcf.2017.01.013 1569-1993/© 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Please cite this article as: Ramsey KA, et al, Effect of posture on lung ventilation distribution and associations with structure in children with cystic fibrosis, J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.01.013
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K.A. Ramsey et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx
in infant [2,3], preschool [4,5] and school-aged [6,7] children with CF. Lung clearance index offers a non-invasive method to monitor structural lung damage in early CF lung disease. Previous studies have shown that LCI in school-aged children with CF is more sensitive than spirometry to detect structural lung damage evident on chest computed tomography (CT) [7–9]. Our group has shown that LCI and moment ratios significantly correlate with the extent of structural lung disease on CT in preschool and school-aged children with CF, but there are only weak correlations between LCI and structural lung disease in infants with CF [1,10]. One factor that may influence the association between ventilation distribution and CT outcomes is posture. Functional residual volume (FRC) decreases when changing from an upright sitting to the supine posture in healthy adults [11–14] and postural changes in FRC are accompanied by changes in ventilation distribution [11,15]. However, we know little about how posture influences ventilation distribution in individuals with lung disease and how this influences relationships with lung imaging. In this study we assessed the effect of posture on ventilation distribution in healthy children and children with CF, and the impact of posture on the associations between markers of ventilation distribution and structural lung disease on chest CT in children with CF. 2. Methods 2.1. Study population School-aged children with CF undergoing chest CT imaging as part of their annual review or when clinically indicated at Princess Margaret Hospital (PMH) in Perth were recruited to perform lung function testing on the day of their scan. Due to the time and energy required to perform the study protocol, children with CF with exacerbated respiratory symptoms, such as productive moist cough, did not participate in the study. Children with no parentally reported history of respiratory disease, preterm birth or current respiratory symptoms or medication were recruited to perform MBW testing only. The PMH ethics committee approved the study, and participants and their parents consented to each aspect of the study separately. 2.2. Multiple breath washout MBW was performed using 100% oxygen to washout resident nitrogen from the lungs (Exhalyzer D; Spiroware 3.1 software; Ecomedics AG, Dürnten, Switzerland) as described previously [16]. The washout curve was used to generate FRC, LCI, the first moment ratio (M1/M0) and second moment ratio (M2/M0). LCI is the number of lung turnovers required to wash out an inert tracer gas to 1/40th of its starting concentration and is calculated by dividing the cumulative net expired volume by the FRC. Moment ratios describe the degree of skewness of the washout curve. Increased moment ratios represent an increased release of inert gas towards the end of the washout [17]. Test sessions with at least two acceptable measurements with no evidence of leak or irregular breathing pattern were included
in this analysis according to the current consensus statement [18]. The MBW test was performed in both the standard seated (seated on a chair) and supine (lying supine on a bed) postures, performed in a random order with 5 min in the test posture before the MBW test commenced. 2.3. Chest CT scans Children with CF underwent a spirometry-assisted volumetric helical inspiratory and expiratory chest CT scan [19]. An experienced respiratory scientist trained children to perform the breathing manoeuvres for the chest CT scan using a portable spirometer. For the inspiratory scan children were instructed to take a full inspiration to total lung capacity from residual volume and breath-hold for 5 s. For the expiratory chest CT scan children were instructed to slowly exhale to residual volume from total lung capacity and breath-hold for 5 s. Inspiratory and expiratory chest CT scans were initiated once 90% of the target vital capacity (best repeatable vital capacity value from the training) was reached. Children in the healthy control group did not complete a chest CT scan. 2.4. Quantitative CT scoring To assess CT-determined structural lung disease, the quantitative Perth-Rotterdam Annotated Grid Morphometric Analysis for Cystic Fibrosis (PRAGMA-CF) scoring method was used [20]. Briefly, in this method, a grid overlaid on 10 equidistant axial slices is annotated for the presence of bronchiectasis (outer-edge bronchus–artery cross-sectional area ratio N 1), mucus plugging (high-density airway occlusion or tree-in-bud appearance), bronchial wall thickening (assessed subjectively as airway walls that are thicker than or have increased signal density relative to normal airways) visualized on inspiratory scans, and trapped air (geographic low-density regions) seen on expiratory scans [20]. The extents (represented as volume proportions of the lung) of total airway disease (%disease), bronchiectasis (%bronchiectasis), and trapped air (%trapped air) were calculated. 2.5. Statistical analysis The upper limit of normal MBW indices was calculated based on our previously published data from a prospective healthy control population of children (n = 72) [1]. The upper limits of normal LCI was 7.71, M1/M0 1.70, and M2/M0 5.53. Height and weight z-scores were calculated using WHO growth standards [21,22]. FEV1 z-scores were calculated using Global Lung Initiative reference equations [23]. Differences in mean MBW outcomes between healthy children and children with CF were determined using independent sample two-tailed t-test. Differences in MBW outcomes with changes in posture in the same individual were determined used paired sample two-tailed t-test. Associations between MBW outcomes and chest CT outcomes were determined using linear regression models adjusted for age. To determine if posture influenced associations between MBW and CT outcomes, we generated interaction
Please cite this article as: Ramsey KA, et al, Effect of posture on lung ventilation distribution and associations with structure in children with cystic fibrosis, J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.01.013
K.A. Ramsey et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx
terms by multiplying the categorical posture variable (0 or 1) by the continuous CT variables (% disease, % air trapping, % bronchiectasis). We included the interaction terms in the linear regression models along with each of the individual independent variables. A significant interaction term in the linear regression model indicated that posture influenced associations between MBW and CT outcomes. Sensitivity, specificity, and positive and negative predictive values for an abnormal LCI to detect the presence of bronchiectasis on CT were calculated. Mean data are presented with either the standard deviation or 95% confidence interval. All statistical analyses were performed using SPSS (version 22, Chicago, IL, USA).
3. Results 3.1. Study population Matched seated and supine MBW data were available in 46 children, including 25 healthy controls and 21 children with CF (Table 1). Children with CF also had a chest CT within the same week of performing MBW testing. There were no differences in age, height, or weight between healthy children and children with CF (p N 0.05). The FRC, LCI and moment ratios in both seated and supine postures were significantly higher in children with CF than those with healthy controls.
Table 1 Demographics of study population.
Number of children Sex (male) Age (years) Height (cm) Height z-score (95% CI) Weight (kg) Weight z-score (95% CI) FEV1 z-score (95% CI) Seated posture Functional residual capacity (FRC: L) Lung clearance index (LCI) Moment ratio 1 (M1/M0) Moment ratio 2 (M2/M0) Supine posture Functional residual capacity (FRC: L) Lung clearance index (LCI) Moment ratio 1 (M1/M0) Moment ratio 2 (M2/M0) Structural lung disease Disease (%) Air trapping presence Air trapping (%) Bronchiectasis presence Bronchiectasis (%)
Healthy
CF
25 13 (52%) 11.1 ± 1.6 148.0 ± 9.5 0.45 (0.18, 0.71) 40.1 ± 9.2 0.27 (-0.01, 0.55) 0.01 (-0.49, 0.50)
21 13 (62%) 12.1 ± 1.7 148.8 ± 11.9 -0.25 (-0.67, 0.18) 42.7 ± 10.7 -0.03 (-0.43, 0.37) -0.17 (-0.74, 0.40)
1.62 7.00 1.59 5.04
± ± ± ±
0.30 0.49 0.11 0.67
1.80 8.87 1.94 8.18
1.23 7.46 1.67 5.78
± ± ± ±
0.21 0.51 0.10 0.79
1.48 ± 0.45 ⁎ 10.73 ± 2.87 ⁎ 2.28 ± 0.59 ⁎ 12.13 ± 6.59 ⁎
± ± ± ±
0.58 ⁎ 1.77 ⁎ 0.35 ⁎ 3.25 ⁎
6.1 ± 8.2 20/21 (95%) 21.5 ± 16.5 14/21 (67%) 2.4 ± 4.2
Data presented as n (percentage) or mean ± standard deviation or 95% confidence interval. Height and weight z-scores were calculated using WHO growth standards [21,22]. FEV1 z-scores were calculated using Global Lung Initiative reference equations [23]. ⁎ Indicates that values are significantly different to healthy controls (p b 0.05).
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3.2. Effect of posture on MBW outcomes We examined the effect of posture on MBW outcomes in children with CF and healthy controls (Table 2; Fig. 1). In both healthy children and children with CF, FRC was lower in the supine posture than in the seated posture. In contrast, outcomes of ventilation distribution from the MBW test were significantly higher in the supine posture than in the seated posture in both healthy children and children with CF. The magnitude of the difference in LCI between seated vs. supine postures was higher in children with CF (21% difference) than those with healthy controls (7% difference). In addition, the magnitude of difference in moment ratios between supine vs. seated postures was higher in children with CF (M1/M0: 18%, M2/M0: 48%) than those with healthy controls (M1/M0: 5%, M2/M0: 15%). Performing the MBW test in different postures changed the proportion of children with abnormal outcomes in both healthy children and children with CF. The proportion of children with an abnormal LCI increased in healthy children from 4% in the seated posture to 24% in the supine posture, and children with CF from 71% to 90%, when compared with reference data collected in the seated posture. 3.3. Impact of posture on associations between MBW and chest CT outcomes We examined the associations between seated and supine MBW outcomes and chest CT outcomes in children with CF (Table 3). There were significant associations between FRCseated and the extent of air trapping and bronchiectasis, and FRC-supine and the extent of air trapping, bronchiectasis, and total disease extent. In both the seated and supine postures, LCI and moment ratios were associated with the extent of air trapping and total disease, but not the extent of bronchiectasis. To determine if posture influenced associations between MBW (LCI and moment ratios) and CT outcomes, interaction terms between posture and CT outcomes were included in the linear regression models. Significant interactions were found between Table 2 Effect of posture on MBW outcomes. Supine posture–seated posture Mean difference (95% CI)
p value
Absolute change
Percent change
Healthy children Functional residual capacity (L) Lung clearance index Moment ratio 1 (M1/M0) Moment ratio 2 (M2/M0)
-0.39 (-0.31, -0.47) 0.46 (0.23, 0.70) 0.08 (0.02, 0.15) 0.74 (0.36, 1.13)
-24% (-19, -29) 7% (3, 10) 5% (1, 9) 15% (7, 22)
b 0.001 0.001 0.02 0.001
Children with cystic fibrosis Functional residual capacity (L) Lung clearance index Moment ratio 1 (M1/M0) Moment ratio 2 (M2/M0)
-0.33 (-0.22, -0.43) 1.86 (1.20, 2.53) 0.34 (0.20, 0.49) 3.95 (2.14, 5.76)
-18% (-12, -24) 21% (14, 29) 18% (10, 25) 48% (26, 70)
b 0.001 b 0.001 b 0.001 b 0.001
Mean difference in multiple breath washout outcomes between supine and seated postures (i.e. supine value–seated value). Percentage difference expressed relative to seated values. 95% CI = 95% confidence interval.
Please cite this article as: Ramsey KA, et al, Effect of posture on lung ventilation distribution and associations with structure in children with cystic fibrosis, J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.01.013
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K.A. Ramsey et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx
Fig. 1. Influence of posture on functional residual capacity (FRC) and lung clearance index (LCI). Healthy children are represented by black circle symbols and children with cystic fibrosis are represented by red square symbols. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
posture-%disease and posture-%trapped air (p b 0.05), but not posture-%bronchiectasis. However, LCI was more sensitive to detect the presence of bronchiectasis on chest CT when performed supine than that with seated (Table 4). The association between LCI and the extent of structural lung disease was stronger when MBW was performed in the supine posture than that in the seated posture (Fig. 2). 4. Discussion The objective of this study was to investigate whether performing the MBW in the same plane as the chest CT would improve the structure-function relationship between the two measures of lung disease in children with CF. We found that children had lower resting lung volumes and higher ventilation inhomogeneity when lying supine than that with seated. The magnitude of the influence of posture on outcomes of ventilation distribution was larger in children with CF than those with healthy children. In addition, associations between outcomes of ventilation distribution and structural lung disease on chest CT were improved when MBW was performed in the supine position. These data may have important implications for the interpretation of MBW data and structure-function relationships in individuals with CF.
We found that FRC was significantly lower in the supine posture than in the seated posture in both healthy children and children with CF. These data support numerous previous studies that have reported lower resting lung volumes when recumbent than those when seated or standing [11–14,24,25]. The decreased FRC is primarily thought to be due to the imposition of the diaphragm into the thoracic cavity, the increase in blood volume into gravity dependent areas of the lung, and the weight of the heart on dorsal pulmonary structures [26,27]. Compared with the seated posture, FRC was reduced by around 20% in the supine position in both the children with CF and healthy children, which is similar to the magnitude reported in previous studies [26,28]. We also found an increase in the heterogeneity of ventilation distribution in the lungs of healthy children and children with CF. We reported significantly higher LCI and moment ratio values in the supine vs. seated postures, which support previous studies [11,12,15]. Together these data indicate that in the supine position inspired gas is distributed less evenly throughout the lungs. This can most likely be explained by the decreased lung volume resulting in changes in lung compliance and time constants within the lung [15]. However, the magnitude of the effect of posture on ventilation distribution was larger in children
Table 3 Associations between MBW outcomes and structural lung disease in children with cystic fibrosis. %disease
%trapped air
%bronchiectasis
Seated posture Functional residual capacity Lung clearance index Moment ratio 1 (M1/M0) Moment ratio 2 (M2/M0)
0.03 (0.01, 0.06); p = 0.14 0.10 (0.02, 0.19); p = 0.02 0.02 (0.005, 0.04); p = 0.01 0.19 (0.02, 0.35); p = 0.03
0.01 0.06 0.01 0.10
(0.002, 0.03); p = 0.03 (0.02, 0.10); p b 0.01 (0.003, 0.02); p = 0.01 (0.03, 0.18); p = 0.01
0.06 (0.02, 0.11) p b 0.01 0.16 (-0.02, 0.34) p = 0.07 0.03 (-0.001, 0.07) p = 0.05 0.29 (-0.05, 0.63) p = 0.09
Supine posture Functional residual capacity Lung clearance index Moment ratio 1 (M1/M0) Moment ratio 2 (M2/M0)
0.03 (0.01, 0.05); p 0.17 (0.05, 0.29); p 0.03 (0.01, 0.06); p 0.39 (0.09, 0.69); p
0.01 (0.003, 0.02); p = 0.01 0.06 (0.003, 0.13); p = 0.04 0.02 (0.001, 0.03); p = 0.04 0.17 (0.01, 0.32); p = 0.04
0.06 (0.02, 0.09); p b 0.01 0.25 (-0.02, 0.52); p = 0.06 0.05 (-0.005, 0.11); p = 0.07 0.57 (-0.06, 1.21); p = 0.07
b 0.01 = 0.01 = 0.02 = 0.01
Data are presented as linear regression coefficients, adjusted for age (95% confidence interval, p value). Bold text indicates significant association (p b 0.05). Please cite this article as: Ramsey KA, et al, Effect of posture on lung ventilation distribution and associations with structure in children with cystic fibrosis, J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.01.013
K.A. Ramsey et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx Table 4 Agreement between the presence of bronchiectasis on chest CT and abnormal LCI when measured in the seated or supine posture. Bronchiectasis presence
Seated LCI
Supine LCI
Sensitivity Specificity Positive predictive value Negative predictive value
76% (62, 89) 67% (50, 83) 93% (89, 99) 33% (23, 44)
94% (87, 99) 33% (19, 47) 89% (81, 96) 50% (31, 74)
Data in brackets contain 95% confidence intervals. The upper limit of normal LCI (7.71) was derived from our prospective healthy population [1].
with CF than those with healthy controls despite similar changes in FRC. Similarly, the supine posture was previously shown to increase gas trapping in asthmatic children but not in healthy controls [28]. These data indicate that airway narrowing and closure occur differently in individuals with airway disease and healthy controls. Pulmonary inflammation, abnormal airway mucus, and structural abnormalities in the CF lung can result in airway obstruction, uncoupling of the airways from the parenchyma, and small airway collapse [29]. Our data indicate that the lungs of children with CF are more susceptible to increased ventilation inhomogeneity in the supine posture than healthy children. The association between markers of ventilation distribution and the extent of structural lung disease was stronger when MBW was performed in the supine posture than that in the seated posture. A shift in posture may lead to small airway closure or narrowing at lower lung volumes. Bronchiectasis is thought to be an irreversible CT abnormality, however, it is possible that reduced lung volumes could cause relatively floppy bronchiectatic airways to close or narrow in the supine posture, thus contributing to the increase in ventilation inhomogeneity. Indeed LCI was more sensitive to detect bronchiectasis on chest CT when performed in the supine position (94%) than that in the seated
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position (76%). It is important to note that small airway occlusion can result in lung regions that no longer communicate with the rest of the lung and therefore do not contribute to measurements of ventilation distribution in the lung. This may contribute to why we did not see large differences in MBW-%trapped air associations with posture. These data have implications for the interpretation of structure-function relationships between MBW and chest imaging outcomes. It is possible that supine MBW testing may enhance the sensitivity of the LCI and moment ratios to detect early lung disease. MBW testing is routinely performed on sleeping infants in the supine position. However, previous studies by our group have found no strong associations between LCI and structural lung disease abnormalities on chest CT in infants with CF [10], despite clear associations at preschool and school age [1,7–9]. These data would suggest that this lack of association may be more likely due to the mild lung disease seen in infants with CF [1] rather than methodological differences in MBW testing that occur in the different age groups. In summary, to our knowledge, this is the first study to assess structure function assessments in children with CF in the supine and seated postures. This study was limited to children with relatively mild CF lung disease who were stable at the time of their chest CT scan. We report strengthened associations between MBW outcomes and structural lung disease on chest CT in the supine compared with the seated position. Our data suggests that performing the MBW test in the supine posture may improve structure function associations in individuals with lung disease. Acknowledgements The authors thank the Radiology Department staff for assistance with chest CT scans and Tim Rosenow for scoring the scans. We would like to thank the participants and their families who contribute to the AREST CF program. References
Fig. 2. The influence of posture on associations between lung clearance index and the extent of structural lung disease in children with cystic fibrosis. Black circle symbols represent lung clearance index performed in the seated posture (r2 = 0.19) and red diamond symbols represent lung clearance index performed in the supine posture (r2 = 0.23). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
[1] Ramsey KA, Rosenow T, Turkovic L, Skoric B, Banton G, Adams AM, et al. Lung clearance index and structural lung disease on computed tomography in early cystic fibrosis. Am J Respir Crit Care Med 2016; 193(1):60–7. [2] Belessis Y, Dixon B, Hawkins G, Pereira J, Peat J, MacDonald R, et al. Early cystic fibrosis lung disease detected by bronchoalveolar lavage and lung clearance index. Am J Respir Crit Care Med 2012;185(8):862–73. [3] Lum S, Gustafsson P, Ljungberg H, Hulskamp G, Bush A, Carr SB, et al. Early detection of cystic fibrosis lung disease: multiple-breath washout versus raised volume tests. Thorax 2007;62(4):341–7. [4] Aurora P, Kozlowska W, Stocks J. Gas mixing efficiency from birth to adulthood measured by multiple-breath washout. Respir Physiol Neurobiol 2005;148(1–2):125–39. [5] Aurora P, Stanojevic S, Wade A, Oliver C, Kozlowska W, Lum S, et al. Lung Clearance Index at 4 years predicts subsequent lung function in children with cystic fibrosis. Am J Respir Crit Care Med 2011;183(6):752–8. [6] Aurora P, Gustafsson P, Bush A, Lindblad A, Oliver C, Wallis CE, et al. Multiple breath inert gas washout as a measure of ventilation distribution in children with cystic fibrosis. Thorax 2004;59(12):1068–73. [7] Gustafsson PM, De Jong PA, Tiddens HA, Lindblad A. Multiple-breath inert gas washout and spirometry versus structural lung disease in cystic fibrosis. Thorax 2008;63(2):129–34.
Please cite this article as: Ramsey KA, et al, Effect of posture on lung ventilation distribution and associations with structure in children with cystic fibrosis, J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.01.013
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[8] Ellemunter H, Fuchs SI, Unsinn KM, Freund MC, Waltner-Romen M, Steinkamp G, et al. Sensitivity of Lung Clearance Index and chest computed tomography in early CF lung disease. Respir Med 2010;104(12):1834–42. [9] Owens CM, Aurora P, Stanojevic S, Bush A, Wade A, Oliver C, et al. Lung Clearance Index and HRCT are complementary markers of lung abnormalities in young children with CF. Thorax 2011;66(6):481–8. [10] Hall GL, Logie KM, Parsons F, Schulzke SM, Nolan G, Murray C, et al. Air trapping on chest CT is associated with worse ventilation distribution in infants with cystic fibrosis diagnosed following newborn screening. PLoS One 2011;6(8):e23932. [11] Svanberg L. Influence of posture on the lung volumes, ventilation and circulation in normals; a spirometric-bronchospirometric investigation. Scand J Clin Lab Invest 1957;9(Suppl. 25):1–195. [12] Blair E, Hickam JB. The effect of change in body position on lung volume and intrapulmonary gas mixing in normal subjects. J Clin Invest 1955; 34(3):383–9. [13] Whitfield AG, Waterhouse JA, Arnott WM. The total lung volume and its subdivisions; a study in physiological norms; the effect of posture. Br J Soc Med 1950;4(2):86–97. [14] Hurtado A, Fray WW. Studies of total pulmonary capacity and its subdivisions. Iii. Changes with body posture. J Clin Invest 1933;12(5):825–32. [15] Bouhuys A, van LH. Effect of body posture on gas distribution in the lungs. J Appl Physiol 1962;17:38–42. [16] Singer F, Houltz B, Latzin P, Robinson P, Gustafsson P. A realistic validation study of a new nitrogen multiple-breath washout system. PLoS One 2012;7(4):e36083. [17] Robinson PD, Goldman MD, Gustafsson PM. Inert gas washout: theoretical background and clinical utility in respiratory disease. Respiration 2009; 78(3):339–55. [18] Robinson PD, Latzin P, Verbanck S, Hall GL, Horsley A, Gappa M, et al. Consensus statement for inert gas washout measurement using multipleand single-breath tests. Eur Respir J 2013;41(3):507–22.
[19] Robinson TE, Leung AN, Moss RB, Blankenberg FG, al-Dabbagh H, Northway WH. Standardized high-resolution CT of the lung using a spirometer-triggered electron beam CT scanner. Am J Roentgenol 1999; 172(6):1636–8. [20] Rosenow T, Oudraad MC, Murray CP, Turkovic L, Kuo W, de Bruijne M, et al. PRAGMA-CF: a quantitative structural lung disease CT outcome in young children with cystic fibrosis. Am J Respir Crit Care Med 2015; 191(10):1158–65. [21] de Onis M, Onyango A, Borghi E, Siyam A, Nishida C, Siekmann J. Development of a WHO growth reference for school-aged children and adolescents. Bull World Health Organ 2007;85:661–8. [22] WHO Multicentre Growth Reference Study Group. WHO child growth standards based on length/height, weight and age. Acta Pædiatrica 2006(Suppl. 450):76–85. [23] Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic reference values for spirometry for the 3–95-yr age range: the global lung function 2012 equations. Eur Respir J 2012;40(6):1324–43. [24] McMichael J, McGibbon J. Postural changes in lung volumes. Clin Sci (Lond) 1939;4:175–83. [25] Moreno F, Lyons HA. Effect of body posture on lung volumes. J Appl Physiol 1961;16:27–9. [26] Gronkvist M, Bergsten E, Gustafsson PM. Effects of body posture and tidal volume on inter- and intraregional ventilation distribution in healthy men. J Appl Physiol (1985) 2002;92(2):634–42. [27] Lai-Fook SJ, Rodarte JR. Pleural pressure distribution and its relationship to lung volume and interstitial pressure. J Appl Physiol (1985) 1991;70(3): 967–78. [28] Gustafsson PM. Pulmonary gas trapping increases in asthmatic children and adolescents in the supine position. Pediatr Pulmonol 2003;36(1):34–42. [29] Macklem PT, Proctor DF, Hogg JC. The stability of peripheral airways. Respir Physiol 1970;8(2):191–203.
Please cite this article as: Ramsey KA, et al, Effect of posture on lung ventilation distribution and associations with structure in children with cystic fibrosis, J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.01.013
Journal of Cystic Fibrosis xx (2017) xxx – xxx www.elsevier.com/locate/jcf
Original Article
Effect of posture on lung ventilation distribution and associations with structure in children with cystic fibrosis☆,☆☆ Kathryn A. Ramsey a,b,c , Caroline McGirr a , Stephen M. Stick a,b,d , Graham L. Hall a,b,e,⁎,1 , Shannon J. Simpson a,b,1 , on behalf of AREST CF 2 a Telethon Kids Institute, Subiaco, Western Australia, Australia Centre for Child Health Research, University of Western Australia, Crawley, Western Australia, Australia Cystic Fibrosis Research and Treatment Centre, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA d Respiratory Medicine, Princess Margaret Hospital for Children, Subiaco, Western Australia, Australia e School of Physiotherapy and Exercise Science, Curtin University, Bentley, Western Australia, Australia b
c
Received 21 October 2016; revised 23 January 2017; accepted 24 January 2017 Available online xxxx
Abstract Background: We assessed the effect of posture on ventilation distribution and the impact on associations with structural lung disease. Methods: Multiple breath washout (MBW) was performed in seated and supine postures in 25 healthy children and 21 children with CF. Children with CF also underwent a chest CT scan. Functional residual capacity (FRC), lung clearance index (LCI) and moment ratios were calculated from the MBW test. CT scans were evaluated for CF-related structural lung disease. Results: FRC was lower in the supine than in the seated posture, whereas LCI was higher in the supine than in the seated posture. In children with CF, associations between LCI and the extent of structural lung disease were stronger when performed in the supine posture. Conclusions: Body posture influences lung volumes and ventilation distribution in both healthy children and children with CF. MBW testing in the supine posture strengthened associations with structural lung damage. © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Keywords: Multiple breath washout; Lung clearance index; Computed tomography; Cystic fibrosis; Child; Posture; Ventilation distribution
☆ Author contributions: KAR performed the literature search, data collection, data analysis, data interpretation, and manuscript writing. CG contributed to data collection, data analysis, data interpretation and manuscript writing. SJS, SMS and GLH contributed to the literature search, were responsible for study design and oversaw the data analysis, data interpretation, and manuscript writing. GLH takes final responsibility for the data and study. ☆☆ Funding: Funding for the AREST CF program was obtained from the Cystic Fibrosis Foundation Therapeutics (SLY04A0, STICK09A0), the National Health and Medical Research Council of Australia (NHMRC; APP513730 and Centre of Research Excellence #1000896) and University of Western Australia (Research Development Award). K Ramsey (APP1088389), G Hall (APP 1025550) and S Simpson (APP1073301) are NHMRC Research Fellows. ⁎ Corresponding author at: Children's Lung Health, Telethon Kids Institute, 100 Roberts Road, Subiaco, WA 6008, Australia. E-mail address: [email protected] (G.L. Hall). 1 These authors jointly contributed as senior authors. 2 The full membership of the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) is available at http://www.arestcf.org.
1. Introduction Multiple breath inert gas washout (MBW) tests measure the efficiency of ventilation distribution by measuring the rate of clearance of a marker gas from the lungs. The MBW test involves tidal breathing of a marker gas that can either be a resident gas (e.g. nitrogen) or inert gas (e.g. sulphur hexafluoride). As a tidal breathing test MBW is feasible across the entire pediatric age range [1]. Infant MBW testing typically involves the use of inert gases with the infant sleeping in a supine position with or without sedation. Assessments of MBW in older children are performed awake, in a seated position with video distraction used to promote relaxed breathing. The lung clearance index (LCI) is a marker of global ventilation distribution derived from the MBW test. LCI is elevated
http://dx.doi.org/10.1016/j.jcf.2017.01.013 1569-1993/© 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Please cite this article as: Ramsey KA, et al, Effect of posture on lung ventilation distribution and associations with structure in children with cystic fibrosis, J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.01.013
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in infant [2,3], preschool [4,5] and school-aged [6,7] children with CF. Lung clearance index offers a non-invasive method to monitor structural lung damage in early CF lung disease. Previous studies have shown that LCI in school-aged children with CF is more sensitive than spirometry to detect structural lung damage evident on chest computed tomography (CT) [7–9]. Our group has shown that LCI and moment ratios significantly correlate with the extent of structural lung disease on CT in preschool and school-aged children with CF, but there are only weak correlations between LCI and structural lung disease in infants with CF [1,10]. One factor that may influence the association between ventilation distribution and CT outcomes is posture. Functional residual volume (FRC) decreases when changing from an upright sitting to the supine posture in healthy adults [11–14] and postural changes in FRC are accompanied by changes in ventilation distribution [11,15]. However, we know little about how posture influences ventilation distribution in individuals with lung disease and how this influences relationships with lung imaging. In this study we assessed the effect of posture on ventilation distribution in healthy children and children with CF, and the impact of posture on the associations between markers of ventilation distribution and structural lung disease on chest CT in children with CF. 2. Methods 2.1. Study population School-aged children with CF undergoing chest CT imaging as part of their annual review or when clinically indicated at Princess Margaret Hospital (PMH) in Perth were recruited to perform lung function testing on the day of their scan. Due to the time and energy required to perform the study protocol, children with CF with exacerbated respiratory symptoms, such as productive moist cough, did not participate in the study. Children with no parentally reported history of respiratory disease, preterm birth or current respiratory symptoms or medication were recruited to perform MBW testing only. The PMH ethics committee approved the study, and participants and their parents consented to each aspect of the study separately. 2.2. Multiple breath washout MBW was performed using 100% oxygen to washout resident nitrogen from the lungs (Exhalyzer D; Spiroware 3.1 software; Ecomedics AG, Dürnten, Switzerland) as described previously [16]. The washout curve was used to generate FRC, LCI, the first moment ratio (M1/M0) and second moment ratio (M2/M0). LCI is the number of lung turnovers required to wash out an inert tracer gas to 1/40th of its starting concentration and is calculated by dividing the cumulative net expired volume by the FRC. Moment ratios describe the degree of skewness of the washout curve. Increased moment ratios represent an increased release of inert gas towards the end of the washout [17]. Test sessions with at least two acceptable measurements with no evidence of leak or irregular breathing pattern were included
in this analysis according to the current consensus statement [18]. The MBW test was performed in both the standard seated (seated on a chair) and supine (lying supine on a bed) postures, performed in a random order with 5 min in the test posture before the MBW test commenced. 2.3. Chest CT scans Children with CF underwent a spirometry-assisted volumetric helical inspiratory and expiratory chest CT scan [19]. An experienced respiratory scientist trained children to perform the breathing manoeuvres for the chest CT scan using a portable spirometer. For the inspiratory scan children were instructed to take a full inspiration to total lung capacity from residual volume and breath-hold for 5 s. For the expiratory chest CT scan children were instructed to slowly exhale to residual volume from total lung capacity and breath-hold for 5 s. Inspiratory and expiratory chest CT scans were initiated once 90% of the target vital capacity (best repeatable vital capacity value from the training) was reached. Children in the healthy control group did not complete a chest CT scan. 2.4. Quantitative CT scoring To assess CT-determined structural lung disease, the quantitative Perth-Rotterdam Annotated Grid Morphometric Analysis for Cystic Fibrosis (PRAGMA-CF) scoring method was used [20]. Briefly, in this method, a grid overlaid on 10 equidistant axial slices is annotated for the presence of bronchiectasis (outer-edge bronchus–artery cross-sectional area ratio N 1), mucus plugging (high-density airway occlusion or tree-in-bud appearance), bronchial wall thickening (assessed subjectively as airway walls that are thicker than or have increased signal density relative to normal airways) visualized on inspiratory scans, and trapped air (geographic low-density regions) seen on expiratory scans [20]. The extents (represented as volume proportions of the lung) of total airway disease (%disease), bronchiectasis (%bronchiectasis), and trapped air (%trapped air) were calculated. 2.5. Statistical analysis The upper limit of normal MBW indices was calculated based on our previously published data from a prospective healthy control population of children (n = 72) [1]. The upper limits of normal LCI was 7.71, M1/M0 1.70, and M2/M0 5.53. Height and weight z-scores were calculated using WHO growth standards [21,22]. FEV1 z-scores were calculated using Global Lung Initiative reference equations [23]. Differences in mean MBW outcomes between healthy children and children with CF were determined using independent sample two-tailed t-test. Differences in MBW outcomes with changes in posture in the same individual were determined used paired sample two-tailed t-test. Associations between MBW outcomes and chest CT outcomes were determined using linear regression models adjusted for age. To determine if posture influenced associations between MBW and CT outcomes, we generated interaction
Please cite this article as: Ramsey KA, et al, Effect of posture on lung ventilation distribution and associations with structure in children with cystic fibrosis, J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.01.013
K.A. Ramsey et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx
terms by multiplying the categorical posture variable (0 or 1) by the continuous CT variables (% disease, % air trapping, % bronchiectasis). We included the interaction terms in the linear regression models along with each of the individual independent variables. A significant interaction term in the linear regression model indicated that posture influenced associations between MBW and CT outcomes. Sensitivity, specificity, and positive and negative predictive values for an abnormal LCI to detect the presence of bronchiectasis on CT were calculated. Mean data are presented with either the standard deviation or 95% confidence interval. All statistical analyses were performed using SPSS (version 22, Chicago, IL, USA).
3. Results 3.1. Study population Matched seated and supine MBW data were available in 46 children, including 25 healthy controls and 21 children with CF (Table 1). Children with CF also had a chest CT within the same week of performing MBW testing. There were no differences in age, height, or weight between healthy children and children with CF (p N 0.05). The FRC, LCI and moment ratios in both seated and supine postures were significantly higher in children with CF than those with healthy controls.
Table 1 Demographics of study population.
Number of children Sex (male) Age (years) Height (cm) Height z-score (95% CI) Weight (kg) Weight z-score (95% CI) FEV1 z-score (95% CI) Seated posture Functional residual capacity (FRC: L) Lung clearance index (LCI) Moment ratio 1 (M1/M0) Moment ratio 2 (M2/M0) Supine posture Functional residual capacity (FRC: L) Lung clearance index (LCI) Moment ratio 1 (M1/M0) Moment ratio 2 (M2/M0) Structural lung disease Disease (%) Air trapping presence Air trapping (%) Bronchiectasis presence Bronchiectasis (%)
Healthy
CF
25 13 (52%) 11.1 ± 1.6 148.0 ± 9.5 0.45 (0.18, 0.71) 40.1 ± 9.2 0.27 (-0.01, 0.55) 0.01 (-0.49, 0.50)
21 13 (62%) 12.1 ± 1.7 148.8 ± 11.9 -0.25 (-0.67, 0.18) 42.7 ± 10.7 -0.03 (-0.43, 0.37) -0.17 (-0.74, 0.40)
1.62 7.00 1.59 5.04
± ± ± ±
0.30 0.49 0.11 0.67
1.80 8.87 1.94 8.18
1.23 7.46 1.67 5.78
± ± ± ±
0.21 0.51 0.10 0.79
1.48 ± 0.45 ⁎ 10.73 ± 2.87 ⁎ 2.28 ± 0.59 ⁎ 12.13 ± 6.59 ⁎
± ± ± ±
0.58 ⁎ 1.77 ⁎ 0.35 ⁎ 3.25 ⁎
6.1 ± 8.2 20/21 (95%) 21.5 ± 16.5 14/21 (67%) 2.4 ± 4.2
Data presented as n (percentage) or mean ± standard deviation or 95% confidence interval. Height and weight z-scores were calculated using WHO growth standards [21,22]. FEV1 z-scores were calculated using Global Lung Initiative reference equations [23]. ⁎ Indicates that values are significantly different to healthy controls (p b 0.05).
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3.2. Effect of posture on MBW outcomes We examined the effect of posture on MBW outcomes in children with CF and healthy controls (Table 2; Fig. 1). In both healthy children and children with CF, FRC was lower in the supine posture than in the seated posture. In contrast, outcomes of ventilation distribution from the MBW test were significantly higher in the supine posture than in the seated posture in both healthy children and children with CF. The magnitude of the difference in LCI between seated vs. supine postures was higher in children with CF (21% difference) than those with healthy controls (7% difference). In addition, the magnitude of difference in moment ratios between supine vs. seated postures was higher in children with CF (M1/M0: 18%, M2/M0: 48%) than those with healthy controls (M1/M0: 5%, M2/M0: 15%). Performing the MBW test in different postures changed the proportion of children with abnormal outcomes in both healthy children and children with CF. The proportion of children with an abnormal LCI increased in healthy children from 4% in the seated posture to 24% in the supine posture, and children with CF from 71% to 90%, when compared with reference data collected in the seated posture. 3.3. Impact of posture on associations between MBW and chest CT outcomes We examined the associations between seated and supine MBW outcomes and chest CT outcomes in children with CF (Table 3). There were significant associations between FRCseated and the extent of air trapping and bronchiectasis, and FRC-supine and the extent of air trapping, bronchiectasis, and total disease extent. In both the seated and supine postures, LCI and moment ratios were associated with the extent of air trapping and total disease, but not the extent of bronchiectasis. To determine if posture influenced associations between MBW (LCI and moment ratios) and CT outcomes, interaction terms between posture and CT outcomes were included in the linear regression models. Significant interactions were found between Table 2 Effect of posture on MBW outcomes. Supine posture–seated posture Mean difference (95% CI)
p value
Absolute change
Percent change
Healthy children Functional residual capacity (L) Lung clearance index Moment ratio 1 (M1/M0) Moment ratio 2 (M2/M0)
-0.39 (-0.31, -0.47) 0.46 (0.23, 0.70) 0.08 (0.02, 0.15) 0.74 (0.36, 1.13)
-24% (-19, -29) 7% (3, 10) 5% (1, 9) 15% (7, 22)
b 0.001 0.001 0.02 0.001
Children with cystic fibrosis Functional residual capacity (L) Lung clearance index Moment ratio 1 (M1/M0) Moment ratio 2 (M2/M0)
-0.33 (-0.22, -0.43) 1.86 (1.20, 2.53) 0.34 (0.20, 0.49) 3.95 (2.14, 5.76)
-18% (-12, -24) 21% (14, 29) 18% (10, 25) 48% (26, 70)
b 0.001 b 0.001 b 0.001 b 0.001
Mean difference in multiple breath washout outcomes between supine and seated postures (i.e. supine value–seated value). Percentage difference expressed relative to seated values. 95% CI = 95% confidence interval.
Please cite this article as: Ramsey KA, et al, Effect of posture on lung ventilation distribution and associations with structure in children with cystic fibrosis, J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.01.013
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K.A. Ramsey et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx
Fig. 1. Influence of posture on functional residual capacity (FRC) and lung clearance index (LCI). Healthy children are represented by black circle symbols and children with cystic fibrosis are represented by red square symbols. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
posture-%disease and posture-%trapped air (p b 0.05), but not posture-%bronchiectasis. However, LCI was more sensitive to detect the presence of bronchiectasis on chest CT when performed supine than that with seated (Table 4). The association between LCI and the extent of structural lung disease was stronger when MBW was performed in the supine posture than that in the seated posture (Fig. 2). 4. Discussion The objective of this study was to investigate whether performing the MBW in the same plane as the chest CT would improve the structure-function relationship between the two measures of lung disease in children with CF. We found that children had lower resting lung volumes and higher ventilation inhomogeneity when lying supine than that with seated. The magnitude of the influence of posture on outcomes of ventilation distribution was larger in children with CF than those with healthy children. In addition, associations between outcomes of ventilation distribution and structural lung disease on chest CT were improved when MBW was performed in the supine position. These data may have important implications for the interpretation of MBW data and structure-function relationships in individuals with CF.
We found that FRC was significantly lower in the supine posture than in the seated posture in both healthy children and children with CF. These data support numerous previous studies that have reported lower resting lung volumes when recumbent than those when seated or standing [11–14,24,25]. The decreased FRC is primarily thought to be due to the imposition of the diaphragm into the thoracic cavity, the increase in blood volume into gravity dependent areas of the lung, and the weight of the heart on dorsal pulmonary structures [26,27]. Compared with the seated posture, FRC was reduced by around 20% in the supine position in both the children with CF and healthy children, which is similar to the magnitude reported in previous studies [26,28]. We also found an increase in the heterogeneity of ventilation distribution in the lungs of healthy children and children with CF. We reported significantly higher LCI and moment ratio values in the supine vs. seated postures, which support previous studies [11,12,15]. Together these data indicate that in the supine position inspired gas is distributed less evenly throughout the lungs. This can most likely be explained by the decreased lung volume resulting in changes in lung compliance and time constants within the lung [15]. However, the magnitude of the effect of posture on ventilation distribution was larger in children
Table 3 Associations between MBW outcomes and structural lung disease in children with cystic fibrosis. %disease
%trapped air
%bronchiectasis
Seated posture Functional residual capacity Lung clearance index Moment ratio 1 (M1/M0) Moment ratio 2 (M2/M0)
0.03 (0.01, 0.06); p = 0.14 0.10 (0.02, 0.19); p = 0.02 0.02 (0.005, 0.04); p = 0.01 0.19 (0.02, 0.35); p = 0.03
0.01 0.06 0.01 0.10
(0.002, 0.03); p = 0.03 (0.02, 0.10); p b 0.01 (0.003, 0.02); p = 0.01 (0.03, 0.18); p = 0.01
0.06 (0.02, 0.11) p b 0.01 0.16 (-0.02, 0.34) p = 0.07 0.03 (-0.001, 0.07) p = 0.05 0.29 (-0.05, 0.63) p = 0.09
Supine posture Functional residual capacity Lung clearance index Moment ratio 1 (M1/M0) Moment ratio 2 (M2/M0)
0.03 (0.01, 0.05); p 0.17 (0.05, 0.29); p 0.03 (0.01, 0.06); p 0.39 (0.09, 0.69); p
0.01 (0.003, 0.02); p = 0.01 0.06 (0.003, 0.13); p = 0.04 0.02 (0.001, 0.03); p = 0.04 0.17 (0.01, 0.32); p = 0.04
0.06 (0.02, 0.09); p b 0.01 0.25 (-0.02, 0.52); p = 0.06 0.05 (-0.005, 0.11); p = 0.07 0.57 (-0.06, 1.21); p = 0.07
b 0.01 = 0.01 = 0.02 = 0.01
Data are presented as linear regression coefficients, adjusted for age (95% confidence interval, p value). Bold text indicates significant association (p b 0.05). Please cite this article as: Ramsey KA, et al, Effect of posture on lung ventilation distribution and associations with structure in children with cystic fibrosis, J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.01.013
K.A. Ramsey et al. / Journal of Cystic Fibrosis xx (2017) xxx–xxx Table 4 Agreement between the presence of bronchiectasis on chest CT and abnormal LCI when measured in the seated or supine posture. Bronchiectasis presence
Seated LCI
Supine LCI
Sensitivity Specificity Positive predictive value Negative predictive value
76% (62, 89) 67% (50, 83) 93% (89, 99) 33% (23, 44)
94% (87, 99) 33% (19, 47) 89% (81, 96) 50% (31, 74)
Data in brackets contain 95% confidence intervals. The upper limit of normal LCI (7.71) was derived from our prospective healthy population [1].
with CF than those with healthy controls despite similar changes in FRC. Similarly, the supine posture was previously shown to increase gas trapping in asthmatic children but not in healthy controls [28]. These data indicate that airway narrowing and closure occur differently in individuals with airway disease and healthy controls. Pulmonary inflammation, abnormal airway mucus, and structural abnormalities in the CF lung can result in airway obstruction, uncoupling of the airways from the parenchyma, and small airway collapse [29]. Our data indicate that the lungs of children with CF are more susceptible to increased ventilation inhomogeneity in the supine posture than healthy children. The association between markers of ventilation distribution and the extent of structural lung disease was stronger when MBW was performed in the supine posture than that in the seated posture. A shift in posture may lead to small airway closure or narrowing at lower lung volumes. Bronchiectasis is thought to be an irreversible CT abnormality, however, it is possible that reduced lung volumes could cause relatively floppy bronchiectatic airways to close or narrow in the supine posture, thus contributing to the increase in ventilation inhomogeneity. Indeed LCI was more sensitive to detect bronchiectasis on chest CT when performed in the supine position (94%) than that in the seated
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position (76%). It is important to note that small airway occlusion can result in lung regions that no longer communicate with the rest of the lung and therefore do not contribute to measurements of ventilation distribution in the lung. This may contribute to why we did not see large differences in MBW-%trapped air associations with posture. These data have implications for the interpretation of structure-function relationships between MBW and chest imaging outcomes. It is possible that supine MBW testing may enhance the sensitivity of the LCI and moment ratios to detect early lung disease. MBW testing is routinely performed on sleeping infants in the supine position. However, previous studies by our group have found no strong associations between LCI and structural lung disease abnormalities on chest CT in infants with CF [10], despite clear associations at preschool and school age [1,7–9]. These data would suggest that this lack of association may be more likely due to the mild lung disease seen in infants with CF [1] rather than methodological differences in MBW testing that occur in the different age groups. In summary, to our knowledge, this is the first study to assess structure function assessments in children with CF in the supine and seated postures. This study was limited to children with relatively mild CF lung disease who were stable at the time of their chest CT scan. We report strengthened associations between MBW outcomes and structural lung disease on chest CT in the supine compared with the seated position. Our data suggests that performing the MBW test in the supine posture may improve structure function associations in individuals with lung disease. Acknowledgements The authors thank the Radiology Department staff for assistance with chest CT scans and Tim Rosenow for scoring the scans. We would like to thank the participants and their families who contribute to the AREST CF program. References
Fig. 2. The influence of posture on associations between lung clearance index and the extent of structural lung disease in children with cystic fibrosis. Black circle symbols represent lung clearance index performed in the seated posture (r2 = 0.19) and red diamond symbols represent lung clearance index performed in the supine posture (r2 = 0.23). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
[1] Ramsey KA, Rosenow T, Turkovic L, Skoric B, Banton G, Adams AM, et al. Lung clearance index and structural lung disease on computed tomography in early cystic fibrosis. Am J Respir Crit Care Med 2016; 193(1):60–7. [2] Belessis Y, Dixon B, Hawkins G, Pereira J, Peat J, MacDonald R, et al. Early cystic fibrosis lung disease detected by bronchoalveolar lavage and lung clearance index. Am J Respir Crit Care Med 2012;185(8):862–73. [3] Lum S, Gustafsson P, Ljungberg H, Hulskamp G, Bush A, Carr SB, et al. Early detection of cystic fibrosis lung disease: multiple-breath washout versus raised volume tests. Thorax 2007;62(4):341–7. [4] Aurora P, Kozlowska W, Stocks J. Gas mixing efficiency from birth to adulthood measured by multiple-breath washout. Respir Physiol Neurobiol 2005;148(1–2):125–39. [5] Aurora P, Stanojevic S, Wade A, Oliver C, Kozlowska W, Lum S, et al. Lung Clearance Index at 4 years predicts subsequent lung function in children with cystic fibrosis. Am J Respir Crit Care Med 2011;183(6):752–8. [6] Aurora P, Gustafsson P, Bush A, Lindblad A, Oliver C, Wallis CE, et al. Multiple breath inert gas washout as a measure of ventilation distribution in children with cystic fibrosis. Thorax 2004;59(12):1068–73. [7] Gustafsson PM, De Jong PA, Tiddens HA, Lindblad A. Multiple-breath inert gas washout and spirometry versus structural lung disease in cystic fibrosis. Thorax 2008;63(2):129–34.
Please cite this article as: Ramsey KA, et al, Effect of posture on lung ventilation distribution and associations with structure in children with cystic fibrosis, J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.01.013
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[8] Ellemunter H, Fuchs SI, Unsinn KM, Freund MC, Waltner-Romen M, Steinkamp G, et al. Sensitivity of Lung Clearance Index and chest computed tomography in early CF lung disease. Respir Med 2010;104(12):1834–42. [9] Owens CM, Aurora P, Stanojevic S, Bush A, Wade A, Oliver C, et al. Lung Clearance Index and HRCT are complementary markers of lung abnormalities in young children with CF. Thorax 2011;66(6):481–8. [10] Hall GL, Logie KM, Parsons F, Schulzke SM, Nolan G, Murray C, et al. Air trapping on chest CT is associated with worse ventilation distribution in infants with cystic fibrosis diagnosed following newborn screening. PLoS One 2011;6(8):e23932. [11] Svanberg L. Influence of posture on the lung volumes, ventilation and circulation in normals; a spirometric-bronchospirometric investigation. Scand J Clin Lab Invest 1957;9(Suppl. 25):1–195. [12] Blair E, Hickam JB. The effect of change in body position on lung volume and intrapulmonary gas mixing in normal subjects. J Clin Invest 1955; 34(3):383–9. [13] Whitfield AG, Waterhouse JA, Arnott WM. The total lung volume and its subdivisions; a study in physiological norms; the effect of posture. Br J Soc Med 1950;4(2):86–97. [14] Hurtado A, Fray WW. Studies of total pulmonary capacity and its subdivisions. Iii. Changes with body posture. J Clin Invest 1933;12(5):825–32. [15] Bouhuys A, van LH. Effect of body posture on gas distribution in the lungs. J Appl Physiol 1962;17:38–42. [16] Singer F, Houltz B, Latzin P, Robinson P, Gustafsson P. A realistic validation study of a new nitrogen multiple-breath washout system. PLoS One 2012;7(4):e36083. [17] Robinson PD, Goldman MD, Gustafsson PM. Inert gas washout: theoretical background and clinical utility in respiratory disease. Respiration 2009; 78(3):339–55. [18] Robinson PD, Latzin P, Verbanck S, Hall GL, Horsley A, Gappa M, et al. Consensus statement for inert gas washout measurement using multipleand single-breath tests. Eur Respir J 2013;41(3):507–22.
[19] Robinson TE, Leung AN, Moss RB, Blankenberg FG, al-Dabbagh H, Northway WH. Standardized high-resolution CT of the lung using a spirometer-triggered electron beam CT scanner. Am J Roentgenol 1999; 172(6):1636–8. [20] Rosenow T, Oudraad MC, Murray CP, Turkovic L, Kuo W, de Bruijne M, et al. PRAGMA-CF: a quantitative structural lung disease CT outcome in young children with cystic fibrosis. Am J Respir Crit Care Med 2015; 191(10):1158–65. [21] de Onis M, Onyango A, Borghi E, Siyam A, Nishida C, Siekmann J. Development of a WHO growth reference for school-aged children and adolescents. Bull World Health Organ 2007;85:661–8. [22] WHO Multicentre Growth Reference Study Group. WHO child growth standards based on length/height, weight and age. Acta Pædiatrica 2006(Suppl. 450):76–85. [23] Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic reference values for spirometry for the 3–95-yr age range: the global lung function 2012 equations. Eur Respir J 2012;40(6):1324–43. [24] McMichael J, McGibbon J. Postural changes in lung volumes. Clin Sci (Lond) 1939;4:175–83. [25] Moreno F, Lyons HA. Effect of body posture on lung volumes. J Appl Physiol 1961;16:27–9. [26] Gronkvist M, Bergsten E, Gustafsson PM. Effects of body posture and tidal volume on inter- and intraregional ventilation distribution in healthy men. J Appl Physiol (1985) 2002;92(2):634–42. [27] Lai-Fook SJ, Rodarte JR. Pleural pressure distribution and its relationship to lung volume and interstitial pressure. J Appl Physiol (1985) 1991;70(3): 967–78. [28] Gustafsson PM. Pulmonary gas trapping increases in asthmatic children and adolescents in the supine position. Pediatr Pulmonol 2003;36(1):34–42. [29] Macklem PT, Proctor DF, Hogg JC. The stability of peripheral airways. Respir Physiol 1970;8(2):191–203.
Please cite this article as: Ramsey KA, et al, Effect of posture on lung ventilation distribution and associations with structure in children with cystic fibrosis, J Cyst Fibros (2017), http://dx.doi.org/10.1016/j.jcf.2017.01.013