- Email: [email protected]
Lung Volume and Ventilation Inhomogeneity in Preterm Infants at 15-18 Months Corrected Age
Lung Volume and Ventilation Inhomogeneity in Preterm Infants at 15-18 Months Corrected Age Sven M. Schulzke, MD, Graham L. Hall, PhD, Elizabeth A. Nathan, BSc, Karen Simmer, MD, PhD, Gary Nolan, MSc, and J. Jane Pillow, MD, PhD Objective To assess whether lung volume and ventilation inhomogeneity in preterm infants at 15-18 months corrected age, and the change in these outcomes from the newborn period to 15-18 months corrected age, depend on gestational age (GA) at birth and the severity of neonatal lung disease. Study design Preterm (GA range, 23-32 weeks) and term healthy control infants were studied in quiet sedated sleep at 15-18 months corrected age by multiple breath washout with 5% sulfur hexafluoride using an ultrasonic flowmeter. Valid measurements were obtained from 58 infants. Multivariate and multilevel regression was used to analyze outcomes. Results Functional residual capacity (FRC), lung clearance index, and first and second to zeroeth moment ratios were calculated. After accounting for body size at test, FRC at follow-up, and the increase in FRC from the newborn period to 15-18 months corrected age were positively associated with GA and negatively associated with the duration of endotracheal ventilation. Indices of ventilation inhomogeneity were unaltered by GA and the duration of endotracheal ventilation. Conclusions In very preterm infants, GA and the duration of endotracheal ventilation are independently associated with reduced lung volume and lung growth during infancy, although the effect size of these findings is small. (J Pediatr 2010;156:542-9). mpaired lung development in preterm infants is characterized by poor alveolarization and abnormal vasculogenesis.1 Although improved ventilatory strategies, better nursing techniques, and the use of prenatal corticosteroids and postnatal surfactant have increased the survival of extremely preterm infants, the incidence of bronchopulmonary dysplasia (BPD) remains high.2 Recent studies in preterm neonates indicate low lung volume and elevated indices of ventilation inhomogeneity (ie, poor gas mixing efficiency) attributable to the degree of preterm birth3 and neonatal lung disease (NLD).4,5 Follow-up investigations from the 1980s and 1990s suggested normalized or elevated lung volume in preterm infants at the end of the first year of life6-8 and increased residual volume/total lung capacity at school age.9 The long-term effects of the degree of prematurity and NLD on lung volume and ventilation inhomogeneity in contemporary cohorts of preterm infants are unknown. Functional residual capacity (FRC) is the only static lung volume that can be readily assessed in spontaneously breathing infants. The multiple-breath inert gas washout (MBW) technique has gained popularity due to its potential for simultaneous evaluation of FRC and ventilation inhomogeneity.10,11 A commercially available mainstream ultrasonic flowmeter12 has been used to measure FRC and ventilation inhomogeneity in spontaneously breathing infants13-15 and children.16 The in vitro14,17 and in vivo13 accuracy of FRC measured by the mainstream ultrasonic flowmeter has been confirmed. We aimed to measure FRC and indices of ventilation inhomogeneity at 15-18 months corrected age in preterm infants with and without BPD and term healthy control infants. This study includes infants (King Edward Memorial Hospital cohort) who underwent MBW studies in the neonatal period and who were included in a recently reported multicenter cohort.5 Low FRC and increased ventilation inhomogeneity in the neonatal period were attributable to the degree of preterm birth (gestational age [GA]) and NLD. Our objectives were to assess whether GA and NLD have a persistent influence on FRC and ventilation inhomogeneity at 15-18 months corrected age and also on the changes in these variables from the neonatal period. We hypothesized that after adjusting for body size, FRC would be positively associated with GA and negatively associated with NLD. We anticipated that indices of ventilation inhomogeneity would show negative associations with GA and positive associations with NLD. From the School of Women’s and Infant’s Health (S.S., K.S., J.P.) and School of Paediatrics and Child Health Some results of this study have been reported previously in abstract form.18 (G.H., K.S., G.N.), University of Western Australia, Perth,
I
BMI BPD FRC GA LCI M1/M0 M2/M0
Body mass index Bronchopulmonary dysplasia Functional residual capacity Gestational age Lung clearance index First to zeroeth moment ratio Second to zeroeth moment ratio
MV NLD PMA RDS RR VT
Minute volume Neonatal lung disease Postmenstrual age Respiratory distress syndrome Respiratory rate Tidal volume
Australia; Department of Neonatal Paediatrics (S.S., K.S.) and Department of Respiratory Medicine (G.H., G.N.) Princess Margaret and King Edward Memorial Hospitals, Perth, Australia; and Women and Infants Research Foundation, King Edward Memorial Hospital, Perth, Australia (E.N.) Supported by a PMH Telethon Clinical Research Fellowship Grant (to S.M.S.), a PMH Research Foundation Grant (to G.L.H.), and a Raine Foundation Priming Grant (to J.J.P.). The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright Ó 2010 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2009.10.017
542
Vol. 156, No. 4 April 2010
Methods This study was designed as a prospective follow-up study of infant lung function at 15-18 months corrected age. The study design was approved by the Women’s and Children’s Health Service Research Ethics Committee. Written informed parental consent was obtained before enrollment. Infants born at King Edward Memorial Hospital (KEMH) in Perth, Western Australia, between April 2005 and September 2006 were recruited for lung function studies at 15-18 months corrected age (i.e., 15-18 months after the expected delivery date). Most of the infants in this local follow-up study had participated in a multicenter study that reported the effects of body size, GA, and indices of NLD on FRC and ventilation inhomogeneity in the newborn period.5 The present study reports local cross-sectional data at follow-up (n = 58) and longitudinal changes in lung function in the local subset of infants who had valid paired measurements in the neonatal period and at 15-18 months corrected age (n = 42). Preterm infants (230-326 weeks GA) with respiratory distress syndrome (RDS) with and without subsequent BPD were eligible for a follow-up study. Term healthy control infants of 370-420 weeks GA also were eligible. An attempt was made to increase the sample size at follow-up by recruiting additional preterm infants with BPD who were not well enough to be studied in the multicenter study in the newborn period (Figure 1). The diagnosis of RDS was based on the presence of prematurity, clinical and radiologic signs of respiratory distress, and the need for supplemental oxygen. All infants of < 28 weeks GA received prophylactic surfactant; preterm infants of $ 28 weeks GA received surfactant if they required intubation for RDS (with the decision of whether or not to intubate left to the discretion of the attending neonatologist). Ventilation strategy (BabyLog 8000+; Draeger Medical, Luebeck, Germany) aimed at ‘‘gentle ventilation’’ and included the following principles: limiting tidal volume (VT) to 4-6 mL kg1 body weight (‘‘volume-guarantee’’ mode), allowing for mild permissive hypercapnia, supporting each respiratory effort by assist-control or pressure support ventilation, and keeping positive end-expiratory pressure at 5-6 cmH2O to avoid atelectasis. Five infants with severe NLD received low-dose dexamethasone (cumulative dose, 0.89 mg/kg over 10 days) after 21 days of life, to facilitate extubation. Exclusion criteria included cardiopulmonary, neuromuscular, or any other significant congenital disease. Clinical and demographic data were recorded from hospital notes and parental questionnaires. Weight and length at the time of testing were measured using standardized methods.19 Sexspecific z-scores were calculated based on postnatal age and were adjusted for prematurity using the 1990 British Growth Reference Curves.20 BPD was defined as the need for supplemental oxygen or assisted ventilation at 36 weeks postmenstrual age (PMA),21 using a target oxygen saturation range of 86%-94%.
Lung Function Tests Measurements were performed in clinically stable children without respiratory infection in the 3 weeks before the test, with the patient in the supine position on one testing occasion. Sleep was induced by oral administration of chloral hydrate 70-100 mg kg1. Heart rate and oxygen saturation were monitored continuously by pulse oximetry (model N-200; Nellcor, Hayward, California). MBW was performed using 5% sulfur hexafluoride (SF6) as a tracer gas, a commercially available ultrasonic flowmeter (Ecomedics AG, Duernten, Switzerland) described previously,13,14 and a size 1 silicone face mask (12 mL of effective dead space, determined by water displacement;22 Homedica AG, Hu¨nenberg, Switzerland). Data acquisition and analysis using an updated temperature model and predefined quality control criteria for technical acceptability of data were established as described previously.5,15 VT, respiratory rate (RR), minute volume (MV), FRC, and indices of ventilation inhomogeneity, including lung clearance index (LCI) and first (M1/M0) and second (M2/M0) to zeroeth moment ratios were determined from the recorded trace.10,13,14 The effective dead space of the mask used was subtracted from the midsensor value to obtain the FRC at the airway opening. LCI and moment ratios mathematically describe the relative amount of ventilation needed to wash out the tracer gas from the lungs. LCI is calculated as the cumulative expired volume/FRC to reduce end-tidal tracer gas concentration to 2.5% of the starting concentration.23 Calculation of moment ratios requires integration of the entire washout curve over the lung turnover number, allowing for differential weightings of tracer gas elimination across the washout period.24 M1/M0 describes ventilation inhomogeneity during the early phase of the washout, while M2/M0 is more reflective of gas mixing inefficiency at the end of the washout. Elevated ventilation inhomogeneity indices reflect poor gas mixing efficiency of the lungs and correlate with the severity of BPD in preterm neonates.4 Three acceptable MBW maneuvers were performed on each infant. Statistical Analyses Aiming for 80% power at the 5% significance level, we calculated a minimum required sample size of n = 76 for a multiple linear regression model with 3 independent continuous predictor variables (body size, GA, and a variable reflecting NLD) of medium effect size (f2 = 0.15).25 Univariate regression analysis established the association between each outcome variable and likely explanatory variables, including body size and body proportions at birth and at test, maturity at birth (GA) and at test (PMA), ethnicity, household smoke exposure, chorioamnionitis, prenatal corticosteroids, presence of NLD (surfactant instillation, BPD), severity of NLD (duration of endotracheal ventilation, duration of supplemental oxygen, duration of respiratory support (endotracheal ventilation and continuous positive airway pressure), presence of severe NLD (postnatal corticosteroids), and additional factors related to respiratory illness after the neonatal period determined from parental questionnaires (physician-diagnosed 543
THE JOURNAL OF PEDIATRICS
www.jpeds.com
Vol. 156, No. 4 as well as between the preterm infants with and without BPD. Preterm infants were tested at marginally higher PMA but were lighter and had lower weight z-score, body mass index (BMI), and BMI z-score compared with term control infants; preterm infants with BPD had lower GA and birth weight but did not differ in body size or body proportions at test compared with preterm infants without BPD (Table I). Preterm infants attending follow-up had significantly longer duration of endotracheal ventilation and supplemental oxygen compared with preterm infants lost to follow-up (Table II; available at www.jpeds.com). Lung Function Results Table III summarizes univariate associations between outcomes and explanatory variables. Here we report explanatory variables demonstrating statistically significant associations with outcome measures in multivariate analyses.
Figure 1. Patient progress through phases of the trial. From the original neonatal cohort, 82 infants met the inclusion criteria for follow-up. Twenty-eight infants (34%) were lost to follow-up. Technically acceptable data were obtained from 58 out of the 64 recruited infants (91%) at 15-18 months corrected age. Forty-two infants had valid tests on both test occasions and were analyzed for longitudinal changes in lung function from the newborn period to 15-18 months corrected age.
wheeze, asthma, or bronchiolitis). Factors found to potentially influence outcome variables in univariate analysis (P < .10) were explored further using stepwise multivariate linear regression, in which a P value < .05 was considered statistically significant. Longitudinal changes in lung function from the newborn period to follow-up were analyzed by generalized linear regression modeling using the method of generalized estimating equations. Stata version 10.0 (StataCorp., College Station, Texas) was used for all statistical analyses.
Results Baseline Characteristics and Test Occasion Details As anticipated, there were significant differences in baseline characteristics between the preterm and term control infants, 544
Functional residual capacity. After adjusting for length and length z-score at test, FRC was negatively associated with the duration of endotracheal ventilation and borderline positively associated with GA (Figure 2 and Table IV; available at www.jpeds.com). A model consisting of length, length z-score, GA, and duration of endotracheal ventilation significantly explained 39% of the FRC variability in preterm infants. The range of GA in this analysis was restricted to 230-306 weeks due to minimal endotracheal ventilation in infants beyond 30 weeks GA (Figure 3 and Table IV; available at www.jpeds.com). In this model, preterm birth resulted in a 2-mL decrement in FRC per week of GA. FRC was further reduced by 2 mL per day of endotracheal ventilation. Longitudinal analysis demonstrated that after adjusting for length, the increase in lung volume from newborn age to 15-18 months corrected age was significantly influenced by GA, duration of respiratory support, and postnatal corticosteroids. For every additional week of gestation (respiratory support not in model), FRC increased by an average of 1.1% (95% confidence interval [CI] = 0.3%-1.9%; P = .009), while for every additional week of respiratory support (GA not in model), FRC decreased by an average of 1.5% (95% CI = 0.1%-2.9%; P = .034) across the 2 time points. After adjusting for length and GA, postnatal corticosteroids and non-Caucasian (primarily Asian) ethnicity reduced FRC by an average of 27% (95% CI = 22%-32%; P < .001) and 13% (95% CI = 4%-21%; P = .006), respectively (Table V; available at www.jpeds.com). Indices of ventilation inhomogeneity (LCI, M1/M0, and M2/M0). In cross-sectional univariate analysis, there was a positive association between these indices and body size, but no association with any of the other variables considered (Table III). This association was limited to the preterm infants, in whom the effect size was small; there was no association between body size and indices of ventilation inhomogeneity in term healthy control infants (eg, simple linear regression of LCI on weight: preterm, R2 = 0.110, P = .042; term healthy, R2 = 0.002, P = .78). Schulzke et al
ORIGINAL ARTICLES
April 2010
Table I. Baseline characteristics of study participants Total follow-up cohort (n = 58)
Subgroup of preterm infants (n = 38)
Variable
Preterm
Term
P value*
RDS
BPD
P value*
Total participants, n (% male) Gestational age, weeks† Postmenstrual age at test, weeks Birth weight, kg Birth weight z-score Test weight, kg Test weight z-score Test length, cm Test length z-score BMI, kg m2 BMI z-score Caucasian ethnicity, n (%) Household smoke exposure, n (%) Chorioamnionitis, n (%) Prenatal corticosteroids, n (%) Respiratory support, daysz Endotracheal ventilation, daysz Supplemental oxygen, daysz Surfactant, n (%) Postnatal corticosteroids, n (%) Wheeze, n (%) Asthma, n (%) Bronchiolitis, n (%)
38 (53) 27.8 (23.0-32.9) 110.9 (5.3) 1.02 (0.39) -0.6 (1.1) 9.9 (1.7) -1.0 (1.6) 77.8 (4.0) -0.7 (1.4) 16.3 (1.6) -0.7 (1.3) 35 (92) 13 (34) 6 (16) 34 (90) 36 (3-64) 2.3 (0-20.6) 29 (0-77) 31 (82) 5 (13) 15 (39) 0 (0) 15 (40)
20 (60) 39.7 (38.0-41.6) 109.3 (3.4) 3.33 (0.55) -0.2 (1.1) 10.8 (1.6) 0.0 (1.1) 78.8 (3.1) -0.2 (1.2) 17.4 (1.4) 0.1 (1.0) 15 (75) 4 (20) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 8 (40) 0 (0) 0 (0)
.59 < .001 .054 < .001 .21 .039 .018 .32 .15 .013 .014 .07 .26 .06 < .001 < .001 < .001 < .001 < .001 .15 .97 NA < .001
22 (46) 29.7 (23.0-32.9) 111.7 (5.1) 1.23 (0.40) -0.7 (1.3) 10.1 (1.8) -0.9 (1.5) 78.1 (4.7) -0.6 (1.5) 16.3 (1.4) -0.6 (1.2) 21 (95) 4 (23) 3 (14) 20 (91) 3 (1-28) 0.4 (0-1) 1 (0-14) 15 (68) 0 (0) 5 (23) 0 (0) 8 (38)
16 (63) 25.2 (23.0-27.3) 109.7 (5.4) 0.73 (0.11) -0.5 (0.6) 9.8 (1.7) 1.1 (1.7) 77.2 (3.0) -0.8 (1.2) 16.3 (1.9) -0.8 (1.5) 14 (88) 8 (50) 3 (19) 14 (88) 66 (55-79) 24 (16-42) 87 (74-103) 16 (100) 5 (31) 10 (63) 0 (0) 7 (44)
.34 < .001 .25 < .001 .49 .61 .65 .50 .74 .90 .66 .38 .10 .68 1.00 < .001 < .001 < .001 .014 .009 .013 NA .75
*Characteristics of infants were compared using the unpaired Student t-test, Mann-Whitney U-test, or Fisher exact test as appropriate. Data are presented as mean (standard deviation) unless stated otherwise. †Data are presented as mean (range). zData are presented as median (interquartile range).
Longitudinal analysis from newborn to 15-18 months corrected age showed significant decreases in LCI (P < .001), M1/M0 (P < .001), and M2/M0 (P < .001) across the 2 time points (Figure 4; available at www.jpeds.com). We found no association between the changes in these indices across the 2 time points and any of the explanatory variables considered.
Tidal breathing. After adjusting for weight at test, only birth weight z-score showed an independent (positive) association with VT (R2 = 0.300; P < .001). We found no association between MV or RR and any of the explanatory variables considered.
Discussion In this follow-up study, FRC at 15-18 months corrected age, and the increase in FRC from the newborn period to followup, were positively associated with maturity at birth and negatively associated with the duration of ventilation and exposure to postnatal corticosteroids after adjusting for length and length z-score at test. LCI and moment ratios at 15-18 months corrected age were unaltered by GA, duration of ventilation, and postnatal corticosteroids. These findings support current concepts of impaired lung volume after preterm birth and NLD, and suggest that catch-up lung growth may not be achieved within the first 1.5 years of life. The lack of association between indices of ventilation inhomogeneity and GA or NLD suggests that indices of ventilation inhomo-
geneity at a follow-up age of 1.5 years of life do not strongly reflect impaired gas mixing in this population. Strengths of the present study include its longitudinal design, the inclusion of extremely preterm infants (20 of the 38 preterm infants were born between 230 and 276 weeks gestation) with significant NLD (median duration of respiratory support in infants with BPD, 66 days), who were exposed to prophylactic exogenous surfactant (all infants of GA < 28 weeks and all ventilated infants received at least 1 dose) and prenatal corticosteroids (90%), reflecting important clinical characteristics of the preterm population in present-day neonatal intensive care. We maintained extensive quality control for data collection and analysis according to international guidelines,5,10 and used multivariate regression modeling for statistical analyses. The sample size of this single-center follow-up study (n = 58) was below the predicted target sample size (n = 76). Thus, the statistical power was limited, and the lack of association between indices of ventilation inhomogeneity and GA or NLD may be due to a type 2 error, although the use of continuous explanatory variables (eg, duration of endotracheal ventilation rather than presence of BPD, GA in weeks rather than presence of prematurity) alleviated this issue. Furthermore, additional recruitment of preterm infants (primarily infants with BPD) who had been too unwell to be studied in the neonatal period allowed for a preterm follow-up cohort with a wide spectrum of NLD ranging from mild RDS to severe BPD. FRC measured by the gas dilution technique measures only the volume of lung regions that communicate readily with
Lung Volume and Ventilation Inhomogeneity in Preterm Infants at 15-18 Months Corrected Age
545
THE JOURNAL OF PEDIATRICS
www.jpeds.com
Table III. Summary of cross-sectional univariate regression analysis Explanatory variable Birth weight, kg Birth weight z-score Test weight, kg Test weight z-score Test length, cm Test length z-score BMI, kg m2 BMI z-score Gestational age, weeks PMA at test, weeks Caucasian ethnicity Household smoke exposure Chorioamnionitis Prenatal corticosteroids Respiratory support, days Endotracheal ventilation, days Supplemental oxygen, days Surfactant BPD Postnatal corticosteroids Wheeze Asthma Bronchiolitis
FRC LCI M1/M0 M2/M0 VT RR MV [ Y [ Y Y Y Y
[ [ [ [ [ [ -
[ [ [ [ [ [ [ -
[ [ -
[ [ [ [ [ [ -
-
[ [ [ [ [ [ -
[ denotes significant positive association per unit increase (P < .10 considered statistically significant); Y denotes significant negative association per unit increase; - denotes nonsignificant association.
the central airways during tidal breathing. Thus, FRC obtained from MBW does not include any trapped gas and may underestimate resting lung volume, particularly in infants with airway obstruction.26,27 Therefore, our regression analysis included potential confounders associated with poor airway function, such as household smoking, wheeze, asthma, and bronchiolitis. Arguably, longitudinal measurements of alveolar volume and carbon monoxide diffusing capacity are superior to FRC for evaluation of lung growth, because FRC in infancy is dynamically elevated above the elastic equilibrium28 and may not be an exact estimate of parenchymal lung volume. But carbon monoxide diffusing capacity is not (yet) applicable to spontaneously breathing, unsedated preterm neonates with BPD, and thus FRC is the best available option for the longitudinal assessment of lung volume and lung growth in this population. This study demonstrates that in very preterm infants, preterm birth per se and the duration of endotracheal ventilation in the newborn period are associated with reduced lung volume at around 18 months of life. Given that comparable results were obtained from the recently reported multicenter study in the newborn period5 and in a longitudinal assessment of the current local cohort, this indicates considerable tracking of lung volume over the first 1.5 years of life. Previous MBW studies suggested similar effects of preterm birth3 and presence of BPD4,6,7 on FRC at neonatal age, but reported normalized lung volume between 6 and 36 months of life.6-8 Similar to our results, there is substantial tracking of airway function over the first year of life in healthy preterm infants.29 546
Vol. 156, No. 4 The multivariate statistical analysis used in this investigation differs considerably from previous studies that used the t-test or analysis of variance.3,4,6-8 Furthermore, the longitudinal study of Gerhardt et al7 originated from the presurfactant era, and FRC was expressed in mL/kg body weight rather than adjusted for body length, with no consideration of equipment dead space. Other follow-up studies investigated significantly more mature infants who may have had less severe NLD6,8 compared with the infants in our follow-up study (5/16 infants with BPD required home oxygen). Comparing the follow-up cohort with infants lost to follow-up after participating in the multicenter study in the newborn period5 showed that the follow-up cohort had significantly longer duration of endotracheal ventilation and supplemental oxygen, indicating more severe NLD. We were surprised to find no association between the duration of endotracheal ventilation and indices of ventilation inhomogeneity (LCI and moment ratios), given that newborn studies by Hjalmarson et al4,5 and the newborn multicenter study involving the current cohort30 had shown a small, but statistically significant, effect of NLD on LCI and moment ratios in preterm infants. This discrepancy suggests that a potential relationship between NLD and indices of ventilation inhomogeneity at newborn age may no longer be detectable by 1.5 years of life, or that the limited sample size of our follow-up study decreased our likelihood of detecting such a relationship. Although a type 2 error cannot be excluded, this study had 89% power at a significance level of 5% to detect an association between a single explanatory factor of moderate predictive value (R2 = 0.15) and indices of ventilation inhomogeneity. Univariate analysis showed no association between GA or NLD and indices of ventilation inhomogeneity; that is, any potentially missed association would be of very limited effect size and thus unlikely to be of clinical relevance. The observed positive association between body size and indices of ventilation inhomogeneity in the preterm infants was not anticipated. Assuming that prematurity and NLD result in poor alveolarization and lung growth, this finding suggests that ventilation inhomogeneity may be associated with increasing discrepancy between lung size/alveolar surface area in relation to body size in preterm infants at 1.5 years of life, warranting further investigation. A decrease in indices of ventilation inhomogeneity from the neonatal period to 1.5 years of life was observed in most infants. This finding contrasts with the widely held belief that these indices are age-independent and thus useful for identifying longitudinal changes in ventilation inhomogeneity. However, whereas the published longitudinal study demonstrating age-independence of these indices was performed in preschool and school-age children (age 515 years) in whom alveolarization is complete,31 our study assessed changes in ventilation inhomogeneity indices between birth and late infancy. Alveolarization is not completed until at least 6 months and up to 2 years after birth; thus, impaired gas mixing efficiency in the neonatal period is biologically plausible, and our observations may reflect a real decrease in ventilation inhomogeneity during early postnatal life. Schulzke et al
ORIGINAL ARTICLES
April 2010
Figure 2. FRC at 15-18 months corrected age. A, FRC per cm of body length plotted against GA, B, FRC per kg of body weight, C, FRC plotted against length at test, D, and duration of endotracheal ventilation in the newborn period. Triangles indicate preterm RDS, squares indicate preterm BPD, and circles indicate term healthy controls. As expected, there were significant differences among groups in terms of body size and markers of NLD (Table I). Although regression analysis demonstrated significant associations among length-adjusted FRC, GA, and duration of endotracheal ventilation, simply expressing results as FRC/kg, as shown in B, would have led to the misleading conclusion that NLD has no major impact on FRC.
Our finding of reduced lung volume at age 18 months supports the current concept of disturbed acinar lung development due to impaired alveolarization after very preterm birth and NLD.32 In infants born between 230 and 306 weeks GA (ie, the group of infants in whom we could assess the association between GA and endotracheal ventilation), we found that the degree of preterm birth per se and duration of endotracheal ventilation independently reduced length-adjusted FRC at 15-18 months corrected age. However, after adjusting for body size and body proportions at test, the additional contribution of preterm birth and endotracheal ventilation to the variability in FRC was relatively small. On average, preterm birth reduced FRC at follow-up by 2 mL/week, and endotracheal ventilation led to a further decrement in FRC of 2 mL/day of mechanical ventilation. No follow-up data are available to extrapolate these effects beyond the second year of life. A long-term follow-up study of infants born in 1991-1992 reported only minimally
decreased total lung capacity but markedly increased residual volume, suggesting air trapping in 8- to 9-year-old children born very preterm compared with near-term/term controls.9 Thus, it is essential to extend the follow-up of current study cohorts to at least school age, to clarify whether catch-up growth of the lung occurs later in childhood and/or air trapping is an issue. Ideally, future longitudinal studies in preterm infants using carbon monoxide diffusing capacity will allow for quantification of parenchymal lung growth in terms of alveolarization, given the recently reported successful application of this technique in healthy infants.33 In the context of cystic fibrosis, LCI detects abnormal lung function earlier than spirometry in infants, children, and teenagers.31,34-36 Arguably, the poor diagnostic utility of LCI and moment ratios in our study may be related to differences in type and severity of functional impairment, and to the progression of disease in cystic fibrosis versus ‘‘recovery’’ from NLD. Potentially, more complex analysis of ventilation inhomogeneity during MBW (using, e.g., normalized slope
Lung Volume and Ventilation Inhomogeneity in Preterm Infants at 15-18 Months Corrected Age
547
THE JOURNAL OF PEDIATRICS
www.jpeds.com
of phase III37) may facilitate detection and monitoring of ventilation inhomogeneity in follow-up of preterm infants by localizing the region of inefficient gas mixing to that occurring within the conductive airways or within the acinus.38 The validity and feasibility of the normalized slope of phase III analysis have not yet been established in infants, however. Very preterm birth per se and the duration of ventilation in the newborn period are independently associated with reduced lung volume and lung growth at 15-18 months corrected age, although the effect size of these findings is small. Indices of ventilation inhomogeneity at 15-18 months corrected age show no clinically important association with preterm birth and markers of NLD. Further research is needed to assess the generalizibility of these findings and to determine whether other indicators of ventilation inhomogeneity have better diagnostic utility in preterm infants. n We thank our study infants and their families for their participation in this study. Submitted for publication May 28, 2009; last revision received Sep 1, 2009; accepted Oct 15, 2009. Reprint requests: Sven Schulzke, MD, FRACP, Neonatal Clinical Care Unit, King Edward Memorial Hospital for Women, 374 Bagot Road, Subiaco, Western Australia 6008, Australia. E-mail: [email protected].
References 1. Coalson JJ. Pathology of new bronchopulmonary dysplasia. Semin Neonatol 2003;8:73-81. 2. Allen J, Zwerdling R, Ehrenkranz R, Gaultier C, Geggel R, Greenough A, et al. Statement on the care of the child with chronic lung disease of infancy and childhood. Am J Respir Crit Care Med 2003;168:356-96. 3. Hjalmarson O, Sandberg K. Abnormal lung function in healthy preterm infants. Am J Respir Crit Care Med 2002;165:83-7. 4. Hjalmarson O, Sandberg KL. Lung function at term reflects severity of bronchopulmonary dysplasia. J Pediatr 2005;146:86-90. 5. Hulskamp G, Lum S, Stocks J, Wade A, Hoo AF, Costeloe K, et al. Association of prematurity, lung disease and body size with lung volume and ventilation inhomogeneity in unsedated neonates: a multicentre study. Thorax 2009;64:240-5. 6. de Winter JP, Merth IT, Brand R, Quanjer PH. Functional residual capacity and static compliance during the first year in preterm infants treated with surfactant. Am J Perinatol 2000;17:377-84. 7. Gerhardt T, Hehre D, Feller R, Reifenberg L, Bancalari E. Serial determination of pulmonary function in infants with chronic lung disease. J Pediatr 1987;110:448-56. 8. Merth IT, de Winter JP, Zonderland HM, Borsboom GJ, Quanjer PH. Pulmonary function in infants with neonatal chronic lung disease with or without hyaline membrane disease at birth. Eur Respir J 1997;10: 1606-13. 9. Doyle LW. Respiratory function at age 8-9 years in extremely low birthweight/very preterm children born in Victoria in 1991-1992. Pediatr Pulmonol 2006;41:570-6. 10. Latzin P, Thamrin C, Kraemer R. Ventilation inhomogeneities assessed by the multibreath washout (MBW) technique. Thorax 2008;63:98-9. 11. Pillow JJ, Frerichs I, Stocks J. Lung function tests in neonates and infants with chronic lung disease: global and regional ventilation inhomogeneity. Pediatr Pulmonol 2006;41:105-21. 12. Buess C, Pietsch P, Guggenbuhl W, Koller EA. A pulsed diagonal-beam ultrasonic airflow meter. J Appl Physiol 1986;61:1195-9. 13. Pillow JJ, Ljungberg H, Hulskamp G, Stocks J. Functional residual capacity measurements in healthy infants: ultrasonic flow meter versus a mass spectrometer. Eur Respir J 2004;23:763-8. 548
Vol. 156, No. 4 14. Schibler A, Hall GL, Businger F, Reinmann B, Wildhaber JH, Cernelc M, et al. Measurement of lung volume and ventilation distribution with an ultrasonic flow meter in healthy infants. Eur Respir J 2002;20:912-8. 15. Schulzke SM, Deeptha K, Sinhal S, Baldwin DN, Pillow JJ. Nasal versus face mask for multiple-breath washout technique in preterm infants. Pediatr Pulmonol 2008;43:858-65. 16. Schibler A, Henning R. Measurement of functional residual capacity in rabbits and children using an ultrasonic flow meter. Pediatr Res 2001; 49:581-8. 17. Wauer J, Leier TU, Henschen M, Wauer RR, Schmalisch G. In vitro validation of an ultrasonic flowmeter in order to measure the functional residual capacity in newborns. Physiol Meas 2003;24:355-65. 18. Schulzke SM, Hall GL, Nolan G, Pillow JJ. Duration of mechanical ventilation influences lung volume in preterm infants at 15-18 months corrected age. Presented at the Annual Meeting of the European Respiratory Society, Berlin, Germany; 2008. Eur Respir J 2008;32(suppl 52):P3905. 19. Gaultier C, Fletcher ME, Beardsmore C, England S, Motoyama E. Respiratory function measurements in infants: measurement conditions. Working Group of the European Respiratory Society and the American Thoracic Society. Eur Respir J 1995;8:1057-66. 20. Freeman JV, Cole TJ, Chinn S, Jones PR, White EM, Preece MA. Crosssectional stature and weight reference curves for the UK, 1990. Arch Dis Child 1995;73:17-24. 21. Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics 1988;82:527-32. 22. Frey U, Stocks J, Coates A, Sly P, Bates J. Specifications for equipment used for infant pulmonary function testing. European Respiratory Society/American Thoracic Society Task Force on Standards for Infant Respiratory Function Testing. Eur Respir J 2000;16:731-40. 23. Larsson A, Jonmarker C, Werner O. Ventilation inhomogeneity during controlled ventilation: which index should be used? J Appl Physiol 1988; 65:2030-9. 24. Saidel GM, Saniie J, Chester EH. Lung washout during spontaneous breathing: parameter estimation with a time-varying model. Comput Biomed Res 1980;13:446-57. 25. Cohen J, Cohen P, West SG, Aiken LS. Applied Multiple Regression/ Correlation Analysis for the Behavioral Sciences. Mahwah, NJ: Lawrence Earlbaum Associates; 2003. 26. Broughton S, Thomas MR, Marston L, Calvert SA, Marlow N, Peacock JL, et al. Very prematurely born infants wheezing at followup: lung function and risk factors. Arch Dis Child 2007;92:776-80. 27. Hulskamp G, Pillow JJ, Dinger J, Stocks J. Lung function tests in neonates and infants with chronic lung disease of infancy: functional residual capacity. Pediatr Pulmonol 2006;41:1-22. 28. Henschen M, Stocks J. Assessment of airway function using partial expiratory flow-volume curves: how reliable are measurements of maximal expiratory flow at FRC during early infancy? Am J Respir Crit Care Med 1999;159:480-6. 29. Hoo AF, Dezateux C, Henschen M, Costeloe K, Stocks J. Development of airway function in infancy after preterm delivery. J Pediatr 2002;141: 652-8. 30. Shao H, Sandberg K, Hjalmarson O. Impaired gas mixing and low lung volume in preterm infants with mild chronic lung disease. Pediatr Res 1998;43:536-41. 31. 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;59:106873. 32. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163:1723-9. 33. Balinotti JE, Tiller CJ, Llapur CJ, Jones MH, Kimmel RN, Coates CE, et al. Growth of the lung parenchyma early in life. Am J Respir Crit Care Med 2009;179:134-7. 34. Gustafsson PM, Aurora P, Lindblad A. Evaluation of ventilation maldistribution as an early indicator of lung disease in children with cystic fibrosis. Eur Respir J 2003;22:972-9.
Schulzke et al
ORIGINAL ARTICLES
April 2010 35. Kraemer R, Blum A, Schibler A, Ammann RA, Gallati S. Ventilation inhomogeneities in relation to standard lung function in patients with cystic fibrosis. Am J Respir Crit Care Med 2005;171: 371-8. 36. 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;62:341-7.
37. Verbanck S, Schuermans D, Van Muylem A, Paiva M, Noppen M, Vincken W. Ventilation distribution during histamine provocation. J Appl Physiol 1997;83:1907-16. 38. Verbanck S, Schuermans D, Van Muylem A, Melot C, Noppen M, Vincken W, et al. Conductive and acinar lung-zone contributions to ventilation inhomogeneity in COPD. Am J Respir Crit Care Med 1998;157:1573-7.
50 Years Ago in THE JOURNAL OF PEDIATRICS Observation on Rheumatic Nodules over a 30-Year Period Baldwin JS, Kerr JM, Kuttner AG, Doyle EF. J Pediatr 1960;56:465-70
C
linicians at the Children’s Cardiac Service, New York University–Bellevue Medical Center compared clinical courses of children with rheumatic fever, with a special focus on rheumatic nodules, over a 30-year period (1928-1958). They grouped patients by onset of disease in an earlier 15-year period (1928-1942) and in a later period (1943-1958). At the time, observers had the impression that both the incidence and severity of rheumatic fever had declined, beginning even before the discovery of penicillin. Because it was agreed that rheumatic nodules were associated with a severe form of rheumatic fever, the authors reviewed the immediate and long-term outcomes of patients with rheumatic nodules diagnosed in the two time periods as an indicator of changes in the pattern of disease. Findings corroborated that the incidence of rheumatic nodules dropped from the earlier period to the later period, from 68 cases to 33 cases. Across both time frames, however, nodules were associated with severe carditis, usually marking protracted active and recrudescent carditis. Mortality in patients with rheumatic carditis fell from 16% in the early period to 4% in the later period; however, for those with nodules, mortality rate did not fall as markedly. For children with recurrent crops of nodules during the same attack or later, overall mortality for the entire study period was 58%, compared with 25% for children with nonrecurring nodules. The authors conclude that nodules still should be considered a sign of severe rheumatic heart disease and should lead to a guarded prognosis and to rigid adherence to (the miraculous) penicillin prophylaxis. There was an accelerating decline in rheumatic fever in the United States from the 1940s through the 1980s. However, a dramatic outbreak of rheumatic fever began in 1985 in the intermountain areas around Salt Lake City, Utah and spread to Ohio and Pittsburgh. Other outbreaks occurred in noncontiguous areas but did not lead to a nationwide increase in cases. The outbreak continues in Utah, where approximately 70% of patients have carditis.1 Nodules are present in <5% of cases. We are agreed that the organism, the host, and the environment each play a part in the clinical manifestations of rheumatic disease and its epidemiology, but assigning the lead and supporting roles has been difficult. Sarah S. Long, MD Section of Infectious Diseases St Christopher’s Hospital for Children Philadelphia, Pennsylvania 10.1016/j.jpeds.2009.11.024
Reference 1. Veasy LG, Tani LY, Hill HR. Persistence of acute rheumatic fever in the intermountain area of the United States. J Pediatr 1994;124:9-16.
Lung Volume and Ventilation Inhomogeneity in Preterm Infants at 15-18 Months Corrected Age
549
THE JOURNAL OF PEDIATRICS
www.jpeds.com
Vol. 156, No. 4
Table II. Baseline characteristics of infants attending follow-up versus dropping out Preterm
Term
Variable
Follow-up (n = 38)
Dropout (n = 19)
P value*
Follow-up (n = 20)
Dropout (n = 15)
P value*
Male, n (%) GA, weeks† Birth weight, kg Birth weight z-score Caucasian ethnicity, n (%) Household smoke exposure, n (%) Chorioamnionitis, n (%) Prenatal corticosteroids, n (%) Respiratory support, daysz Endotracheal ventilation, daysz Supplemental oxygen, daysz Surfactant, n (%) BPD, n (%) Postnatal corticosteroids, n (%)
20 (53) 27.8 (23.0-32.9) 1.02 (0.39) -0.6 (1.1) 35 (92) 13 (34) 6 (16) 34 (90) 36 (3-64) 2.3 (0-20.6) 29 (0-77) 31 (82) 16 (42) 5 (13)
11 (58) 28.8 (23.6-32.9) 1.17 (0.44) -0.6 (1.1) 17 (89) 3 (16) 3 (16) 15 (79) 24 (1.2-47) 0 (0-5) 0 (0-70) 10 (53) 5 (26) 2 (11)
.71 .23 .20 1.00 .74 .14 1.00 .28 .16 .016 .034 .02 .24 .78
12 (60) 39.7 (38.0-41.6) 3.33 (0.55) -0.2 (1.1) 15 (75) 4 (20) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
7 (47) 39.5 (37.9-41.4) 3.48 (0.45) 0.2 (0.9) 13 (87) 1 (7) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
.43 .72 .40 .26 .39 .26 NA NA NA NA NA NA NA NA
*Characteristics of infants were compared using the unpaired Student t-test, Mann-Whitney U-test, or Fisher exact test as appropriate. Data are presented as mean (standard deviation) unless stated otherwise. † Data are presented as mean (range). z Data are presented as median (interquartile range).
Table IV. Multivariate analysis of FRC at 15-18 months corrected age Explanatory variable Model 1 (R2† = 0.171; P < .016); intercept, 1.26 Test length, cm Test length z-score GA, weeks Model 2 (R2† = 0.198; P = .008) intercept, 1.86 Test length, cm Test length z-score Endotracheal ventilation, days Model 3 (R2† = 0.199; P = .018); intercept, 1.67 Test length, cm Test length z-score GA, weeks Endotracheal ventilation, days ‘‘Best model’’ GA # 306 weeks (R2† = 0.392; P = .022); intercept, 4.05 Test length, cm Test length z-score GA, weeks Endotracheal ventilation, days
b*
95% CI
P value
0.05 -0.12 0.08
0.01 to 0.08 -0.22 to -0.02 >-0.001 to 0.02
.008 .017 .063
0.04 -0.12 -0.01
0.01 to 0.08 -0.22 to -0.02 -0.01 to -0.001
.015 .021 .027
0.05 -0.12 0.003 -0.003
0.01 to 0.08 -0.22 to -0.02 -0.01 to 0.01 -0.01 to 0.01
.013 .019 .55 .19
0.04 -0.10 -0.01 -0.01
-0.003 to 0.08 -0.22 to 0.03 -0.12 to -0.02 -0.01 to -0.002
.066 .12 .008 .050
In this analysis, FRC was log-transformed to achieve normal distribution of residuals. *Regression coefficients b. †Coefficient of determination.
549.e1
Table V. Factors influencing the increase in lung volume from newborn age to 15-18 months corrected age Explanatory variable
Mean effect*
95% CI
P value
Length GA Time Newborn 15-18 months corrected age Ethnicity Caucasian Other (primarily Asian) Postnatal corticosteroids
1.02 1.01
1.01-1.03 1.00-1.02
< .001 .009
1.00 1.88
1.44-2.45
< .001
1.00 0.87 0.73
0.79-0.96 0.68-0.78
.006 < .001
*FRC was log-transformed for analysis to achieve normality. Effect estimates and 95% CIs have been back-transformed to the original scale.
Schulzke et al
ORIGINAL ARTICLES
April 2010
Figure 3. Duration of endotracheal ventilation in the newborn period versus GA. Triangles indicate preterm RDS, squares indicate preterm BPD, and circles indicate term healthy controls. There appears to be an inverse linear relationship between GA and endotracheal ventilation up to approximately 30 weeks GA. Above 30 weeks GA, only 1 preterm infant was ventilated for more than 1 day, and all term control infants were nonventilated, resulting in a significant change in the relationship between these 2 covariates. Thus, regression models that included the variable endotracheal ventilation were restricted to a GA range of 236-306 weeks.
Figure 4. Indices of ventilation inhomogeneity at newborn age and at 15-18 months corrected age: A, LCI, B, M1/M0, and C, M2/M0. Triangles indicate preterm SDS, squares indicate preterm BPD, and circles indicate term healthy controls. There was a significant decrease in LCI, M1M0, and M2/M0 in RDS, BPD, and term healthy control infants across the 2 time points. Cross-sectional analysis demonstrated no significant associations between these indices of ventilation inhomogeneity and GA, NLD, or any other explanatory variable considered. *P < .001.
Lung Volume and Ventilation Inhomogeneity in Preterm Infants at 15-18 Months Corrected Age
549.e2
I
BMI BPD FRC GA LCI M1/M0 M2/M0
Body mass index Bronchopulmonary dysplasia Functional residual capacity Gestational age Lung clearance index First to zeroeth moment ratio Second to zeroeth moment ratio
MV NLD PMA RDS RR VT
Minute volume Neonatal lung disease Postmenstrual age Respiratory distress syndrome Respiratory rate Tidal volume
Australia; Department of Neonatal Paediatrics (S.S., K.S.) and Department of Respiratory Medicine (G.H., G.N.) Princess Margaret and King Edward Memorial Hospitals, Perth, Australia; and Women and Infants Research Foundation, King Edward Memorial Hospital, Perth, Australia (E.N.) Supported by a PMH Telethon Clinical Research Fellowship Grant (to S.M.S.), a PMH Research Foundation Grant (to G.L.H.), and a Raine Foundation Priming Grant (to J.J.P.). The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright Ó 2010 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2009.10.017
542
Vol. 156, No. 4 April 2010
Methods This study was designed as a prospective follow-up study of infant lung function at 15-18 months corrected age. The study design was approved by the Women’s and Children’s Health Service Research Ethics Committee. Written informed parental consent was obtained before enrollment. Infants born at King Edward Memorial Hospital (KEMH) in Perth, Western Australia, between April 2005 and September 2006 were recruited for lung function studies at 15-18 months corrected age (i.e., 15-18 months after the expected delivery date). Most of the infants in this local follow-up study had participated in a multicenter study that reported the effects of body size, GA, and indices of NLD on FRC and ventilation inhomogeneity in the newborn period.5 The present study reports local cross-sectional data at follow-up (n = 58) and longitudinal changes in lung function in the local subset of infants who had valid paired measurements in the neonatal period and at 15-18 months corrected age (n = 42). Preterm infants (230-326 weeks GA) with respiratory distress syndrome (RDS) with and without subsequent BPD were eligible for a follow-up study. Term healthy control infants of 370-420 weeks GA also were eligible. An attempt was made to increase the sample size at follow-up by recruiting additional preterm infants with BPD who were not well enough to be studied in the multicenter study in the newborn period (Figure 1). The diagnosis of RDS was based on the presence of prematurity, clinical and radiologic signs of respiratory distress, and the need for supplemental oxygen. All infants of < 28 weeks GA received prophylactic surfactant; preterm infants of $ 28 weeks GA received surfactant if they required intubation for RDS (with the decision of whether or not to intubate left to the discretion of the attending neonatologist). Ventilation strategy (BabyLog 8000+; Draeger Medical, Luebeck, Germany) aimed at ‘‘gentle ventilation’’ and included the following principles: limiting tidal volume (VT) to 4-6 mL kg1 body weight (‘‘volume-guarantee’’ mode), allowing for mild permissive hypercapnia, supporting each respiratory effort by assist-control or pressure support ventilation, and keeping positive end-expiratory pressure at 5-6 cmH2O to avoid atelectasis. Five infants with severe NLD received low-dose dexamethasone (cumulative dose, 0.89 mg/kg over 10 days) after 21 days of life, to facilitate extubation. Exclusion criteria included cardiopulmonary, neuromuscular, or any other significant congenital disease. Clinical and demographic data were recorded from hospital notes and parental questionnaires. Weight and length at the time of testing were measured using standardized methods.19 Sexspecific z-scores were calculated based on postnatal age and were adjusted for prematurity using the 1990 British Growth Reference Curves.20 BPD was defined as the need for supplemental oxygen or assisted ventilation at 36 weeks postmenstrual age (PMA),21 using a target oxygen saturation range of 86%-94%.
Lung Function Tests Measurements were performed in clinically stable children without respiratory infection in the 3 weeks before the test, with the patient in the supine position on one testing occasion. Sleep was induced by oral administration of chloral hydrate 70-100 mg kg1. Heart rate and oxygen saturation were monitored continuously by pulse oximetry (model N-200; Nellcor, Hayward, California). MBW was performed using 5% sulfur hexafluoride (SF6) as a tracer gas, a commercially available ultrasonic flowmeter (Ecomedics AG, Duernten, Switzerland) described previously,13,14 and a size 1 silicone face mask (12 mL of effective dead space, determined by water displacement;22 Homedica AG, Hu¨nenberg, Switzerland). Data acquisition and analysis using an updated temperature model and predefined quality control criteria for technical acceptability of data were established as described previously.5,15 VT, respiratory rate (RR), minute volume (MV), FRC, and indices of ventilation inhomogeneity, including lung clearance index (LCI) and first (M1/M0) and second (M2/M0) to zeroeth moment ratios were determined from the recorded trace.10,13,14 The effective dead space of the mask used was subtracted from the midsensor value to obtain the FRC at the airway opening. LCI and moment ratios mathematically describe the relative amount of ventilation needed to wash out the tracer gas from the lungs. LCI is calculated as the cumulative expired volume/FRC to reduce end-tidal tracer gas concentration to 2.5% of the starting concentration.23 Calculation of moment ratios requires integration of the entire washout curve over the lung turnover number, allowing for differential weightings of tracer gas elimination across the washout period.24 M1/M0 describes ventilation inhomogeneity during the early phase of the washout, while M2/M0 is more reflective of gas mixing inefficiency at the end of the washout. Elevated ventilation inhomogeneity indices reflect poor gas mixing efficiency of the lungs and correlate with the severity of BPD in preterm neonates.4 Three acceptable MBW maneuvers were performed on each infant. Statistical Analyses Aiming for 80% power at the 5% significance level, we calculated a minimum required sample size of n = 76 for a multiple linear regression model with 3 independent continuous predictor variables (body size, GA, and a variable reflecting NLD) of medium effect size (f2 = 0.15).25 Univariate regression analysis established the association between each outcome variable and likely explanatory variables, including body size and body proportions at birth and at test, maturity at birth (GA) and at test (PMA), ethnicity, household smoke exposure, chorioamnionitis, prenatal corticosteroids, presence of NLD (surfactant instillation, BPD), severity of NLD (duration of endotracheal ventilation, duration of supplemental oxygen, duration of respiratory support (endotracheal ventilation and continuous positive airway pressure), presence of severe NLD (postnatal corticosteroids), and additional factors related to respiratory illness after the neonatal period determined from parental questionnaires (physician-diagnosed 543
THE JOURNAL OF PEDIATRICS
www.jpeds.com
Vol. 156, No. 4 as well as between the preterm infants with and without BPD. Preterm infants were tested at marginally higher PMA but were lighter and had lower weight z-score, body mass index (BMI), and BMI z-score compared with term control infants; preterm infants with BPD had lower GA and birth weight but did not differ in body size or body proportions at test compared with preterm infants without BPD (Table I). Preterm infants attending follow-up had significantly longer duration of endotracheal ventilation and supplemental oxygen compared with preterm infants lost to follow-up (Table II; available at www.jpeds.com). Lung Function Results Table III summarizes univariate associations between outcomes and explanatory variables. Here we report explanatory variables demonstrating statistically significant associations with outcome measures in multivariate analyses.
Figure 1. Patient progress through phases of the trial. From the original neonatal cohort, 82 infants met the inclusion criteria for follow-up. Twenty-eight infants (34%) were lost to follow-up. Technically acceptable data were obtained from 58 out of the 64 recruited infants (91%) at 15-18 months corrected age. Forty-two infants had valid tests on both test occasions and were analyzed for longitudinal changes in lung function from the newborn period to 15-18 months corrected age.
wheeze, asthma, or bronchiolitis). Factors found to potentially influence outcome variables in univariate analysis (P < .10) were explored further using stepwise multivariate linear regression, in which a P value < .05 was considered statistically significant. Longitudinal changes in lung function from the newborn period to follow-up were analyzed by generalized linear regression modeling using the method of generalized estimating equations. Stata version 10.0 (StataCorp., College Station, Texas) was used for all statistical analyses.
Results Baseline Characteristics and Test Occasion Details As anticipated, there were significant differences in baseline characteristics between the preterm and term control infants, 544
Functional residual capacity. After adjusting for length and length z-score at test, FRC was negatively associated with the duration of endotracheal ventilation and borderline positively associated with GA (Figure 2 and Table IV; available at www.jpeds.com). A model consisting of length, length z-score, GA, and duration of endotracheal ventilation significantly explained 39% of the FRC variability in preterm infants. The range of GA in this analysis was restricted to 230-306 weeks due to minimal endotracheal ventilation in infants beyond 30 weeks GA (Figure 3 and Table IV; available at www.jpeds.com). In this model, preterm birth resulted in a 2-mL decrement in FRC per week of GA. FRC was further reduced by 2 mL per day of endotracheal ventilation. Longitudinal analysis demonstrated that after adjusting for length, the increase in lung volume from newborn age to 15-18 months corrected age was significantly influenced by GA, duration of respiratory support, and postnatal corticosteroids. For every additional week of gestation (respiratory support not in model), FRC increased by an average of 1.1% (95% confidence interval [CI] = 0.3%-1.9%; P = .009), while for every additional week of respiratory support (GA not in model), FRC decreased by an average of 1.5% (95% CI = 0.1%-2.9%; P = .034) across the 2 time points. After adjusting for length and GA, postnatal corticosteroids and non-Caucasian (primarily Asian) ethnicity reduced FRC by an average of 27% (95% CI = 22%-32%; P < .001) and 13% (95% CI = 4%-21%; P = .006), respectively (Table V; available at www.jpeds.com). Indices of ventilation inhomogeneity (LCI, M1/M0, and M2/M0). In cross-sectional univariate analysis, there was a positive association between these indices and body size, but no association with any of the other variables considered (Table III). This association was limited to the preterm infants, in whom the effect size was small; there was no association between body size and indices of ventilation inhomogeneity in term healthy control infants (eg, simple linear regression of LCI on weight: preterm, R2 = 0.110, P = .042; term healthy, R2 = 0.002, P = .78). Schulzke et al
ORIGINAL ARTICLES
April 2010
Table I. Baseline characteristics of study participants Total follow-up cohort (n = 58)
Subgroup of preterm infants (n = 38)
Variable
Preterm
Term
P value*
RDS
BPD
P value*
Total participants, n (% male) Gestational age, weeks† Postmenstrual age at test, weeks Birth weight, kg Birth weight z-score Test weight, kg Test weight z-score Test length, cm Test length z-score BMI, kg m2 BMI z-score Caucasian ethnicity, n (%) Household smoke exposure, n (%) Chorioamnionitis, n (%) Prenatal corticosteroids, n (%) Respiratory support, daysz Endotracheal ventilation, daysz Supplemental oxygen, daysz Surfactant, n (%) Postnatal corticosteroids, n (%) Wheeze, n (%) Asthma, n (%) Bronchiolitis, n (%)
38 (53) 27.8 (23.0-32.9) 110.9 (5.3) 1.02 (0.39) -0.6 (1.1) 9.9 (1.7) -1.0 (1.6) 77.8 (4.0) -0.7 (1.4) 16.3 (1.6) -0.7 (1.3) 35 (92) 13 (34) 6 (16) 34 (90) 36 (3-64) 2.3 (0-20.6) 29 (0-77) 31 (82) 5 (13) 15 (39) 0 (0) 15 (40)
20 (60) 39.7 (38.0-41.6) 109.3 (3.4) 3.33 (0.55) -0.2 (1.1) 10.8 (1.6) 0.0 (1.1) 78.8 (3.1) -0.2 (1.2) 17.4 (1.4) 0.1 (1.0) 15 (75) 4 (20) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 8 (40) 0 (0) 0 (0)
.59 < .001 .054 < .001 .21 .039 .018 .32 .15 .013 .014 .07 .26 .06 < .001 < .001 < .001 < .001 < .001 .15 .97 NA < .001
22 (46) 29.7 (23.0-32.9) 111.7 (5.1) 1.23 (0.40) -0.7 (1.3) 10.1 (1.8) -0.9 (1.5) 78.1 (4.7) -0.6 (1.5) 16.3 (1.4) -0.6 (1.2) 21 (95) 4 (23) 3 (14) 20 (91) 3 (1-28) 0.4 (0-1) 1 (0-14) 15 (68) 0 (0) 5 (23) 0 (0) 8 (38)
16 (63) 25.2 (23.0-27.3) 109.7 (5.4) 0.73 (0.11) -0.5 (0.6) 9.8 (1.7) 1.1 (1.7) 77.2 (3.0) -0.8 (1.2) 16.3 (1.9) -0.8 (1.5) 14 (88) 8 (50) 3 (19) 14 (88) 66 (55-79) 24 (16-42) 87 (74-103) 16 (100) 5 (31) 10 (63) 0 (0) 7 (44)
.34 < .001 .25 < .001 .49 .61 .65 .50 .74 .90 .66 .38 .10 .68 1.00 < .001 < .001 < .001 .014 .009 .013 NA .75
*Characteristics of infants were compared using the unpaired Student t-test, Mann-Whitney U-test, or Fisher exact test as appropriate. Data are presented as mean (standard deviation) unless stated otherwise. †Data are presented as mean (range). zData are presented as median (interquartile range).
Longitudinal analysis from newborn to 15-18 months corrected age showed significant decreases in LCI (P < .001), M1/M0 (P < .001), and M2/M0 (P < .001) across the 2 time points (Figure 4; available at www.jpeds.com). We found no association between the changes in these indices across the 2 time points and any of the explanatory variables considered.
Tidal breathing. After adjusting for weight at test, only birth weight z-score showed an independent (positive) association with VT (R2 = 0.300; P < .001). We found no association between MV or RR and any of the explanatory variables considered.
Discussion In this follow-up study, FRC at 15-18 months corrected age, and the increase in FRC from the newborn period to followup, were positively associated with maturity at birth and negatively associated with the duration of ventilation and exposure to postnatal corticosteroids after adjusting for length and length z-score at test. LCI and moment ratios at 15-18 months corrected age were unaltered by GA, duration of ventilation, and postnatal corticosteroids. These findings support current concepts of impaired lung volume after preterm birth and NLD, and suggest that catch-up lung growth may not be achieved within the first 1.5 years of life. The lack of association between indices of ventilation inhomogeneity and GA or NLD suggests that indices of ventilation inhomo-
geneity at a follow-up age of 1.5 years of life do not strongly reflect impaired gas mixing in this population. Strengths of the present study include its longitudinal design, the inclusion of extremely preterm infants (20 of the 38 preterm infants were born between 230 and 276 weeks gestation) with significant NLD (median duration of respiratory support in infants with BPD, 66 days), who were exposed to prophylactic exogenous surfactant (all infants of GA < 28 weeks and all ventilated infants received at least 1 dose) and prenatal corticosteroids (90%), reflecting important clinical characteristics of the preterm population in present-day neonatal intensive care. We maintained extensive quality control for data collection and analysis according to international guidelines,5,10 and used multivariate regression modeling for statistical analyses. The sample size of this single-center follow-up study (n = 58) was below the predicted target sample size (n = 76). Thus, the statistical power was limited, and the lack of association between indices of ventilation inhomogeneity and GA or NLD may be due to a type 2 error, although the use of continuous explanatory variables (eg, duration of endotracheal ventilation rather than presence of BPD, GA in weeks rather than presence of prematurity) alleviated this issue. Furthermore, additional recruitment of preterm infants (primarily infants with BPD) who had been too unwell to be studied in the neonatal period allowed for a preterm follow-up cohort with a wide spectrum of NLD ranging from mild RDS to severe BPD. FRC measured by the gas dilution technique measures only the volume of lung regions that communicate readily with
Lung Volume and Ventilation Inhomogeneity in Preterm Infants at 15-18 Months Corrected Age
545
THE JOURNAL OF PEDIATRICS
www.jpeds.com
Table III. Summary of cross-sectional univariate regression analysis Explanatory variable Birth weight, kg Birth weight z-score Test weight, kg Test weight z-score Test length, cm Test length z-score BMI, kg m2 BMI z-score Gestational age, weeks PMA at test, weeks Caucasian ethnicity Household smoke exposure Chorioamnionitis Prenatal corticosteroids Respiratory support, days Endotracheal ventilation, days Supplemental oxygen, days Surfactant BPD Postnatal corticosteroids Wheeze Asthma Bronchiolitis
FRC LCI M1/M0 M2/M0 VT RR MV [ Y [ Y Y Y Y
[ [ [ [ [ [ -
[ [ [ [ [ [ [ -
[ [ -
[ [ [ [ [ [ -
-
[ [ [ [ [ [ -
[ denotes significant positive association per unit increase (P < .10 considered statistically significant); Y denotes significant negative association per unit increase; - denotes nonsignificant association.
the central airways during tidal breathing. Thus, FRC obtained from MBW does not include any trapped gas and may underestimate resting lung volume, particularly in infants with airway obstruction.26,27 Therefore, our regression analysis included potential confounders associated with poor airway function, such as household smoking, wheeze, asthma, and bronchiolitis. Arguably, longitudinal measurements of alveolar volume and carbon monoxide diffusing capacity are superior to FRC for evaluation of lung growth, because FRC in infancy is dynamically elevated above the elastic equilibrium28 and may not be an exact estimate of parenchymal lung volume. But carbon monoxide diffusing capacity is not (yet) applicable to spontaneously breathing, unsedated preterm neonates with BPD, and thus FRC is the best available option for the longitudinal assessment of lung volume and lung growth in this population. This study demonstrates that in very preterm infants, preterm birth per se and the duration of endotracheal ventilation in the newborn period are associated with reduced lung volume at around 18 months of life. Given that comparable results were obtained from the recently reported multicenter study in the newborn period5 and in a longitudinal assessment of the current local cohort, this indicates considerable tracking of lung volume over the first 1.5 years of life. Previous MBW studies suggested similar effects of preterm birth3 and presence of BPD4,6,7 on FRC at neonatal age, but reported normalized lung volume between 6 and 36 months of life.6-8 Similar to our results, there is substantial tracking of airway function over the first year of life in healthy preterm infants.29 546
Vol. 156, No. 4 The multivariate statistical analysis used in this investigation differs considerably from previous studies that used the t-test or analysis of variance.3,4,6-8 Furthermore, the longitudinal study of Gerhardt et al7 originated from the presurfactant era, and FRC was expressed in mL/kg body weight rather than adjusted for body length, with no consideration of equipment dead space. Other follow-up studies investigated significantly more mature infants who may have had less severe NLD6,8 compared with the infants in our follow-up study (5/16 infants with BPD required home oxygen). Comparing the follow-up cohort with infants lost to follow-up after participating in the multicenter study in the newborn period5 showed that the follow-up cohort had significantly longer duration of endotracheal ventilation and supplemental oxygen, indicating more severe NLD. We were surprised to find no association between the duration of endotracheal ventilation and indices of ventilation inhomogeneity (LCI and moment ratios), given that newborn studies by Hjalmarson et al4,5 and the newborn multicenter study involving the current cohort30 had shown a small, but statistically significant, effect of NLD on LCI and moment ratios in preterm infants. This discrepancy suggests that a potential relationship between NLD and indices of ventilation inhomogeneity at newborn age may no longer be detectable by 1.5 years of life, or that the limited sample size of our follow-up study decreased our likelihood of detecting such a relationship. Although a type 2 error cannot be excluded, this study had 89% power at a significance level of 5% to detect an association between a single explanatory factor of moderate predictive value (R2 = 0.15) and indices of ventilation inhomogeneity. Univariate analysis showed no association between GA or NLD and indices of ventilation inhomogeneity; that is, any potentially missed association would be of very limited effect size and thus unlikely to be of clinical relevance. The observed positive association between body size and indices of ventilation inhomogeneity in the preterm infants was not anticipated. Assuming that prematurity and NLD result in poor alveolarization and lung growth, this finding suggests that ventilation inhomogeneity may be associated with increasing discrepancy between lung size/alveolar surface area in relation to body size in preterm infants at 1.5 years of life, warranting further investigation. A decrease in indices of ventilation inhomogeneity from the neonatal period to 1.5 years of life was observed in most infants. This finding contrasts with the widely held belief that these indices are age-independent and thus useful for identifying longitudinal changes in ventilation inhomogeneity. However, whereas the published longitudinal study demonstrating age-independence of these indices was performed in preschool and school-age children (age 515 years) in whom alveolarization is complete,31 our study assessed changes in ventilation inhomogeneity indices between birth and late infancy. Alveolarization is not completed until at least 6 months and up to 2 years after birth; thus, impaired gas mixing efficiency in the neonatal period is biologically plausible, and our observations may reflect a real decrease in ventilation inhomogeneity during early postnatal life. Schulzke et al
ORIGINAL ARTICLES
April 2010
Figure 2. FRC at 15-18 months corrected age. A, FRC per cm of body length plotted against GA, B, FRC per kg of body weight, C, FRC plotted against length at test, D, and duration of endotracheal ventilation in the newborn period. Triangles indicate preterm RDS, squares indicate preterm BPD, and circles indicate term healthy controls. As expected, there were significant differences among groups in terms of body size and markers of NLD (Table I). Although regression analysis demonstrated significant associations among length-adjusted FRC, GA, and duration of endotracheal ventilation, simply expressing results as FRC/kg, as shown in B, would have led to the misleading conclusion that NLD has no major impact on FRC.
Our finding of reduced lung volume at age 18 months supports the current concept of disturbed acinar lung development due to impaired alveolarization after very preterm birth and NLD.32 In infants born between 230 and 306 weeks GA (ie, the group of infants in whom we could assess the association between GA and endotracheal ventilation), we found that the degree of preterm birth per se and duration of endotracheal ventilation independently reduced length-adjusted FRC at 15-18 months corrected age. However, after adjusting for body size and body proportions at test, the additional contribution of preterm birth and endotracheal ventilation to the variability in FRC was relatively small. On average, preterm birth reduced FRC at follow-up by 2 mL/week, and endotracheal ventilation led to a further decrement in FRC of 2 mL/day of mechanical ventilation. No follow-up data are available to extrapolate these effects beyond the second year of life. A long-term follow-up study of infants born in 1991-1992 reported only minimally
decreased total lung capacity but markedly increased residual volume, suggesting air trapping in 8- to 9-year-old children born very preterm compared with near-term/term controls.9 Thus, it is essential to extend the follow-up of current study cohorts to at least school age, to clarify whether catch-up growth of the lung occurs later in childhood and/or air trapping is an issue. Ideally, future longitudinal studies in preterm infants using carbon monoxide diffusing capacity will allow for quantification of parenchymal lung growth in terms of alveolarization, given the recently reported successful application of this technique in healthy infants.33 In the context of cystic fibrosis, LCI detects abnormal lung function earlier than spirometry in infants, children, and teenagers.31,34-36 Arguably, the poor diagnostic utility of LCI and moment ratios in our study may be related to differences in type and severity of functional impairment, and to the progression of disease in cystic fibrosis versus ‘‘recovery’’ from NLD. Potentially, more complex analysis of ventilation inhomogeneity during MBW (using, e.g., normalized slope
Lung Volume and Ventilation Inhomogeneity in Preterm Infants at 15-18 Months Corrected Age
547
THE JOURNAL OF PEDIATRICS
www.jpeds.com
of phase III37) may facilitate detection and monitoring of ventilation inhomogeneity in follow-up of preterm infants by localizing the region of inefficient gas mixing to that occurring within the conductive airways or within the acinus.38 The validity and feasibility of the normalized slope of phase III analysis have not yet been established in infants, however. Very preterm birth per se and the duration of ventilation in the newborn period are independently associated with reduced lung volume and lung growth at 15-18 months corrected age, although the effect size of these findings is small. Indices of ventilation inhomogeneity at 15-18 months corrected age show no clinically important association with preterm birth and markers of NLD. Further research is needed to assess the generalizibility of these findings and to determine whether other indicators of ventilation inhomogeneity have better diagnostic utility in preterm infants. n We thank our study infants and their families for their participation in this study. Submitted for publication May 28, 2009; last revision received Sep 1, 2009; accepted Oct 15, 2009. Reprint requests: Sven Schulzke, MD, FRACP, Neonatal Clinical Care Unit, King Edward Memorial Hospital for Women, 374 Bagot Road, Subiaco, Western Australia 6008, Australia. E-mail: [email protected].
References 1. Coalson JJ. Pathology of new bronchopulmonary dysplasia. Semin Neonatol 2003;8:73-81. 2. Allen J, Zwerdling R, Ehrenkranz R, Gaultier C, Geggel R, Greenough A, et al. Statement on the care of the child with chronic lung disease of infancy and childhood. Am J Respir Crit Care Med 2003;168:356-96. 3. Hjalmarson O, Sandberg K. Abnormal lung function in healthy preterm infants. Am J Respir Crit Care Med 2002;165:83-7. 4. Hjalmarson O, Sandberg KL. Lung function at term reflects severity of bronchopulmonary dysplasia. J Pediatr 2005;146:86-90. 5. Hulskamp G, Lum S, Stocks J, Wade A, Hoo AF, Costeloe K, et al. Association of prematurity, lung disease and body size with lung volume and ventilation inhomogeneity in unsedated neonates: a multicentre study. Thorax 2009;64:240-5. 6. de Winter JP, Merth IT, Brand R, Quanjer PH. Functional residual capacity and static compliance during the first year in preterm infants treated with surfactant. Am J Perinatol 2000;17:377-84. 7. Gerhardt T, Hehre D, Feller R, Reifenberg L, Bancalari E. Serial determination of pulmonary function in infants with chronic lung disease. J Pediatr 1987;110:448-56. 8. Merth IT, de Winter JP, Zonderland HM, Borsboom GJ, Quanjer PH. Pulmonary function in infants with neonatal chronic lung disease with or without hyaline membrane disease at birth. Eur Respir J 1997;10: 1606-13. 9. Doyle LW. Respiratory function at age 8-9 years in extremely low birthweight/very preterm children born in Victoria in 1991-1992. Pediatr Pulmonol 2006;41:570-6. 10. Latzin P, Thamrin C, Kraemer R. Ventilation inhomogeneities assessed by the multibreath washout (MBW) technique. Thorax 2008;63:98-9. 11. Pillow JJ, Frerichs I, Stocks J. Lung function tests in neonates and infants with chronic lung disease: global and regional ventilation inhomogeneity. Pediatr Pulmonol 2006;41:105-21. 12. Buess C, Pietsch P, Guggenbuhl W, Koller EA. A pulsed diagonal-beam ultrasonic airflow meter. J Appl Physiol 1986;61:1195-9. 13. Pillow JJ, Ljungberg H, Hulskamp G, Stocks J. Functional residual capacity measurements in healthy infants: ultrasonic flow meter versus a mass spectrometer. Eur Respir J 2004;23:763-8. 548
Vol. 156, No. 4 14. Schibler A, Hall GL, Businger F, Reinmann B, Wildhaber JH, Cernelc M, et al. Measurement of lung volume and ventilation distribution with an ultrasonic flow meter in healthy infants. Eur Respir J 2002;20:912-8. 15. Schulzke SM, Deeptha K, Sinhal S, Baldwin DN, Pillow JJ. Nasal versus face mask for multiple-breath washout technique in preterm infants. Pediatr Pulmonol 2008;43:858-65. 16. Schibler A, Henning R. Measurement of functional residual capacity in rabbits and children using an ultrasonic flow meter. Pediatr Res 2001; 49:581-8. 17. Wauer J, Leier TU, Henschen M, Wauer RR, Schmalisch G. In vitro validation of an ultrasonic flowmeter in order to measure the functional residual capacity in newborns. Physiol Meas 2003;24:355-65. 18. Schulzke SM, Hall GL, Nolan G, Pillow JJ. Duration of mechanical ventilation influences lung volume in preterm infants at 15-18 months corrected age. Presented at the Annual Meeting of the European Respiratory Society, Berlin, Germany; 2008. Eur Respir J 2008;32(suppl 52):P3905. 19. Gaultier C, Fletcher ME, Beardsmore C, England S, Motoyama E. Respiratory function measurements in infants: measurement conditions. Working Group of the European Respiratory Society and the American Thoracic Society. Eur Respir J 1995;8:1057-66. 20. Freeman JV, Cole TJ, Chinn S, Jones PR, White EM, Preece MA. Crosssectional stature and weight reference curves for the UK, 1990. Arch Dis Child 1995;73:17-24. 21. Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics 1988;82:527-32. 22. Frey U, Stocks J, Coates A, Sly P, Bates J. Specifications for equipment used for infant pulmonary function testing. European Respiratory Society/American Thoracic Society Task Force on Standards for Infant Respiratory Function Testing. Eur Respir J 2000;16:731-40. 23. Larsson A, Jonmarker C, Werner O. Ventilation inhomogeneity during controlled ventilation: which index should be used? J Appl Physiol 1988; 65:2030-9. 24. Saidel GM, Saniie J, Chester EH. Lung washout during spontaneous breathing: parameter estimation with a time-varying model. Comput Biomed Res 1980;13:446-57. 25. Cohen J, Cohen P, West SG, Aiken LS. Applied Multiple Regression/ Correlation Analysis for the Behavioral Sciences. Mahwah, NJ: Lawrence Earlbaum Associates; 2003. 26. Broughton S, Thomas MR, Marston L, Calvert SA, Marlow N, Peacock JL, et al. Very prematurely born infants wheezing at followup: lung function and risk factors. Arch Dis Child 2007;92:776-80. 27. Hulskamp G, Pillow JJ, Dinger J, Stocks J. Lung function tests in neonates and infants with chronic lung disease of infancy: functional residual capacity. Pediatr Pulmonol 2006;41:1-22. 28. Henschen M, Stocks J. Assessment of airway function using partial expiratory flow-volume curves: how reliable are measurements of maximal expiratory flow at FRC during early infancy? Am J Respir Crit Care Med 1999;159:480-6. 29. Hoo AF, Dezateux C, Henschen M, Costeloe K, Stocks J. Development of airway function in infancy after preterm delivery. J Pediatr 2002;141: 652-8. 30. Shao H, Sandberg K, Hjalmarson O. Impaired gas mixing and low lung volume in preterm infants with mild chronic lung disease. Pediatr Res 1998;43:536-41. 31. 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;59:106873. 32. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163:1723-9. 33. Balinotti JE, Tiller CJ, Llapur CJ, Jones MH, Kimmel RN, Coates CE, et al. Growth of the lung parenchyma early in life. Am J Respir Crit Care Med 2009;179:134-7. 34. Gustafsson PM, Aurora P, Lindblad A. Evaluation of ventilation maldistribution as an early indicator of lung disease in children with cystic fibrosis. Eur Respir J 2003;22:972-9.
Schulzke et al
ORIGINAL ARTICLES
April 2010 35. Kraemer R, Blum A, Schibler A, Ammann RA, Gallati S. Ventilation inhomogeneities in relation to standard lung function in patients with cystic fibrosis. Am J Respir Crit Care Med 2005;171: 371-8. 36. 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;62:341-7.
37. Verbanck S, Schuermans D, Van Muylem A, Paiva M, Noppen M, Vincken W. Ventilation distribution during histamine provocation. J Appl Physiol 1997;83:1907-16. 38. Verbanck S, Schuermans D, Van Muylem A, Melot C, Noppen M, Vincken W, et al. Conductive and acinar lung-zone contributions to ventilation inhomogeneity in COPD. Am J Respir Crit Care Med 1998;157:1573-7.
50 Years Ago in THE JOURNAL OF PEDIATRICS Observation on Rheumatic Nodules over a 30-Year Period Baldwin JS, Kerr JM, Kuttner AG, Doyle EF. J Pediatr 1960;56:465-70
C
linicians at the Children’s Cardiac Service, New York University–Bellevue Medical Center compared clinical courses of children with rheumatic fever, with a special focus on rheumatic nodules, over a 30-year period (1928-1958). They grouped patients by onset of disease in an earlier 15-year period (1928-1942) and in a later period (1943-1958). At the time, observers had the impression that both the incidence and severity of rheumatic fever had declined, beginning even before the discovery of penicillin. Because it was agreed that rheumatic nodules were associated with a severe form of rheumatic fever, the authors reviewed the immediate and long-term outcomes of patients with rheumatic nodules diagnosed in the two time periods as an indicator of changes in the pattern of disease. Findings corroborated that the incidence of rheumatic nodules dropped from the earlier period to the later period, from 68 cases to 33 cases. Across both time frames, however, nodules were associated with severe carditis, usually marking protracted active and recrudescent carditis. Mortality in patients with rheumatic carditis fell from 16% in the early period to 4% in the later period; however, for those with nodules, mortality rate did not fall as markedly. For children with recurrent crops of nodules during the same attack or later, overall mortality for the entire study period was 58%, compared with 25% for children with nonrecurring nodules. The authors conclude that nodules still should be considered a sign of severe rheumatic heart disease and should lead to a guarded prognosis and to rigid adherence to (the miraculous) penicillin prophylaxis. There was an accelerating decline in rheumatic fever in the United States from the 1940s through the 1980s. However, a dramatic outbreak of rheumatic fever began in 1985 in the intermountain areas around Salt Lake City, Utah and spread to Ohio and Pittsburgh. Other outbreaks occurred in noncontiguous areas but did not lead to a nationwide increase in cases. The outbreak continues in Utah, where approximately 70% of patients have carditis.1 Nodules are present in <5% of cases. We are agreed that the organism, the host, and the environment each play a part in the clinical manifestations of rheumatic disease and its epidemiology, but assigning the lead and supporting roles has been difficult. Sarah S. Long, MD Section of Infectious Diseases St Christopher’s Hospital for Children Philadelphia, Pennsylvania 10.1016/j.jpeds.2009.11.024
Reference 1. Veasy LG, Tani LY, Hill HR. Persistence of acute rheumatic fever in the intermountain area of the United States. J Pediatr 1994;124:9-16.
Lung Volume and Ventilation Inhomogeneity in Preterm Infants at 15-18 Months Corrected Age
549
THE JOURNAL OF PEDIATRICS
www.jpeds.com
Vol. 156, No. 4
Table II. Baseline characteristics of infants attending follow-up versus dropping out Preterm
Term
Variable
Follow-up (n = 38)
Dropout (n = 19)
P value*
Follow-up (n = 20)
Dropout (n = 15)
P value*
Male, n (%) GA, weeks† Birth weight, kg Birth weight z-score Caucasian ethnicity, n (%) Household smoke exposure, n (%) Chorioamnionitis, n (%) Prenatal corticosteroids, n (%) Respiratory support, daysz Endotracheal ventilation, daysz Supplemental oxygen, daysz Surfactant, n (%) BPD, n (%) Postnatal corticosteroids, n (%)
20 (53) 27.8 (23.0-32.9) 1.02 (0.39) -0.6 (1.1) 35 (92) 13 (34) 6 (16) 34 (90) 36 (3-64) 2.3 (0-20.6) 29 (0-77) 31 (82) 16 (42) 5 (13)
11 (58) 28.8 (23.6-32.9) 1.17 (0.44) -0.6 (1.1) 17 (89) 3 (16) 3 (16) 15 (79) 24 (1.2-47) 0 (0-5) 0 (0-70) 10 (53) 5 (26) 2 (11)
.71 .23 .20 1.00 .74 .14 1.00 .28 .16 .016 .034 .02 .24 .78
12 (60) 39.7 (38.0-41.6) 3.33 (0.55) -0.2 (1.1) 15 (75) 4 (20) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
7 (47) 39.5 (37.9-41.4) 3.48 (0.45) 0.2 (0.9) 13 (87) 1 (7) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
.43 .72 .40 .26 .39 .26 NA NA NA NA NA NA NA NA
*Characteristics of infants were compared using the unpaired Student t-test, Mann-Whitney U-test, or Fisher exact test as appropriate. Data are presented as mean (standard deviation) unless stated otherwise. † Data are presented as mean (range). z Data are presented as median (interquartile range).
Table IV. Multivariate analysis of FRC at 15-18 months corrected age Explanatory variable Model 1 (R2† = 0.171; P < .016); intercept, 1.26 Test length, cm Test length z-score GA, weeks Model 2 (R2† = 0.198; P = .008) intercept, 1.86 Test length, cm Test length z-score Endotracheal ventilation, days Model 3 (R2† = 0.199; P = .018); intercept, 1.67 Test length, cm Test length z-score GA, weeks Endotracheal ventilation, days ‘‘Best model’’ GA # 306 weeks (R2† = 0.392; P = .022); intercept, 4.05 Test length, cm Test length z-score GA, weeks Endotracheal ventilation, days
b*
95% CI
P value
0.05 -0.12 0.08
0.01 to 0.08 -0.22 to -0.02 >-0.001 to 0.02
.008 .017 .063
0.04 -0.12 -0.01
0.01 to 0.08 -0.22 to -0.02 -0.01 to -0.001
.015 .021 .027
0.05 -0.12 0.003 -0.003
0.01 to 0.08 -0.22 to -0.02 -0.01 to 0.01 -0.01 to 0.01
.013 .019 .55 .19
0.04 -0.10 -0.01 -0.01
-0.003 to 0.08 -0.22 to 0.03 -0.12 to -0.02 -0.01 to -0.002
.066 .12 .008 .050
In this analysis, FRC was log-transformed to achieve normal distribution of residuals. *Regression coefficients b. †Coefficient of determination.
549.e1
Table V. Factors influencing the increase in lung volume from newborn age to 15-18 months corrected age Explanatory variable
Mean effect*
95% CI
P value
Length GA Time Newborn 15-18 months corrected age Ethnicity Caucasian Other (primarily Asian) Postnatal corticosteroids
1.02 1.01
1.01-1.03 1.00-1.02
< .001 .009
1.00 1.88
1.44-2.45
< .001
1.00 0.87 0.73
0.79-0.96 0.68-0.78
.006 < .001
*FRC was log-transformed for analysis to achieve normality. Effect estimates and 95% CIs have been back-transformed to the original scale.
Schulzke et al
ORIGINAL ARTICLES
April 2010
Figure 3. Duration of endotracheal ventilation in the newborn period versus GA. Triangles indicate preterm RDS, squares indicate preterm BPD, and circles indicate term healthy controls. There appears to be an inverse linear relationship between GA and endotracheal ventilation up to approximately 30 weeks GA. Above 30 weeks GA, only 1 preterm infant was ventilated for more than 1 day, and all term control infants were nonventilated, resulting in a significant change in the relationship between these 2 covariates. Thus, regression models that included the variable endotracheal ventilation were restricted to a GA range of 236-306 weeks.
Figure 4. Indices of ventilation inhomogeneity at newborn age and at 15-18 months corrected age: A, LCI, B, M1/M0, and C, M2/M0. Triangles indicate preterm SDS, squares indicate preterm BPD, and circles indicate term healthy controls. There was a significant decrease in LCI, M1M0, and M2/M0 in RDS, BPD, and term healthy control infants across the 2 time points. Cross-sectional analysis demonstrated no significant associations between these indices of ventilation inhomogeneity and GA, NLD, or any other explanatory variable considered. *P < .001.
Lung Volume and Ventilation Inhomogeneity in Preterm Infants at 15-18 Months Corrected Age
549.e2