plethysmograph (E. Jaeger, Würzburg, Germany) was used, and total lung capacity (TLC), thoracic gas vol- ume (TGV), residual volume (RV), airway resistance.
Copyright ERS Journals Ltd 1997 European Respiratory Journal ISSN 0903 - 1936
Eur Respir J 1997; 10: 880–885 DOI: 10.1183/09031936.97.10040880 Printed in UK - all rights reserved
Lung function and airway responsiveness in children and adolescents after hyaline membrane disease: a matched cohort study A. Cano*, F. Payo** Lung function and airway responsiveness in children and adolescents after hyaline membrane disease: a matched cohort study. A. Cano, F. Payo. ERS Journals Ltd 1997. ABSTRACT: Some investigators consider prematurity to be responsible for the lung function abnormalities found in prematurely born children and adolescents who had neonatal respiratory diseases. This study attempts to measure the effect of neonatal respiratory disease on lung function during school age and adolescence, by controlling the confounding effect due to prematurity. Lung volumes, airway resistance and specific airway conductance measured by plethysmography, maximum expiratory flow-volume curves, pulmonary diffusion of carbon monoxide, and the airway responsiveness to a challenge with methacholine, were determined in a cohort of children aged 8–14 yrs, who had suffered from hyaline membrane disease but who did not develop bronchopulmonary dysplasia. The values obtained were compared with those of children without hyaline membrane disease, not ventilated for other causes, and matched for gestational age, sex and age. Thirty six pairs of children were enrolled, of which 26 participated in the methacholine test. Compared to their paired controls, children with hyaline membrane disease had a significantly lower forced expiratory volume in one second (FEV1), forced mid-expiratory flow (FEF25–75), and maximal expiratory flow when 75, 50 and 25% of the forced vital capacity remained in the lung (MEF75, MEF50 and MEF25 , respectively), and a significantly higher airway resistance (Raw). The effect was less in children born more prematurely, who showed less difference in FEF25–75, MEF75 and MEF25. The duration of treatment with steroids in the neonatal period was associated with a reduction in the differences in FEV1, MEF25 and Raw. Independent of prematurity, hyaline membrane disease and its treatment is associated with alterations in long-term lung function, even in children who do not develop bronchopulmonary dysplasia. The effect can be less in more premature children, and neonatal steroids can have a long-term preventive effect. Eur Respir J 1997; 10: 880–885.
Neonatal respiratory diseases are frequent in children born prematurely, and have been related to anomalies in lung function that persist for years, even into adulthood. In premature infants who develop bronchopulmonary dysplasia (BPD), a decrease has been found in maximum expiratory flows, airway conductance and pulmonary compliance, as well as airway hyperresponsiveness and improvement of lung mechanics with bronchodilators [1–3]. School children with BPD continue to show low expiratory flows, air-trapping and airway hyperresponsiveness, and the same abnormalities persist throughout adolescence and into adult life [4–6] Although less severe, the same pulmonary result is found in the long-term in children who had milder neonatal respiratory disease and did not develop BPD. It has been suggested that aggressive respiratory treatment, including artificial ventilation [7] and high concentrations of oxygen [8], play an important role in the appearance of these pulmonary alterations. However, not all children born prematurely have
*Dept of Pediatrics, and **Respiratory Physiology Service, Instituto Nacional de Silicosis, Hospital Central de Asturias, Oviedo, Spain. Correspondence: F. Payo Servicio de Fisiología Respiratoria Instituto Nacional de Silicosis Dr. Bellmunt s/n 33006 Oviedo Spain Keywords: Cohort studies hyaline membrane disease infant (premature) pulmonary function tests steroids Received: May 8 1996 Accepted after revision December 2 1996
neonatal respiratory diseases, nor do they receive aggressive respiratory treatment. Various studies have shown that prematurity could be the main factor related to the persistent alterations of lung function, and this could reduce the importance of the respiratory treatment received [8, 9]. Unfortunately, all these factors are so interrelated that it is very difficult to separate the relative contribution of each one. Our aim was to measure the modifications in lung function detectable several years after mild or moderate neonatal respiratory disease. We have considered prematurity as a confounding factor capable of biasing the results, and in order to control this variable we have planned a matched, retrospective, cohort study. A cohort of schoolchildren and adolescents, who suffered hyaline membrane disease (HMD) in the neonatal period but did not develop BPD, was selected. The lung function of these children was compared with that of children without HMD, who were not ventilated for other causes, and who were matched for gestational age, sex, and chronological
LUNG FUNCTION AFTER HYALINE MEMBRANE DISEASE
age. Subsequently, we attempted to determine whether lung function after HMD is related to certain aspects of the treatment received. Subjects and methods
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presence of "wheeze" was considered if the parents referred to audible wheeze which occurred with or without colds. Data on parental educational level, history of asthma in first degree relatives, and admissions to hospital for respiratory diseases were also collected.
Subjects and study design
Lung function tests
The study cohort was formed retrospectively with all those children with HMD who survived without evident BPD, who were born between 1978 and 1984, and attended for treatment in the Hospital Central de Asturias, a tertiary care centre in Oviedo, Spain. HMD was defined as the presence of respiratory distress (tachypnoea, chest retractions, nasal flapping) in the first 24 h, with the need for supplementary oxygen (administered if arterial oxygen tension (Pa,O2) was 0.10 1.00 1.00 1.00 0.69 0.69 1.00
Values are presented as mean±SD and range in parenthesis, or as percentage of the initial cohort. HMD: hyaline membrane disease.
883
LUNG FUNCTION AFTER HYALINE MEMBRANE DISEASE
without HMD decreased with greater duration of this treatment. No effect of the duration of IPPV nor the oxygen therapy score was found in any of the models tested. The differences in MEF50 were not modified by any of the variables tested.
Lung function Statistically significant reductions in FEV1, FEF25–75, MEF75, MEF50 and MEF25 were found, and also a statistically higher Raw, in children with HMD compared to their controls (table 2). The magnitude of these differences was only slight or moderate. The measurements of lung volumes, SGaw, TL,CO and TL/VA were comparable. Multivariate models were constructed for those variables that were found to be statistically different between patients and controls in the univariate analysis. The results are shown in table 3. Gestational age modified results in FEF25–75, MEF75 and MEF25. The differences between the groups decreased with lower gestational age, i.e., the influence of HMD on lung function was less at a lower gestational age. The duration of neonatal corticotherapy played a role in the models of FEV1, MEF25 and Raw. The differences between children with and
Airway responsiveness Participation in the methacholine challenge was smaller, and 26 matched pairs of children were finally analysed (41% of the initial cohort). Gestational age and birth weight, sex ratio, level of neonatal respiratory treatment, and answers to the questionnaire were comparable among children with HMD who underwent the methacholine challenge and the rest of the HMD cohort. No differences were found in relation to gestational age, birth weight, sex, Apgar scores, and respiratory morbidity in the answers to questionnaires, nor in family history of asthma between children with and without HMD. A decrease of FEV1 with methacholine was found in nine children with HMD (35%) and in six of the controls (23%), but without significant differences (p=0.58). The median of the PD20 was 0.54 mg (IQR 0.12–0.69 mg) in the patients, and 0.11 mg (IQR 0.05–0.72 mg) in the controls (p=0.53). None of the variables tested showed any significant influence in the response to methacholine in the logistic regression model.
Table 2. – Lung function in children with HMD and controls as percentage of predicted values HMD FEV1 FVC FEV1/FVC PEF FEF25–75 MEF75 MEF50 MEF25 TLC TGV RV RV/TLC Raw sGaw sbTL,CO TL/VA
101±12 100±10 102±11 90±18 93±21 92±20 91±21 83±28 106±17 118±32 148±60 130±34 107±34 88±30 104±19 111±15
Controls Mean difference 95% CI 108±12 -13.2 to -0.4 103±11 -8.6 to 1.5 105±6 -7.5 to 1.2 96±16 -13.7 to 0.8 107±22 -25.0 to -2.8 103±16 -18.4 to -2.2 103±22 -22.5 to -1.6 98±25 -28.8 to 0.2 113±16 -14.3 to 1.3 129±32 -26.9 to 4.6 168±65 -51.2 to 10.4 140±34 -27.8 to 6.7 84±32 6.5 to 39.7 113±83 -57.3 to 7.2 114±28 -20.4 to 0.3 115±26 -13.3 to 6.2
p-value 0.04 0.17 0.15 0.08 0.02 0.01 0.03 0.05 0.10 0.16 0.19 0.22 0.01 0.12 0.06 0.46
Discussion The present study shows the existence of modifications in lung function in schoolchildren and adolescents who suffered from HMD but who did not develop BPD, in comparison with other prematurely born children without HMD and nonventilated. Children with HMD had lower maximum respiratory flows and a higher Raw. By matching for gestational age, we can rule out the fact that these differences could be due to prematurity. The functional alterations, however, were slight or moderate, and were not related to a greater respiratory morbidity. It is possible that a memory bias existed in the responses to the questionnaire. Parents of children with HMD or with other previous respiratory diseases can better recall respiratory troubles occurring later. Although the responses to the questionnaire must be interpreted with caution, the differences in lung function related to HMD found in this study do not appear to be clinically correlated.
Values are presented as mean±SD. HMD: hyaline membrane disease; 95% CI: 95% confidence interval; FEV1: forced expiratory volume in one second; FVC: forced vital capacity; PEF: peak expiratory flow; FEF25–75: forced mid-expiratory flow; MEF75, MEF50 and MEF25: maximal expiratory flow when 25, 50 and 75% of the FVC, respectively, remained in the lung; TLC: total lung capacity; TGV: thoracic gas volume; RV: residual volume; Raw: airways resistance; sGaw: specific airways conductance; sbTL,CO: single-breath transfer factor of the lungs for carbon monoxide; TL/VA: transfer coefficient (transfer factor of the lung/alveolar volume).
Table 3. – Multiple regression analysis of the variables showing significant differences in the univariant analysis
Gestational age (weeks)
FEV1 β (95% CI) p-value
FEF25–75 β (95% CI) p-value
MEF75 β (95% CI) p-value
MEF50 β (95% CI) p-value
-
-7.2 (-11.9 to -2.5)
